Advanced Therapy in Thoracic Surgery

CHAPTER 1

POSTOPERATIVE ANALGESIA FOR THORACOTOMY PATIENTS: A CURRENT REVIEW PETER H. NORMAN, MD, FRCPC M. DENISE DALEY, MD, FRCPC ALICIA KOWALSKI, MD niques for post-thoracotomy pain.2,3 Soon continuous infusions were advocated,4 and the effect of better postoperative analgesia on pulmonary function was investigated.5 This led to an increased ability to control post-thoracotomy pain and also stimulated the overall interest in finding other useful modalities for post-thoracotomy pain relief. Older or abandoned techniques were investigated with renewed interest and used singly or in combinations. For at least the past 10 years, the immediate postoperative pain of most thoracotomy patients has been well handled. There are occasional patients whose pain is difficult to manage because of coexisting disease processes that contraindicate epidural analgesia, anatomic factors, and/or pre-existing chronic pain, but currently there are techniques to help even these patients. As an unintentional consequence of relieving the severe, acute incisional pain of surgery, we may have unmasked other sources of equally troubling pain such as referred pain and sympathetically mediated pain. Much research is focused on treating these “new” modalities. This unbundling of postoperative pain has been termed disaggregation.6 Another area of increasing interest is the pathogenesis of chronic postoperative pain. Whether we can affect or even prevent this unhappy outcome remains to be seen.

It is natural to want to relieve pain and suffering. None are more aware of this than those professionals who have devoted their lives to the provision of anesthesia, yet we have often been prevented from alleviating pain by not understanding its pathogenesis or by a lack of appropriate tools to deal with it. Intraoperative pain is now only of historic concern. It is our fervent hope that postoperative pain will follow intraoperative pain into the history books. Not so long ago, certainly within the professional experience of some of us, a minimalist approach was taken to the management of pain after thoracic surgery. Anesthesiology residents and faculty alike were admonished to keep total opioid dosage low so the patient would “want to breathe” after surgery. During this era, the classic thoracotomy patient would be nearly apneic from pain in the postanesthesia care unit. Hypoxic and hypercarbic, diaphoretic and hypertensive, patients would gradually improve to the point at which they could actually breathe and complain of pain only after large doses of opioids. Frequent arterial blood gas analyses often demonstrated the unusual observation that the administration of opioids led to a decrease in carbon dioxide tension and an increase in oxygen tension in this setting. In 1973 Gibbons and colleagues suggested that thoracic epidural blockade was the treatment of choice for relief of pain after a chest injury.1 The major limitation was sympathetic blockade causing hypotension. To prevent this complication, they advocated intercostal blockade for fractures at or above the fifth rib. The modern era of pain management after thoracic surgery began with the introduction of epidural narcotic tech-

Post-Thoracotomy Pain Acute Pain Pain in the first few weeks after a thoracotomy arises from a variety of different mechanisms. The best characterized mechanism is somatic pain, which is localized to the area around the incision and chest tube insertion 1

2 / Advanced Therapy in Thoracic Surgery

sites. It is produced by direct injury to the skin and underlying subcutaneous tissues, fasciae, ligaments, muscles, and ribs. Damaged tissue releases a variety of algesic substances, including substance P, prostaglandins, and serotonin, which stimulate the peripheral nerve endings.7 Intercostal nerves from the area conduct these pain impulses to the spinal cord and thence to the brain via the spinothalamic and spinoreticular tracts. Somatic pain is responsible for the sharp, severe postoperative pain that is exacerbated by movement and is believed to be primarily mediated by type A delta nerve fibers. 8 Visceral, or nonincisional, pain is responsible for the dull, nauseating, diffuse thoracic wall “aching” sensation experienced after a thoracotomy. It is mediated by type C nerve fibers, which travel with the autonomic nerves. Both the vagus and sympathetic nerves probably contribute to this type of pain.8 Another form of pain frequently reported in postthoracotomy patients is localized to the ipsilateral shoulder region. Although it is often moderate to severe in intensity and present in 75 to 85% of patients who have had a thoracotomy,9–11 this type of pain has received little attention in the literature. It has been attributed to a variety of factors, including distraction of the posterior thoracic ligaments or shoulder joint due to patient positioning; stretching of the brachial plexus, also as a consequence of intraoperative positioning; transection of a major bronchus; and referred pain from the phrenic nerve.9 As the latter provides sensory innervation to the pericardium and pleura, mechanical trauma to these regions during surgery and irritation of the pleural surfaces by chest tubes postoperatively can result in phrenic nerve stimulation, with referral to the shoulder. Scawn and colleagues have demonstrated a reduction in the incidence of post-thoracotomy shoulder pain from 85 to 33% with the injection of 10 mL of 1% lidocaine into the periphrenic fat at the level of the diaphragm.9 In this same study, there was a small but insignificant increase in arterial partial pressure of carbon dioxide (PaCO2) in the first 2 postoperative hours in patients receiving a phrenic nerve block, thereby suggesting the possibility of diaphragmatic paresis. The technique may thus be inappropriate in patients with severely compromised respiratory function. The lack of efficacy of suprascapular nerve blockade in relieving post-thoracotomy shoulder pain demonstrated by Tan and colleagues provides further evidence that distraction of the shoulder joint does not play a major role in the generation of this type of pain.11 The extent to which the surgical approach contributes to the severity of post-thoracotomy pain is unclear. Anteroaxillary and anterior limited thoracotomies are less painful procedures than are posterolateral thoraco-

tomies. 12,13 When muscle-sparing thoracotomies have been compared with traditional posterolateral thoracotomies (involving a transection of the latissimus dorsi muscle), some studies have demonstrated less postoperative pain with the former,14 whereas others have revealed no difference between the two techniques.15,16 It is well appreciated that thoracoscopic procedures result in less pain than do traditional thoracotomies in the early postoperative period, but Nomori and colleagues have demonstrated this benefit to be lost by 14 days after surgery. 17 The lack of a consistent and/or persistent decrease in post-thoracotomy pain with less extensive surgical incisions provides further evidence that the actual surgical incision is just one of several mechanisms responsible for post-thoracotomy pain. Chronic Pain Post-thoracotomy pain syndrome is defined as “pain that recurs or persists along a thoracotomy scar at least two months following the surgical procedure.” 18 There is “usually tenderness, sensory loss, and absence of sweating along the thoracotomy scar.”18 The incidence is variable, ranging from 2 to 67%.19 Dajczman and colleagues studied 59 of 206 sequential patients who had undergone a unilateral thoracotomy; all procedures were performed by one surgeon over a period of 5 years.20 Thirty to 73% of the patients available for evaluation were experiencing pain (Table 1-1), which most rated at a visual analog scale (VAS) of two to four (Figure 1-1). These results were confirmed by Perttunen and colleagues,21 who found an incidence of post-thoracotomy pain of 80% at 3 months, 75% at 6 months, and 61% after 1 year. More than 50% of these patients had limitations of their activities of daily living imposed by the chronic pain. There was also a 3 to 5% incidence of severe pain. Intriguingly, early consumption of larger quantities of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased incidence of long-term problems. As suggested by Perttunen and colleagues, this could TABLE 1-1. Frequency of Post-Thoracotomy Pain at Various Intervals following Surgery Time since Thoracotomy (yr)

No. of Patients with Pain

Total No. of Patients Evaluable

Percentage of Evaluable Patients with Pain

≤ 1* 1–2 2–3 3–4 4–5 Total

6 11 7 3 3 30

12 15 13 6 10 56

50 73 54 50 30 —

Adapted from Dajczman E et al.20 *At least 2 months post-thoracotomy.

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 3 TABLE 1-2. Chronic Postoperative Pain Dysfunction Less Than 1 Year after VATS or Conventional Thoracotomy

Number of Patients

10 8

VATS 6

Pain Pain scale (0–5) Pain treatment Function

4 2 0 0- 1

1-2

2-3

3- 4

4-5

5-6

6- 7

7- 8

8-9

9-10

VAS

Thoracotomy

30% 1.2 11% 10%

p Value

44% 2.2 18% 26%

.03 .01 NS .001

Adapted from Landreneau RJ et al.24 NS = not significant; VATS = video-assisted thoracic surgery.

FIGURE 1-1. The distribution of visual analog scale (VAS) scores among patients reporting pain. Most patients chose a VAS of four or less. Reproduced with permission from Dajczman E et al.20

TABLE 1-3. Chronic Postoperative Pain/Dysfunction More Than 1 Year after VATS or Conventional Thoracotomy

imply that patients with more severe acute postoperative pain have a greater likelihood of developing chronic pain; alternatively, it may just imply that patients with a lower pain threshold are more likely to develop chronic pain. A study by Katz and colleagues also suggested that increased postoperative pain intensity at 24 and 48 hours predicted the later development of chronic pain.22 Better pain relief may not be the only factor and, in fact, may negatively affect outcome. Although the study was only carried out to 12 days, Nomori and colleagues found that continuing epidural analgesia beyond 3 postoperative days led to a rebound increase in pain when the epidural was removed, such that the prolonged epidural group had more pain on postoperative days 8 and 9.23 Video-assisted thoracotomy is not a panacea. Although the acute pain experienced is less, the pain still present from video-assisted thoracotomy after 1 year (Tables 1-2 and 1-3) is indistinguishable from that resulting from conventional thoracotomy.24 Much work remains to be done, and it is not possible to predict whether any analgesic approach or combination of approaches will lessen the development of postthoracotomy pain syndrome.

Pain Pain scale (0–5) Pain treatment Function

Systemic Analgesia Opioids Opioids have been the mainstay of pain relief for thousands of years but were restricted to oral or inhalation use until the invention of hollow needles by Alexander Wood in 1853. Intravenous use was employed only in the

VATS

Thoracotomy

p Value

22% 1.0 6% 14%

29% 1.7 16% 15%

NS NS NS NS

Adapted from Landreneau RJ et al.24 NS = not significant; VATS = video-assisted thoracic surgery.

operating room until the development of syringe pumps and patient-controlled systems, giving rise to patientcontrolled analgesia (PCA). From its modest beginnings, PCA has evolved from a specialized tool of pain specialists into a routine modality employed by any surgeon. PCA has also allowed the use of shorter-acting agents that must be given by continuous infusion owing to their evanescent action, such as fentanyl, sufentanil, and remifentanil. Because of the extreme potency of the latter, it should probably be restricted to perioperative use by an anesthesia provider. Oral opioids are still very much a part of perioperative analgesia because most patients are discharged on them and then maintained on them for months. The past 10 years has seen a decreasing reluctance to employ stronger opioids such as oxycodone, hydromorphone, and methadone out of hospital. Typical conversion ratios are given in Table 1-4. Some novel delivery systems should be mentioned. Highly lipid-soluble opioids may be absorbed directly across the skin or mucous membranes. Currently only fentanyl is used for direct transfer across the skin (Duragesic, Alza Corporation, Palo Alto, CA). Through the incorporation of a rate-limiting membrane, the

TABLE 1-4. Conversion Table for Opioids* Opioid Hydromorphone Meperidine Oxycodone Hydrocodone

IV/SQ Opioid to IV/SQ Morphine 5 0.13 — —

IV/SQ Morphine to IV/SQ Opioid 0.2 8 — —

Oral Opioid to Oral Morphine 5 0.1 1.5 0.5

Adapted with permission from Cancer Pain Guideline: M. D. Anderson Cancer Center internal document, 1994. *Oral morphine to intravenous/subcutaneous (IV/SQ) morphine, divide by 3; IV/SC morphine to oral morphine, multiply by 3.

Oral Morphine to Oral Opioid 0.2 10 0.7 2

4 / Advanced Therapy in Thoracic Surgery

influence of the variable permeability of the skin is decreased. Nevertheless, there is a significant variability in the systemic drug levels and analgesic effects. As well, there is an accumulation of fentanyl under the patch, providing appreciable serum levels for up to 24 hours after patch removal.25 Because of the possibility of apnea owing to high serum levels in opioid-naive patients,26 transdermal fentanyl is not currently recommended for acute postoperative pain. One approach that may permit its use in the future is to combine a low-dose transdermal fentanyl patch with an NSAID.27 Another possibility is to add electrical control to enhance the rate of fentanyl absorption across the skin. This iontophoretic route of administration is currently experimental but may offer the possibility of patient-controlled transdermal fentanyl in the future.28 Fentanyl can be delivered across the mucous membranes of the mouth. Oral transmucosal fentanyl citrate (OTFC, Actiq Abbott Laboratories, Abbott Park, IL) has been used for breakthrough chronic cancer pain as well as acute postoperative pain.29,30 It would be a good choice if the intravenous route was temporarily unavailable for acute postoperative analgesia. Fentanyl, sufentanil, butorphanol, heroin, oxycodone, and meperidine have been administered through the nasal mucosa, and morphine, codeine, fentanyl, heroin, and hydromorphone have been administered by inhalation.31 Ketamine Ketamine is a phencyclidine derivative occasionally employed as an anesthetic induction agent. Uniquely among induction agents, it produces what has been termed dissociative anesthesia. The analgesia does outlast the anesthetic effects and occurs at lower serum levels, so it can be useful in a decreased dosage as a postoperative analgesic. Ketamine may be given by intravenous, subcutaneous, epidural (see below), oral, and transdermal routes.32 Ketamine produces analgesia by multiple mechanisms, including inhibition of N-methyl- D -aspartate (NMDA) receptors, depression of the thalamus while activating the limbic system, and direct spinal effects. NMDA receptors are involved in hyperalgesia or neuropathic pain, which suggests that ketamine would be a good choice for analgesia for these patients.33 A recent study in rats demonstrated that ketamine had different mechanisms of action depending on the presence or absence of inflammation. Antinociceptive effects were created by activation of the monoaminergic descending inhibitory system, whereas in a hyperalgesic state induced by inflammation, inhibition of NMDA activation was the likely mechanism of the antihyperalgesia.34 Ketamine is a useful agent when narcotics and neuraxial agents are contraindicated or working poorly. Chow

and colleagues described a patient undergoing multiple thoracotomies whose pain management was complicated by infection and the development of neuropathic pain.35 Low-dose ketamine was used to decrease the need for narcotics after his fourth thoracotomy, with good results. It has also been suggested that ketamine should have preemptive effects because of its action at NMDA receptors. A landmark study in cholecystectomy patients found less postoperative pain, as measured by VAS scores and morphine consumption, in the group given low-dose intraoperative ketamine.36 An alternative explanation for the observed improved analgesia is that ketamine prevents the development of acute tolerance to opioids.37 Nonsteroidal Anti-inflammatory Drugs NSAIDs have proven to be a useful component of postoperative pain relief. Many oral NSAIDs have been used including ibuprofen, naproxen, and ketoprofen. The only currently available parenteral NSAID is ketorolac tromethamine (Toradol, Roche Laboratories, Nutley, NJ). The addition of ketorolac to a patient-controlled epidural analgesia (PCEA) regimen employing hydromorphone alone significantly decreased the incidence of nonincisional pain.38 Ketorolac is also employed in the treatment of breakthrough pain with otherwise satisfactory epidural analgesia. Ketorolac has several other features that make it useful in postoperative thoracotomy patients. These include its moderate potency (equivalent to morphine in some studies39); ease of administration by the intravenous and intramuscular routes; lack of acute tolerance, which may occur with even a single dose of opioid40; and lack of significant cardiorespiratory or central nervous system side effects. NSAIDs inhibit cyclooxygenase (COX), the enzyme that regulates the conversion of arachidonic acid to prostaglandins. There are two isoenzyme forms of COX. COX-1 is always present (constitutive). It modulates platelet activity and gastrointestinal cytoprotection and is involved in maintaining renal function in hypovolemic states. COX-2 is thought to be inducible by inflammatory stimuli and is involved with inflammation and pain. Conventional NSAIDs, such as indomethacin and ketorolac, which inhibit both COX-1 and COX-2, have been implicated in postoperative bleeding and gastric ulceration. They also may predispose to renal failure if the patient is concomitantly hypovolemic or even just relatively “dry,” as post-thoracotomy patients often are. Specific inhibitors of COX-2 were developed in an attempt to prevent the side effects of conventional NSAIDs while maintaining the benefits. Current selective COX-2 inhibitors still exhibit some predilection for causing renal failure and gastric ulceration but debatably to a lesser extent than conventional,

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 5

nonselective NSAIDs.41–43 The selective COX-2 inhibitors do not affect platelet function and have not been shown to increase postoperative blood loss. As a result they can be used perioperatively with relative impunity from hemorrhage. As of this writing, there is no parenteral COX-2 inhibitor available, although one is in US Food and Drug Administration trials.

Regional Analgesia Techniques In the past two decades, regional analgesia techniques have become the primary means of providing optimal pain relief after a thoracotomy. Although the type C nerve fibers responsible for autonomically mediated visceral pain have abundant opioid receptors, type A delta nerve fibers, which mediate somatic incisional pain, contain a paucity of these receptors. 44 Accordingly, systemically administered opioids have limited efficacy in controlling acute post-thoracotomy pain, especially that associated with activity. In contrast, local anesthetics, which are an integral component of most regional analgesia techniques, are very effective in blocking conduction in both type A delta and C nerve fibers. The main blocks used for thoracotomy patients are intercostal nerve blocks, interpleural analgesia, thoracic paravertebral nerve blocks (TPVBs), and epidural analgesia. Characteristics of these blocks are summarized in Table 1-5. Each may be performed as a single injection through a needle, but owing to the prolonged period of substantial pain experienced after a thoracotomy, catheter techniques are used more commonly (with the possible exception of intercostal nerve blocks, as discussed below). A standard 18- or 20-gauge epidural catheter may be placed through a hollow needle into the appropriate area for each block, and analgesic medication is administered

through this catheter either as intermittent boluses or a continuous infusion. The former has the disadvantage of supplying fluctuating levels of analgesic in the area of the block and thus providing varying degrees of pain relief for the patient. The latter has the disadvantages of providing more analgesic than is necessary during periods of less painful stimulation, and promoting the accumulation of analgesic medication over time, 45 unless appropriate decrements in infusion rates are made. With the goal of minimizing the disadvantages of both methods, low continuous (“basal”) infusion rates have been combined with intermittent boluses administered on an as-needed basis (which is usually patient controlled). Regional analgesia use in thoracotomies has several unique features compared with use in other types of surgery. First, all techniques except epidurals may be performed under direct vision from an internal approach before the chest is closed. This not only increases the ease with which the blocks are performed, but may also improve their success rate when compared with blocks performed via percutaneous techniques (although no studies have directly addressed this issue). As well, the risk of developing a pneumothorax, which is a potentially limiting factor for intercostal nerve blocks and interpleural analgesia, is irrelevant because the thoracic cavity is open intraoperatively and chest tubes are used postoperatively. Finally, hypovolemia is a relatively common occurrence in patients after thoracotomy because extensive fluid administration has been implicated in the development of postoperative pulmonary edema, especially after pneumonectomy.46 Therefore, regional analgesia techniques producing extensive blockade of the sympathetic nervous system and peripheral vasodilation may be accompanied by a significant risk of hypotension, and are often avoided.

TABLE 1-5. Summary of Factors Related to Regional Analgesia Techniques* Technique

Ease of Insertion

Analgesic Efficacy

Preservation of Pulmonary Function

Modification of Stress Response

Hypotension

Motor Blockade

Urinary Retention

Respiratory Depression

Intercostal nerve blocks +++

+

+
















Interpleural analgesia

±

±
















Thoracic paravertebral block ++

+

++

+













Epidural analgesia†

+

+







±

++

±

++++

++


= not a factor; ± = sometimes a factor; + to ++++ = degrees of being somewhat a factor to being an important factor. *For post-thoracotomy pain. †

With opioid/low-dose local anesthetic infusions.

6 / Advanced Therapy in Thoracic Surgery

Of the four types of regional analgesia discussed in this chapter, epidural analgesia is the only technique for which agents other than local anesthetics have been successfully used. This is not surprising because the intercostal nerve block, interpleural analgesia, and paravertebral nerve block techniques depend primarily on blocking impulse transmission within somatic nerves. By contrast, blockade of pain pathways within the spinal cord may be accomplished by other drugs, most commonly opioids, delivered into the epidural space. Although several local anesthetic agents are available, bupivacaine has been the most popular choice for postthoracotomy blocks over the past couple of decades, primarily because of its prolonged duration of action. Concentrations of 0.25 to 0.5% are necessary to provide adequate sensory blockade with most of the blocks discussed below, although lower concentrations have been used in the epidural space, when combined with opioids. Since its release in 1996, ropivacaine has been used increasingly for a variety of intraoperative and postoperative situations, and although the current literature regarding post-thoracotomy regional analgesia focuses on bupivacaine, ropivacaine will probably play a major role in clinical practice and the literature in the future. It is an amide local anesthetic structurally similar to bupivacaine that has the unique quality of being supplied as the pure S-(
)-enantiomer. This contrasts with the other local anesthetics, which exist as racemic mixtures of both the R-(+)- and S-(
)-enantiomers. Consequently, ropivacaine produces less cardiovascular and central nervous system toxicity,47,48 similar analgesia, and a less intense and shorter duration of motor blockade than does bupivacaine when administered into the epidural space.49,50 Low concentrations of epinephrine (1:100,000–1:400,000) are frequently added to the solution used for the regional analgesia techniques to decrease the quantity of medication absorbed into the systemic circulation. This should extend the duration and possibly improve the degree of analgesia, and decrease the risk of systemic toxicity from the drug. Lower peak plasma concentrations have been convincingly demonstrated when epinephrine has been added to the solutions used in intercostal nerve blocks,51 interpleural analgesia,52 and epidural analgesia,53,54 but data regarding the duration and quality of analgesia and systemic toxicity are more variable. There is even evidence that the addition of epinephrine to epidural opioid solutions may increase the incidence of some opioid-related side effects, especially pruritus.55–57 Epinephrine may also directly contribute to the pain relief achieved with epidural analgesic techniques by stimulation of 2-adrenergic receptors in the dorsal horn of the spinal cord.58

Ultralong-acting local anesthetics and opioids currently under development have been advocated as a means of providing prolonged analgesia from a single dose. However, their eventual role in the management of acute post-thoracotomy pain is unclear because prolongation of analgesic effects is accompanied by a prolongation of the duration of adverse events, which has particular relevance in the case of life-threatening cardiovascular and respiratory depression. Despite their apparent usefulness in post-thoracotomy patients, regional analgesia techniques are not appropriate for all individuals. Absolute contraindications for all types of regional analgesia include patient refusal, an allergy to the medication to be used, a lack of resuscitative equipment, a lack of ability to use the resuscitative equipment, and an infection or tumor at the site of injection. Relative contraindications are often specific for the type of block and are discussed below for the individual techniques. Knowledge of the contraindications may be critical in choosing the specific block for a particular patient. Intercostal Nerve Block definition and technique Intercostal nerve block is a technique in which a local anesthetic is injected into the immediate vicinity of the intercostal nerve as it lies in the costal groove on the internal surface of the rib. In this position, the intercostal nerve traverses between the internal intercostal and intercostalis intimus muscles and is located just caudad to the intercostal artery and vein. Local anesthetic is injected 7 to 8 cm from the posterior midline, proximal to the origin of the lateral cutaneous branch in the midaxillary line.59 Because there is a considerable overlap of sensory innervation of the thoracic dermatomes, it is necessary to block at least one level above and below the desired dermatomal level. Intercostal nerve blocks are often performed by a “single-shot” injection through a needle. There is limited spread of local anesthetic from one intercostal space to the next; therefore, separate injections at each level are usually necessary. For posterolateral thoracotomy incisions, intercostal nerve blocks are usually performed at T3 to T7. Three to 5 mL of local anesthetic is administered with each block; thus, a total of 20 to 25 mL of local anesthetic is used. Analgesia persists for 5 to 12 hours after a single injection,60–63 and intercostal nerve blocks may be repeated as necessary. A variety of catheter techniques have also been described,62,64,65 although most of these studies involved the use of more than one catheter, which creates a cumbersome situation.

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 7

mechanism of action Intercostal nerve blocks produce analgesia by direct blockade of the intercostal nerves. There is usually minimal or no spread of anesthetic proximally to the dorsal rami of the intercostal nerves or the sympathetic chain. efficacy Intercostal nerve blocks are moderately effective for post-thoracotomy pain. For example, Kolvenbach and colleagues detected “adequate” analgesia in approximately 76% of their group of patients, as measured by the lack of need for supplemental opioids. 6 2 When compared with placebo or parenteral opioids, intercostal nerve blocks have usually been shown to produce better pain control with lower pain scores and/or fewer supplemental opioids.64–68 Only two studies have compared intercostal nerve blocks with other regional techniques for post-thoracotomy pain. Asantila and colleagues compared intercostal nerve blocks with epidural analgesia with either bupivacaine or morphine, and found no significant differences between treatments with respect to pain scores or supplemental parenteral opioid requirements.69 More recently, Perttunen and colleagues randomized 45 patients to receive intercostal nerve blocks (performed at T3–T7 via an internal approach and administered as a single injection just prior to wound closure), TPVBs, or continuous epidural analgesia with bupivacaine.70 In the first 4 hours after surgery, pain scores during coughing were significantly lower in the intercostal nerve block group than in the other two groups. No differences were noted in supplemental morphine consumption, pain scores at rest, or pain scores with coughing after the initial 4-hour period. However, the authors emphasize that pain relief in all patients was only fair (VAS pain scores of 28–62/100 at rest and 62–91/100 with coughing), and optimizing the management of these techniques may have produced different results. Analgesic efficacy may be limited in intercostal nerve blocks owing to a lack of blockade of the dorsal rami, which can result in persistent pain at the medial edge of the incision, and muscles and ligaments in the surrounding area. Failure to block the sympathetic chain, vagus, and phrenic nerves may further limit the ability of intercostal nerve blocks to provide optimal pain relief after thoracotomy. Intercostal nerve blocks also appear to be moderately effective in improving pulmonary function. This is suggested in several,64,66,71,72 but not all,65 studies by higher values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and/or peak expiratory flow rate (PEFR) in patients receiving these blocks compared

with values in patients receiving a placebo or parenteral opioids. Compiling the results of several studies, Richardson and colleagues demonstrated an overall 55% preservation of spirometric function (vs preoperative values) with intercostal nerve blocks by 48 hours postthoracotomy.8 Despite the above observations, most studies have failed to demonstrate that intercostal nerve blocks decrease the incidence of postoperative complications in post-thoracotomy patients. Furthermore, although Deneuville and colleagues showed that intercostal nerve blocks were associated with fewer postoperative respiratory complications than was as-needed parenteral opioid, the incidence of complications with intercostal nerve blocks was identical to that with “fixedschedule” intramuscular opioid injections.65 advantages and disadvantages The main advantage of intercostal nerve blocks is the ease with which they can be performed.61 They require little training and no special equipment. The technique is quite safe, and any significant complication usually occurs within 30 minutes of performing the block. As such, no special monitoring is necessary for patients with these blocks beyond the immediate post-block time period. The main disadvantages of intercostal nerve blocks are the necessity of performing separate blocks at multiple levels, and the relatively short duration of analgesia achieved via the single-injection techniques. adverse effects The most common adverse effect associated with the use of intercostal nerve blocks for thoracotomy is the development of high systemic blood levels of local anesthetic. This is a consequence of both the volume needed for injections at multiple levels and the vascularity of the area of injection. Peak blood levels of local anesthetic occur at 5 to 20 minutes,61,64,73 and they are higher than with interpleural analgesia, TPVBs, and epidural analgesia.70,74 Case reports of spinal anesthesia associated with the use of intercostal nerve blocks have also been reported.75,76 This has been postulated to be due to retrograde intraneural spread of local anesthetic to the subarachnoid space. Most cases have involved intercostal nerve blocks performed by an internal approach during thoracotomy, possibly because of the more medial injection of the local anesthetic in these circumstances. contraindications There are no absolute contraindications specific to intercostal nerve blocks. The main relative contraindication of intercostal nerve blocks when used for post-thoracotomy analgesia is in patients for whom the effects of high

8 / Advanced Therapy in Thoracic Surgery

systemic blood levels of local anesthetic may be particularly detrimental, which includes patients with cardiac conduction defects and seizure disorders. Interpleural Analgesia definition and technique The term interpleural analgesia refers to a technique whereby local anesthetic is placed into the interpleural space, located between the visceral and parietal pleurae. The term intrapleural analgesia is often used interchangeably with interpleural analgesia, but the former is anatomically incorrect. For thoracotomy patients, a multiorifice epidural catheter is usually inserted into the interpleural space under direct vision by the surgeon prior to chest closure, and a local anesthetic is administered either as a continuous infusion or intermittent bolus doses. Some authors emphasize suturing the internal tip of the catheter high in the interpleural space (in the cranial portion of the thoracic cage) to prevent dislodgment,77 whereas others recommend placing the tip at the level of the incision.78 Table 1-6 presents examples of dosage regimens. None has been demonstrated to be superior to the others. mechanism of action Interpleural analgesia produces pain relief primarily by diffusion or bulk flow of local anesthetic through the parietal pleura, into the subpleural space, and finally to the intercostal nerves. The resultant effect is a multilevel intercostal nerve block. 79 Interpleural analgesia techniques may also block other nervous structures including the vagus and phrenic nerves as they traverse through the interpleural space,77 pain receptors in the parietal pleura, and the thoracic sympathetic chain, by diffusion of local anesthetic into the paravertebral space. The clinical importance of blockade at these secondary sites is unclear and may contribute to the variable results in studies examining the efficacy of interpleural analgesia. efficacy The efficacy of interpleural analgesia for post-thoracotomy pain is controversial. 8 0 Compared with placebo or parenteral opioids, interpleural analgesia has been shown to improve analgesia in some studies,81,82 and to have minimal or no effect in others.83–85 Interpleural analgesia has also been demonstrated to produce a degree of analgesia similar to TPVB and thoracic epidural analgesia with bupivacaine in some studies, 7 8 , 8 6 but less than thoracic epidural bupivacaine, lumbar epidural hydromorphone, and lumbar epidural morphine in others.74,87,88 The lack of consistent efficacy for post-thoracotomy pain has been primarily attributed to the loss of local

TABLE 1-6. Examples of Dosing Regimens for Interpleural Analgesia Study

Intraoperative Regimen

Postoperative Regimen

Tartiere et al, 199181 Richardson et al, 199578 Stromskag et al, 199090 Schneider et al, 199384 Mann et al, 199282

—

10 mL 0.25% bupivacaine q8h 0.5% bupivacaine 0.1 mL/kg/h infusion 20 mL 0.375% bupivacaine prn 30 mL 0.5% bupivacaine q4h 20 mL 0.25% bupivacaine q4h 20 mL 0.5% bupivacaine q4h 0.05 mL/kg/h 2% lidocaine with 1:200,000 epinephrine infusion

20 mL 0.25% bupivacaine at chest closure — — —

Silomon et al, — 200083 Raffin et al, 199485 0.15 mL/kg 2% lidocaine with 1:200,000 epinephrine after chest closure prn = according to circumstances.

anesthetic by drainage through chest tubes. Ferrante and colleagues documented a 30 to 40% loss of an injected dose of bupivacaine over a 4-hour period through the chest tubes.89 For interpleural analgesia administered via the bolus method, clamping the chest tubes for 15 to 30 minutes after each dose has been advocated to help circumvent this problem,77 although the safety and efficacy of such a maneuver has been questioned.8 Other factors that may contribute to the lack of analgesic efficacy are dilution of local anesthetic with pleural exudate, and uneven distribution of local anesthetic throughout the pleural space. The latter may occur because of inflammation of the pleura by the current surgical procedure and/or the presence of fibrous tissue from previous pleural disease or thoracotomy. As well, the distribution of local anesthetic within the interpleural space is gravity dependent.90 The upright position assumed by post-thoracotomy patients, because of its beneficial effects on pulmonary function, encourages pooling of the local anesthetic in the inferior thoracic cage, thereby contributing to lesser analgesia at the more cranial thoracic dermatomes. Finally, the dorsal rami of the thoracic spinal nerves are not blocked by interpleural techniques; thus, patients may experience pain in the medial part of the incision and paravertebral surrounding muscles and ligaments.64 The effects of interpleural analgesia on postoperative pulmonary function are likewise unimpressive. Most studies have failed to demonstrate an improvement in FEV 1 , FVC, PEFR, arterial blood gas values, and/or pulmonary complications compared with these effects when placebo or parenteral opioids are used. 74,83,84 In Richardson and colleagues’ review of spirometric function with different analgesic techniques post-thoracotomy,

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 9

an overall 35% preservation of function (vs the preoperative values) was noted for interpleural analgesia by 48 hours postoperatively.8 This was lower than for all the other techniques examined, including intercostal nerve blocks, thoracic paravertebral, and epidural analgesia. In two randomized studies comparing interpleural analgesia and TPVB, analgesia for the two techniques was equivalent, but patients receiving interpleural analgesia demonstrated significantly worse FVC and FEV1 values.78,91 This observation led to the suggestion that interpleural analgesia may cause direct impairment of diaphragmatic and intercostal muscle function, either by diffusion of local anesthetic into the diaphragm and/or intercostal muscles, with direct inhibition of their contractile function,91 or by blockade of the phrenic nerve as it travels through the mediastinum and/or at its terminal branches innervating the diaphragm. No studies to date have confirmed the validity of either theory.92 advantages and disadvantages The primary advantage of interpleural analgesia for postthoracotomy pain is the ease with which the technique can be performed. It is also relatively safe, and no special monitoring is necessary for patients receiving this form of analgesia.77 The main disadvantage of interpleural analgesia is the lack of consistent beneficial effects on pain relief and pulmonary function in the post-thoracotomy patient. Possible explanations for this have been discussed above. adverse effects The main adverse effects of interpleural analgesia for postthoracotomy analgesia include toxicity owing to excessive systemic absorption of local anesthetic, blockade of the thoracic sympathetic chain, and stellate ganglion blockade (with an ipsilateral Horner syndrome).93 Systemic local anesthetic toxicity is rare because plasma concentrations usually remain below levels associated with significant toxicity.81,94,95 When administered as a bolus dose, peak blood levels occur 5 to 30 minutes after injection. Similarly, blockade of the thoracic sympathetic chain rarely produces clinically significant hypotension and bradycardia. This lack of hemodynamic effects has traditionally been attributed to the unilateral nature of the sympathetic block, although Ramajoli and De Amici have convincingly demonstrated bilateral sympathetic blockade of the thorax and abdomen with unilateral interpleural instillation of both 0.25 and 0.5% bupivacaine.96 Thus, hemodynamic stability is probably due to incomplete blockade of the upper thoracic ganglion, resulting in little or no effect on the cardiac sympathetic fibers and allowing compensatory vasoconstriction of the upper extremities.

contraindications There are no absolute contraindications specifically related to the technique of interpleural analgesia. Relative contraindications include conditions in which there is an anticipated lack of efficacy, such as with pleural fibrosis, previous surgical or chemical pleurodesis, and bronchopleural fistula or empyema; and patients for whom the effects of high systemic blood levels of local anesthetic may be particularly detrimental (as discussed above under “Intercostal Nerve Block”). Thoracic Paravertebral Nerve Block definition and technique After its first performance in 1905 by Hugo Sellheim, TPVB enjoyed an initial period of popularity, followed by a dramatic decline in use in the middle of the twentieth century.97 In the past two decades, however, there has been a resurgence of interest in the technique, particularly in Europe. TPVB is a technique whereby local anesthetic is injected into the paravertebral space in the thoracic region. It has also been referred to as extrapleural, extrapleural paravertebral, and extrapleural intercostal analgesia. As depicted in Figure 1-2, the paravertebral space is a wedge-shaped region adjacent to the thoracic vertebrae in the vicinity where the spinal nerves emerge from the intervertebral foramina. Its boundaries are as follows: posteriorly, the superior costotransverse ligament; laterally, the posterior intercostal membrane; anteriorly, the parietal pleura; and medially, the posterolateral aspect of the vertebrae, intervertebral disk, and intervertebral foramen. The origin of the psoas muscle forms the inferior boundary of the paravertebral space; thus, spread of local anesthetic below T12 is uncommon. The cranial boundary of the paravertebral space has not been Subserous fascia

Endothoracic fascia

Pleura Visceral Parietal

Esophagus Azygos vein

Thoracic duct Descending aorta Sympathetic chain Interpleural space

Right lung

Left lung

Extrapleural compartment

Subendothoracic compartment Intercostal nerve Posterior primary rami Superior costotransverse ligament

FIGURE 1-2. Anatomy of the thoracic paravertebral space. Reproduced with permission from Karmaker MK.98

10 / Advanced Therapy in Thoracic Surgery

defined, and radiocontrast dye has been observed in the cervical region after thoracic paravertebral injection.98 The thoracic paravertebral space is in continuity with the epidural space medially via the intervertebral foramen, the intercostal space laterally, and the contralateral paravertebral space via the prevertebral and epidural spaces.98 The paravertebral space is traversed by the intercostal nerves, their dorsal rami, the rami communicantes, and the sympathetic chain. As with other techniques, TPVB may be performed by direct injection through a needle or an indwelling catheter, both of which may be introduced either percutaneously or under direct vision before the chest is closed. Sabanathan and colleagues have described a technique for use during thoracotomy that involves reflecting the parietal pleura from the posterior wound margin onto the vertebral bodies to form an extrapleural pocket.99 A percutaneously placed catheter is then placed into this pocket and positioned under direct vision so that it lies against the angles of the exposed ribs. Richardson and Lonnqvist have employed combined techniques whereby a percutaneously placed catheter is inserted before the surgery begins and a bolus dose of local anesthetic is administered to provide intraoperative anesthesia. 9 7 Before chest closure, methylene blue is injected through the catheter, and if the spread of dye is not optimal, the catheter is reinserted by the surgeon. Video-assisted placement of a paravertebral catheter during thoracoscopy has also been reported.100 Table 1-7 presents various dosage regimens for TPVB. Continuous infusion of local anesthetic through a paravertebral catheter provides better pain control than do intermittent bolus injections.101 mechanism of action TPVB produces analgesia by blockade not only of the intercostal nerves but also of their dorsal rami and the sympathetic chain. Owing to the continuous nature of the paravertebral space, local anesthetic applied at one level spreads to multiple contiguous dermatomes. Using 15 mL 0.5% bupivacaine, Cheema and colleagues demonstrated a somatic sensory block extending for a

mean of 5 (range 1 to 9) dermatomes, and a sympathetic block over an average of 8 (range 6 to 10) dermatomes.102 However, the extent of spread is variable, as is evidenced by these large ranges; thus, it may be necessary to perform injections at more than one site to reliably anesthetize more than three to four segments. A small amount of local anesthetic may also exit the intervertebral foramina to enter the epidural space, but whether this contributes significantly to the analgesic effects of TPVB is questionable.98 efficacy The efficacy of TPVB for post-thoracotomy pain control has been well established. Lower pain score and opioidsparing effects have been noted in several studies comparing TPVB with placebo and parenteral opioids, 103–106 although supplemental opioids were often still necessary. In comparison to epidural blockade with local anesthetics and/or opioids, TPVB has frequently demonstrated similar or better pain relief, accompanied by less nausea, vomiting, hypotension, and urinary retention.107–110 Most studies have demonstrated a significant improvement of post-thoracotomy pulmonary dysfunction with TPVB compared with placebo or parenteral opioids, as demonstrated by higher FEV 1 , FVC, and/or PEFR values.104,105,106,111 In Richardson and colleagues’ review of various techniques for post-thoracotomy analgesia, TPVB demonstrated the best preservation of pulmonary function.8 FEV1, FVC, and/or PEFR values had all returned to approximately 75% of their preoperative value by 48 hours postoperatively in patients who had received TPVB. When TPVB has been compared directly with thoracic epidural analgesia, most studies have demonstrated similar effects on pulmonary function for the two techniques, 109,110 although TPVB was associated with higher values of PEFR and oxygen saturation as measured by pulse oximetry (SpO 2 ) in one study by Richardson and colleagues’ group. 1 0 7 As noted previously (see “Interpleural Analgesia”), TPVB has been demonstrated to produce both better and similar effects on pulmonary function tests when directly compared with interpleural analgesia.70,112 Likewise, there is a limited quantity of evidence that

TABLE 1-7. Examples of Dosage Regimens for Thoracic Paravertebral Blockade Study

Intraoperative Regimen

Postoperative Regimen

Carabine et al, 1995103 Catala et al, 1996101

5 mL 0.25% bupivacaine after chest closure —

Barron et al, 1999105

0.3 mL/kg 1% lidocaine before chest closure or 0.3 mL/kg 0.25% bupivacaine before chest closure 20 mL 0.5% bupivacaine after chest closure 10 mL 0.25% bupivacaine after chest closure 20 mL 0.25% bupivacaine during chest closure

0.25% bupivacaine 5 mL/h infusion 20 mL 0.375% bupivacaine q6h or 15 mL 0.375% bupivacaine loading dose, then 5 mL/h 0.375% bupivacaine infusion 0.1 mL/kg/h 1% lidocaine infusion or 0.1 mL/kg/h 0.25% bupivacaine infusion Approximately 0.1 mL/kg/h 0.5% bupivacaine 3–10 mL/h 0.25% bupivacaine 0.1 mL/kg/h 0.5% bupivacaine infusion

Berrisford et al, 1990111 Mathews and Govenden, 1989108 Richardson et al, 1999107

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 11

TPVB may decrease the risk of pulmonary complications compared with placebo and parenteral opioids. Sabanathan, Berrisford, and colleagues, in two separate studies (with possibly overlapping subjects), have reported fewer pulmonary complications in patients receiving TPVB compared with placebo.104,111 TPVB has also been shown to suppress the stress response, as measured by serum cortisol and glucose levels, and in this respect it functioned better than thoracic epidural analgesia.107 advantages and disadvantages TPVB has been described as being quick and easy to perform. 98,112,113 This statement should be interpreted cautiously, however, as it was made by the main authors regarding TPVB in the literature today, and their experiences may not be applicable to other institutions. This caution may be especially relevant for centers in North America, where TPVB is rarely taught in the anesthesiology and surgery training programs. Other advantages of TPVB include the lack of urinary retention and motor blockade of the lower extremities owing to the thoracic and unilateral location of the block.102,114 As well, the unilateral nature of the block results in little/no direct effects on hemodynamics,102 and the doses of local anesthetic are usually less than those associated with systemic toxicity.70 Even when higher levels have occurred, there has been no evidence of systemic toxicity.45,110 Accordingly, no special monitoring is necessary for patients with these blocks beyond the usual postoperative care.112 As TPVB is dependent on the use of local anesthetics for postoperative use, opioidrelated risks are theoretically avoided. However, supplementation with systemic opioids is often used; thus, opioid adverse effects may be minimized but not absent. The main disadvantage of this technique is that it is more difficult to perform than the intercostal nerve and interpleural blocks. As well, patients with a previous thoracotomy are usually inappropriate candidates for the block since the paravertebral space may be obliterated by scar tissue. The technique may likewise be unsuitable for patients undergoing a pleurectomy, although successful use of TPVB has been reported, provided the parietal pleura covering the vertebral bodies and a few centimeters distally is left intact.106 adverse effects The incidence of adverse effects with TPVB in the postthoracotomy population is 10% or lower.112,115 The most frequent adverse event is hypotension,115 which has been primarily attributed to the unmasking of relative hypovolemia as hypotension does not occur in well-hydrated patients receiving TPVB for the treatment of chronic

pain syndromes.98,102,112 Other complications, which occur much less frequently, are inadvertent puncture of the epidural or subarachnoid space owing to a faulty technique,97 and unilateral Horner syndrome because of the cephalad spread of anesthetic to the cervical sympathetic structures. No fatality directly related to TPVB has been reported in the literature.98,112 contraindications As alluded to above, a previous ipsilateral thoracotomy would be a relative contraindication to the technique because of a possible obliteration of the paravertebral space. An empyema is not directly affected by manipulations in the paravertebral space, but the accompanying acidosis and hyperemia may limit the efficacy of the TPVB and increase the risk of systemic absorption of local anesthetic. Anticoagulation is a relative contraindication to the technique, but the paravertebral space is less vascular than the epidural space; thus, the risk of venous puncture is less than with epidural analgesia. As well, the consequences of a unilateral paravertebral space hematoma are small compared with the potentially catastrophic consequences of an epidural hematoma. 112 Similarly, TPVB is relatively contraindicated in patients with raised intracranial pressure because of the possibility of inadvertent dural puncture and subsequent brainstem herniation. However, the risk of puncture is less than with epidural analgesia, so in this situation, TPVB would be the best choice of the two techniques. Epidural Analgesia definition and technique Epidural analgesia refers to the technique of injecting analgesic medication into the epidural space, surrounding the spinal cord. As with most of the other regional techniques discussed heretofore, epidural analgesia is almost exclusively administered via an indwelling catheter when used for post-thoracotomy pain relief. Similar effects may be achieved by injecting analgesic medication into the subarachnoid space (albeit with lower doses),116 but the technique is rarely used in the United States because of concerns with introducing a catheter into this space. The intimate proximity of the subarachnoid space to the spinal cord poses a risk of injury to the spinal cord, and an association between the development of cauda equina syndrome and subarachnoid microcatheters (also known as spinal microcatheters) has been suggested.117 Local anesthetics and opioids are the two main classes of drugs used for epidural analgesia in post-thoracotomy patients. Other drugs that have been used in the epidural space, either alone or as adjuncts, are discussed later (see

12 / Advanced Therapy in Thoracic Surgery

“Other Agents”). In the early 1980s, epidural morphine was popular, primarily because of its hemodynamic stability compared with epidural local anesthetics and its relatively long duration of action.5 The latter permitted bolus dosing on an as-needed basis every 6 to 24 hours. The risk of respiratory depression and slow onset of action with epidural morphine promoted the search for alternative opioids,118 thus leading to the use of more lipophilic epidural opioids such as fentanyl and its analog, sufentanil. Owing to the short duration of action of these opioids, continuous infusions are necessary. Most recently the synergistic effects of combining local anesthetics and opioids in the epidural space have been recognized.119 This synergism has been attributed to the facilitation of opioid transport from the epidural space to the subarachnoid space by local anesthetic,120 and production of a conformational change in the spinal  opioid receptor by local anesthetic agents, such that opioid binding is facilitated.121 Accordingly, continuous infusions of opioid–local anesthetic combinations have become popular, with the goal of providing similar or improved analgesia with lower doses of both agents, so that the incidence of adverse effects is reduced. Although similar or improved analgesia has been achieved in several studies,122–126 a reduction in adverse effects has not been universally accomplished (see “Effects Related to Injection of Epidural Local Anesthetic–Opioid Combinations,” below). Current literature suggests that the combination of 10 to 12.5 µg/mL fentanyl (or 1 µg/mL sufentanil) and 0.1 to 0.125% bupivacaine is closest to the ideal for post-thoracotomy patients, producing a maximum of pain relief and minimum of side effects.6,127 Of interest, the addition of bupivacaine does not seem to improve analgesia when added to epidural meperidine.128 This may be because meperidine has significant local anesthetic properties itself and has even been used as the sole anesthetic for lower abdominal surgery when administered in the subarachnoid space.129 Table 1-8 presents several examples of epidural analgesia regimens. There is controversy as to whether epidural catheters should be inserted into the thoracic or lumbar region for thoracotomy patients. Owing to the proximity of the spinal cord to the epidural space in the thoracic region and the greater technical difficulty of entering the epidural space at this level of the spinal column, many anesthesiologists are hesitant to insert a thoracic epidural catheter. They are supported by evidence that equivalent analgesia may be achieved by lumbar and thoracic epidural injections in post-thoracotomy patients.120,130–134 In contrast, advocates of thoracic epidural catheters emphasize that higher volumes and/or higher doses of epidural opioids and/or local anesthetics were needed

TABLE 1-8. Examples of Dosing Regimens for Epidural Analgesia Solution

Infusion Rate

Bolus Doses

Fentanyl 10 µg/mL

0.5–1 µg/kg/h

Sufentanil 1 µg/mL

0.1–0.2 µg/kg/h

Morphine Morphine 0.01%

— 0.5–0.8 mg/h

Hydromorphone Hydromorphone 0.005%

— 0.15–0.3 mg/h

Fentanyl 10 µg/mL + bupivacaine 0.75–0.125% Sufentanil 1 µg/mL + bupivacaine 0.75–0.125% Morphine 0.01% + bupivacaine 0.75–0.125% Hydromorphone 0.0025% –0.005%+ bupivacaine 0.75–0.125%

6–8 mL/h

10–15 µg q10–15 min prn 5–7 µg q10–15 min prn 3–6 mg q6–12h prn 0.2–0.3 mg q10–15 min prn 0.8–1.5 mg q4–6h prn 0.15–0.3 mg q10–15 min prn 1–2 mL q10–15 min prn

6–8 mL/h

1–2 mL q10–15 min prn

6–8 mL/h

1–2 mL q10–15 min prn

6–8 mL/h

1–3 mL q10–15 min prn

Data from University of Texas M. D. Anderson Cancer Center protocol and DeLeon-Casasola OA and Lema M.154 prn = according to circumstances.

with the lumbar route to produce equivalent analgesia in many of these studies, thereby suggesting that the lumbar route may be acceptable but not optimal. As well, there is no evidence that complication rates are higher with thoracic than with lumbar epidural catheters, 135 and many of the potential advantages of epidural analgesia discussed below rely on blockade of the cardiac sympathetic fibers at T1 to T5, which is more easily accomplished with a thoracic than with a lumbar epidural catheter. With these considerations in mind, the approach at our institution is to preferentially place a thoracic epidural catheter; however, a high lumbar catheter is used if this is unsuccessful. mechanism of action The mechanism of action of epidural opioids and local anesthetics differs. Local anesthetics applied to the epidural space act primarily by blockade of nerve impulse conduction in the axonal membrane of the spinal nerve roots as they traverse the epidural space.136 Diffusion of local anesthetic into the long tracts of the spinal cord may further contribute to the analgesia produced by epidural local anesthetics. The various types of nerve fibers exhibit differential sensitivity to local anesthetics: sympathetic fibers are the most easily blocked, and motor fibers are the most resistant. 137 Consequently, the concentration of local anesthetic is the primary determinant of the depth of blockade, with higher concentrations producing more motor blockade. The actual extent of blockade along the spinal canal

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 13

depends primarily on the volume administered, and because of the greater sensitivity of the sympathetic fibers, the extent of sympathetic blockade may be greater than the somatic sensory block. Epidural opioids exert their primary therapeutic effects by binding to specific opioid receptors in the substantia gelatinosa of the dorsal horn of the spinal cord gray mater. 1 3 6 , 1 3 8 This region contains interneurons involved in the ascending pain pathways (the spinothalamic and spinoreticular tracts). Opioid receptors are located both presynaptically and postsynaptically, and they function to inhibit the release of neurotransmitters from primary sensory neurons and block the depolarization of post-synaptic neurons, respectively.44 The term selective spinal analgesia has been used to denote analgesia attributable to these spinal cord opioid receptors. Before reaching the spinal cord, opioids injected into the epidural space must first travel through the dura mater, subdural space, arachnoid mater, subarachnoid space (containing the cerebrospinal fluid), and pia mater. The epidural space contains an abundance of fat tissue and an extensive venous plexus, and 90 to 97% of an injected dose is absorbed into these compartments,139–141 thereby never reaching the subarachnoid space. Epidural opioids may also produce analgesia at a supraspinal level (termed supraspinal analgesia) by binding to opioid receptors in the brain. Opioids gain access to these sites via two main pathways: absorption into the epidural veins and subsequent entry into the systemic circulation, and rostral travel through the cerebrospinal fluid to the brain. After a bolus injection of all epidural opioids, plasma levels peak at approximately the same time as with an intramuscular injection,139,142,143 and in some studies have achieved values high enough to contribute to analgesia.139,142,144–146 Plasma opioid levels fall quickly, however, and are of little importance beyond the first hour after epidural bolus administration for all agents.139,142,146 A different scenario arises when lipophilic agents (such as fentanyl and sufentanil) are administered by continuous epidural infusion or repeat bolus. Continuing systemic absorption of these agents results in accumulation, and some studies have recorded systemic plasma levels within the usual therapeutic range for these drugs, when administered by these methods.123,143 Similarly, Miguel and colleagues and Sandler and colleagues have demonstrated that epidural infusions of fentanyl and sufentanil produce plasma levels similar to those with intravenous infusion, when titrated to equivalent analgesia. 1 4 7 , 1 4 8 This suggests that supraspinal analgesia may be a major contributor to the overall analgesic effect when lipophilic opioids are administered in this manner.

Rostral travel through the cerebrospinal fluid of opioids injected into the epidural space is most prominent with morphine, as its relative hydrophilic properties limit its diffusion out of the subarachnoid space, thereby allowing greater quantities of morphine to be retained in the cerebrospinal fluid for a prolonged period of time.149 Morphine travels cranially via the slow process of cerebrospinal fluid bulk flow, leading to peak levels of morphine in the cervical cord region by 3 to 5 hours after lumbar epidural injection.136,150 Movement through the cerebrospinal fluid for more lipophilic opioids may also occur, especially with large bolus doses, but the quantities of drug detected in the cervical cord and/or cisterna magna have been small, and their contribution to the analgesia achieved with these agents is unknown.146,151 efficacy The efficacy of epidural analgesia in providing pain relief after thoracotomy depends on the drug(s) used. Epidural analgesia with local anesthetics alone is more effective in providing analgesia than are parenteral opioids, but the concentrations needed to accomplish this (eg, 0.5% bupivacaine) are accompanied by a significant risk of hypotension. When lower concentrations have been used, supplemental parenteral opioids are usually necessary.70,107,152 The efficacy of epidural morphine in providing post-thoracotomy analgesia is undisputed. It is considered the “gold standard” for epidural opioid analgesia. Pain scores and/or the need for supplemental analgesics are universally lower for epidural morphine than for parenteral morphine, and these effects are accomplished using lower doses of epidural morphine, which last longer than parenteral morphine. 5 , 1 5 2 , 1 5 3 The lipophilic opioids are also effective in providing analgesia after thoracotomy when administered via the epidural route. However, as discussed previously, there is evidence that continuous epidural infusions of these agents produce post-thoracotomy pain relief primarily by the systemic absorption of the opioid and may offer little advantage over the less complicated intravenous route of administration.154 The opioid–local anesthetic combinations popular today are also very effective in providing pain relief after thoracotomy. As combinations are relatively new techniques and the efficacy of epidural analgesia for postthoracotomy pain has already been established, there has been little interest in performing studies comparing the efficacy of combinations to that of parenteral opioids or placebos. Nevertheless, improved analgesia has been noted with both epidural morphine–bupivacaine and epidural fentanyl–bupivacaine infusions compared with parental opioids.152,155

14 / Advanced Therapy in Thoracic Surgery

Studies comparing epidural analgesia with other modes of regional analgesia in post-thoracotomy patients are few, and their interpretation has been confounded by the use of a variety of different medications in the epidural space. Three studies have used epidural local anesthetics alone. Brockmeier and colleagues showed no difference in analgesic efficacy between 0.375% epidural bupivacaine and interpleural analgesia.86 Richardson and colleagues demonstrated better analgesia with TPVB than with epidural analgesia, but the TPVB group received 0.5% bupivacaine and the epidural group received only 0.25% bupivacaine. 1 0 7 A final study compared 0.25% epidural bupivacaine with 0.25% TPVB bupivacaine and 0.5% interpleural bupivacaine. 70 All techniques produced similar analgesia at rest, but the intercostal nerve blocks group had better dynamic pain relief for the first 4 hours after thoracotomy. In a study of epidural analgesia using a combination of fentanyl and bupivacaine, analgesia was superior to that produced by TPVB,114 although this effect did not persist beyond the first postoperative day. Evidence regarding the efficacy of epidural analgesia in improving pulmonary function and decreasing pulmonary morbidity in the post-thoracotomy patient is conflicting. Many studies have revealed no difference in arterial blood gas results, spirometry measurements, or pulmonary complications when epidural analgesia has been compared with parenteral opioids or other types of regional analgesia in this population. 6 9 , 8 8 , 1 0 9 , 1 5 3 , 1 5 6 – 1 6 0 In Richardson and colleagues’ review of different techniques for post-thoracotomy analgesia discussed previously, epidural analgesia with local anesthetics and/or opioids resulted in a moderate preservation of pulmonary function.8 By 48 hours after surgery, FEV1, FVC and/or PEFR values had returned to approximately 55% of their preoperative values in patients who had received epidural analgesia, which was similar to the results obtained with intercostal nerve blocks but worse than the 75% values observed with TPVB. For those studies that have shown an improvement in pulmonar y parameters, most have demonstrated improvement in only some of the parameters measured. For example, Guinard and colleagues demonstrated higher FVC and FEV 1 values for thoracic epidural fentanyl when compared with intravenous fentanyl, but no difference in arterial blood gas results or the number of patients with abnormalities on chest radiographs.132 Salomaki and colleagues have shown lower PaCO2 values with epidural fentanyl but similar PaO2 and incidences of atelectasis compared with intravenous fentanyl.161 Two articles from Hasenbos and colleagues are the only studies that have found both improved arterial blood gases (PaCO 2 less elevated above preoperative levels) and reduced incidence of pulmonary complications. 162,163

However, these studies were not blinded, and the opioid examined was nicomorphine, the 3,6-dinicotinoyl ester of morphine, which is not available in North America. As well, the sole analgesic in the nonepidural groups was intramuscular nicomorphine, administered in as-needed doses by the nursing staff. By providing parenteral opioid in this manner, analgesic therapy in these groups may not have been optimized. A recent meta-analysis of the pulmonary effects of various analgesic regimens in a wide variety of surgical procedures (including but not restricted to thoracotomies) revealed only a diminished incidence of atelectasis with epidural opioids and a decreased incidence of pulmonary infection and overall pulmonary complications, plus an increased PaO2 with epidural local anesthetics.164 Of interest, the authors emphasize the lack of difference in spirometry results between the different methods of analgesia and suggest that there is no rationale for using these surrogate measures of pulmonary outcomes. Epidural analgesia has little, if any, impact on modifying the stress response to surgery in the post-thoracotomy population.107,165 This has been attributed to incomplete blockade of the afferent sensory nervous input from the site of surgery and the release of components of the stress response, such as cytokines, directly into the bloodstream from the site of tissue injury.166 advantages and disadvantages One major advantage of epidural analgesia is related to the use of opioids in the epidural space. Systemic absorption and/or cephalad spread of epidural opioid may alleviate the shoulder pain commonly associated with thoracotomies, and even neck incisions for esophagectomies. In our institution, we do not routinely use supplemental parenteral opioids for pain in these two locations. If necessary, NSAIDs and acetaminophen are almost always sufficient adjuvants to our epidural analgesia. Thoracic epidural analgesia with local anesthetics (alone or in combination with opioids) may have unique advantages in patients with coronary artery disease. Blockade of the cardiac sympathetic fibers innervating the heart (T1–T5) results in small reductions in heart rate, systemic vascular resistance, and possibly cardiac output,167,168 thereby decreasing myocardial oxygen demand. At the same time, myocardial oxygen supply may improve, particularly in areas at most risk of ischemia. Thoracic epidural analgesia with local anesthetic has been demonstrated to produce dilatation of stenotic coronary arteries,169 redistribution of blood flow from the epicardium to endocardium,170 and redistribution of blood flow specifically toward ischemic regions of the myocardium.170 Maintaining the systemic blood pressure close to the normal range (eg, mean arterial

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 15

pressure < 20% below baseline) is necessary for these effects to be most evident.171 Another potential benefit of epidural analgesia in the patient with coronary artery disease relates to coagulation. Local anesthetic may be absorbed from the epidural space in quantities sufficient to interfere with platelet aggregation,172,173 thereby counteracting the hypercoagulable state associated with major surgery and potentially diminishing the risk of coronary artery thrombosis formation. Despite the above observations, there have been no properly conducted randomized controlled trials demonstrating decreased risk of myocardial ischemia/infarction through the use of epidural analgesia in any group of patients postoperatively, let alone those having thoracotomies. As well, there is concern that blockade of the sensory innervation of the upper thoracic region may simply obliterate the pain of myocardial ischemia, thus removing an important warning signal of impending myocardial infarction.174 Epidural analgesia may also decrease the risk of postoperative arrhythmias. This is of particular relevance in the post-thoracotomy situation as supraventricular arrhythmias (especially atrial fibrillation) occur in approximately 15% of patients after lung surgery, and recurrent episodes have been associated with increased perioperative mortality.175 Animal studies suggest that thoracic epidural analgesia with local anesthetic may reduce the risk of ventricular tachyarrhythmias and reentry supraventricular arrhythmias,176–178 an effect that has been attributed to cardiac sympathetic blockade. In humans a retrospective review by Groban and colleagues noted a significantly lower incidence of atrial arrhythmias while thoracic epidural analgesia (with opioid or opioid plus local anesthetic) was in use compared with the incidence after the epidural was removed on the second or third postoperative day.179 In a prospective, randomized study comparing thoracic epidural bupivacaine with thoracic epidural morphine, Oka and colleagues demonstrated a lower incidence of supraventricular tachyarrhythmias with epidural bupivacaine when administered for 3 days after thoracotomy.180 The aforementioned cardiovascular benefits of thoracic epidural analgesia with local anesthetics cannot be extrapolated to the use of epidural opioids or to epidural local anesthetics administered by the lumbar route. In the former instance, there is no direct inhibition of sympathetic input to the heart. In the latter, blockade of T1 to T5 would require such an extensive blockade of the sympathetic nervous system that the resultant decrease in blood pressure would very likely counteract any beneficial effects attributable to the blockade of the cardiac sympathetic fibers. The main disadvantage of epidural analgesia is that, of the regional techniques described heretofore, it is

probably the most difficult to perform and is almost exclusively performed by an anesthesiologist or nurse anesthetist. Although many of these individuals have had extensive training and/or experience in performing epidurals for obstetric indications, and thus can facilely insert an epidural in the lumbar region, thoracic epidurals for analgesia after thoracotomy are different. Not only is the thoracic epidural space more difficult to identify owing to anatomic differences in the spinal architecture of the thoracic region, but the majority of thoracotomy patients are elderly, with calcified supraspinous and interspinous ligaments and compressed intervertebral spaces, all of which add to the difficulty of successfully inserting an epidural. adverse effects Effects Related to Insertion of a Needle or Catheter into the Epidural Space. Adverse effects of epidural analgesia related to the insertion of the needle and/or catheter into the epidural space include inadvertent spinal puncture, inability to insert a needle or catheter into the epidural space, premature dislodgment of the catheter from the epidural space, temporary back pain at the insertion site, epidural hematoma, epidural abscess, and permanent neurologic deficits. The most common of these is an inadvertent spinal puncture, which occurs with an incidence of approximately 0.3 to 5%. 136,181,182 Although rare, subdural hematoma and pneumocephalus have been reported after spinal puncture. 1 8 2 More commonly, a medication intended for the epidural space is injected into the subarachnoid space instead, which may have disastrous consequences. An epidural dose of either local anesthetic or opioid would be clearly excessive in the subarachnoid space, potentially producing major motor blockade, hypotension and “total spinal anesthesia” with the former class of drugs, and lifethreatening respiratory depression with opioids. An inadvertent spinal puncture may also produce a headache, which can be incapacitating. This postdural puncture headache may be frontal and/or occipital, usually develops 24 to 72 hours after the spinal puncture, and is due to leakage of cerebrospinal fluid through the hole in the subarachnoid membrane and subsequent traction on pain-sensitive structures at the base of the brainstem.183 It may be associated with nausea/vomiting and cranial nerve palsies and auditory disturbances,184,185 and it is clearly differentiated from other causes of headache by its prominent exacerbation with the upright position and complete resolution with the supine position. Therapy is important, not only from a humanitarian point of view, but because the headache may discourage the patient from coughing and assuming the upright position, thereby potentially interfering with

16 / Advanced Therapy in Thoracic Surgery

recovery. In addition to nonopioid and opioid analgesics, more specific therapy with oral or intravenous caffeine and aggressive fluid intake instillation is usually successful in alleviating the postdural puncture headache. The latter is often undesirable in the post-thoracotomy patient, however. When these measures fail, instillation of 10 to 30 mL of normal saline or 20 mL of freshly obtained autologous blood (an “epidural blood patch”) into the epidural space, is indicated.186 The potentially catastrophic complications of epidural needle or catheter insertion, epidural hematoma and abscess, and permanent neurologic deficits are, fortunately, very rare. Incidence rates have been estimated to be ≤ 1 in 150,000 to 190,000,187,188 ≤ 1 in 1,000 to 6,500,189–191 and ≤ 1 in 3,000 to 4,500,135,192 respectively. Permanent neurologic deficits (usually paraplegia) may occur as a consequence of cord compression and ischemia induced by an epidural hematoma or abscess. Additionally, they may be related to mechanical trauma from the epidural needle or catheter, inadvertent injection of a neurotoxic substance into the epidural space, or spinal cord ischemia from other causes, such as epinephrine-induced vasoconstriction of arteries supplying the cord, pressure effect from the volume of epidural injectate, and hypotension induced by the sympathetic block.193 Epidural abscesses may arise from direct extension of infection in the local area of the epidural insertion site, or from infection at a remote part of the body, with bacteremia and subsequent seeding of the epidural space. 194,195 Factors associated with the occurrence of epidural abscesses are duration of epidural catheterization ≥ 3 days190; immunocompromise associated with one or more complicating disease, such as cancer, acquired immunodeficiency syndrome, diabetes, multiple trauma, chronic renal failure, or chronic obstructive pulmonary disease190,195,196; multiple attempts at inserting the epidural needle/catheter191; and the use of low-dose unfractionated or low molecular weight heparin.190 The association with the latter two factors may reflect the development of a hematoma within the epidural space, which subsequently acts as a nidus for infection. Direct puncture of the extensive epidural venous plexus during epidural needle or catheter insertion may result in the development of an epidural hematoma. Although it may initially be small and clinically unimportant, this hematoma may later enlarge when the clot is disrupted by a coagulation abnormality or direct trauma. The latter may occur at any time while the catheter is being used as epidural catheters are well-known to migrate within the spinal canal. 1 8 2 However, a clot is most likely to be disrupted when an epidural catheter is removed from the patient. Approximately half of the epidural hematomas attributed to epidural analgesia in Vandermeulen and

colleagues’ 1994 review of the literature occurred immediately upon removal of the epidural catheter.197 Risk factors associated with the development of an epidural hematoma include increased age,198 multiple attempts at inserting the epidural needle or catheter,198 and coagulation defects.188,198 It is controversial whether the appearance of blood in the needle or catheter during epidural insertion (known as a “traumatic” needle/catheter insertion) is a risk factor for the development of a significant epidural hematoma. Given the extensive vascularity of the epidural space and the 3 to 12% incidence of puncture of a blood vessel or vessels during epidural catheter insertion,182 there are obviously a large number of epidural hematomas that are too small to attain clinical importance. The association between epidural hematomas and coagulation defects has been recognized for decades.197 Defects in either the platelet-mediated or coagulation factor–dependent phases of the coagulation system enhance the possibility of epidural hematoma formation, and combinations of defects increase the risk further.198–200 Therapeutic anticoagulation with heparin, warfarin, and antifibrinolytics are known offenders, as are therapeutic and prophylactic doses of low molecular weight heparin.187,197,201 The use of NSAIDs and low-dose prophylactic unfractionated heparin has not been associated with a significantly increased risk of epidural hematoma formation.187,188,202 Effects Related to Epidural Injection of Local Anesthetics. Adverse effects of local anesthetics injected into the epidural space include hypotension, motor blockade, urinary retention, and systemic toxicity. These effects are usually dose related, being most pronounced when higher concentrations of local anesthetic are used. Hypotension is a frequent occurrence as the sympathetic blockade produces peripheral vasodilation and bradycardia, and it is generally the limiting factor in the use of high concentrations of local anesthetic. For example, El-Baz and colleagues reported a 23% incidence of systolic blood pressure < 60 mm Hg with heart rate < 60 beats per minute in the first 24 hours after surgery, using 5 mL bolus doses of 0.5% bupivacaine administered on an as-needed basis through a thoracic epidural catheter.4 Motor blockade of the legs interfering with ambulation is uncommon if the epidural catheter is inserted in the thoracic region.203 In contrast, weakness of the upper extremities may develop with an epidural at this level and may be distressing to patients.4 Urinary retention should not occur with thoracic epidurals if the volume of local anesthetic is limited to that necessary for blockade of just the thoracic dermatomes. Toxicity owing to systemic absorption is a rare occurrence at the usual recommended doses. Effects Related to Epidural Injection of Opioids. Epidural opioid adverse effects are similar to those antici-

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 17

pated with parenteral administration of this class of drugs. The most frequent are nausea/vomiting, pruritus, urinary retention, and intestinal hypomotility and somnolence, and the most important is respiratory depression. Many of these effects are dose related and occur more frequently in patients who are opioid naive.204 They are usually mediated by opioid receptors, such that opioid antagonists should be effective in the prevention and treatment of these effects.205 Unfortunately, the doses of antagonist needed for this purpose may overlap with the doses that will antagonize the analgesic effects; therefore, other treatment modalities are usually employed first, and opioid antagonists are reserved for instances when they fail. Compared with parenteral opioid administration, the epidural route is associated with a greater incidence of pruritus and urinary retention, a lower incidence of somnolence, and an equivalent incidence of nausea/vomiting and respiratory depression.204 Pruritus, nausea/vomiting, and urinary retention occur less frequently when epidural morphine is administered as a continuous infusion than as intermittent bolus injections.4 Respiratory Depression. Respiratory depression is the most feared complication of epidural opioids. Large series have reported 0.1 to 3% incidences of “clinically significant” respiratory depression,118,189,203,206–208 defined as that requiring intervention. These represent combined data from patients having a wide variety of surgical procedures, who have received different types of medication, administered by varying protocols, through catheters inserted at both lumbar and thoracic levels of the spinal column. The incidence appears to be similar for most opioids,209 with the possible exception of an increased incidence with high bolus doses of sufentanil.210 After a single bolus dose of epidural opioid, respiratory depression classically follows two distinct patterns, which have been designated early and late.204 Early respiratory depression occurs within the first 2 to 4 hours after administration of the epidural opioid, has been observed with most opioids used during epidural analgesia, correlates with high peak plasma levels, and is thus thought to be primarily due to systemic absorption of the opioid. Late depression occurs at > 2 to 4 hours after a dose of epidural opioid—most often at 6 to 12 hours204,211—but there have been reports of respiratory depression persisting as long as 22 hours after administration of a bolus dose of epidural opioid.205,212,213 This type of respiratory depression has been evidenced almost exclusively with morphine and is due to the rostral spread of opioid through the cerebrospinal fluid to the respiratory control centers in the brainstem. With the frequent use of infusions in recent years, the concepts of early and late have become obscured, and respiratory depression may occur at any time.

Respiratory depression with epidural opioids usually presents with a slow respiratory rate, although there have been reports of severe hypercarbia with a normal respiratory rate.214,215 In these examples, somnolence was present; hence, there is a need for the assessment of the level of consciousness as an indicator of respiratory depression. Well-established risk factors for the development of respiratory depression include older age, American Society of Anesthesiologists physical status classes III to IV, respiratory disease, sleep apnea syndrome, elevated intrathoracic pressure, and concomitant use of systemic opioids and/or other central nervous system depressants.118 More controversial risk factors are bolus injections, compared with continuous epidural infusions154,216; and thoracic epidural catheters, in contrast to lumbar epidurals.118,130 The latter has been demonstrated only with morphine. Efforts to prevent postoperative respiratory depression associated with epidural opioids have focused on using the minimally effective dose of epidural opioid, limiting the quantity of all opioids and sedatives used intraoperatively, and avoiding concomitant use of parenteral opioids and other central nervous system depressants.214 Frequent monitoring of patients for evidence of respiratory depression is necessary, most often with intermittent assessment of respiratory rate and level of consciousness every 0.5 to 2 hours, plus continuous pulse oximetry. Reliance on pulse oximetry alone is not recommended as a decrease in oxyhemoglobin saturation may be a late sign of respiratory depression when supplemental oxygen is used. Arterial blood gases and/or continuous ventilatory monitors may be considered for high-risk patients. 2 1 5 Monitoring should be applied throughout the course of administration of the epidural opioids and continued for 4 to 6 hours after the last dose or after stopping an infusion.118,204 Morphine is the exception as the risk of delayed respiratory depression mandates a more protracted period of monitoring: 12 to 24 hours after the last dose has been recommended.118,182,204,205,214 The location of the monitoring has changed over the last few years. In the 1980s it was recommended that all patients with epidural opioids (with the possible exception of the obstetric population) be observed in a setting such as an intensive care unit or postanesthesia care unit.118 More recently, large series have demonstrated the apparent safety of caring for these patients on a ward, provided the staff is well educated and the aforementioned level of monitoring is maintained.189,203,208,217 Effects Related to Injection of Epidural Local Anesthetic–Opioid Combinations. The currently popular technique of using combinations of opioids and local anesthetics to decrease the dose of each may reduce the incidence of drug-related adverse effects, although the

18 / Advanced Therapy in Thoracic Surgery

evidence for this varies between studies. Most consistently, the incidence and severity of hypotension is less than that associated with local anesthetic alone,126,171,218 and the incidence of somnolence is lower than that associated with epidural opioids alone.123 At our institution we usually initiate epidural analgesia therapy with a solution containing fentanyl 10 µg/mL and bupivacaine 0.075% and subsequently adjust the two drugs independently, in accordance with the adverse effect profile of the individual patient. contraindications Relative contraindications to the use of epidural analgesia include elevated intracranial pressure, preexisting disease of the spinal cord or peripheral nervous system, infection, and coagulopathy. Elevated intracranial pressure is listed here because of the risk of inadvertent dural puncture and subsequent brainstem herniation. With neurologic disease, there is concern that the epidural analgesia may exacerbate the underlying disease, as has been suggested for demyelinating diseases such as multiple sclerosis,219 or that a coincidental deterioration in neurologic function may be incorrectly attributed to the epidural. Owing to the potential risk of epidural abscess formation, infection at the intended site of epidural insertion is considered an absolute contraindication, and evidence of infection at a more distant site is a relative contraindication to the use of epidural analgesia. Although no studies have properly addressed this issue, epidural analgesia is probably acceptable if the distant infection is completely localized, but it is generally recommended that epidural analgesia be avoided in the possible presence of bacteremia, as evidenced by an elevated white blood cell count or temperature. The situation becomes more controversial if appropriate antibiotics have been started. The literature also does not address the issue of epidural analgesia in the patient with an empyema but no evidence of systemic infection, but many anesthesiologists would be reluctant to insert an epidural in this scenario. Furthermore, the question of whether the catheter should be

removed when an infection develops in a patient with an indwelling epidural catheter also has not been discussed in the literature. At our institution we approach each case on an individual basis, taking into consideration such factors as the duration of epidural use, whether the patient appears to be benefiting from the epidural, and whether appropriate antibiotics have been initiated. To diminish the risk of epidural hematoma formation, epidural analgesia is usually avoided in patients with a preexisting coagulopathy. It has traditionally been taught that the prothrombin time, activated partial thromboplastin time (aPTT), and international normalized ratio (INR) should all be within the normal range and that platelets should number ≥ 100,000/mm 3 before an epidural needle or catheter is inserted.220 More recent recommendations have suggested that epidural analgesia may be safely considered with an INR up to 1.4 and platelet counts as low as 80,000/mm3.197 Bleeding times are no longer advocated as a reliable method of determining platelet function.187 If patients have been on any medications effecting coagulation preoperatively, these drugs should ideally be stopped before the epidural is inserted, and the epidural catheter should be removed before they are restarted. Guidelines for specific medications are presented in Table 1-9. A more difficult situation arises when medications interfering with coagulation are administered in the perioperative period. The most conservative approach is to completely avoid epidural analgesia in these patients. In institutions with the expertise to provide good postthoracotomy analgesia by other methods (especially TPVB and continuous intercostal nerve blockade), this is a reasonable approach. Postoperative use of NSAIDs and subcutaneous unfractionated heparin appears to be safe when used in conjunction with epidural analgesia, based on the very small number of case reports of patients developing epidural hematomas in these circumstances and the lack of hematoma development in the few larger studies that have addressed this issue.198,221 However, the response to subcutaneous unfractionated heparin can be variable,222,223 and patients with cachexia and/or liver dysfunc-

TABLE 1-9. Epidural Management in Patients Receiving Agents Affecting Coagulation Preoperatively Agent

Insertion Recommendations

Laboratory Tests before Insertion

Subcutaneous unfractionated heparin (1,000 U q8–12h)

Insert EP ≥ 4 h after last dose

LMWH Intravenous heparin Warfarin Thrombolytics and fibrinolytics (eg, streptokinase, t-PA) Ticlopidine

Insert EP ≥ 12 h (ideally 24 h) after last dose Insert EP ≥ 2–4 h after last dose Insert EP ≥ 4–7 d after last dose Insert EP ≥ 1–2 d after last dose Insert ≥ 7 d

aPTT if cachectic or liver dysfunction; platelets if heparin taken for > 4 d None recommended aPTT; platelets if heparin taken for > 4 d PT, INR Fibrinogen None recommended

Data from Horlocker TT,187 Vandermeulen EP et al,197 Horlocker TT et al,198 Tryba M,201 Heit JA.254 aPTT = activated partial thromboplastin time; EP = epidural; INR = international normalized ratio; LMWH = low molecular weight heparin; PT = prothrombin time; t-PA = tissue plasminogen activator.

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 19

tion may be particularly sensitive to the anticoagulant effects of the drug. As well, use of any form of heparin beyond approximately 4 days may lead to thrombocytopenia.201 It is therefore most prudent to monitor the aPTT and platelet count regularly in these patients. Guidelines for the use of other agents are summarized in Table 1-10. If one decides to perform epidural analgesia in patients at risk of developing an epidural hematoma or abscess, frequent assessment of neurologic function (optimally every 2 hours 187 ) is essential. As well, the concentrations of local anesthetics in the epidural solution should be minimized, or local anesthetics avoided entirely, so that if a neurologic abnormality is detected, there is no confusion between drug effect and actual pathology. Immediate diagnosis of an epidural hematoma is essential as permanent neurologic deficit is more likely if surgical decompression is delayed beyond the first 8 to 12 hours after presentation.197 Although it is controversial whether blood in the epidural needle or catheter is a risk factor for the development of hematoma, the policy at many institutions is to cancel or delay surgery for up to 24 hours if blood is noted during needle or catheter insertion, and systemic heparinization is planned.187,197 Another approach, employed by Loik and colleagues, for patients undergoing cardiac surgery has been to routinely insert the epidural catheter the day before surgery, thereby maximizing the time interval between catheter insertion and heparinization.224 duration The optimal duration for epidural analgesia after thoracotomy has not been established. Depending on the institution, epidural catheters may be removed at 48 to 72 hours postoperatively or continued for up to 7 days, or even longer. As much of the pain after thoracotomy is attributable to the chest tubes, the general guideline at our institution is to maintain the epidural until these tubes are removed. Thus, epidural catheters usually remain in place for 3 to 7 days postoperatively. Pneumonectomy patients

are an exception to the “chest tube rule” as these tubes are generally removed 24 hours postoperatively but epidural analgesia is continued for at least 3 days. At the other extreme, patients with esophagectomies often have their chest tubes continued for more than a week. As epidural medication requirements are usually minimal by 7 days after this surgery, we generally remove the catheter on the seventh operative day in these patients. The only study that has addressed this issue is by Nomori and colleagues, who performed a retrospective review of data from patients having an anterior limited thoracotomy who received epidural morphine by continuous infusion for either 3 or 8 days postoperatively.23 There were no differences between groups with respect to pulmonary function tests or pain scores for the first 7 postoperative days, but the day 8 group had more pain than did the day 3 group on the eighth and ninth postoperative days. As well, the pain scores on day 8 after the epidural was removed in the day 8 group were significantly higher than the pain scores on the seventh postoperative day. By contrast, the day 3 group experienced no such “rebound” after their catheters were removed. These observations suggest that, at least for an anterior limited thoracotomy, extending the use of epidural analgesia beyond the first 3 postoperative days has no benefit and may even exert a negative impact on overall pain control. Despite the limitations of the study design, the results of this study are intriguing, and future randomized controlled trials are warranted to establish the optimal duration of epidural analgesia from a riskbenefit perspective. other agents In addition to local anesthetics and opioids, many other agents have been examined as potential candidates for epidural analgesia. These include clonidine, opioid agonistantagonists, ketamine, verapamil, and methylprednisolone. Epidural clonidine has been used for postoperative analgesia in a variety of procedures. Its mechanism of

TABLE 1-10. Epidural Management in Patients to Receive Agents Affecting Coagulation Perioperatively* Agent

Initiation of Agent

Removal of Epidural Catheter

Laboratory Tests before Removing Epidural Catheter

Subcutaneous unfractionated heparin (1,000 U q8–12h) LMWH

Start ≥ 1 h after EP insertion

Remove ≥ 4 h after last dose

Start ≥ 4 h after EP insertion

Intravenous heparin Warfarin

Start ≥ 1 h after EP insertion start ≤ 24 hours before EP insertion

Remove ≥ 12 h (ideally 24 h) after last dose and wait ≥ 2 h after removal before injecting next dose Remove ≥ 2–4 h after last dose No specific recommendations

aPTT if cachectic or liver dysfunction; platelets if heparin taken for > 4 d None recommended

aPTT; platelets if heparin taken for > 4 d PT, INR

Data from Horlocker TT,187 Vandermeulen EP et al,197 Horlocker TT et al,198 Tryba M,201 and Enneking FK, and Nenzon H.255 aPTT = activated partial thromboplastin time; EP = epidural; INR = international normalized ratio; LMWH = low molecular weight heparin; PT = prothrombin time. *The use of EP catheters in patients who will receive thrombolytics and fibrinolytics is strongly discouraged.

20 / Advanced Therapy in Thoracic Surgery

action is primarily by stimulation of 2-adrenergic receptors in the dorsal horn of the spinal cord,58 although clonidine also produces direct blockade of conduction in A delta and C nerve fibers. The main advantage of epidural clonidine relates to its lack of most of the classic opioid-related adverse effects, such as nausea/vomiting, pruritus, and respiratory depression. However, epidural clonidine may produce sedation, hypotension, and bradycardia owing to stimulation of intracranial  2adrenergic receptors secondary to systemic absorption of the drug. In nonthoracic surgery, clonidine is an effective analgesic when administered alone in the epidural space, but the doses required are high enough to produce a significant incidence and severity of these clonidinerelated adverse effects.225,226 Combinations of clonidine and local anesthetics or opioids produce additive, and possibly synergistic, analgesic effects, resulting in improved analgesia with relatively low doses of clonidine.227,228 However, sedation and mild hypotension have still been a problem in these studies. In the single investigation focusing on post-thoracotomy patients, a single bolus of epidural clonidine exhibited no effect on pain relief compared with placebo. 229 Further studies are necessary in this population. Medications with opioid agonist-antagonist properties have been used for epidural analgesia with the goal of reducing the opioid-related side effects, especially respiratory depression. In the only two studies focusing on post-thoracotomy patients, lumbar epidural nalbuphine provided significantly less analgesia than did lumbar epidural morphine.230,231 It is unknown whether a thoracic approach would have produced different results. In a group of 20 gynecologic patients, epidural pentazocine produced good postoperative analgesia, with 16 patients being completely pain free and the other 4 reporting mild pain but requiring no additional analgesics.232 A further benefit in this study was the lack of urinary retention in all 16 epidural pentazocine patients who did not have an indwelling urinary catheter. Accordingly, this drug appears to be promising but needs to be examined in the post-thoracotomy population. Discovery of the integral role of NMDA receptors in processing nociceptive information in the spinal cord has led to much interest in ketamine as an epidural analgesic agent.233 Ketamine is a potent, noncompetitive inhibitor of the NMDA receptor and has the major clinical advantage of exhibiting no respiratory depressant effects. Epidural ketamine has not been studied in the postthoracotomy population, but for other types of surgery ketamine, appears to have little or no analgesic efficacy when used as a sole agent in the epidural space.234–236 More promising results have occurred when epidural ketamine has been combined with epidural opioids and/or local

anesthetics. In many of these investigations, ketamine potentiated the analgesic effects of the other agents.237,238 A disadvantage of ketamine relates to its propensity to cause psychomimetic effects, which have been reported in up to 15% of patients receiving ketamine by the epidural route.239 These effects have been successfully treated with discontinuation of the drug and/or with systemic benzodiazepines. Verapamil has been advocated as a possibly useful epidural analgesic agent based on observations that neurotransmitter release is mediated by calcium influx into the synaptic terminals of neurons.240 By interfering with this influx, normal sensory processing in the spinal cord is disrupted, and verapamil has been shown to potentiate the antinociceptive effects of morphine at the spinal cord level in an animal model.239 In a preliminary study of patients having lower abdominal surgery, verapamil added to an epidural bupivacaine solution decreased supplemental opioid requirements.241 Further investigations are necessary to establish the safety of verapamil in the epidural space from a perspective of neurotoxicity and to examine the analgesic efficacy of epidural verapamil in the post-thoracotomy population. Investigations of patients having spinal surgery have demonstrated moderate effectiveness of epidural glucocorticoids as analgesic agents.241 This has been primarily attributed to localized anti-inflammatory activity of these drugs, but evidence that glucocorticoids may also influence synaptic transmission in the spinal cord has led to the suggestion that epidural glucocorticoids may be useful for other types of surgery as well.242 Blanloeil and colleagues examined the effects of a continuous infusion of epidural methylprednisolone on pain relief after posterolateral thoracotomy, but they found no difference in analgesia between patients who received methylprednisolone and those who received placebo.243 Accordingly, there is no evidence at present that epidural glucocorticoids will be useful agents for post-thoracotomy analgesia.

Management of Pain The management of postoperative pain in general has long been the sole responsibility of the surgeon after the acute phase in the postanesthesia care unit. Probably concomitantly with the introduction of epidural analgesia, anesthesiologists have undertaken some shared responsibility for the control of post-thoracotomy pain. This has improved postoperative analgesia and arguably improved intraoperative management. Whether a formal “thoracic team,” which incorporates representatives from thoracic surgery, anesthesiology, nursing, and pain management, improves outcome is debatable. Improved outcome has only been suggested for pediatric fellowship

Postoperative Analgesia for Thoracotomy Patients: A Current Review / 21

training,244 and the mechanism of the improved outcome still may just be due to more opportunity to maintain skills.245 It is likely, however, that the simple existence of a group of identifiable individuals with an interest in pain relief both during and after thoracic surgery would enhance immediate feedback within the group. This would predispose to rapid adoption of needed improvements and facilitate adherence to the principles of continuous quality improvement. Familiarity and repetition should increase the success rate of procedures and the satisfaction felt by patients. Certainly epidural anesthesia should be managed solely by an anesthesia provider due to the specialized knowledge required for implementing and safely providing this service. Most large hospitals have an acute pain service or postoperative pain service in addition to the anesthesiologists in the operating rooms. The postoperative pain service not only helps manage the ongoing needs of patients with epidural analgesia, but is also available to manage or consult on other postoperative analgesia–related dilemmas. In addition, almost all medical communities have available chronic pain specialists or even a chronic pain service. Specialists in chronic pain come from the disciplines of anesthesiology, surgery, neurology, and others. They have undertaken extensive training about pain, its causes, and its control, and as such they represent a major resource for other health care professionals. At the University of Texas M. D. Anderson Cancer Center, we are fortunate to have the availability of all three above-mentioned components of pain manage-

ment, namely a thoracic team, postoperative pain service, and chronic pain service. The management of an individual patient is strongly dependant on the root cause of the pain and whether there was preexisting pain. Tolerance is a phenomenon common to almost all drugs. Chronic pain patients can be expected to have much increased needs postoperatively. Optimum management is facilitated by early involvement of the chronic pain service when indicated. Figure 1-3 shows the organization of postoperative pain control and use of pain services at M. D. Anderson Cancer Center. Most commonly, patients undergoing thoracic surgery are opioid naive. In our setting they receive an epidural placed by a member of the thoracic team or postoperative pain service, undergo surgery, and, after activation of the epidural analgesia near the end of surgery, have their pain managed by the postoperative pain service. The postoperative pain service writes the epidural orders, deals with complications, treats breakthrough pain, and is proficient in relieving disaggregated pain. Each patient is seen twice per day by a combination of pain service nurses, rotating residents, and dedicated anesthesia faculty member, either singly or together. Complete around-the-clock coverage is provided, backed up, if necessary, by the in-house anesthesiologist on call. At all stages the thoracic surgeon is involved and consulted. After the epidural is discontinued, usually at the time of chest tube removal, the patient’s pain management reverts completely to the attending thoracic surgeon. The postoperative pain and chronic pain services are still available in case of need.

Thoracotomy Patient

PCEA by PPS Until Epidural Discontinued

IV – PCA by Thoracic Surgery

Opiod Naive

Chronic Pain on Narcotics Preoperatively

Successful Good Pain Relief

PPS

CPS

Discharge

Discharge

Discharge

Inadequate Poor Pain Relief Other Symptoms

Normal

Chronic Pain

PPS

CPS

Discharge

Discharge

FIGURE 1-3. Organization of postoperative thoracic pain management at the University of Texas M. D. Anderson Cancer Center. CPS = chronic pain service; IV-PCA = intravenous, patient-controlled analgesia; PCEA = patient-controlled epidural analgesia; PPS = postoperative pain service.

22 / Advanced Therapy in Thoracic Surgery

Patients with chronic pain, defined variously as being on > 10 mg or the equivalent of morphine per day, are equally common at M. D. Anderson. Their management is similar until discontinuation of the epidural analgesia. At this point the chronic pain service continues their pain management. The chronic pain service is consulted early in the postoperative period to facilitate changeover. It has been noted that although chronic pain patients require higher initial and continuing concentrations of epidural narcotics, their pain relief can still be well managed by epidural analgesia. If epidural analgesia is impossible, then conventional intravenous analgesia is employed and initial management is by the operating room anesthesiologist. After the patient’s time in the postanesthesia care unit, pain management falls squarely on the thoracic surgeon. Only if the patient’s pain is impossible to control does the postoperative pain service become involved. Its staff may be able to suggest different drug regimens or dosages. Chronic pain patients are managed similarly, except that when intravenous patient-controlled analgesia fails, the chronic pain service is consulted first.

Pre-emptive Analgesia Pre-emptive analgesia is a subject of endless fascination to most anesthesiologists. It has been defined as the phenomenon by which analgesia administered prior to a painful event, such as a thoracotomy, decreases the later intensity of perceived pain, even after the duration of action of the initial analgesic.246 More recently, the definition has been widened to include treatment that “prevents the development of hyperexcitability, even if it takes place after surgery.”247 It must be distinguished from merely improved analgesia following earlier administration of analgesia compared with nonadministration of an analgesic or lesser doses of the same analgesic. In a welldesigned study, Doyle and Bowler found that pre-emptive intravenous morphine, intramuscular diclofenac, and intercostal nerve blocks with bupivacaine only demonstrated a decrease in VAS pain scores during a vital capacity breath postoperatively.248 No other measure of pain was different between groups, and the long-term pain was indistinguishable between groups. Early activation of epidural analgesia might be expected to demonstrate preemptive analgesia, but this expectation was shown to be incorrect in a study using epidural bupivacaine.249 Preemptive analgesia has been suggested with the opioids fentanyl and morphine in nonthoracic models,250,251 raising the suspicion that higher intraoperative opioid doses may have a beneficial effect beyond the operative period, but this has not been demonstrated for thoracotomy patients. It is possible that the high-dose opioid employed for

cardiac surgery in the 1980s and 1990s, using a median sternotomy approach, led to the oft-repeated observation that median sternotomy is not as painful as the traditional thoracotomy. With the current fast-track micromanagement of cardiac anesthesia, post-sternotomy pain is becoming a bigger issue for thoracic surgeons. It is not clear how an appropriately blinded study could be designed to investigate this intriguing possibility. NSAIDs have also been investigated for pre-emptive effects but, again, not in thoracic models. Using ketorolac, Fletcher and colleagues demonstrated improved pain relief in a hip-fracture model at the price of increased blood loss,252 and Norman and colleagues showed less postoperative pain in an ankle fracture model.253 The selective COX-2 inhibitors may have a role to play in postoperative, pre-emptive, and multimodal analgesia, but so far, proof is lacking.

Summary We have reviewed the provision of postoperative analgesia for patients who have undergone thoracotomy from its humble beginnings to the current state of this art— and an art it is, indeed, as the identical drugs and techniques in different hands give quite different degrees of success. The provision of pain relief after thoracotomy is a complicated but still rewarding proposition. Newer multimodal analgesia techniques show promise for improving the overall experience in future patients. It is likely that methods to ameliorate or even prevent the development of chronic post-thoracotomy pain will be elucidated. We must all continue to investigate, try different strategies, improvise, and experiment to ensure continued progress in this challenging field.

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CHAPTER 2

ADVANCES IN DIAGNOSTIC IMAGING OF THE THORAX AND SCREENING REGINALD F. MUNDEN, DMD, MD, GREGORY W. GLADISH, MD To get radiologic images to the PACS, radiologic examinations need to be produced digitally. Many conventional chest radiographs are still produced with screen film technology. However, a large percentage of chest radiography is now produced with computed radiography or direct digital radiography techniques. Both techniques are good, and the decision to use one or the other depends on the radiologist and the hospital’s needs. Computed radiology techniques use a cassette to record the image and, similar to screen film systems, require processing of the cassette to generate an image that can be sent to the PACS. The image produced by a digital direct radiography system is sent directly from the x-ray detector to a computer for distribution into the PACS. CT, MRI, nuclear medicine, PET, and ultrasound images can be relayed as digital data that can be sent directly to PACS. Even conventional film can be digitized into an electronic format for distribution, but in the conversion process some of the resolution is lost, and the digitized images cannot be used for diagnostic purposes. Of course, any digital image can be sent to a printer to generate a hard copy of the image onto film. Radiologists and staff of radiology departments are leading the way to a totally electronic imaging system. In addition to the benefits of improved storage, retrieval, and distribution of images that electronic imaging allows, radiologists can use computer programs to facilitate viewing and interpretation of images. Electronic distributions over the Web will eventually allow physicians to access a patient’s images from anywhere. However, reliable and secure network communication is needed to protect patient confidentiality. This chapter reviews the common methods of radiologic evaluation of the thorax, with an emphasis on the application of newer technology. It should be mentioned

The past decade of radiologic imaging has seen dramatic improvements, with advances in picture archiving and communication system (PACS), digital chest imaging, computed tomography (CT), and magnetic resonance imaging (MRI) and the transition of positron emission tomography (PET) from experimental to clinical usage. No subspecialty of radiology has benefited more from these improvements than thoracic radiology. One of the greatest improvements has been the increased speed with which an examination is performed. Rapid image acquisition is such that excellent-quality images of the chest can be obtained in seconds and distributed throughout an institution before the patient leaves the radiology department. In fact, the acquisition of CT and MRI data is fast enough to image the heart at a specific phase of the cardiac cycle. Another advance is that images can be distributed electronically for clinical care. The desire to have electronic storage and distribution of images using a PACS has been a driving force behind the conversion of conventional (filmbased) radiology to electronic (digital) radiology. Other factors driving the conversion to digital imaging are the decrease in the expense of on-site hospital storage of films, the elimination of the dreaded “lost” film or wasted time at the file room window, and the ability for multiple health care personnel to review images simultaneously and at remote sites. Virtually all of these improvements are the result of faster and more reliable computers and computer software. PACSs and Web-based distributions of images are rapidly changing technologies and will not be reviewed in depth in this chapter. Suffice it to say, as computers continue to improve, electronic distribution of images using PACS and Web-based systems will also improve. These advancements will impact and hopefully better the way radiology is practiced. 32

Advances in Diagnostic Imaging of the Thorax and Screening / 33

that the latest innovation of thoracic imaging, which will likely prove beneficial in oncologic imaging of the thorax, is PET/CT imaging. Units acquire PET and CT images simultaneously and allow a fusion of the two studies. This process allows the production of an anatomic image (CT) with a functional image (PET) as a single image.

Conventional Chest Radiography and PACS The chest radiograph is the most frequently performed radiographic examination, constituting > 40% of the volume of radiographs in most radiology departments. In the United States alone, there are more than 50 million chest radiographs performed per year. 1,2 Chest radiographs are obtained with screen film or digital methods. All of these methods can produce excellent images. Conventional radiography consists of a screen film system that is characterized by high spatial resolution and good uniformity. However, there is a large difference between the attenuation of x-ray beams by the lungs compared with that of the mediastinal structures. This difference requires a compromise between exposures for the lungs and adequate penetration for the mediastinum. Several methods to improve conventional film imaging of the chest have been developed. However, because these methods rely on exposure to film, the images cannot be altered once they are acquired. In particular, the enhancement of a specific region of the chest cannot be performed after the image is acquired. Also, while conventional methods produce excellent radiographs, they cannot be transferred into a PACS system as digital images. Digital chest imaging consists of two methods: computed radiology, which uses storage phosphor plates to capture an image and require processing by a laser readout of the plate, and digital direct radiography, which uses similar detector methods but different electronics to generate an image, thus eliminating the need for a laser readout. Computed radiology is commonly used for the intensive care unit because the storage plates are portable. Both methods are used in dedicated chest systems. One major advantage of a digitally acquired image over a conventional image is that the image quality is maintained with digital images when sent to the PACS. In addition, computer programs to facilitate interpretation of images can be applied to digital images. For example, dual-energy technology allows the separation of images of the lungs from the overlying bony structures. This is accomplished by a rapid double exposure using high (for the lungs) and low (for the bones) energy exposures. Computer software is then used to superimpose the images and to subtract the overlying structures to produce the images (Figure 2-1).

FIGURE 2-1. Dual-energy chest radiograph. All three images are generated at the same time. A, Conventional posteroanterior view of the chest. B, Soft tissue view results from subtraction of the overlying bones. C, Bone view, with soft tissues removed, enhances the visualization of the ribs

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This method has been shown to improve the detection of pulmonary nodules. It can also improve the detection of bony lesions. Computer-aided diagnosis is a method of using computer software to prescreen radiologic images. Most development of computer-aided diagnosis systems has pertained to chest radiographs, but with the generation of a large number of images using current multislice CT examination techniques, there is increasing research in the application of computer-aided diagnosis to CT. Using models of standard radiology examinations, the software is trained to recognize normal anatomic structures. Variations from normal structures are detected by the computer software and highlighted. These guide the radiologist to review the area in question. When the study is reviewed by the radiologist, a determination can be made as to whether the abnormality is a significant lesion such as a pulmonary nodule or an insignificant lesion such as a nipple shadow or artifact. Computer-aided diagnosis systems have been used experimentally to detect lung nodules, interstitial lung disease, and cardiomegaly. Nodule detection was improved using a computer-aided diagnosis system in retrospective clinical trials.3,4

Computed Tomography Since the clinical introduction of helical (spiral) CT in 1991, there has been dramatic improvement in image quality of CT scans of the chest. This rapid imaging technique has also resulted in new applications for CT, including CT angiography for pulmonary embolism and imaging of the coronary arteries. Helical CT has recently been advanced further with the introduction of multislice CT. The method allows the acquisition of four channels (essentially four images) of helical data simultaneously and has reduced scanning times of the entire chest to < 20 seconds.5,6 Multichannel CT scanners continue to be developed such that eight- and 16-slice scanners will be common in the near future. Because the entire chest can be imaged much faster, thinner slices can be obtained while the patient holds a single breath. With thinner slices and minimal motion artifact, excellent quality three-dimensional reconstructions can be generated. These prove to be beneficial when axial images are inconclusive, and they can facilitate treatment planning for therapy (Figure 2-2). The two main disadvantages of multislice CT are the increased numbers of images and higher radiation dosages to the patient.7 These disadvantages are significant because CT examinations are a large part of radiology studies. In the United States alone, over 27 million CT examinations were performed in 1997, and that number is expected to increase by 10% per year.8 The large number of images results in increased costs for

film printing and time for radiologists’ interpretations. Because of the large number of images generated from multislice CT, a PACS is almost always required to efficiently review the images. This is one of the reasons that interest in computer-aided diagnosis is increasing—these systems can preview the numerous CT images for the radiologist.

Magnetic Resonance Imaging MRI has been shown to be useful in the evaluation of the heart and thoracic diseases, particularly anatomy and diseases not well imaged by CT. The multiplanar imaging of magnetic resonance is valuable in defining the extent of diseases of the diaphragm and soft tissues of the lung apex or superior sulcus. MRI of the diaphragm is especially useful for differentiating diaphragmatic rupture from hernia in the post-traumatic setting and also for evaluating transdiaphragmatic extension in mesothelioma and other malignancies.9 MRI of the lung apex is predominately used for evaluation of superior sulcus lung cancer that may involve the brachial plexus (Figure 2-3).10 Both of these anatomic regions are not well evaluated in the axial plane of CT. Variations in the signal of magnetic resonance are also useful in characterizing masses in the chest, such as assessing whether lesions are cysts or hematomas. These signal characteristics can be used to distinguish between simple fluid, blood products, and solid masses. Tumor assessment in the mediastinum predominantly includes determining the origin of the tumor and what adjacent structures may be involved. Recent advances in MRI include the development of rapid acquisition sequences that provide cardiac gated images during breath holding. Such rapid acquisitions minimize motion artifacts, resulting in an improved demonstration of anatomic details. Black blood sequences use an extra radiofrequency pulse to suppress the signal from the blood pool.11,12 These images can be obtained in a single breath hold of about 10 seconds and give excellent detail at a single phase of the cardiac cycle. White blood images are obtained more rapidly at the cost of decreased resolution and increased noise (Figure 2-4).13 An image series is obtained in a 10-second breath hold, consisting of 20 phases of the cardiac cycle at a single level. Cine display of these images shows the relationships between moving structures in the heart. This is particularly useful to show valve motion to demonstrate whether the valve leaflets have tumor involvement or their motion is impaired by tumor or distortion of the cardiac structures. The cine display can also demonstrate ventricular wall motion abnormalities from prior infarcts. In addition, these images can be used to calculate functional parameters,

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including ejection fraction, and can demonstrate flow abnormalities such as valvular regurgitation or flow jets associated with stenotic valves.14 Multiplanar acquisition and cardiac gating of MRI allows better demonstration than does CT of the relationships between the heart and aorta to adjacent structures. The assessment of these relationships is most important in the preoperative evaluation for resection of cardiac and mediastinal tumors and their relationships to vital structures (Figure 2-5). Assessment of the aorta and heart for invasion can be performed with white blood sequences that show whether the tumor is affixed or moves independently throughout the cardiac cycle.

FIGURE 2-2. Right infrahilar adenocarcinoma. A, Axial image shows the mass inferior to the right pulmonary artery. The exact relationship to the pulmonary vein and atrium is difficult to appreciate. B, Coronal reconstruction shows the relationship of the mass (arrow) to the right pulmonary artery, left atrium, and bronchus intermedius. C, Sagittal view confirms the mass location is inferior to the pulmonary artery. D, Maximum intensity projection (MIP) image shows the three-dimensional relationship of the structures.

Applications of Advanced Technology Even with significant improvements in the imaging equipment, the evaluation of thoracic disease using radiologic imaging requires a disciplined approach to interpretation. Errors in radiologic evaluations are divided into miss and misinterpretation rates. Obviously, if one does not see an abnormality (miss), there is no possibility of a correct interpretation. For this reason, reviewing films under conditions of correct lighting and settings is crucial.15,16 Using the correct parameters for processing

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FIGURE 2-3. Pancoast’s tumor. A, Posteroanterior chest radiograph shows a large right apical tumor with extensive rib erosion. B, Axial computed tomography scan shows the tumor mass and rib destruction. C, Coronal magnetic resonance image shows tumor extension into the apical chest wall. D, Sagittal magnetic resonance image shows tumor involving the brachial plexus (arrow).

and production of a’n image (either film or display if PACS) is also a prerequisite for the correct interpretation of radiologic images. Equally important in evaluating digital images is using the appropriate viewing settings (window and level).17,18 Emergency Evaluation of the Thorax Multislice CT development has significantly improved emergent cross-sectional imaging of acutely ill patients.

Because of the widespread availability, ease of administration, uniform image quality, and ability to evaluate the entire thorax, helical CT is the mainstay for evaluating the aorta. Aortic aneurysm, dissection, intramural hematoma, atherosclerotic ulceration, and traumatic injury are well evaluated by helical CT. Thoracic aortic aneurysms are classified as true and false (pseudoaneurysm) aneurysms. Helical CT is the method of choice for evaluation of aneurysms. True

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FIGURE 2-5. Right atrial angiosarcoma. A, Black blood cardiac gated imaging sequences are obtained parallel to the horizontal long axis of the heart while the breath is held. The mass (M) arises along the anterolateral wall of the right atrium (RA) but does not involve the right coronary artery (RCA). B, White blood image demonstrates that the tumor (T) does not involve the tricuspid valve. FIGURE 2-4. Left atrial myxoma, four-chamber view. A, Black blood sequence shows a mass (M) on the interatrial septum on the side of the left atrium (LA), a typical location for myxoma. B, White blood sequence demonstrates that the mass is separate from the mitral valve (MV). LV = left ventricle; RA = right atrium; RV = right ventricle.

aortic aneurysms involve all layers (intima, media, adventitia) of the aorta and result in fusiform dilatation of the aorta. Pseudoaneurysms arise from the aorta and usually have a neck at their origin from the aorta and lack an intimal layer. This results in a saccular shape. The anatomic differences of true and false aneurysms can be depicted accurately with CT angiography and MRI. The extent of the aneurysm and its relationship to adjacent

structures and vessels can also be assessed with crosssectional imaging. Abdominal aortic aneurysms are seen in 28% of patients with thoracic aneurysms.19 Multislice CT allows efficient evaluation of the entire thoracoabdominal aorta in these patients. Helical CT has been shown to be 100% sensitive and specific in the detection of aortic dissection.20,21 In addition, secondary information about related complications, such as mediastinal hematoma, pericardial hemorrhage, or extension into branch vessels, are also well depicted on CT (Figure 2-6). Detection of aortic intramural hematoma with CT is reported to be 96% sensitive. Typically a crescent shape of high attenuation blood is seen on the unenhanced CT, and after contrast administration, the

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crescent does not enhance. Atherosclerotic ulcerations are typically in the descending thoracic aorta and appear as localized defects of the intima.22 Aortography remains the “gold standard” for evaluation of the aorta in the trauma patient. However, because helical CT is quicker and easier to obtain and is less invasive, it has become the imaging modality of choice in many centers. Several large series have shown that in certain clinical settings, CT angiography is as effective as aortography for evaluation of the aorta. 23–26 Further refinement and application of techniques in this clinical setting using multislice CT will most likely improve acceptance of CT angiography as the preferred method of evaluation of the aorta in the trauma patient. The evaluation of a patient for pulmonary embolus and deep venous thrombosis remains a difficult proposition. Imaging of the patient includes ventilationperfusion scanning, pulmonary angiography, computed

FIGURE 2-6. Aortic dissection. Helical computed tomography scan shows a dissection of the descending aorta (arrow). Note the secondary finding of a hemorrhage into the left pleura.

tomographic angiography and venography, and ultrasonography. Although there are many algorithms for using these imaging modalities and there is no agreement as to which is best, there is a general agreement that advancements in multislice CT have significantly improved the ability of computed tomographic angiography to detect pulmonary embolus.27 The initial application of CT as the primary imaging modality for diagnosing pulmonary embolus was performed by Remy-Jardin and colleagues.28 They concluded that CT was a safe and complementary procedure to angiography for evaluation of a suspected pulmonary embolus. Detection of acute pulmonary emboli to the segmental artery branch has subsequently been reported to have a sensitivity range of 53 to 100% and a specificity of 81 to 100%.29 In many institutions helical CT angiography is the primary method for evaluation of a pulmonary embolus because it is readily available, rapid, and essentially noninvasive and therefore safe. Multiplanar images can also be produced rapidly to facilitate evaluation for pulmonary embolus (Figure 2-7). Contributing to the rapid acceptance of CT for embolus evaluation is the high frequency of detection of other significant disease in the chest. It has been reported that up to 67% of patients without pulmonary embolus have other significant disease found on CT evaluations for pulmonary embolus.30 Large, randomized, and controlled collaborative studies are planned to further evaluate CT in the diagnosis of pulmonary embolus. Until then, the popularity of computed tomographic angiography for pulmonary embolus will increase and likely become the imaging study of choice. In patients with contraindications to IV iodine-based contrast material, rapid sequence MRI and contrast (gadolinium)-enhanced MR angiography allow excellent evaluation of the aorta and pulmonary vessels. MRI also provides multiplanar evaluation and physiologic assessment of blood flow. Detection of pulmonary embolus with MRI has been reported to have a sensitivity of 90 to 100% and a specificity of 62 to 77%.31,32 Unfortunately, MRI has not been successful in detecting peripheral emboli beyond the subsegmental artery branch level, even with administration of a contrast medium.33,34 Lung Cancer Screening It is well known that the majority of patients with lung cancer present with symptoms that indicate an advanced stage at diagnosis.35 In an effort to detect lung cancer earlier, four randomized, controlled studies have been performed: the Memorial Sloan-Kettering Lung Project, the Johns Hopkins Lung Project, the Mayo Lung Project, and the Czechoslovak study.36–41 Although different in

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experimental design, the purpose of the studies was the same—to assess the benefits of sputum cytology analysis and chest radiography for detection of lung cancer. The Mayo and Czechoslovak studies demonstrated an advantage for screening with respect to stage distribution, resectability, survival, and fatality. However, the experimental groups demonstrated increases in the cumulative index of lung cancer above those of control group, and, thus, no significant reduction in mortality was demonstrated. The discrepancies between the control and experimental groups with regard to mortality, stage distribution, resectability, and survival in the Mayo project have been discussed extensively and have been partly attributed to biases of lead time, length, and overdiagnosis. The use of mortality as a method to accurately reflect lung cancer death rates has also been challenged recently, resulting in a renewed interest in evaluating radiographic screening for lung cancer.42,43

FIGURE 2-7. Pulmonary embolus. A, Axial image shows pulmonary embolus of the right and left main pulmonary arteries (arrows). Extensive hilar adenopathy is also present. B, Coronal reconstruction confirms a large left pulmonary artery embolus (arrow). C, Sagittal reconstruction at the level of the left pulmonary artery shows the large embolus (arrow) and surrounding adenopathy. D, Maximum intensity projection (MIP) image shows the large left pulmonary embolus. Details of the pulmonary arteries and veins are well demonstrated with this method. Also note the numerous small metastatic nodules.

However, since 1980 there has been widespread acceptance that screening for lung cancer is not indicated.44 As discussed above, considerable advances in radiographic imaging of the chest have been developed since the studies for screening of lung cancer.36–41 These methods have improved the detection and analysis of focal lung lesions and have led to a renewed interest in lung cancer screening. Most importantly, helical CT has significantly improved the quality of CT scans by reducing artifacts from patient motion. This advance has increased the ability to detect small lung lesions that are not apparent on conventional chest radiographs (Figure 2-8).45,46 Another study showed that patients with smaller lung lesions detected by CT had a

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clinically milder disease and better prognosis.47 Recent reports by two separate groups have also shown that lowdose helical CT in high-risk patients can detect lung cancers at an earlier stage than can conventional chest radiography. The Anti-Lung Cancer Association, a group in Japan, has screened 1,369 patients who were considered at high risk for lung cancer by performing annual helical CT using low dosage to limit radiation exposure (low-dose helical CT). This study showed that CT was superior to chest radiography for detecting peripheral lung cancer. Of 15 lung cancers detected by CT, only 11 cancers were detectable with chest radiography. Fourteen (93%) of the 15 cancers were at stage I. 45 The Early Lung Cancer Action Project is a study performed in the United States that also used low-dose helical CT to screen for lung cancer in 1,000 patients who were at high risk for lung cancer. Malignant disease was detected in 2.7% using CT but in only 0.7% with chest radiography. Of the 27 lung cancers detected by CT, 23 were at stage I. Only 4 (0.4%) of the lesions detected by chest radiography were at stage I.48 In both groups, high-risk patients were defined as those with a significant cigarette smoking history and no previous malignancy.

FIGURE 2-8. Spiral computed tomography scan shows a 4 mm adenocarcinoma (arrow) that was not evident on a chest radiograph.

However, there is much debate about the effectiveness of CT screening on the overall impact of lung cancer, in particular, disease-specific mortality.49–51 In an attempt to further evaluate the effectiveness of low-dose helical CT for lung cancer, a large, randomized controlled study is being funded by National Cancer Institute. After starting in September 2002, the trial enrolled 50,000 participants by February 2004. Follow-up analysis is being performed with completion of the study targeted for 2009.This trial compares low-dose helical (spiral) CT to chest radiographs for screening cancer. Quality of life, smoking cessation, smoking addiction, and biomarkers are also part of this trial. Evaluation of the Solitary Pulmonary Nodule The solitary pulmonary nodule remains one of the most, if not the most, difficult diagnostic problems in radiology. Most of the advances in imaging have resulted in an increased ability to detect a solitary pulmonary nodule, but characterization of the lesion often requires longterm surveillance or biopsy. There are numerous etiologies for such nodules, with the large majority consisting of a malignant nodule, a benign nodule, or an infection.52 With the renewed interest in lung cancer screening with CT, it is anticipated that the magnitude of this diagnostic dilemma will greatly increase. In the 1950s and 1960s, reports concerning solitary pulmonary nodules in the general population attributed < 5% of cases to cancer.53 In patients referred for resection of the nodules, the malignant lesions represented approximately 40% of cases and granulomas another 40%.54 More recent data concerning resected nodules shows that single pulmonary nodules represent malignancies in up to 60% of cases.54,55 This is attributed to the consideration of benign lesions being eliminated with CT imaging. Newer imaging techniques including helical CT and PET have improved the predictability of a lesion representing a malignancy. However until an ideal radiologic imaging technique is developed that eliminates benign lesions, radiologist will depend on existing criteria for determining a benign lesion. Even with exciting advances in imaging modalities, the evaluation of the solitary pulmonary nodule still begins with the morphologic evaluation of the lesion. This includes an evaluation of the size, edge characteristics, rate of growth, and calcification. Whereas there are a few radiologic features of benign lesions, there is no specific radiologic feature for a malignant lesion. Therefore, based on radiologic criteria, a solitary pulmonary nodule is classified as a benign or an indeterminate nodule. Despite being limited to morphologic evaluation, multislice CT advances have improved our ability to evaluate a solitary pulmonary nodule. This is predominately

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because of the ability to image the chest rapidly during a single breath hold. The end result is less motion artifact and thinner-slice images, which improve characterization compared with single-slice CT. size Lesions 3 cm or larger are most likely to be malignant, but this size criterion is not useful in assessing a solitary pulmonary nodule. Size criteria for potential malignancy was initially based on chest radiograph findings, but more recent CT studies showed that the malignant potential of small lesions detected by CT was significant.55,56 CT examinations also detect smaller lesions better than does conventional chest radiography, and an increase in detection of small lesions will occur as the use of multislice CT increases. Although size is not reliable for characterization, it should be noted that some lesions that were indeterminate on chest radiographs have been proven benign with CT. Therefore, lesions that remain indeterminate by CT have a greater chance of being malignant. edge characteristics There is no characteristic appearance of the edge of a nodule that indicates a malignant lesion. However, the interface that a nodule makes with the adjacent lung can suggest a greater probability for a malignant lesion than a benign one. Although these edge characteristics have been reported to be more indicative of a malignant nodule, they also occur in benign lesions. Nonetheless, in the management of a nodule, assessment of the edge characteristics has value. A lobulated border of a nodule is reported to be predictive of a malignant lesion in over 80% of cases (Figure 2-9).57 Spiculated margins or linear striations extending from the margins of the lesion into the parenchyma are often seen in malignant lesions and are therefore highly suggestive.58,59 The spicules can reflect extension of the tumor into the parenchyma or a reaction of the parenchyma to the tumor. Unfortunately, this reaction can occur in benign lesions such as granulomas; therefore, this appearance is useful but not diagnostic. An extension of one of these spicules of a peripherally located lesion to the pleural surface has been termed the pleural tail sign and was thought to be indicative of a malignancy (Figure 2-10). However, this sign has been proven unreliable because it is seen in malignant and benign lesions, particularly granulomas.58,60–62 The presence of a patent bronchus leading into a peripheral lesion was called the bronchus sign by Kuriyama and colleagues and was reported to have an association with adenocarcinoma.63 However, a patent bronchus or air bronchogram is more commonly seen in benign lesions. The value of a bronchus sign may lie in the fact that it is useful in predicting a successful sampling by transbronchial biopsy.64

FIGURE 2-9. Multislice computed tomography scan shows a lobulated mass of the right lower lobe that proved to be squamous cell carcinoma.

FIGURE 2-10. Computed tomography scan of a left upper lobe squamous cell carcinoma. Note the spicules of the tumor borders and the linear extension (pleural tail) that extends to the pleural surface.

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rate of growth To adequately assess a lesion for an interval change in growth, it is necessary to obtain the appropriate prior radiograph for comparison, an exercise that is becoming more difficult with the transient nature of our society and the influence of managed care contracts. As noted previously, it is hoped that digital imaging and Webbased distribution of images will greatly help the clinician to provide this comparison for patients. Radiologic assessment of nodule stability was first published by Good and Wilson in 1958. In this article they introduced the concept that 2 years of stability of a lesion on chest radiographs implied a benign process.65 Since then, this concept has become radiology dogma, based on studies reporting that the majority of malignant nodules double in volume between 20 and 400 days.66,67 A nodule that doubles in size in < 1 month is probably infectious, and one that takes 18 months or longer to double is usually benign.68 Exceptions to these guidelines are slow-growing adenocarcinoma and carcinoid tumors that take years to double in size, and the development of hemorrhage in a malignant lesion that results in a rapid increase in size. Additionally, some malignancies grow more rapidly than expected (Figure 2-11). Despite these exceptions, the evaluation of doubling times of pulmonary nodules remains useful in establishing the diagnosis of a solitary pulmonary nodule.

calcification The most reliable radiologic characteristic to differentiate a benign from a malignant lesion is the presence or absence of calcification. Calcification is usually indicative of a benign lesion; however, more important than its presence is the pattern of calcification. Characteristically benign patterns include lesions that are totally calcified, densely calcified, or laminated in appearance. When a bronchogenic carcinoma calcifies, the pattern is usually stippled or eccentric. 69 Eccentric calcification occurs when a malignancy engulfs a calcified granuloma (Figure 2-12). Some metastatic nodules can exhibit calcification, but these are usually multiple and in the appropriate clinical setting. Calcification is best evaluated with CT,55 but digital radiography with dual-energy subtraction may prove to be as useful.70 “ditzels” Because of the improvement in image quality with the increase in helical CT use, there has been a rise in the detection of tiny nodules, such that it is common to see 2 mm nodules on CT scans. Of course, these nodules are too small to characterize and therefore present diagnostic and management dilemmas; as a result, these are often referred to as “ditzels.” What is to be done with these tiny nodules? A survey of thoracic radiologists concerning these ditzels was performed in an attempt to gather recom-

FIGURE 2-11. Rapid growth of bronchioalveolar carcinoma. A, Baseline CT shows a 4 mm left lower nodule (arrow). B, Seven weeks later, a repeat computed tomography scan shows a rapid increase in size.

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the technique. Of course, a major problem with this concept of volumetric growth is that the concept of a lesion doubling in size assumes a spherical lesion, which is not true of all malignancies; therefore asymmetric growth may lead to an underestimation of the size.

CT Enhancement and Positron Emission Tomography

FIGURE 2-12. Computed tomography scan of a left upper lobe carcinoma that has engulfed a calcified granuloma.

mendations. 5 6 Respondents were presented with a number of clinical settings in which a single ditzel or multiple small ditzels were present on a CT scans. In this survey a ditzel was defined as a nodule of 3 to 5 mm. The most common response overall was short-term followup. For younger, healthy patients and those without a history of a prior malignancy, the most common response was to do nothing or perform short-term follow-up. In patients considered to be at high risk for malignancy, the most common recommendations were to do short-term follow-up or a biopsy. In patients with a known malignancy, there was a tendency to recommend biopsy or to consider the lesion metastatic disease. The problem with short-term follow-up of nodules < 5 mm trying to recognize a change in size. Larger lesions appear to grow more rapidly because their diameter is increasing by a larger dimension. A doubling in size of a lesion ≤ 5 mm is harder to detect. For example, a 4 mm lesion measured in the axial plane on CT that has doubled in volume would have a change in radius from 2 mm to 2.5 mm. Overall, the new lesion would only measure 5 mm, which means the radiologist would have to detect a 1 mm change is size. Even with helical CT and a thin-section technique, this size increase is virtually impossible to appreciate because of differences in respiration, partial volume artifacts, and variations in interobserver and intraobserver measurements. If a change in size were recognized, it would be hard to prove that the change was due to growth and not a slight variation in

Radiologic imaging to assess disease is predominantly an anatomic evaluation. Although this is an excellent method of evaluation, it is not surprising that it is limited and often results in indeterminate findings. Recent radiologic investigations of disease taken advantage of the different biologic activities of benign and malignant lesions; this approach is referred to as functional or molecular imaging. The most common and successful methods to date are CT nodule enhancement and PET. In general, malignant lesions are more biologically active than is benign disease, and these methods assess a component of this activity. CT enhancement evaluation of pulmonary lesions is performed using helical CT. An IV contrast medium is injected at a rapid rate, and images of the nodule are obtained at 1-minute intervals for 4 minutes. Over this time, because of the increased tumor vascularity, there is an increase in enhancement of malignant lesions. Benign lesions do not tend to enhance because they are less vascular. Pre- and postenhancement Hounsfield unit measurements are taken, and an increase of > 20 units is considered indicative of a malignant nodule. Swensen and colleagues reported the positive predictive rate to be > 90% using this method.71 This method is used predominantly for the evaluation of solitary pulmonary nodule. Nodules < 1 cm are not well characterized with this method because of partial volume artifacts from the adjacent lung. There is ongoing research to use CT enhancement to assess the angiogenesis of larger tumors. It is hoped that changes in the neovascularity of a tumor can be quantified by correlating the enhancement of the tumor before and after therapy. PET is a nuclear medicine study that uses fludeoxyglucose F 18 (FDG) to differentiate benign from malignant lesions.72 The glucose analog FDG is taken up by the malignant cells but cannot be further metabolized after initial phosphorylation to FDG-6-phosphate and thus allow imaging.

Summary Advances in imaging technologies have greatly benefited the evaluation of thoracic disease. Patient care has been improved by the rapid distribution of images through

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PACSs. Fast image-acquisition technology improves visualization and characterization of diseases in the thorax and results in faster and more confident diagnoses by radiologists. Computer-aided diagnosis systems and computer applications for image interpretation show promise. As progress in thoracic imaging continues, new applications will undoubtedly refine and even revolutionize the way thoracic diseases are evaluated and managed.

14. Schulen V, Schick F, Loichat J, et al. Evaluation of K-space segmented cine sequences for fast functional cardiac imaging. Invest Radiol 1996;31:512–22.

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22. Hayashi H, Matsuoka Y, Sakamoto I, et al. Penetrating atherosclerotic ulcer of the aorta: imaging features and disease concept. Radiographics 2000;20:995–1005. 23. Gavant ML, Flick P, Menke P, Gold RE. CT aortography of thoracic aortic rupture. AJR Am J Roentgenol 1996;166:955–61. 24. Gavant ML, Menke PG, Fabian T, et al. Blunt traumatic aortic rupture: detection with helical CT of the chest. Radiology 1995;197:125–33. 25. Dyer DS, Moore EE, Ilke DN, et al. Thoracic aortic injury: how predictive is mechanism and is chest computed tomography a reliable screening tool? A prospective study of 1,561 patients. J Trauma 2000;48:673–83. 26. Dyer DS, Moore EE, Mestek MF, et al. Can chest CT be used to exclude aortic injury? Radiology 1999;213:195–202. 27. Remy-Jardin M, Tillie-Leblond I, Szapiro D, et al. CT angiography of pulmonary embolism in patients with underlying respiratory disease: impact of multislice CT on image quality and negative predictive value. Eur J Radiol 2002;12:1971–8. 28. Remy-Jardin M, Remy J, Wattinne L, Giraud F. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold technique— comparison with pulmonary angiography. Radiology 1992;185:381–7.

Advances in Diagnostic Imaging of the Thorax and Screening / 45 29. Remy-Jardin M, Remy J. Spiral CT angiography of the pulmonary circulation. Radiology 1999;212:615–36.

cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996;201:798–802.

30. Kim KI, Muller NL, Mayo JR. Clinically suspected pulmonary embolism: utility of spiral CT. Radiology 1999;210:693–7.

46. Mori K, Tominaga K, Hirose T, et al. Utility of low-dose helical CT as a second step after plain chest radiography for mass screening for lung cancer. J Thorac Imaging 1997;12:173–80.

31. Erdman WA, Peshock RM, Redman HC, et al. Pulmonary embolism: comparison of MR images with radionuclide and angiographic studies. Radiology 1994;190:499–508. 32. Grist TM, Sostman HD, MacFall JR, et al. Pulmonary angiography with MR imaging: preliminary clinical experience. Radiology 1993;189:523–30. 33. Gupta A, Frazer CK, Ferguson JM, et al. Acute pulmonary embolism: diagnosis with MR angiography. Radiology 1999;210:353–9. 34. Meaney JF, Weg JG, Chenevert TL, et al. Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med 1997;336:1422–7. 35. Rosenow EC, Carr DT. Bronchogenic carcinoma. CA Cancer J Clin 1979;29:233–45. 36. Melamed MR, Flehinger BJ, Zaman MB, et al. Screening for early lung cancer. Results of the Memorial Sloan-Kettering study in New York. Chest 1984;86:44–53. 37. Kubik A, Parkin DM, Khlat M, et al. Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial on a population of high-risk males in Czechoslovakia. Int J Cancer 1990;45:26–33.

47. Koike T, Terashima M, Takizawa T, et al. Clinical analysis of small-sized peripheral lung cancer. J Thorac Cardiovasc Surg 1998;115:1015–20. 48. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99–105. 49. Aberle DR, Gamsu G, Henschke CI, et al. A consensus statement of the Society of Thoracic Radiology: screening for lung cancer with helical computed tomography. J Thorac Imaging 2001;16:65–8. 50. Patz EF Jr, Black WC, Goodman PC. CT screening for lung cancer: not ready for routine practice. Radiology 2001;221:587–91, 598–9. 51. Miettinen OS, Henschke CI. CT screening for lung cancer: coping with nihilistic recommendations. Radiology 2001;221:592–7. 52. Godwin JD. The solitary pulmonary nodule. Radiol Clin North Am 1983;21:709–21. 53. Holin SM, Dwork RE, Glaser S, et al. Solitary pulmonary nodules found in a community-wide chest roentgenogram survey: a five-year follow-up study. Am Rev Tuberc 1959;79:427.

38. Kubik A, Polak J. Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 1986;57:2427–37.

54. Steele J. The solitary pulmonary nodule: report of a cooperative study of resected asymptomatic solitary pulmonary nodules in males. J Thorac Cardiovasc Surg 1963;46:21–39.

39. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 1984;130:561–5.

55. Zerhouni EA, Stitik FP, Siegelman SS, et al. CT of the pulmonar y nodule: a cooperative study. Radiology 1986;160:319–27.

40. Frost JK, Ball WC, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis 1984;130:549–54. 41. Flehinger BJ, Melamed MR, Zaman MB, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Memorial SloanKettering study. Am Rev Respir Dis 1984;130:555–60. 42. Strauss GM. Measuring effectiveness of lung cancer screening: from consensus to controversy and back. Chest 1997;112:216–28S. 43. Strauss GM, Gleason RE, Sugarbaker DJ. Chest x-ray screening improves outcome in lung cancer. A reappraisal of randomized trials on lung cancer screening. Chest 1995;107:270–9S. 44. Richert-Boe KE, Humphrey LL. Screening for cancers of the lung and colon. Arch Intern Med 1992;152:2398–404. 45. Kaneko M, Eguchi K, Ohmatsu H, et al. Peripheral lung

56. Munden RF, Pugatch RD, Liptay MJ, et al. Small pulmonary lesions detected at CT: clinical importance. Radiology 1997;202:105–10. 57. Armstrong P. Basic patterns in lung disease. In: Armstrong P, Wilson AG, Dee P, Hansell DM, editors. Imaging of diseases of the chest. 2nd ed.St Louis (MO): Mosby; 1995. p 58–124. 58. Zwirewich CV, Vedal S, Miller RR, Muller NL. Solitary pulmonary nodule: high-resolution CT and radiologicpathologic correlation. Radiology 1991;179:469–76. 59. Huston J III, Muhm JR. Solitary pulmonary opacities: plain tomography. Radiology 1987;163:481–5. 60. Bryk D. The participating tail. A roentgenographic sign of pulmonary granuloma. Am Rev Respir Dis 1969;100:406–8. 61. Hill CA. “Tail” signs associated with pulmonary lesions: critical reappraisal. AJR Am J Roentgenol 1982;139:311–6. 62. Shapiro R, Wilson GL, Yesner R, Shuman H. A useful roentgen sign in the diagnosis of localized bronchioloalveolar carcinoma. Am J Roentgenol Radium Ther Nucl Med 1972;114:516–24.

46 / Advanced Therapy in Thoracic Surgery 63. Kuriyama K, Tateishi R, Doi O, et al. Prevalence of air bronchograms in small peripheral carcinomas of the lung on thin-section CT: comparison with benign tumors. AJR Am J Roentgenol 1991;156:921–4. 64. Gaeta M, Pandolfo I, Volta S, et al. Bronchus sign on CT in peripheral carcinoma of the lung: value in predicting results of transbronchial biopsy. AJR Am J Roentgenol 1991;157:1181–5. 65. Good CA, Wilson TW. The solitary circumscribed pulmonary nodule: study of seven hundred five cases encountered roentgenologically in a period of three and one-half years. JAMA 1958;166:210–5. 66. Steele JD, Buell P. Asymptomatic solitary pulmonary nodules. Host survival, tumor size, and growth rate. J Thorac Cardiovasc Surg 1973;65:140–51. 67. Weiss W. Peripheral measurable bronchogenic carcinoma. Growth rate and period of risk after therapy. Am Rev Respir Dis 1971;103:198–208.

68. Nathan MH, Collins VP, Adams RA. Differentiation of benign and malignant pulmonary nodules by growth rate. Radiology 1962;79:221–32. 69. Mahoney MC, Shipley RT, Corcoran HL, Dickson BA. CT demonstration of calcification in carcinoma of the lung. AJR Am J Roentgenol 1990;154:255–8. 70. Fraser RG, Hickey NM, Niklason LT, et al. Calcification in pulmonary nodules: detection with dual-energy digital radiography. Radiology 1986;160:595–601. 71. Swensen SJ, Brown LR, Colby TV, Weaver AL. Pulmonary nodules: CT evaluation of enhancement with iodinated contrast material. Radiology 1995;194:393–8. 72. Patz EF. Imaging lung cancer. Semin Oncol 1999;26:21–6.

CHAPTER 3

TISSUE ADHESIVES IN THORACIC AND CARDIOVASCULAR SURGERY ROSS M. REUL, MD GARRETT L. WALSH, MD body reactions. If blood products are used, the risk of viral transmission must be minimized. Tissue adherence must be rapid and strong, but the adhesive must not penetrate deeply into tissues. Tissue adhesives must remain flexible after polymerization, especially when used on dynamic pulmonary, cardiac, or vascular tissues.

For decades surgeons have been using tissue adhesives as an adjunct to conventional surgical techniques for a variety of indications. Improvements in the safety and availability of tissue adhesives have led to their widespread use. With increasing experience and the development of newer compounds and modifications to existing tissue adhesives, the number of potential applications will continue to grow. The ideal tissue adhesive has not yet been developed, and until this happens, the properties of each type will determine its usefulness for particular situations. An understanding of the various properties and mechanisms of action of the available compounds therefore helps surgeons decide when to use one of these adhesives and which is the most appropriate for each clinical situation. Tissue adhesives are most commonly used to enhance hemostasis. Tissue adhesives are also being used increasingly to seal or prevent air leaks after thoracic surgery. Their use to seal friable tissues in the repair of acute type A aortic dissections is also becoming routine. Tissue adhesives have been used in desperate situations to seal subacute ruptures after myocardial infarctions and to close bronchopleural fistulas. Some agents are used to prevent postoperative adhesion formation. Tissue adhesives are also used as carriers for the slow, local release of antibiotics, chemotherapeutic agents, or other medications, and they hold promise for the delivery of gene therapy. For a tissue sealant to be clinically useful, it must be safe and effective. Preparation time, ease of delivery, and cost are also important considerations. Tissue adhesives and their products of degradation must also be nontoxic, noninfectious, nonimmunogenic, and noninflammatory. They should promote—and must not impede—healing. The materials must be biodegradable to avoid foreign

Historical Perspective Fibrin sealants, also known as fibrin glues, are the most widely used and extensively studied tissue sealants currently in use. Commercially available fibrin sealants are composed of fibrinogen, thrombin, calcium chloride, and usually an antifibrinolytic such as aprotinin. Bergel first used fibrin as an experimental hemostatic agent in 1909. 1 Others used fibrin-impregnated materials to control parenchymal bleeding. 2,3 The combination of fibrinogen and thrombin to anchor skin grafts was first used clinically in 1944,4 but the lack of concentrated fibrinogen limited its adhesive strength. The risk of hepatitis transmission associated with its use also complicated its application. Techniques to provide concentrated and purified human fibrinogen allowed for more reproducible results.5 Cyanoacrylate was used as a hemostatic agent in the 1960s and to seal pulmonary tissue after recurrent spontaneous pneumothorax in 1967.6,7 However, extensive tissue reaction and toxicity prevented the widespread clinical use of this synthetic tissue sealant. Cyanoacrylate derivatives are currently used externally as skin adhesives.8 Matras and colleagues used cryoprecipitated plasma with a high fibrinogen concentration combined with bovine thrombin to create a fibrin sealant for reuniting transected peripheral nerves in rabbits in 1972.9 Fibrin 47

48 / Advanced Therapy in Thoracic Surgery

sealant was subsequently used in human nerve anastomoses using autologous and then single-donor plasma cryoprecipitate combined with bovine thrombin in 1974. 10 Fibrin sealant was then used as a hemostatic adjunct for repairing bleeding parenchymal lesions.11,12 Spangler first used fibrin sealant in cardiovascular surgery in 1976.13 In 1978 Akrami and colleagues used fibrin glue to preseal polyethylene terephthalate fiber (Dacron, L. R. Bard, Tempe, AZ) prosthetic grafts. 14 Koveker and colleagues expanded the use of fibrin sealants to include the control of bleeding from polytetrafluoroethylene graft suture lines and coronary artery anastomoses and from myocardial and cardiac venous bleeding sites.15 In 1982 Borst and colleagues reported a 95% success rate using fibrin sealant as a hemostatic agent in 340 patients undergoing cardiac surgical procedures with cardiopulmonary bypass.16 They used commercially available fibrinogen (Tissucol, Immuno AG, Vienna, Austria) combined with bovine thrombin, calcium chloride, and aprotinin applied to collagen fleece or delivered by a dual-syringe system.16 Despite the increasing use of fibrin sealants in Europe and Japan, early experience was limited in the United States because the US Food and Drug Administration (FDA) revoked the approval of fibrin human fibrinogen concentrates in 1978 owing to the risk of viral transmission through the use of human donor plasma products. Rousou and colleagues,17 with investigational approval by the FDA, conducted a multicenter, prospective, randomized, controlled clinical trial comparing fibrin sealant (Tisseel, Immuno AG) with conventional topical hemostatic agents for patients undergoing cardiac reoperations in 1989. They reported improvements in the time required for complete hemostasis, the amount of postoperative blood loss, and re-sternotomy rates17 in the fibrin sealant group. Although experience with commercially manufactured fibrin sealants continued to be gained outside the

United States, American surgeons were using fibrinogen from autologous plasma and local blood bank sources.18,19 The theoretic risk of virus transmission from donor plasma sources prompted the development of synthetic and nonhuman-derived biologic tissue adhesives. Gelatinresorcinol-formaldehyde (GRF) glue, also known as “French glue,” has been used for many years in Europe for reinforcing the layers of the aortic wall during the repair of aortic dissections. GRF glue and a modification (gelatinresorcinol-formaldehyde-glutaraldehyde [GRFG] glue) have also been used for hemostasis and for sealing air leaks, with mixed results. Concerns about the in vivo toxicity of formaldehyde have kept these agents from gaining FDA approval. BioGlue Surgical Adhesive (CryoLife, Inc., Kennesaw, GA) is composed of bovine serum albumin and 10% glutaraldehyde. It is a less toxic alternative to GRF glue and has been approved by the FDA for use in the repair of thoracic aortic dissections and hemostasis. It has also shown utility in sealing pulmonary air leaks, but there are currently no clinical data in the literature to support the use of BioGlue in this setting. FocalSeal-L (Genzyme Biosurgery, Cambridge, MA) is a polyethylene glycol hydrogel that is photopolymerized after tissue application. It is currently the only tissue adhesive that is FDA approved for use in lung surgery to seal air leaks. Although experimental evidence has shown its utility as a hemostatic agent, proper application in the presence of bleeding can be challenging. FloSeal Matrix (Fusion Medical Technologies, Inc., Mountain View, CA) is a combination of gelatin and collagen that has recently been approved as a hemostatic agent. CoSeal surgical sealant (Cohesion Technologies Inc., Palo Alto, CA) is a hydrogel composed of polyethylene that has been approved as a vascular sealant to enhance hemostasis at the suture lines of prosthetic grafts when applied before releasing the cross-clamps. CoStasis (Cohesion Technologies) is a hemostatic agent that uses autologous

TABLE 3-1. FDA-Approved Tissue Adhesives Trade Name*

Components

Adjuncts to hemostasis Hemaseel APR Tisseel VH BioGlue FloSeal CoSeal CoStasis

Human fibrinogen, human thrombin, bovine aprotinin, CaCl Human fibrinogen, human thrombin, bovine aprotinin, CaCl Bovine serum albumin, glutaraldehyde Bovine thrombin, collagen-gelatin matrix Two-component polyethylene glycol Autogenous fibrinogen and platelets, bovine thrombin, collagen

Pulmonary sealant FocalSeal-L

Polyethylene glycol (photocross-linked with xenon light source)

External wound closure Dermabond (Closure Medical Corporation, Raleigh, NC)

2-octyl-cyanoacrylate

FDA = US Food and Drug Administration. *See text for manufacturer details.

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 49

plasma, including platelets and fibrinogen, combined with bovine thrombin and bovine collagen. Although experimental and early clinical studies have shown the efficacy of each of these newer agents, long-term studies and large, randomized clinical trials are lacking.

Hemostatic Agents and Vascular Sealants Tissue adhesives currently approved for use as adjuncts to enhance hemostasis include the fibrin sealants Tisseel VH (Baxter Healthcare Corp., Deerfield, IL) and Hemaseel APR (Haemacure Corp., Montreal, PQ), FloSeal, BioGlue, CoSeal, and CoStasis (Table 3-1). Each has unique properties that must be considered when using these agents clinically. The fibrin sealants, as noted already, have been studied extensively for a wide range of indications, with reported efficacy and safety. Long-term clinical follow-up data are not yet available for FloSeal, BioGlue, CoSeal, or CoStasis. Other adhesives used clinically for hemostasis, but not approved for this use by the FDA, include GRF glue, FocalSeal-L, and cyanoacrylate. The advantage of a fibrin sealant is its biocompatibility. The components and packaging of Tisseel VH and Hemaseel APR are similar. Each is supplied as two separate vials, one containing human fibrinogen and bovine aprotinin and the other containing human thrombin and calcium chloride. The two vials are reconstituted separately and delivered using a dual-syringe system to apply equal volumes of each to the target tissue (Figure 3-1). The delivery systems include blunt-tip applicators for direct application or spray tips for more diffuse areas of coverage (see Figure 3-1). Fibrin sealant is designed to mimic the final stage of the coagulation cascade. In the presence of calcium ions, thrombin catalyzes the conversion of fibrinogen to fibrin and activates factor XIII in the plasma. Activated factor XIII then mediates the cross-linking of fibrin monomers to polymerize the clot. This occurs within seconds to minutes after the two components of fibrin sealant combine at the target site in vivo. Aprotinin is included to inhibit fibrinolysis, resulting in more prolonged clot stability (Figure 3-2). The tensile strength of the resultant clot is determined by the fibrinogen concentration, and the rate of clot adherence is determined by the concentration of thrombin. The use of fibrin sealants derived from autologous plasma and local blood bank cryoprecipitates has been reported to achieve good results, but the concentrations of fibrinogen and thrombin may be less reproducible than those achieved in the commercially prepared products. The largest controlled study of the use of fibrin sealants in cardiothoracic surgery was a multicenter,

prospective, randomized trial reported by Rousou and colleagues in 1989.17 At 11 US centers, 333 patients were studied who underwent reoperation for cardiac surgery or emergency re-sternotomy within 24 hours after cardiac surgery. Patients with bleeding that was not controllable with conventional suture techniques were randomized to treatment with fibrin sealant (Tisseel) or with conventional topical hemostats, including Avitene (Avicon, Inc., Humacao, Puerto Rico), Gelfoam (Johnson & Johnson Products, Inc., New Brunswick, NJ), Oxycel (Deseret, Sandy, UT), Surgicel (Upjohn Company, Needham Heights, MA), and Thrombinar (Armour Pharmaceuticals, Tarrytown, NY). The fibrin sealant was applied either directly to the bleeding site with a dualsyringe applicator or onto a Helistat (Citagenix Inc, Laval, PQ, Canada) carrier that was applied to the target site. The end point of the randomized portion of the study was the cessation of bleeding within 5 minutes of

FIGURE 3-1. Tisseel-VH Duploject applicator (A) and Fibrinotherm heating and stirring device (B). The dual-syringe system allows the two components of the fibrin sealant to remain separated until direct application to the target tissue. (Courtesy of Baxter Healthcare Corp.)

50 / Advanced Therapy in Thoracic Surgery

Component I Factor XIII

Fibrinogen

Component II

Inhibitors:

Antithrombin III Fibrin Adsorption

Ca2+ + Thrombin

X

X

Fibrin (Monomer---Polymer) Factor XIIIa

Adjuncts:

Initiators:

α2-Antiplasmin Fibronectin Plasminogen

Streptokinase tPA Urokinase Prekallikrein Kininogen

Fibrin X-Linked

X

Plasmin

X

Inhibitors:

α2-Macroglobulin α2-Antiplasmin Aprotinin εACA

Plasminogen

Inhibitors:

εACA Aprotinin AMCA

Fibrin Degradation Products Phagocytosis Other Proteases Further Metabolites FIGURE 3-2. Final steps in the coagulation cascade showing the interaction of the components of fibrin sealant and their degradation. AMCA = aminocaproic acid; tPA = tissue plasminogen activator. Adapted from Sierra DH.89 p. 310.

application. Crossovers were permitted between groups if hemostasis failed to occur. The fibrin sealant treatment group, including patients treated with fibrin sealant after the failure of conventional hemostats, was then compared with matched historical controls with respect to postoperative chest tube drainage, re-sternotomy rates, and length of hospital stays. Re-sternotomy rates and operative mortality were also studied in the fibrin sealant

treatment group and nonmatched historical controls.17 In the randomized study, hemostasis was achieved within 5 minutes in the fibrin sealant group, with a success rate of 92.6% as opposed to 12.4% in the conventional hemostatic agent treatment group (p < .001) (Figure 3-3). In the crossover group, fibrin sealant was successful in 82.0% of 78 bleeding episodes after initial treatment with conventional topical hemostatic agents

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 51 100

**

** *

75

50

25

0 Redo Control

Re-sternotomy

Fibrin Sealant

Total

* p < .005

** p < .001

FIGURE 3-3. Percentage of hemostatic success within 5 minutes for patients with fibrin sealants versus controls. Adapted from Rousou J et al.17 p. 199.

had failed. In the nonrandomized portion of the study, there was no statistically significant difference between the groups in terms of chest tube drainage 12 hours postoperatively. The quantity of drainage fluid was 740 mL in the fibrin sealant treatment group versus 819 mL in the matched historical control group (p = .348). However, when the number of patients in whom more than 1,499 mL of fluid drained in the first 12 hours postoperatively was analyzed (in only 56 matched pairs with these data available), there was a significant difference (fibrin sealant 1.8% versus control 14.3%, p < .05). There were also no significant differences in re-sternotomy rates (fibrin sealant 4.5% versus control 6.8%), hospital stays (fibrin sealant 12 d versus control 12.9 d), or blood products transfused (odds ratios for no blood products transfused: fibrin sealant 0.9 versus control 1.1) (Figure 3-4). When the fibrin sealant group was compared with nonmatched historical controls, there was no significant difference in operative mortality.17 Despite its limitations, 15

*

10

5

0 Blood Loss Re-sternotomy (%) Hospital Stay (d) > 1,499 cc/12 h (%)

Blood Products (Odds)

End Points

Control

Fibrin Sealant

* p < .05

FIGURE 3-4. Various end points for patients receiving fibrin sealant versus historical matched controls. Adapted from Rousou J et al.17 p. 199.

this study has been extensively referenced as evidence of the benefits of fibrin sealants as topical hemostatic agents. Spotnitz and colleagues sprayed fibrin sealant over the anterior mediastinum before closing the sternum in 20 patients undergoing cardiac operations and reported a decrease in average chest tube output compared with matched controls at 12 hours (461 mL vs 731 mL, respectively; p < .05) and 24 hours postoperatively (714 mL vs 1,016 mL, respectively; p < .05). 2 0 Matthew and colleagues used single-donor concentrated fibrinogen and bovine thrombin applied by individual syringes, spray applicators, or endoscopic cannula delivery in 634 cardiac operations and reported a 94% success rate in controlling bleeding as assessed by the surgeon.21 Other clinical studies with small cohorts of patients have shown decreased chest tube drainage after reoperative cardiac surgery and congenital heart surgery.22,23 The greatest advantage of fibrin sealant over other available tissue adhesives for hemostasis in cardiothoracic surgery is the lack of serious complications associated with many years of its clinical use involving several million applications. 24 The fibrin clot resulting from fibrin sealant is degraded by natural fibrinolysis and phagocytosis and is completely broken down within 2 to 6 weeks. Studies have shown minimal inflammatory reaction to the clot other than routine wound healing mechanisms. Adhesion formation and fibrosis at the site of experimental application have been shown to resolve within 4 to 6 months. Human fibrinogen and thrombin in Tisseel VH and Hemaseel are obtained from human donors; therefore, the potential exists for viral transmission. However, donors undergo a rigorous screening process, and the plasma is screened for hepatitis B and C viruses and human immunodeficiency virus (HIV). The human components then undergo a two-step vapor heating viral inactivation process. Of the ≥ 6 million applications reported, there have been no confirmed cases of the transmission of viral hepatitis or HIV from the use of fibrin sealant.24 There have been some cases reported of transmission of parvovirus B19 infection,7 however, and one of the limitations of the viral inactivation process is that it is not effective against nonenveloped viruses. The most serious complications reported to date have been immunologic responses to bovine antigens or to impurities present in earlier preparations of fibrin sealants. Inhibitory antibodies to thrombin and factor V have developed in a few patients after treatment with local fibrin sealant containing bovine thrombin and aprotinin.25–28 The fibrin sealants currently available for hemostasis use bovine aprotinin, not human thrombin and fibrinogen. Although the risk of immunologic

52 / Advanced Therapy in Thoracic Surgery

response to locally applied aprotinin exists, the incidence remains quite low and is usually associated with repeat exposures. All tissue adhesives used for hemostasis have the potential to produce thrombotic complications.29 In clinical use, however, thrombogenic events are rare and are most often associated with intraluminal contamination with the tissue adhesive. CoStasis is an FDA-approved hemostatic agent that uses autologous plasma as a source of fibrinogen. The apparatus includes a centrifuge kit for autologous plasma that can be obtained before or after heparinization.30 Bovine thrombin and fibrillar bovine collagen are prepared in one syringe and fibrinogen in a second syringe. When applied in situ using a dual-syringe applicator, the sealant polymerizes into a stable clot. Similar to fibrin sealant, CoStasis can be delivered directly with a blunt-tip applicator or sprayed diffusely to cover larger areas. The mechanism of action is similar to that previously described for fibrin sealants. Its advantage is the avoidance of donor human plasma as the source of fibrinogen. In a study of the effectiveness of CoStasis as a hemostatic agent in experimental rabbit spleen and kidney injuries, the application of CoStasis resulted in more complete and more rapid hemostasis than did fibrin sealant or collagen sponge treatment. The efficacy was maintained after platelet or fibrinogen depletion. 3 1 Turner and colleagues showed more rapid control of bleeding in sheep liver, spleen, and kidney injuries with the use of CoStasis than with a fibrin sealant (p < .005) or a collagen sponge (p < .013).30 In heparinized sheep, the hemostasis times were similar between CoStasis and the fibrin sealant, but the overall blood loss was less in the CoStasis group. A randomized, controlled, multicenter study compared the use of sprayable CoStasis in 167 patients versus 151 control patients undergoing general, hepatic, cardiac, and orthopedic operations at 10 US medical centers.32 Hemostasis with collagen or gauze sponges was attempted in the control patients. Overall, hemostasis was achieved within 10 minutes in 92% of the CoStasis group compared with 58% in the control group (p = .01). In the cardiac surgical cohort, CoStasis treatment resulted in hemostasis within 10 minutes in 28 of 37 patients (76%) versus 17 of 37 patients (46%) in the control group (p = .02). The time to controlled bleeding and the time to complete hemostasis were also superior in the CoStasis arm of each surgical specialty investigated.32 CoStasis has also been used clinically to achieve more rapid and complete hemostasis of sternal edges and iliac bone grafts than was accomplished with conventional surgical techniques.33 Although CoStasis may be an alter-

native to the use of donor plasma–derived fibrin sealants, the risk of immunologic reactions to bovine antigens remains, and clinical experience and long-term data are lacking. Preparation time and cost must also be factored into the clinical equation. FloSeal Matrix consists of granular bovine collagen that is premixed with bovine thrombin and then delivered topically to a bleeding site. The granular collagen swells to tamponade bleeding, and the thrombin promotes local clot formation. The clot is reabsorbed naturally within 6 to 8 weeks. FloSeal has been used as a hemostatic agent in peripheral vascular surgery with good results in a small number of patients.34 A recent multicenter, prospective, randomized clinical trial compared 93 patients undergoing cardiac operations treated with either FloSeal or Gelfoam-Thrombin to control bleeding sites.35 In the FloSeal group, 48 patients had 104 bleeding sites treated, and in the Gelfoam-Thrombin group, 45 patients had 61 bleeding sites treated. Hemostasis was achieved within 10 minutes in 88% of the bleeding sites treated with FloSeal versus 57% treated with Gelfoam-Thrombin (p < .001) (Figure 3-5). The time to hemostasis was also shorter in the FloSeal group (p < .001).35 The advantages of this preparation include its ability to conform geometrically to the bleeding site, rapidity of preparation, and ease of delivery. CoSeal was approved by the FDA for use as a vascular sealant in December 2001. It is packaged as a dualsyringe system containing two distinct types of polyethylene glycol that polymerize rapidly into a clear hydrogel. The low-viscosity gel conforms to surrounding tissues, then polymerizes within seconds and adheres to tissues and vascular grafts to create a strong, flexible seal. The hydrogel is biodegradable and is broken down after 4 to 6 weeks. Unique among the hemostatic agents previously discussed, CoSeal contains no human or animal plasma products (Figure 3-6). Experimental studies have shown CoSeal to be effective in controlling suture hole bleeding at vascular graft anastomotic sites.36,37 In a multicenter, randomized, controlled clinical trial, CoSeal was compared with Gelfoam-Thrombin for hemostatic effectiveness in patients undergoing peripheral vascular surgery using polytetrafluoroethylene grafts.38 Seventy-four patients had anastomotic bleeding sites sealed with CoSeal, with a 10-minute sealing success rate of 86% versus 80% in 74 patients treated with Gelfoam-Thrombin (p = .29). However, immediate sealing (p < .001) and the time required for complete sealing (p = .01) were better in the CoSeal group.38 CoSeal is currently approved as a vascular sealant as opposed to a hemostatic agent. It should be applied to vascular anastomoses in a dry field, avoiding sites of active bleeding. This often requires either prophylactic use before

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 53

Control

FloSeal

1.00

Cumulative Proportion of Sites Still Bleeding

0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 0.0

2.0

4.0

6.0

8.0

10.0

12.0

Time (min)

FIGURE 3-5. Time to hemostasis for all bleeding sites treated with FloSeal versus controls (treated with Gelfoam-Thrombin). Adapted from Oz MC et al.35 p. 1379.

Component A

Reactive PEG +

Component B

Reactive PEG

In Situ Polymerization

T i s s u e

S e a l i n g

Hydrogel

removal of vascular clamps or reclamping of the vessel prior to application. BioGlue has been shown to reduce blood loss from experimental vascular graft anastomoses in heparinized sheep.39 Although clinical data on BioGlue as a hemostatic agent is scarce, clinical experience using BioGlue as an adhesive in aortic dissections is rapidly expanding. BioGlue was recently approved by the FDA for use as an adjunct to sutures and staples in cardiac surgery and vascular anastomoses. FocalSeal-L has been reported to decrease bleeding in a canine model of cardiac surgery. 4 0 FocalSeal-L is currently FDA approved only as a pulmonary sealant, however, and its ability to adhere to tissues is limited in the presence of even small amounts of blood.

Pulmonary Sealants

FIGURE 3-6. CoSeal Surgical Sealant. Two distinct types of polyethylene glycol (PEG) polymerize to form a hydrogel that adheres strongly to tissue or graft material. (Courtesy of Cohesion Technologies Inc.)

During thoracic surgical procedures, air leaks at sites of pulmonary injuries often result from surgical dissection, resection, retraction, and suture or staple trauma. Small parenchymal air leaks often seal within hours to days; however, prolonged air leaks, defined as persistent air leakage for ≥ 7 days, can lead to increased morbidity, longer hospital stays, and increased costs.41 There are many factors (ie, surgical technique, patient characteristics, postoperative chest tube management, and several adjuncts to conventional surgical techniques) that can affect the duration of air leaks after thoracic surgery.42,43 Controversy continues over whether stapled or sutured

54 / Advanced Therapy in Thoracic Surgery

closure, with or without reinforcement, offers any benefit in reducing the occurrence or duration of air leaks.42,44–47 Authors have advocated the use of water seal over suction and the early removal of chest tubes to decrease small air leaks and infection rates.42,48 Prolonged air leaks are seen in as many as 15% of patients after elective pulmonary resections and as many as 50% of patients after pulmonary volume reduction.42,49 Tissue sealants have been used as an adjunct to conventional surgical techniques in an attempt to decrease the incidence and duration of postoperative air leaks. Fibrin sealants have been used as pulmonary sealants for 20 years but with inconsistent results.50–58 This failure has been attributed to the relatively low tissue adherence of fibrin sealants. Tissue adhesives such as cyanoacrylate and GRF glue result in more extensive tissue adherence but may further injure the dynamic pulmonary tissue with volume changes. Also, the toxicity of these agents has precluded their routine use in pulmonary surgery.59,60 A recent experimental study in sheep showed that BioGlue was effective as an adjunct to conventional surgical techniques in sealing bronchial anastomoses and pulmonary parenchymal defects.60 FocalSeal-L is currently the only tissue sealant that is approved by the FDA to seal or prevent air leaks. It can also be used as an adjunct to staples or sutures to seal pulmonary parenchymal closures. It is not currently recommended for use on bronchial anastomoses or stumps. FocalSeal-L is a synthetic, water-soluble, bioabsorbable hydrogel. A primer composed of polyethylene glycol is first brushed onto the target site to prepare the tissue for adhesion. The sealant polymer is then gently brushed into the primer for mixing. A second layer of sealant is then applied over the target site in a thin layer. A xenon light wand is used to photopolymerize the sealant to solidify the gel (Figure 3-7). After polymerization the gel is adherent and elastic, which allows it to accommodate the dynamic nature of the lung. In experienced hands the application process takes 10 to 20 minutes. 61,62 Optimal application can be challenging, however, and a learning curve should be expected. The target site should be deflated and free of blood and active air leakage. The sealant should be applied as a thin layer without air bubbles. The primer and sealant are applied to the target site and 1 cm of surrounding tissue. In an experimental study, 10 dogs underwent thoracotomy and amputation of the lung apex.63 Dogs were then randomized to treatment with FocalSeal or no further treatment and were observed for 24 hours after surgery. All 5 control animals had persistent air leaks, whereas none of the 5 animals in the FocalSeal group had detectable air leaks immediately after surgery. Only 1 of 5 dogs in the FocalSeal group developed an air leak 17

hours after surgery. 6 3 Macchiarini and colleagues performed left upper lobectomy on 15 pigs, then randomized them to have the bronchial stumps either stapled (n = 5), sealed with FocalSeal (n = 5), or stapled and sealed with FocalSeal (n = 5).61 The divided fissure was stapled and sealed with FocalSeal in all animals. There were no air leaks in any of the pigs postoperatively. Histopathologic findings after the pigs were euthanized 6 weeks postoperatively showed similar healing and inflammation characteristics among the groups.61 This latter group also conducted a prospective, randomized clinical study in which pulmonary parenchymal surgical sites were treated with conventional closure plus FocalSeal (n = 15) or conventional closure alone (n = 11).61 None of the patients in the FocalSeal group had detectable air leaks intraoperatively, whereas only 18% of the control group was free of air leaks prior to chest closure (p = .001). In the FocalSeal group, only 23% had an air leak from the time of surgery until chest tube removal versus 91% of the control group (p = .001). However, there was no significant difference between the groups in the time to chest tube removal or the length of the hospital stay.61 Porte and colleagues randomized 124 patients undergoing lobectomies to treatment with conventional closure alone (n = 62) or conventional closure plus treatment of parenchymal surgical sites with Advaseal (Johnson & Johnson) (n = 62).64 In this study all patients had chest tubes removed after 6 days, regardless of the presence of air leaks. Four patients in the sealant group developed empyema and drained “infected surgical lung sealant.” Patients in the sealant group had fewer perioperative air leaks and shorter time from surgery until the last detectable air leak than did those in the control group;

FIGURE 3-7. FocalSeal-L pulmonary sealant system contents include a xenon light source and light wand and application devices for the primer and sealant. (Courtesy of Genzyme Biosurgery)

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 55

morbidity and cost. However, this has not been supported by any of the studies currently in the literature. FocalSeal appears to be safe, but its efficacy depends on the proper application, which can be tedious as well as difficult, especially in poorly exposed areas of the lung.

Biologic Glue The natural history of acute type A aortic dissection carries an extremely grim prognosis without surgery, with mortality rates of 38% in the first day and up to 120 Control (n = 55) FocalSeal (n = 177)

Patients without air leaks (%)

100

p = < .001

80

60

p = < .001 40

20

0 Intraoperative

From Wound Closure to Hospital Discharge

FIGURE 3-8. Percentage of patients without air leaks intraoperatively and from wound closure to hospital discharge for patients treated with FocalSeal-L versus controls. Adapted from Wain JC et al. 62 p. 1626.

12

p = NS T

Control (n = 55) 10

FocalSeal (n = 117)

8 Mean Time (d)

there was no significant difference in the length of the hospital stay.64 A major criticism of this study is the chest tube management, which may have contributed to the incidence of empyema and the extended hospital stay. Wain and colleagues reported a multicenter, randomized, controlled trial of patients undergoing pulmonary resection, comparing conventional closure with conventional closure plus treatment of all surgical sites at risk for air leak with FocalSeal-L.62 Each surgeon was trained in the proper application of FocalSeal, and each individual surgeon or institution determined protocol for chest tube management. Of the 117 patients in the FocalSeal group and the 55 patients in the control group, there was no statistically significant difference in the extent of prerandomization air leak. The FocalSeal group had no air leak detectable prior to chest closure in 92% of patients compared with 29% in the control group (p < .001). In the time from operation to hospital discharge, 39% of the patients in the FocalSeal group had no air leak versus 11% in the control group (p < .001) (Figure 3-8). The mean time from skin closure to the last detectable air leak was less in the FocalSeal group than in controls (30.9 ± 4.8 h vs 52.3 ± 11.6 h, respectively; p = .006). However, as in the previous studies, there was not a statistical difference between the groups in time to chest tube removal or length of hospital stay, although the trend favored the FocalSeal group (Figure 3-9). FocalSeal has also been used to seal air leaks that develop during cardiac reoperations. Fifteen patients that had air leaks recognized intraoperatively had the pulmonary injuries treated with FocalSeal. All leaks were controlled intraoperatively, and 73% of patients had air leaks recognized postoperatively. Three of four patients with a recurrent air leak had the air leak resolved in 3 days, but seal was never accomplished in one patient who was immunosuppressed.65 Interestingly, in all of the clinical trials, several patients appeared to have no air leak intraoperatively as assessed by submersion and controlled positive pressure ventilation, and then developed air leaks postoperatively. This may be due to improper application of the sealant or ineffective adhesion of the sealant to the pulmonary tissue. Another possibility is that negative intrathoracic pressure from suction on chest tubes postoperatively impeded closure of small air leaks. Some have therefore advocated the avoidance of suction on chest tubes unless there is both an air leak and a pneumothorax, with a goal of removing the chest tubes as soon as drainage is ≤ 20 mL/h (John C. Wain, personal communication, January 2003). The ability to seal most of the air leaks at the time of chest closure along with avoidance of chest tube suction may decrease postoperative chest tube duration and hospital stay, ultimately resulting in decreased

T

p = NS 6 4 2

T T

p = .006 T T

0 From Skin Closure to Last Observed Air Leak

From Skin Closure to Chest Tube Removal

From Skin Closure to Hospital discharge

FIGURE 3-9. Mean time to last air leak in patients treated with FocalSeal-L versus controls. NS = not significant. Adapted from Wain JC et al.62 p. 1627.

56 / Advanced Therapy in Thoracic Surgery

90% after 2 weeks from the onset of symptoms. The best chance of survival in patients with this disease depends on immediate diagnosis and emergent surgical intervention, although reported mortality after surgery remains 10 to 20%. The dissection is occasionally limited to the ascending aorta but often extends to the arch and descending aorta. Proximal extension of the dissection can involve the aortic valve or coronary arteries. The friability of the remaining proximal and distal aorta makes anastomosis extremely tenuous, and severe bleeding or re-dissection can complicate the repair. Many techniques to reinforce the aortic tissues have been advocated, including the use of pledgeted sutures or sandwiching the separated layers of the aortic wall with polytef strips prior to sewing on the graft. Several authors have attributed improvements in outcomes in their experiences to the use of biologic glues to adhere the separated aortic wall layers, thus reinforcing the tissues enough to hold sutures. The most frequently used biologic glue for this indication has been GRF glue. In 1977, frustrated by the poor prognosis of treatment for acute type A aortic dissection, Guilmet and colleagues began using GRF glue clinically to seal the layers of the aortic wall during the repair of acute type A aortic dissections.66 Since then many surgeons have used GRF glue in every case of acute type A aortic dissection. Although randomized, controlled studies in this patient population are impractical, surgeons advocating the use of GRF glue report that significantly decreased bleeding and simplification of the repair leads to decreased cardiopulmonary bypass times and improved overall survival. 67 Some continue to oversew and reinforce the native aorta with polytef strips in addition to using the sealant, whereas others have abandoned this technique and rely on the GRF glue to reinforce the aorta for suturing to the graft. Great care must be taken to avoid contamination of the lumen with glue, especially near the coronary ostia (Figure 3-10).68 Reports of glue emboli are infrequent, but these emboli can occur.69 GRF glue is not approved by the FDA owing to concerns about the toxicity of the formaldehyde component.70 Although GRF glue has been used extensively in Europe and several studies have reported the benefits, safety, and reliability of this sealant, recent reports of reoperations owing to aortic medial necrosis of sites previously repaired using this product are refocusing attention on its potential toxicity. Bingley and colleagues recently reported high rates of aortic regurgitation requiring reoperation in patients who had the aortic root reinforced with GRF glue with resuspension of the aortic valve. 71 Late aortic insufficiency occurred in 7 of 18 patients (39%), and 6 of these had re-dissection at the site of the GRF glue reinforcement. Histologic findings were

consistent with tissue necrosis at the site of glue use (Figure 3-11). Their conclusion was that this necrosis could be attributed to either an improper glue application A

FIGURE 3-10. A–C, Suggested technique to reconstruct the aortic root and proximal aortic arch using GRF glue. Gauze sponges are used to prevent intraluminal glue. Adapted from and B and C reproduced with permission from Laas J et al.68 p. 227.

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 57 Proximal Repair (with Glue)

Cannula to protect coronary ostia from glue embolization

Commissures are resuspended

Glue applied between dissecied layers

FIGURE 3-11. Photomicrograph showing re-dissected ascending aorta at site of GRF glue use consisting of dense acellular fibrous tissue with islands of hyaline material and widespread hemosiderin deposition (
200 original magnification). Reproduced with permission from Bingley JA et al.71

technique or tissue damage caused by the glue itself. Other groups have also attributed late re-dissections and false aneurysms to the use of GRF glue.72–74 BioGlue has been approved by the FDA since December 2001 for use as an adjunct to suture closure in the repair of aortic dissections. The elimination of formaldehyde and a reduction in the concentration of glutaraldehyde to 10% theoretically decrease the risks of tissue toxicity compared with those encountered with GRF glue.75 The applicator is rapidly available (Figure 3-12). Tissue and graft adherence occurs within 30 seconds, with firm adhesion in 2 minutes. The polymerization involves glutaraldehyde binding of bovine serum albumin molecules to each other and to proteins on cell surfaces and in the extracellular matrix. Although no randomized clinical trials have been performed using BioGlue, several researchers have advocated its use to enhance the suture-holding properties of the friable aortic tissues resulting from acute dissection, and they report improved outcomes with its clinical application.75–77 As with GRF glue, care must be taken to avoid intraluminal—especially intracoronary—contamination with BioGlue (Figure 3-13).

FIGURE 3-12. BioGlue applicator. (Courtesy of CryoLife, Inc.)

FIGURE 3-13. Suggested technique to avoid intracoronary contamination with BioGlue during proximal aortic root reconstruction. Soft balloon catheters protect the coronary ostia. Adapted from Raanani E et al.75 p. 640.

Recent reports have implicated BioGlue in redissection after successful aortic repairs with medial degeneration at sites of BioGlue application.78 The incidence has been sporadic, and it is difficult to determine whether medial degeneration is due to the original pathology or tissue toxicity from BioGlue. LeMaire and colleagues showed experimental evidence of strictures in sites of circumferential BioGlue application at vascular anastomoses. 7 9 Others have shown histopathologic evidence of inflammatory responses at sites where BioGlue was applied.80 Until long-term data are available, however, the risk-to-benefit ratio seems to favor the use of BioGlue to adhere the dissected aortic wall and both the proximal and distal aortic-graft anastomoses.

Summary Various biologic glues have been used in clinical situations when suture closure is unreliable or impossible. Fibrin sealant and other glues have been used to close complicated bronchopleural fistulas, directly and through thoracoscopic (Ross M. Reul, personal communication, March 2003), bronchoscopic, and transthoracic approaches, with mixed results.81–83 Postinfarction ventricular septal ruptures and free wall ruptures have been repaired with patches fixed to the friable, infarcted ventricular tissues with cyanoacrylate and GRF glues.84–87 In one study fibrin glue was used to reinforce esophageal anastomoses, without showing any benefit.88 Although these indications are not currently approved and the clinical studies are underpowered to confirm clinical superiority over conventional techniques, they reinforce the clinical versatility and potential usefulness of certain types of tissue glues in desperate situations.

58 / Advanced Therapy in Thoracic Surgery

Other potential indications under investigation include the use of tissue adhesives to avoid postoperative adhesions, allow the local release of pharmacologic agents, carry gene or protein therapeutic agents, or enhance endothelialization of prosthetic or tissueengineered grafts. The clinical utility of tissue adhesives has shown great promise over the past century. As the technology and experience with tissue adhesives continue to grow, we must expand our comprehension of the proper use and limitations of these agents to take full advantage of the clinical benefits they offer our patients.

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75. Raanani E, Latter DA, Errett LE, et al. Use of “BioGlue” in aortic surgical repair. Ann Thorac Surg 2001;72:638–40.

88. Fekete F, Gayet B, Panis Y. Apport de la colle de fibrine dans le renforcement des anastomoses oesophagiennes. Presse Med 1992;21:157–9.

76. Passage J, Jalali H, Tam RK, et al. BioGlue surgical adhesive—an appraisal of its indications in cardiac surgery. Ann Thorac Surg 2002;74:432–7.

89. Sierra DH. Fibrin sealant adhesive systems: a review of their chemistry, material properties and clinical applications. J Biomater Appl 1993;7:309–51.

CHAPTER 4

MULTIMODALITY MANAGEMENT OF EARLY-STAGE LUNG CANCER KATHERINE M.W. PISTERS, MD

benefit and will be reviewed in this chapter. Chemotherapy administered prior to surgery or definitive irradiation has improved survival for patients with stage III NSCLC. 2 – 5 The role of induction chemotherapy in patients with early-stage (stage I and II) NSCLC is currently under investigation.

For patients with early-stage nonsmall cell lung cancer (NSCLC), surgery remains the best treatment modality for potential cure. Unfortunately, at the time of initial presentation, the majority of patients with NSCLC have disease that is not amenable to resection. For patients who do undergo surgical resection with curative intent, the 5-year survival rates are disappointing, ranging from 67% for T1N0 disease to 23% for patients with T1–3N2 disease extent.1 The stage; tumor, node, and metastasis (TNM) subsets; and 5-year survival rates for clinical and pathologic staging are shown in Table 4-1. Efforts at improving survival for patients with resectable NSCLC have examined the use of combined modality therapy, employing chemotherapy and/or radiation in the postoperative (adjuvant) or preoperative (neoadjuvant or induction) settings. Until recently, randomized trials of adjuvant therapy have been disappointing, with the majority of trials demonstrating no survival benefit. However, recent data from randomized clinical trials has shown a survival

Part I: Adjuvant Therapy Radiation Although postoperative radiation has been associated with improved local control in patients with mediastinal nodal involvement,6 no trials have found an improvement in overall survival. Many of the trials of postoperative radiotherapy have not involved adequate numbers of patients to detect small but clinically relevant survival differences. A meta-analysis examining the effect of postoperative radiotherapy was published in 1998. 7 This analysis found a detrimental effect of postoperative radiotherapy for patients with completely resected NSCLC. A 21% relative increase in the risk of death associated with radiotherapy (absolute reduction in survival from 55 to 48% at 2 yr) was found. This effect was greatest for patients with earlier-stage disease or minimal nodal involvement. No patient subgroup defined by stage or nodal status showed evidence of a clear benefit from postoperative radiotherapy.7 Although a decrease in local recurrence was seen, the authors cautioned that this effect was small and was outweighed by the adverse effect of postoperative radiotherapy on survival. This metaanalysis must be interpreted with caution as many of the trials included used outdated radiotherapy techniques. At present, the use of postoperative radiotherapy should be restricted to those patients at highest risk for

TABLE 4-1. Survival Rates for Early-Stage NSCLC Based on Clinical and Pathologic Staging Stage

TNM Classification

IA IB IIA IIB

T1N0M0 T2N0M0 T1N1M0 T2N1M0 T3N0M0 T3N1M0 T1–3N2M0

5-Year Survival (%) Clinical

IIIA

Pathologic

61 38 34 24 22 9 13

67 57 55 39 38 25 23

Adapted from Mountain CF.1 NSCLC = nonsmall cell lung cancer; TNM = tumor, node, metastasis.

61

62 / Advanced Therapy in Thoracic Surgery

local recurrence (positive surgical margins, residual local disease, or selected patients with multiple lymph node involvement). Further research employing modern radiotherapy techniques, such as conformal radiotherapy or hyperfractionated radiotherapy, is warranted. Chemotherapy Initial trials exploring the use of postoperative chemotherapy were conducted in the 1960s and 1970s.8–12 No survival benefit was found; however, these early trials were flawed as factors such as histology, nodal involvement, performance status, age, and intraoperative staging were not considered in their design. Moreover, the chemotherapeutic agents studied had minimal activity in NSCLC. Platin-based Regimens Many NSCLC adjuvant chemotherapy trials have examined the efficacy of cisplatin-based regimens. Only those trials involving postoperative chemotherapy (and no radiation) are reviewed in this chapter. The Lung Cancer Study Group (LCSG) has conducted two postoperative chemotherapy trials. The first trial, LCSG trial 772, randomized patients with completely resected stage II and III adenocarcinoma and large cell cancer to receive postoperative CAP (cyclophosphamide, doxorubicin [Adriamycin], cisplatin [Platinol]) chemotherapy or immunotherapy (intrapleural bacille Calmette-Guérin and 18 mo of oral levamisole). 1 3 Disease-free survival was significantly prolonged in the CAP arm (p = .018); however, the overall survival difference, although increased by 7 to 8 months (median), was not statistically significant. The second LCSG trial enrolled patients with completely resected T2N1 and T2N0 NSCLC.14 This trial randomized patients to four courses of postoperative CAP chemotherapy or no postoperative treatment. No difference in time to recurrence or overall survival was found. CAP chemotherapy was also evaluated in a trial conducted in Finland. 1 5 This trial randomized 110 patients with completely resected T1–3N0 NSCLC to postoperative CAP chemotherapy for six cycles or no further therapy. In contrast to the LCSG studies, survival at 10 years in the chemotherapy arm was significantly better than for the control arm (61% vs 48%, p = .050). Twice as many pneumonectomy patients were assigned to the surgery-only arm, which may have influenced the results of this study. A trial conducted in Japan randomized patients with completely resected stage III NSCLC to postoperative vindesine and cisplatin chemotherapy versus control.16 There was no difference in disease-free survival or overall survival in this study.

Trials comparing postoperative chemotherapy with surgery alone were reviewed as part of a meta-analysis examining the role of chemotherapy in the treatment of NSCLC.17 The results showed considerable diversity and evidence of a difference in direction of effect between the predefined categories of chemotherapy (Table 4-2). The results for long-term alkylating agents were consistent. The hazard ratio estimates all favored surgery alone with a combined hazard ratio of 1.15 (p = .005). This 15% increase in the risk of death translated to an absolute detriment of chemotherapy of 5% at 5 years. For regimens containing cisplatin, the pattern of results was consistent with most trials favoring chemotherapy. An overall hazard ratio of 0.87 (p = .08), or a 13% reduction in the risk of death was found. The absolute benefit from cisplatin-based chemotherapy was 5% at 5 years. The trials that were classified as using other regimens were found to have an estimated hazard ratio of 0.89 in favor of chemotherapy (p = .30), but there was insufficient information to draw reliable conclusions. Since the time of the meta-analysis, data from six additional studies has become available which has clarified the role of postoperative adjuvant platin-based chemotherapy. A small trial from Japan randomized 119 patients with completely resected stage IIIA/N2 disease and randomized patients to postoperative vindesine and cisplatin chemotherapy for 3 cycles versus no further treatment. No significant differences in overall survival were seen.18 Investigators in Italy and the EORTC (European Organisation for Research and Treatment of Cancer) conducted a trial enrolling 1209 eligible patients with completely resected stage I to III NSCLC and randomized patients to postoperative mitomycin, vindesine and cisplatin chemotherapy for 3 cycles versus no postoperative chemotherapy. 19 Forty-three percent of patients received postoperative radiotherapy. In the ALPI (Adjuvant Lung Project Italy) trial, no significant difference in overall survival was seen with a hazard risk of death of 0.96, 95% confidence intervals (CI) 0.81–1.13, p = .589. The IALT (International Adjuvant Lung Trial) results were recently published and has been the largest trial of postoperative adjuvant chemotherapy in NSCLC conducted to date.20 This trial randomized 1867 eligible patients with completely resected stage I, II, and III TABLE 4-2 Meta-analysis: Postoperative Chemotherapy Category Alkylating agents Other drugs Cisplatin based

Hazard Ratio (95% CI)

p Value

1.15 (1.04–1.27) 0.89 (0.72–1.11) 0.87 (0.74–1.02)

.005 .30 .08

5-Year Survival (%)

Adapted from Non-small Cell Lung Cancer Collaborative Group.17


5 4 5

Multimodality Management of Early-Stage Lung Cancer / 63

NSCLC to postoperative cisplatin-based chemotherapy for 3 or 4 cycles versus no postoperative chemotherapy. In addition to cisplatin, patients received either etoposide, vindesine, vinblastine or vinorelbine. In this trial, 27% of patients also received postoperative radiation. This study found a 4% improvement in 5-year survival favoring chemotherapy. This corresponded to a hazard ratio of 0.86 (95% CI 0.76–0.98), with a statistically significant p value of < .03. The BLT (Big Lung Trial) was conducted in Great Britain and randomized 381 patients with completely resected stage I-III NSCLC to 3 cycles of postoperative cisplatin-based chemotherapy.21 In this study, 14% of patients received postoperative radiation. No significant differences in survival in the 1-year survival data presented. The NCIC (National Cancer Institute of Canada) presented the results of their phase III randomized trial of postoperative vinorelbine/cisplatin chemotherapy in 482 patients with completely resected stage IB and II NSCLC at the annual meeting of the American Society of Clinical Oncology (ASCO) 2004.22 This trial found a 15% improvement in the overall 5-year survival rate for those patients randomized to received 4 cycles of postoperative chemotherapy. The hazard rate was 0.70 (95% CI 0.52–0.92, p = .012). Also presented at ASCO 2004 was the results of the Cancer and Leukemia Group B (CALGB) randomized study of postoperative paclitaxel and carboplatin for 4 cycles versus no further therapy in 344 patients with completely resected stage IB (T2N0) NSCLC.23 Like the NCIC study, this trial found a marked benefit in favor of postoperative chemotherapy with a 12% improvement in survival at 4 years and a hazard rate of 0.62 (95% CI 0.41–0.95, p = .028). These recent trial results have now changed the standard of care for patients with completely resected NSCLC. Consistent reductions in the risk of death have been observed in recent platin-based adjuvant chemotherapy trials. Postoperative platin-based chemotherapy should be recommended to completely resected NSCLC patients with good performance status. UFT Regimens Studies examining the use of adjuvant oral fluorouracil derivatives have been conducted in Japan. These trials have examined the use of tegafur (FT) and UFT (Taiho Pharmaceuticals, Japan) (a combination of tegafur and uracil at a molar ratio of 1:4). The Chuba Oncology group examined the effect of one cycle of postoperative cisplatin and doxorubicin followed by oral UFT for 6 months on completely resected stage I to III NSCLC.24 This trial did not stratify for known prognostic factors,

and there was an imbalance with respect to pathologic N stage, with more advanced cases assigned to the combined modality arm (p = .018). On an intention-totreat analysis, the overall 5-year survival rate was 62% for surgery and chemotherapy versus 58% for surgery alone (not significant). A reanalysis of the data incorporating prognostic factors using the Cox proportional hazards model was performed, and a significant difference in overall and disease-free survival rates favoring the use of adjuvant chemotherapy was found (p = .044 and p = .036, respectively). Wada and colleagues also evaluated the use of UFT in the postoperative setting. 2 5 This trial enrolled 310 patients with completely resected NSCLC (stages I–III). After surgery patients were randomly assigned to receive one cycle of cisplatin and vindesine followed by oral UFT for 1 year (CVUFT), 1 year of oral UFT, or no postoperative therapy. The 5-year survival rates were 61% for CVUFT, 64% for UFT, and 49% for the control group (differences among the three groups: p = .053 by logrank test, and p = .044 by Wilcoxon rank sum test). Adverse effects were generally mild. The UFT administered in these studies was well tolerated and appeared to inhibit recurrence and prolong survival when administered over 6 to 12 months following surgery. The single largest trial studying the effects of postoperative UFT therapy in resected NSCLC was conducted in Japan. 2 6 This study randomized 999 patients with completely resected stage I adenocarcinoma to either oral UFT for 2 years or no postoperative treatment. There was a survival benefit favoring the use of UFT, p = .04. Toxicity was minimal in this group of patients. The results of a meta-analysis examining the effectiveness of postoperative UFT were presented at ASCO 2004.27 This meta-analysis included results from 2003 patients and was restricted to studies where patients received postoperative UFT only. In this meta-analysis, 95% of patients had stage I disease, 84% had adenocarcinoma, 45% were women, and the median age was 62 years. An overall benefit favoring the use of postoperative UFT was seen with a hazard rate of 0.74 (95% CI 0.61–0.88, p = .001). There is no confirmatory data concerning the use of UFT in the postoperative NSCLC setting outside of Japan. In addition, UFT is not available for use in the United States. Future trials of chemotherapy and surger y in resectable NSCLC will likely focus on the incorporation of targeted therapies and sequencing of modalities.

64 / Advanced Therapy in Thoracic Surgery

Part II: Preoperative Therapy Chemotherapy Numerous phase II trials of induction chemotherapy followed by surgery for stage III NSCLC have been conducted.28–31 These trials will be discussed more extensively in another chapter. In general, preoperative cisplatin-based combination chemotherapy is feasible and has higher response rates than have been previously seen in the metastatic patient population. Treatment has usually consisted of two to four induction chemotherapy cycles. Some of the trials included attempted postoperative chemotherapy and radiation. Major objective response rates following chemotherapy have been as high as 70 to 80%, with clinical complete responses occurring in approximately 10% of patients. Complete resection rates have ranged from 50 to 75%, and pathologic complete responses (no viable tumor found in the resection specimen) have been found in approximately 5 to 15% of patients treated. Those patients who have been found to have pathologic complete responses have been noteworthy for significantly prolonged survival.32 The median survival rates in these trials were similar around 18 to 25 months, with 5-year survival rates in the range of 25%. These figures compared favorably to historical controls. Two prospective, randomized trials comparing surgery alone with induction chemotherapy and surgery have been conducted in stage IIIA NSCLC.2,3 One study was conducted by Rosell and colleagues from the University of Barcelona and the other by Roth and colleagues at M. D. Anderson Cancer Center. Both studies enrolled a total of 60 patients (both trials were terminated early after interim analyses indicated a significant survival advantage in the chemotherapy arm). Cisplatin-based chemotherapy was administered in both studies, and both found a significant improvement in survival for patients treated with induction chemotherapy. Given the survival statistics following surgery alone and the lack of evidence to support postoperative therapy at that time, a multicenter phase II trial of induction chemotherapy followed by surgery was undertaken (the Bimodality Lung Oncology Team [BLOT] trial) in patients with early stage NSCLC. Patients with clinical stage IB (T2N0), II (T1–2N1, T3N0), and selected IIIA (T3N1) disease received perioperative chemotherapy consisting of paclitaxel (225 mg/m2, 3 h infusion) and carboplatin (area under the curve [AUC] = 6). The initial cohort of 94 patients received two preoperative chemotherapy cycles and three cycles after surgery and has been previously reported. 33 The BLOT trial had a second cohort of 40 patients treated with three induction and two postoperative chemotherapy cycles.34 There were no

differences in age, gender, race, stage, or performance status between the cohorts. The number of patients, major radiographic response rate and 95% confidence intervals to induction chemotherapy, operative mortality, and 1- and 3-year survival rates are listed in Table 4–3. This trial established the feasibility and safety of this approach with encouraging survival rates compared with historical controls.1,33,34 TABLE 4–3. Results of Phase II Bimodality Lung Oncology Team Trial Induction N Chemotherapy 2 cycles 3 cycles Total

94 40 134

Major Response (%) (95% CI)

Operative Mortality (%)

56 (46–67) 38 (23–54) 51

2 0 1

Survival (%) 1 Year 3 Year 86 83 85

64 NA 63

Adapted from Pisters K et al.34 NA = not available.

Based on the phase II BLOT experience, a phase III trial, (Southwest Oncology Group [SWOG] 9900), was initiated to compare the bimodality approach (induction paclitaxel and carboplatin plus surgery) to surgical resection alone in patients with early-stage NSCLC (Figure 4–1). The primary objective of this trial was to assess whether preoperative chemotherapy with paclitaxel and carboplatin for three cycles improved survival compared with surgery alone in previously untreated patients with clinical stage IB, II, and selected IIIA NSCLC. Secondary objectives include a comparison of time to progression, sites of relapse, operative mortality, and toxicity between the two study arms. The response rates and toxicities associated with the combination of paclitaxel and carboplatin will also be evaluated. The study planned to enroll 600 patients (300 in each arm) to detect an improvement of 33% in median survival, or increase in 5-year survival from 28 to 38%. Patients were stratified by clinical stage IB/IIA versus IIB/IIIA and randomized to induction chemotherapy followed by surgery versus immediate surgery.. All patients entered into the trial are to be followed for survival, recurrence, and toxicity data. Accrual to this trial was suspended in July 2004 after the results of the NCIC and CALGB adjuvant trials were presented. Total accrual reached 354 out of a planned 600 patients. No data regarding outcome is available at this time. Depierre and colleagues have reported the French experience of a phase III randomized trial of induction chemotherapy in early-stage NSCLC (stages IB, II, and IIIA).35 The aim of the study was to assess the impact of induction chemotherapy prior to surgery on survival. Three hundred fifty-five eligible patients were random-

Multimodality Management of Early-Stage Lung Cancer / 65

Center, no significant increases in operative morbidity or mortality were found based on clinical stage, pathologic stage, extent of resection, or protocol enrollment. 36 Investigators at Memorial Sloan-Kettering Cancer Center reported similar findings, with the exception that patients undergoing right pneumonectomy following induction therapy had increased operative risk.37

Eligible Patients

Stratification

(IB/IIA vs IIB/IIIA)

Conclusions Randomization

Paclitaxel/Carboplatin
3 Cycles

Surgery

Surgery

FIGURE 4–1. Treatment Schema used in Swog 9900 trial.

ized to surgery alone or combined modality therapy with two cycles of mitomycin, ifosfamide, and cisplatin followed by surgery. The arms were balanced for patient characteristics, with the exception that less clinical N2 patients were assigned to the surgery-only arm (28% vs 40%, p = .065). Surgical and survival results are displayed in Table 4–4. A nonsignificant excess of postoperative morbidity in the chemotherapy arm was seen (14% or 24/167 vs 13% or 22/171). The total number of treamentrelated deaths after surgery was 16 in the chemotherapy arm and 9 in the surgery-only arm (p = .16). In a subset analysis, the benefit of chemotherapy was confined to patients with N0 to N1 disease with a relative risk of death of 0.68 (95% CI 0.49–0.96, p = .027) for those patients. In addition, the estimated instantaneous risks of death in the two arms were not proportional over time, with an early crossing at around 5 months. Estimated relative risk of death within the first 5 months in the chemotherapy arm was 1.32 (95% CI 0.72–2.43, p = .37), although thereafter it became 0.74 (95% CI 0.56–0.99, p = .044). Therefore, after a nonsignificant excess of deaths in the combined modality arm during the treatment period, the effect of combined modality therapy after 5 months was significantly favorable on survival. No difference was seen in local recurrence rates; however, a significant decrease in distant metastases was seen favoring the chemotherapy arm relative risk 0.54 (95% CI 0.33–0.88, p = .01). Disease-free survival was significantly longer in the chemotherapy arm (p = .033). Concern that induction treatment may increase operative morbidity and mortality should be diminished by data from large surgical series. At M. D. Anderson Cancer

Surgery has long been the the cornerstone of therapy for patients with early-stage NSCLC. Recent data has established the role of postoperative platin-based chemotherapy in patients with completely resected disease and good performance status. Treatment involving induction chemotherapy prior to surgery has demonstrated improved survival in stage III disease. 2–5 The French phase III trial of induction chemotherapy in early-stage disease found an 11-month improvement in median survival and a significant decrease in the risk of death for patients with stage I or II disease.35 Data from additional international randomized trials of preoperative chemotherapy in early stage NSCLC is eagerly awaited. TABLE 4–4. Results of French Trial of Induction Chemotherapy in Early-Stage NSCLC No. patients eligible No. patients explored Survival Median (mo) 1 yr 3 yr

Surgery Alone

Induction Chemotherapy

176 174 (99%)

179 167 (93%)

26 73% 41%

37 (p = .15) 77% 52%

Adapted from Depierre A et al.35 NSCLC = nonsmall cell lung cancer.

References 1. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710–7. 2. Roth JA, Atkinson EN, Fossella F, et al. Long term follow-up of patients enrolled in a randomized trial comparing preoperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. Lung Cancer 1998;21:1–6. 3. Rosell R, Gomez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA non-small cell lung cancer: a 7year assessment of a randomized controlled trial. Lung Cancer 1999;26:7–14. 4. Dillman RO, Seagren SL, Herndon J, et al. Improved survival in stage III non-small cell lung cancer: seven-year follow-up of CALGB 8433. J Natl Cancer Inst 1996;88:1210–5.

66 / Advanced Therapy in Thoracic Surgery 5. Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group 88–08 and Eastern Cooperative Oncology Group 4588: preliminary results of a phase III trial of regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 1995;87:198–205. 6. The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected stage II and stage III squamous cell carcinoma of the lung. N Engl J Med 1986;315:1377–81. 7. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 1998;352:257–63. 8. Slack N. Bronchogenic carcinoma: nitrogen mustard as a surgical adjuvant and factor influencing survival. Cancer 1970;25:987–1002. 9. Higgins GA, Shields TW. Experience of the veterans administration surgical adjuvant group. In: Muggia FM, Bozencweig M, editors. Lung cancer: progress in therapeutic research. 11th ed. New York: Raven Press; 1979. p. 433–42. 10. Brunner KW, Marthaler T, Muller W. Effects of long-term adjuvant chemotherapy with cyclophosphamide (NSC2627,2) for radically resected bronchogenic carcinoma. Cancer Chemother Rep 1973;4:125–32. 11. Girling DJ, Stott H, Stephens RJ, et al. Fifteen-year followup of all patients in a study of postoperative chemotherapy for bronchial carcinoma. Br J Cancer 1985;52:867–73. 12. Shields TW, Higgins GA Jr, Humphrey EW, et al. Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung. Cancer 1982;50:1713–21. 13. Holmes EC, Gail M. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 1986;4:710–5. 14. Feld R, Rubinstein L, Thomas PA, and the Lung Cancer Study Group. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I NSCLC. J Natl Cancer Inst 1993;85:299–306. 15. Niiranen A, Niitamo-Korhonen S, Kouri M, et al. Adjuvant chemotherapy after radical surgery for non-small cell lung cancer: a randomized study. J Clin Oncol 1992;10:1927–32. 16. Ohta M, Tsuchiya R, Shimoyama M, et al. Adjuvant chemotherapy for completely resected stage III non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:703–8. 17. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995;311:899–909. 18. Tada H, Tsuchiya R, Ichinose Y, et al. A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304). Lung Cancer 2004; 43; 167–73.

19. Scagliotti SV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II or IIIA non-small cell lung cancer. J Natl Cancer Inst 2003;95:1453–61. 20. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. New Engl J Med 2004;350:3351–60. 21. Waller D, Fairlamb DJ, Gower N, et al. The Big Lung Trial (BLT): Determining the value of cispaltin-based chemotherapy for all patinets with non-small cell lung cancer. Preliminary results in the surgical setting [abstract 2543]. Proc Am Soc Clin Oncol 2003;22:632. 22. Winton TL, Livingston R, Johnson D, et al. A prospective randomised trial of adjuvant vinorelbine and cisplatin in completely resected stage IB and II non small cell lung cancer Intergroup [abstract 7018] JBR.10. J Clin Oncol 2004;22(14 Suppl):621S. 23. Strauss, GM, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633 [abstract 7019]. J Clin Oncol 2004;22(14 Suppl):621S. 24. Imaizumi M and The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chuba, Japan). A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). Eur J Surg Oncol 1995;21:69–77. 25. Wada H, Hitomi S, Teramatsu T, et al. Adjuvant chemotherapy after complete resection in non-small cell lung cancer. J Clin Oncol 1996;14:1048–54. 26. Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemothearpy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713–21. 27. Hamada C, Ohta M, Wada H et al. Survival benefit of oral UFT of adjuvant chemtoherapy after comletely resected non-small cell lung cancer [abstract 7002]. J Clin Oncol 2004;22(14 Suppl):617S. 28. Burkes RL, Ginsberg RJ, Shepherd FA, et al. Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small cell lung cancer: results of the Toronto phase II trial. J Clin Oncol 1992;10:580–6. 29. Darwish S, Minotti V, Crino L, et al. Neoadjuvant cisplatin and etoposide for stage IIIA (clinical N2) non-small cell lung cancer. Am J Clin Oncol 1994;17:64–7. 30. Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIA (N2) lung cancer: the Memorial Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993;55:1365–74. 31. Vokes EE, Bitran JD, Hoffman PC, et al. Neoadjuvant vindesine, etoposide, and cisplatin for locally advanced non-small cell lung cancer. Chest 1989;96:110–3.

Multimodality Management of Early-Stage Lung Cancer / 67 32. Pisters KMW, Kris MG, Gralla RJ, et al. Pathologic complete response in advanced non-small cell lung cancer following preoperative chemotherapy: implications for the design of future non-small cell lung cancer combined modality trials. J Clin Oncol 1993;11:1757–62. 33. Pisters KMW, Ginsberg RJ, Giroux DJ, et al. Induction chemotherapy before surgery for early-stage lung cancer: a novel approach. J Thorac Cardiovasc Surg 2000;119:429–39. 34. Pisters K, Ginsberg R, Giroux D, et al. Phase II Bimodality Lung Oncology Team trial of induction paclitaxel/carboplatin in early stage non-small cell lung cancer: effect of number of induction cycles, sites of relapse and survival [abstract]. Proc Am Soc Clin Oncol 2001;20:323a.

35. Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIA NSCLC. J Clin Oncol 2002;20:247–53. 36. Siegenthaler MP, Pisters KMW, Merriman KW, et al. Preoperative chemotherapy for lung cancer does not increase surgical morbidity. Ann Thorac Surg 2001;71:1105–12. 37. Martin J, Abolhoda A, Bains MS, et al. Long-term results of combined modality therapy in resectable non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 2001;20:311a.

CHAPTER 5

ANATOMIC PULMONARY RESECTIONS BY VIDEOASSISTED THORACIC SURGERY ROBERT J. MCKENNA JR, MD

Video-assisted thoracic surgery (VATS) has developed to the point at which standard thoracic procedures are being performed on a regular basis with minimally invasive surgery. Anatomic pulmonary resections by VATS have been developed in the hope of reducing morbidity, mortality, and hospital stay lengths, while allowing a quicker return to regular activities for patients after procedures that formerly required major incisions. There is mounting evidence that VATS procedures do have benefits over open procedures. This chapter describes the techniques and results of VATS pulmonary resections.

make an open procedure safer than a VATS approach. A sleeve resection is challenging but can be performed with VATS.2

General Approach for VATS Procedures The general technique used is similar for all major VATS pulmonary resections. Under one-lung general anesthesia, the patient is placed in a full lateral, decubitus position, as for a posterolateral thoracotomy. Good collapse of the lung is imperative to give the surgeon adequate exposure and enough room to operate in the closed chest. A double-lumen tube usually provides better lung collapse than does a bronchial blocker. The anesthesiologist stops ventilating the lung to be operated as soon as the patient is positioned and the surgeon goes to scrub. If the lung is not adequately collapsed when the surgeon looks into the chest, then suction with a catheter or bronchoscope in the main stem bronchus helps.

Indications and Contraindications Tables 5–1 and 5–2 show the indications and contraindications for a VATS lobectomy.1 If a tumor is > 6 cm, then it cannot be removed through the utility incision without the ribs being spread. Any process that produces inflammation or fibrosis, such as benign or malignant nodal disease or preoperative chemotherapy or radiation, may

Incisions The procedures are usually performed with either three or four incisions. The surgeon stands on the anterior side of the patient. The procedure starts with a 2 cm incision in the midclavicular line in the sixth intercostal space. Palpation through this incision confirms that there are no significant adhesions in the lower part of the chest. Either a finger or a ring forceps through this incision pushes the diaphragm away from the chest wall to make placement of the trocar safer by minimizing the chance of injuring the liver on the right or the spleen on the left. A trocar and thoracoscope are placed through the eighth intercostal space to obtain the optimal panoramic view of the thoracic cavity. This is in the midaxillary line

TABLE 5-1. Relative Contraindications for Video-Assisted Thoracic Surgical Lobectomy Nodal disease (benign or malignant) Chest wall or mediastinal invasion (T3 or T4 stage) Neoadjuvant chemotherapy Neoadjuvant radiation therapy Positive mediastinoscopy

TABLE 5-2. Indications for Video-Assisted Thoracic Surgical Lobectomy Clinical stage I lung cancer Tumor size ≤ 6 cm Benign disease (giant bulla, bronchiectasis)

68

Anatomic Pulmonary Resections by Video-Assisted Thoracic Surgery / 69

on the right side and slightly more posteriorly on the left to avoid the pericardium and pericardial fat pad. Preferred are the 5 mm thoracoscope because it causes less trauma than the larger scopes, and the 30
lens because it allows the surgeon to look around structures better than a 0
lens. The utility incision through which the surgeon performs the operation is in the midaxillary line. It starts at the anterior border of the latissimus dorsi muscle and proceeds anteriorly for 4 to 6 cm. This location avoids the long thoracic nerve that is located on the serratus anterior muscle 1 cm posterior to the anterior border of the latissimus. Precise placement of the location of this incision is important for the ease of performing a VATS resection. Through the midaxillary incision, a ring forceps retracts the lung posteriorly so that the superior pulmonary vein can be visualized. For an upper lobectomy, the utility incision is placed directly up from the vein. For a middle or lower lobectomy, the utility incision is made one interspace lower. The ribs are not spread for the procedure. A Weitlaner retractor holds the soft tissues of the chest wall open to facilitate passage of instruments into the chest, and so that suctioning in the chest does not create negative pressure that causes the lung to expand. A fourth incision is sometimes made in the auscultatory triangle. This allows retraction of the lung and provides a good angle for stapling some structures (Table 5-3). Localization of Lung Nodules by VATS Through an understanding anatomy and computed tomography (CT) scans, an experienced thoracic surgeon should be able to find almost all lung nodules. The lung is mobile and can be brought to a finger passed through the utility incision. Occasionally, preoperative localiza-

tion of a lung nodule with a wire is helpful when a lung mass is small (≤ 5 mm) or ≥ 2 cm below the pleura.3 Preoperatively, the radiologist places a hooked wire in the nodule. Complications from this procedure are rare. Wire localization has been performed more recently with the increasing use of screening CT scans that find tiny nodules that may be difficult to palpate.

General Technique for VATS Lobectomy A lobectomy should follow the same procedures whether it is performed with a thoracotomy or VATS, that is, an anatomic resection with individual ligation of vessels and the bronchus for the lobectomy and a lymph node dissection or sampling.1 Hilar Dissection Vessels in the hilum are dissected sharply through the utility incision with standard thoracotomy instruments such as Metzenbaum scissors and DeBakey forceps. Removal of hilar lymph nodes facilitates pathologic staging and enhances mobilization of vessels for transection with a nonarticulating endoscopic stapler (EZ 35, Ethicon, or Endo-GIA; US Surgical, Norwalk, CT). Spreading a right-angled clamp widely behind the vessel facilitates the passage of the stapler (Figure 5-1). Alternatively, the surgeon can place a tie around a vessel. A properly placed utility incision allows the surgeon to tie extracorporeal knots and follow the tie with a finger in the same fashion as for an open procedure. Stapling Devices The fissure, bronchus, and pulmonary vessels > 5 mm are transected with an endoscopic stapler (Figures 5-2–5-4). The vascular (20 mm) staples are used for the vessels, and the green cartridge (48 mm) staples are used on the

TABLE 5-3. Incisions through Which the Stapler Is Passed* Incision

Tissue to Be Stapled

Utility

Minor fissure RUL bronchus Inferior pulmonary vein Major fissure Minor fissure Lower lobe artery Inferior pulmonary vein Lower lobe bronchus Superior pulmonary vein Anterior trunk artery RML artery RML vein LUL bronchus

Midclavicular incision

Auscultatory triangle incision

LUL = left upper lobe; RML = right middle lobe; RUL = right upper lobe. *To transect the various structures that need to be stapled for a VATS lobtomy or pneumonectomy.

FIGURE 5-1. Right-angled clamp mobilizing the middle lobe vein. The clamp is widely spread to allow easy passage of the stapler.

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fissure and bronchus. Elevating the vessel with a tie may aid the placement of the stapler across the vessels. Articulation of the stapling devices is not necessary if the

incisions are placed optimally. Table 5–3 outlines which incisions offer the best angle for stapling the various structures in the chest. Completeness of the Fissure The vessels and bronchus are usually transected prior to completion of the fissure. The completeness of the fissure is therefore not a prerequisite for a VATS lobectomy.1,4 Specimen Removal To minimize the risk of contaminating the incision with the tumor, the lung specimens are removed in a bag. Wedge resections and the middle lobe fit in an Endocatch (US Surgical). The other lobes and the entire lung require the LapSac (Cook Urological, Bloomington, IN). It is rarely necessary to spread the ribs to remove the specimen.

FIGURE 5-2. Stapler placed across the middle lobe vein.

FIGURE 5-3. Stapler placed across the bronchus.

FIGURE 5-4. Completion of the fissure with the stapler after transaction of the vein, bronchus, and artery.

Lymph Node Dissection Either a mediastinal node sampling or a complete lymph node dissection can be performed by VATS. Kaseda and colleagues reported that lymph node dissection with a VATS lobectomy yielded an average of 23 lymph nodes (range 10–51). 5 A more complete paratracheal node dissection can be performed if the azygos vein is transected with an endoscopic vascular stapler. The pleura is incised anteriorly along the superior vena cava and posteriorly along the vagus nerve. All of the soft tissue is removed from the superior vena cava to the trachea and from the pulmonary artery to the innominate artery. Subcarinal node dissection begins with retracting the lung anteriorly with a ring forceps through the midclavicular incision. The pleura is incised along the vagus nerve and the intermediate bronchus from the inferior pulmonary vein to the azygos vein. The planes of dissection are then the intermediate bronchus, both main stem bronchi, the esophagus, and the pericardium. Clips are applied to any tissue that does not easily separate when spreading along the bronchus and pericardium. Care is taken not to injure the vagus nerve or the esophagus. Resection of level 5 and 6 nodes begins with incising the pleura from the superior pulmonary vein to the aorta, and incising the pleura along the superior pulmonary vein and along its most superior branch as it crosses the anterior trunk. The removal of the hilar tissue denudes the superior pulmonary vein and branches. The nodes and pleura are lifted to mobilize the tissue from the pulmonary artery (Figure 5-5). The planes of dissection are then the pulmonary artery, aorta, and pericardium. Care is taken to identify and preserve the vagus and recurrent nerves.

Anatomic Pulmonary Resections by Video-Assisted Thoracic Surgery / 71

stapler from the midclavicular incision then completes the fissure between the middle and lower lobes. The middle lobe is retracted superiorly. If there is a second artery, this manuever exposes the artery so that it can be tied. The bronchus is thus exposed for a stapler from the auscultatory traingle. This exposes the middle lobe artery, which can be tied or clipped. The final maneuver is stapling the minor fissure through the utility thoracotomy incision.

FIGURE 5-5. Level 10 nodes after the pleura has been incised along the superior vena cava, azygos vein, and hilum.

Simultaneous Stapling Lobectomy VATS lobectomy without individual stapling of the vessels and bronchus has been reported, 6 rather than individual ligation, as described. Most surgeons believe that a lobectomy should be performed with anatomic dissection whether the procedure is performed as an open or a VATS procedure.

Techniques for Specific Lobectomies Right Upper Lobectomy A right upper lobectomy begins with the dissection of the superior pulmonary vein. Removal of hilar nodes defines the middle and the upper lobe veins, which aids definition of the anatomy for completion of the minor fissure with the stapler. The completed minor fissure creates a pathway for a vascular stapler from the auscultatory triangle incision to the upper lobe vein. Removal of lobar nodes along the artery provides exposure of the arterial branches to the upper lobe. A vascular stapler from the auscultatory triangle transects the anterior trunk. Any additional, smaller arterial branches are tied or clipped. A stapler from the midclavicular incision further completes the minor fissure. This exposes the posterior ascending artery. A lymph node between the upper and intermediate lobe bronchi is removed. A stapler from the midclavicular incision is placed on the upper lobe bronchus. Finally, the remainder of the fissure is completed with the stapler through the midclavicular incision. Middle Lobectomy Middle lobectomy begins with hilar dissection to remove hilar lymph nodes and mobilize the middle lobe vein. The vein is small, so it can be tied, clipped, or stapled. A

Lower Lobectomy with Complete Fissure The approach for a lower lobectomy depends on the completeness of the fissure. The operation is simpler when the fissure is well developed. After opening the pleura, the artery is mobilized in the fissure and transected with a stapler through the midclavicular incision. Through the same incision, a stapler completes the major fissure to the level of the transected artery. The surgeon takes down the pulmonary ligament and harvests level 7 and 9 lymph nodes. Removal of the lymph node on the superior edge of the inferior pulmonary vein and incision of the pleura on the anterior aspect of the inferior pulmonary vein expose the vein for transection with a vascular stapler. Lobar nodes are removed, the bronchus is stapled, and the fissure is completed. Lower Lobectomy with Incomplete Fissure The operation for a lower lobectomy is different when the fissure is poorly developed. First, the pulmonary ligament is taken down and the inferior pulmonary vein is mobilized and transected as noted above. The fissure is completed between the middle and lower lobes. Superior retraction of the lobe exposes the bronchus. Dissection along the bronchus exposes the artery. Along the surface of the artery, a plane is created for the placement of a stapler to complete the fissure. Thus, the artery is exposed and transected. The lobar nodes are removed; the bronchus and the fissure are stapled. Left Upper Lobectomy The technique for a left upper lobectomy is similar to that for a right upper lobectomy. The approach begins anteriorly with a hilar dissection, stapling of the superior pulmonary vein, and stapling of the anterior trunk of the artery. A stapler through the midclavicular incision completes the major fissure between the lingula and the lower lobe to expose the lingular artery, which can be tied from an anterior position or stapled from a posterior position. The lobe is retracted superiorly to expose the bronchus. The most dangerous part of a left upper lobectomy is mobilization of the bronchus as a right-angled clamp is passed between the bronchus and the artery. After mobilization, the bronchus is stapled from a poste-

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rior position. The remaining branches of the artery are thus exposed. Dissection through the utility thoracotomy incision mobilizes these arteries to be tied or clipped. Finally, the fissure is closed with multiple firings of the stapler through the midclavicular incision. Left Lower Lobectomy A left lower lobectomy is performed with the same technique as is used for a right lower lobectomy. Pneumonectomy A pneumonectomy on either side is simpler than a lobectomy. The superior pulmonary vein is mobilized through the utility incision and stapled through the midclavicular or ascultatory incision. Lymph nodes are removed to expose the artery. Concern about the endoscopic stapler cutting without applying the staples on the vessel has led surgeons to use either an endoscopic stapler with the knife removed or a noncutting stapler. The inferior pulmonary ligament is taken down so that the vein can be exposed and stapled. Subcarinal nodes and pericardium are separated from the main stem bronchus to the level of the carina. Through the utility incision, a 30 mm TA stapler is then fired on the bronchus. If the apex of the lung is passed first through the incision, an entire lung can usually be removed through the same size incision as is used to remove a lobe.

Results of VATS Lobectomy Although there is no contemporary, randomized trial comparing VATS and open lobectomies, there is mounting evidence that a VATS approach offers the same operation with less morbidity and mortality. The literature suggests that concerns regarding the safety of the procedure appear to be unfounded. The acceptance of VATS lobectomy has been slow because of a lack of knowledge regarding the literature, the difficulty of performing VATS resections, and not enough training for the procedure. Results of VATS lobectomies and pneumonectomies published in several larger, published series compare favor-

ably with those expected with thoracotomies (Table 5-4).5–12 Seven (0.7%) deaths in 1,232 patients were caused by venous mesenteric infarct, myocardial infarction, respiratory failure, or unknown reasons. The incidence of complications in these series varied from 10.0 to 21.9% for patients after VATS lobectomy. Complications included the following: prolonged air leak (5–10%), arrhythmias, pneumonia, respiratory failure, the need for a transfusion (0–3%), and bronchial stump leak (0.36%). There is no contemporary randomized trial to compare VATS and open approaches for lobectomy. Clinical trials groups have discussed conducting such a trial, but investigators feel that it would not be feasable. Comparisons of series suggest that the VATS approach may have advantages. In the series shown in Table 5-4,5–12 complication rates are lower for the VATS procedures than in reported series for thoracotomy. One small, randomized trial showed a significant benefit that favored VATS. 1 3 Compared with patients who have undergone a thoracotomy, patients who have undergone VATS have better shoulder function,14 a better 6-minute walk, and less impairment of vital capacity.15 A VATS approach may be easier for older patients.16 Conversion to Thoracotomy Overall, conversion from VATS to a thoracotomy was necessary in 119 of 1,232 operations (9.7%).5–12 The incidence for the individual series was 0 to 19.5%. In 70% of the cases, the conversion to thoracotomy was prompted for oncologic reasons, such as centrally located tumors requiring vascular control, a sleeve resection, or unsuspected T3 tumors attached to the chest wall, diaphragm, or superior vena cava. There were also nononcologic reasons for conversion, such as abnormal, benign hilar nodes and pleural symphysis. Intraoperative Hemorrhage A major concern for VATS procedures is that trying to dissect a pulmonary vessel during a VATS procedure can lead to bleeding that is difficult to control with limited

TABLE 5-4. VATS Lobectomies and Pneumonectomies Study Lewis and Caccavale, 19986 Yim et al, 19987 Kaseda et al, 19985 Hermansson et al, 19988 Walker, 19989 Roviaro et al, 199810 Solaini et al, 200111 McKenna et al, 199812 Total

No. of Procedures 200 214 145 30 150 169 112 212 1,232

NA = not available; VATS = video-assisted thoracic surgery.

Incidences of Cancer 171 168 103 15 123 142 99 212 1,033

Incidences of Mortality (%) 0 1 (0.4) 1 (0.8) 0 3 (2) 1 (0.5) 0 1 (0.5) 7 (0.7)

Length of Hospital Stay (d) 3.07 6.8 NA 4.4 7.2 NA 5.8 4.6 5.28

Anatomic Pulmonary Resections by Video-Assisted Thoracic Surgery / 73

access. However, it appears that the risk is low when the operation is performed by surgeons experienced in VATS. At our institution, we keep a sponge stick available to immediately apply pressure to control hemorrhage if bleeding occurs. With the bleeding thus controlled, a decision is made as to whether a thoracotomy is needed. In these series, bleeding led to conversion to a thoracotomy in 10 cases (0.9%). No deaths resulted from the bleeding episodes, and not all patients required transfusion. A multi-institutional survey of 1,560 VATS lobectomies reported by Mackinlay found that the only intraoperative death was related to an intraoperative myocardial infarction, not bleeding.17

used for esophagectomy. A lobectomy is a complicated procedure that involves firing the stapler multiple times, so the addition of robotics technology would simply make the current procedure more complicated.

Postoperative Pain Several studies now suggest that patients experience less pain after a VATS lobectomy than after a lobectomy by thoracotomy.18–20 In patients who had a lobectomy done by VATS (n = 83) or by thoracotomy (n = 110), the VATS group averaged less morphine use than did the thoracotomy group (57 vs 83 mg of morphine, p < .001).18 In a randomized, prospective trial of lobectomy in 67 patients (47 by VATS and 23 by muscle-sparing thoracotomies), Giudicelli and colleagues reported that postoperative pain was significantly less (p < .02) after a VATS procedure. 1 9 The incidence of post-thoracotomy pain syndrome after VATS lobectomy (2.2%) is lower than expected after thoracotomy.1 A randomized trial showed that patients experienced less pain and greater shoulder strength in the first 6 months after VATS than after a thoracotomy, but there was no difference after 1 year.20

References

Tumor Seeding of the Incision In these series, seeding of the VATS incisions has occurred in 3 of 1,033 (0.3%) lobectomies performed for cancer. The risk of tumor recurrence in a VATS incision therefore appears to be low and can perhaps be even lower with the use of proper bags to protect the incisions during the removal of specimens.21 Adequacy of Cancer Operation Long-term disease-free survival is the ultimate measure for the adequacy of any cancer operation. After VATS lobectomy for cancer, 5-year survival has been reported as 76 to 94%.5–13 The cure rate for lung cancer does not seem to be compromised when a complete cancer operation is performed by VATS. The immunologic impact of a VATS lobectomy may be less than the immunologic impact of an open procedure.17 Robotics in Cardiothoracic Surgery In cardiothoracic surgery, robotics have been used primarily for cardiac procedures. The robot has been successfully

Summary In experienced hands, a VATS lobectomy appears to be a safe procedure with low morbidity and mortality rates that may be lower than those for a thoracotomy. A VATS is a complete cancer operation that offers patients at least the same survival as a lobectomy via a thoracotomy. The procedure is not for all tumors or all thoracic surgeons.

1. McKenna RJ Jr. VATS lobectomy with mediastinal lymph node sampling or dissection. Chest Surg Clin N Am 1995;4:223–32. 2. Santambrogio L, Cioffi U, De Simone M, et al. Videoassisted sleeve lobectomy for mucoepidermoid carcinoma of the left lower lobar bronchus: a case report [comment]. Chest 2002;121:635–6. 3. Mack MJ, Gordon MJ, Postma TW, et al. Techniques for localization of pulmonary nodules for thoracoscopic resection. J Thorac Cardiovasc Surg 1993;106;550. 4. Nomori H, Ohtsuka T, Horio H, et al. Thoracoscopic lobectomy for lung cancer with a largely fused fissure. Chest 2003;123:619–22. 5. Kaseda S, Aoki T, Hangai N. Video-assisted thoracic surgery (VATS) lobectomy: the Japanese experience. Semin Thorac Cardiovasc Surg 1998;10:300. 6. Lewis RJ, Caccavale RJ. Video-assisted thoracic surgical non-rib spreading simultaneously stapled lobectomy (VATS(n)SSL). Semin Thorac Cardiovasc Surg 1998;10:332. 7. Yim APC, Izzat MB, Lui HP, et al. Thoracoscopic major lung resections: an Asian perspective. Semin Thorac Cardiovasc Surg 1998;10:326. 8. Hermansson U, Konstantinov IE, Aren C. Video-assisted thoracic surgery (VATS) lobectomy: the initial Swedish experience. Semin Thorac Cardiovasc Surg 1998;10:285. 9. Walker WS. Video-assisted thoracic surgery (VATS) lobectomy: the Edinburgh experience. Semin Thorac Cardiovasc Surg 1998;10:291. 10. Roviaro G, Varoli F, Vergani C, Maciocco M. Video-assisted thoracoscopic surgery (VATS) major pulmonary resections: the Italian experience. Semin Thorac Cardiovasc Surg 1998;10:313. 11. Solaini L, Prusciano F, Bagioni P, et al. Video-assisted thoracic surgery major pulmonary resections. Present experience. Eur J Cardiothoracic Surgery 2001;20:437–42. 12. McKenna RJ Jr, et al. VATS lobectomy: the Los Angeles experience. Semin Thorac Cardiovasc Surg 1998;10:321.

74 / Advanced Therapy in Thoracic Surgery 13. Hoksch B, Ablassmaier B, Walter M, Muller JM. Complication rate after thoracoscopic and conventional lobectomy. Zentralblatt fur Chirurgie 2003;128:106–10. 14. Li WW, Lee RL, Lee TW, et al. Impact of thoracic surgical access on early shoulder function: video-assisted thoracic surger y versus posterolateral thoracotomy. Eur J Cardiothoracic Surgery 2003;23:390–6. 15. Nomori H, Ohtsuka T, Horio H, et al. Difference in the impairment of vital capacity and 6-minute walking after a lobectomy performed by thoracoscopic surgery, an anterior limited thoracotomy, an anteroaxillary thoracotomy, and a posterolateral thoracotomy. Surg Today 2003;33:7–12. 16. McKenna RJ Jr, Fischel RJ. VATS lobectomy and lymph node dissection or sampling in eighty-year-old patients. Chest 1994;106:1902. 17. Mackinlay TA. VATS lobectomy: an international survey. Presented at the IVth International Symposium on

Thoracoscopy and Video-Assisted Thoracic Surgery; May 1997; Sao Paulo, Brazil. 18. Leaver HA, et al. Phagocyte activation after minimally invasive and conventional pulmonary lobectomy. Eur J Clin Invest 1996;26 Suppl 1:210. 19. Giudicelli R, Thomas P, Lonjon T, et al. Video-assisted minithoracotomy versus muscle-sparing thoracotomy for performing lobectomy. Ann Thorac Surg 1994;8:712. 20. Landreneau RJ, Mack MJ, Hazelrigg SR, et al. Prevalence of chronic pain following pulmonary resection by thoracotomy or video-assisted thoracic surger y. J Thorac Cardiovasc Surg 1994;107:1079. 21. Downey RJ, McCormack P, LoCicero J III. Dissemination of malignant tumors after video-assisted thoracic surgery: a report of twenty-one cases. J Thorac Cardiovasc Surg 1996;111:954.

CHAPTER 6

RADIO FREQUENCY ABLATION OF THORACIC MALIGNANCIES SHARON THOMSEN, MD

Heat treatment of human disease with cautery of open wounds and ulcerating tumors has been reported and observed among many societies since prehistoric times.1,2 Currently, electrocautery, fulguration, and hot wire resection are popular methods used to treat superficial tumors, small cancers, and scar tissue adhesions found among various organ mucosal lumens and mesothelial surfaces. The advent and frequent use of endoscopic and laparoscopic techniques allow clinicians to explore the far recesses of the body to attack superficial lesions with minimally invasive procedures. In the past, thermal treatments of deep-seated lesions in solid organs have centered on total body or regional hyperthermia, in which tissue temperatures are raised to 42
C for hours, theoretically to kill heat-sensitive cancer cells while sparing the more heat-tolerant normal cells.3 Recent technologic advances in producing and controlling heat generation by different energy sources have sparked a new interest in using various delivery methods to produce sufficient heat in deep-seated tissues to thermally coagulate and lethally injure cells and tissues, including cancers. This treatment approach is called interstitial thermal therapy (ITT), and it uses energy sources such as lasers, radio frequency and microwave generators, and focused ultrasound transducers. Equally important to ITT are the exciting advances in diagnostic imaging, including ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), and the development of other feedback systems based on tissue temperature and electric-conductivity changes. These technologies allow real-time, high-resolution monitoring of thermal lesion formation to control lesion size and extent during treatment.4–9

The general therapeutic concerns of ITT regardless of the energy source include (1) distribution and extent of lethal thermal injury in the cancer and the surrounding tissues, (2) the delayed effects of the treatment on the cancer and the patient, and (3) noninvasive methods of determining therapeutic efficacy over time. The diagnostic imaging technologies described above have been found to be useful to monitor the post-treatment tissue effects, responses, and lesion resolution and to detect tumor eradication or recurrence over time. The successes and limitations of ITT are related to several engineering, physical, biologic, and medical factors. The energies of nonionizing radiations, such as light, microwave radiation, radio frequency radiation, and focused ultrasound, are transformed into heat by the interactions of the radiation or acoustic waves with the tissues.10–13 Therefore, the ultimate generation of heat energy in the tissue depends on the following: (1) the type of radiant or acoustic energy produced by the source instrument, (2) the physical mechanisms that transfer the energy from the source to the tissues, (3) the delivered energy power or current, (4) the geometry of the energy-delivery system, (5) the physical properties of the tissues limiting the deposition of the energy, (6) the mechanisms that transform the delivered energy to heat energy within the tissues, (7) the physical and physiologic properties of tissues that limit heat transfer within them, (8) the tissue and organ anatomy, and (9) the acute, intermediate, and delayed responses of the patient to thermal injury.1,14–17 Over the past 20 years, radio frequency interstitial thermal therapies (RF-ITTs) for treatment of primary and metastatic cancers in the liver or lung have been tested and reported in preclinical phantom and animal 75

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experiments, clinical case reports, and phase I clinical trials.4–6 The driving force for these new treatments has been the need to find new, relatively less invasive methods by which either cure or palliation of local pulmonary cancer growth could be accomplished in those patients who cannot tolerate the rigors of surgery or systemic chemotherapy. In these cases the therapeutic ideal is to destroy the tumor and a small margin of surrounding liver or lung tissue, while saving as much normal tissue and function as possible, thus not compromising the patient’s general health. Monopolar RF-ITT of a lung lesion was first reported in 1983.18 A conducting wire, 120 cm long, was woven into an unresectable 5 cm lung cancer, and radio frequency power at 5 MHz was applied for 1 hour. However, the tissue temperatures did not go above 42
C. The nature and extent of tumor necrosis were not reported at autopsy after the patient’s death of aspiration pneumonia 2 months after placement of the wire. However, it was noted that the surrounding noncancerous lung tissue appeared normal. Since that time, RF-ITT using needle monopolar electrodes has been used with reasonable success in the treatment of solid tumors in solid organs. The most experience and success has been in the interstitial thermal coagulation of primary and metastatic liver tumors (over 3,000 cases).19–21 It is with these tumors that the quirks of RF-ITT instrumentation, probe design, energy and heat distribution, and feedback mechanisms have been tested, modified, and validated as demonstrated in the excellent reviews of Goldberg and Dupuy. 4,5 The results of the liver applications have led to the production of reasonably reliable machines and delivery and feedback systems that are now being applied to other organs and tissues including the lung.

electrodes are configured to different geometries that govern the size and shape of the electric field and thus the heated treatment volume (Figure 6-1).7,11,22–24 Heat is generated by resistive dissipation (joule heat) owing to movement of charged molecules such as ions moving within the electric fields.4,10,11,25 The heated treatment volume is not determined only by the geometry of the electrodes but also by the electric and thermal properties of the tissue that limit the distribution of these energies within the tissues.7,8,18 It is to be remembered that the tissue electric and thermal properties change as the heated tissue desiccates (increasing impedance, decreasing electric conductivity, and decreasing heat transfer) during the interstitial treatment.11,15 Therefore, several modifications of the electrodes have been implemented to better control the creation of the electric field in the tissues, the thermal lesion size, and the uniformity of the heating process.4,26,27 The tissue effects of ITT including RF-ITT are due to heat production sufficient to raise tissue temperatures to a range of 60
to 90
C and maintain those temperatures for some time interval that results in lethal thermal damage to cells and tissues in the treatment volume. Lethal thermal damage is the thermal denaturation of proteins including enzymes, disruption of cellular membranes and organelles, and loss of vital functions, which lead to cell and tissue death.1,28 Effective tissue heating in ITT usually takes several seconds (for lasers) to several minutes (for radio frequency, microwaves, and focused ultrasound). These time intervals are characterized by the creation of heat gradients extending from the hot heat source volume to the cooler periphery. The extent of the gradients depends on the power delivered at the heat source, the thermal properties of the native and heated tissues, and the blood flow in living tissues leading to convective heat loss.14 If the volume heat

RF-ITT: Mechanisms of Tissue Heating and Electrode Design Radio frequency electromagnetic fields (usually ranging from 500 kHz to 500 MHz) are delivered into tissues by conductive electrodes (antennas) to form electric fields in the tissues. In monopolar applications an applicator electrode formed in some variation of needle arrays is inserted into the target tissue. The electric current disperses from the tips and sides of the exposed portions of the applicator electrodes to flow through the body tissues to the reference electrode, which is a relatively large sheet of conductive material electrically coupled to the skin surface (thighs or back) of the patient. The field strength at any distance around a single-volume-point electrode drops off proportional to 1/r2, and the power delivered is proportional to 1/r4. Therefore, the applicator

FIGURE 6-1. General configuration of radio frequency electrode probes being used in radio frequency interstitial thermal therapy. The applicator electrode probe diameters are usually about 17- or 18gauge trochars.

Radio Frequency Ablation of Thoracic Malignancies / 77

source is flat, parallel layers of damage zones develop along the heat gradient that extends perpendicularly from the hot surface to the cooler periphery of the underlying tissues. If the volume heat source is a point, then the zones of thermal damage form as concentric spherical bands extending from the hot center along the heat gradients that radiate from the hot center to form generally spherical, targetoid lesions. Cylindrical volume heat sources behave as a series of point sources along the long axis of the cylinders, thus producing elliptical thermal lesions (Figure 6-2).1,2,17,29–31 Distinct zones of pathologic thermal damage occur along these thermal gradients. The thermal damage zones and the mechanisms of their production have been described pathologically and are useful to map and measure thermal injury produced by various energy sources and delivery instruments. 31 Some markers of biologic thermal damage can be produced both in vitro and in vivo, but others can only form in living tissues with an intact blood flow and in animals and humans that survive (Table 6-1). In the past, the patient and cancer responses to ITT have been hard to detect and measure clinically without some kind of destructive diagnostic intervention such as biopsy or excision. 30 Practically, the most important histopathologic treatment marker to determine efficacy at the time of treatment is the detection of the outer boundary of the red thermal damage zone in the thermal lesion. This boundary has been demonstrated to coincide with the boundary of tissue necrosis, the “gold standard” of tissue death, 2 to 4 days after heating. This coincidence has been demonstrated in several different tissues in numerous vertebrate species, including humans.2,32 Other histopathologic methods of determining lethal thermal damage have included using vital dyes to indicate tissue viability and immunohistochemistry to detect proteins associated with the cell cycle. But, these procedures have their limitations, including the need to extract tissue by biopsy or excision to map tissue death and some-

what cumbersome, multistep techniques.33–35 Vital dyes that depend on the oxidation-reduction reactions of certain mitochondrial enzymes are useful to delineate relative lethal thermal damage. However, besides requiring tissue, the dyes have to be applied to fresh tissue immediately after removal from the body. False-positive reactions can occur because some moribund cells still contain active mitochondrial membrane fragments at the time of staining but die later. False-negative reactions can result from allowing the tissues to sit at room temperature for ≥ 1 hour prior to staining, the “magic time” during which the mitochondrial enzymes remain active after severing of the blood supply.2,31,33,34,36–38 Immunohistochemistry is based on the use of specific antibodies that bind with specific cellular or tissue antigens. Thermal coagulation of a protein may not destroy its antibody-binding site; therefore, there can be an immunologic localization of the antigen in dead tissues. I have observed that immunologic localization of cell cycle proteins in thermally coagulated tissues does not imply viability.

FIGURE 6-2. Heat gradient vectors and zones of heat damage from different volume heat sources.

TABLE 6-1. Thermal Damage Zones In Vitro/In Vivo

In Vivo Only

Survival Only

Ablation: removal of tissue solids

Red thermal damage: thrombosis, hemostasis, hemorrhage, hyperhemia Tissue lytic necrosis: enzymatic degradation of tissues

Tissue lytic necrosis: outer boundary established at 2–3 d Wound healing: organization begins at 3–5 d, vascular and fibrous granulation tissue formation begins at 4–6

Carbonization of tissue: carbon formation at tissue/electrode interface d,

fibrous scar tissue formation begins at 5–7 d Tissue water vaporization; steam vacuole formation, tissue desiccation Structural protein denaturation: cell shrinkage, cell hyperchromasia, collagen hyalinization, collagen birefringence loss Vital enzyme protein denaturization: loss of vital enzyme function

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Pathologic Processes and Interpretation of Diagnostic Images: Suggested Correlations Fortunately, recent advances in CT, MRI, and ultrasonographic imaging are suggesting that almost real-time imaging for monitoring thermal treatment is possible.4,8,39–41 The addition of contrast agents that enhance pathophysiologic events occurring as a result of the interstitial heating may prove to be useful in the near future. The few pathologic and image comparison studies done in the past have been helpful, but more work has to be done because image resolution has improved allowing more accurate correlation to pathologic events. The ultrasonographic, MR, and CT image changes reported to be characteristic of the thermal lesion in ITT have been related to the development of the peripheral red damage zone in the treatment field. This damage zone is formed by hemostasis, thrombosis, hyperhemia, edema, and hemorrhage at the edge of the treatment field. The outer damage zone image changes gradually diminish over the following few days, probably due to the resolution of the hyperhemia and edema in these peripheral, surviving tissues. In contrast, the images of the lethally damaged cancer and adjacent tissues remain approximately the same size for a few weeks after treatment because of the persistence of the peripheral damage zones formed by hemostasis, thrombosis, and hemorrhage that surround the more central volumes of lytic and thermal coagulation necrosis.31 Ultimately, organization and wound healing of the necrotic lesions are associated with gradual diminution and possible disappearance of the abnormal image.Wound healing generally originates from the viable peripheral tissues with the infiltration of macrophages and inflammatory cells to clean up the necrotic tissues (wound organization). Early lytic necrosis in the peripheral lesion first occurs as the result of the release of proteolytic lysosomal enzymes from the heat-damaged cells. On the other hand, lytic necrosis of the central thermal coagulum depends on the resumption of blood flow into the coagulum and the delivery of inflammatory cells with their proteolytic enzymes from the outside because the thermally denatured, intrinsic lytic enzymes of the cells of the coagulum no longer function. Therefore, neovascularization (vascular granulation tissue formation) also originating from the periphery provides a constant supply of inflammatory cells to the necrotic tissues over time. Because of these complicated cellular logistics, total organization of the whole coagulum can take several weeks to complete. As neovascularization and wound organization progress across the necrotic zones, they are soon followed by fibrous granulation tissue formation replacing the necrotic tissue.

Last, fibrous scar tissue forms. The early stages of wound healing are slow; thus, the image does not seem to change in size until some of the bulk of the necrotic cancer and tissue is removed during early organization and granulation tissue formation. Later the fibrous scar tissue undergoes remodeling and contraction with further shrinkage of the lesion as long as there is no recurrence of the cancer.32,42 Because of the persistent image density due to the slow events of organization and healing of the wound, the detection of recurrent cancer, especially cancer within the treatment field, using currently available imaging techniques is possible but fraught with problems. Diagnostic CT and MRI with or without contrast can be helpful. 4,5 Accurate interpretation is enhanced by the availability of previous pre- and post-treatment images for comparisons. If the outer boundary of the treatment lesion shows increased irregularity and/or size, then cancer recurrence should be suspected. At this time, confirmation of recurrent cancer is best accomplished by biopsy showing viable cancer cells or, in those institutions with the facilities, PET scans demonstrating new cancer growth. However, biopsies, especially fineneedle biopsies, are hampered by false-negative results because of sampling error.35 In addition, false-positive histologic identification of “viable” cancer cells in the central thermal coagulum is all too frequent. Thermal coagulation “fixes” the cells by denaturation and deposition of all proteins in situ. In addition, nuclear deoxyribonucleic acid and nuclear and cytoplasmic ribonucleic acids are codeposited in situ with their associated proteins. These substances still react with histologic dyes such as hematoxylin and eosin; thus, the cells of the central coagulum appear to be normal or viable at the light microscopic level. However, transmission electron microscopy shows coarse aggregation of the denatured proteins and cytoplasmic organelles, clumping of chromatin, and rupture of cellular membranes, all providing unequivocal structural evidence of dead cells (Figure 6-3). False-positive interpretations of PET scans can result because of the increased metabolism of the rapidly proliferating cells in the granulation tissue at the periphery of the healing lesion.5,27

RF-ITT of Malignant Lung Tumors in Humans RF-ITT of malignant lung tumors, that is, the thermal coagulation of primary and metastatic lung cancers for cure or palliation, is in its early stages. Nearly all the literature on the treatment of human lung cancer consists of case reports or small series (Table 6-2).18,40,43–52 Nearly all cases involved patients who had unresectable or multiple lung cancers or who could not tolerate the rigors of surgical resection, full field ionizing irradiation, or chemotherapy because of seri-

Radio Frequency Ablation of Thoracic Malignancies / 79

ous pulmonary and/or systemic disease. Treatment efficacy, that is, ablation of individual cancers, has been reported in some patients establishing that local control of cancer growth can be achieved using RF-ITT. One case reported a patient who enjoyed significant relief of signs and symptoms of hypertrophic pulmonary osteoarthropathy after RF-ITT debulking of a 5 cm primary lung carcinoma, thus demonstrating the potential usefulness of RF-ITT for palliation of symptoms and lesions owing to paraneoplastic syndromes.46 The most frequent complications were mild pneumothorax, which did not require any interventional treatment, and symptoms of pleurisy. The most severe complication involved massive pleural and intrapulmonary hemorrhage that occurred during RF-ITT in a patient who had a drug-induced platelet dysfunction. This patient eventually suffered a myocardial infarction and aspiration pneumonia, and died 28 days after treatment.52 Another potential but yet not documented complication is suggested by the detection of microbubbles in the carotid arteries of three patients during RF-ITT. Neurologic examination and clinical follow-up did not reveal any neurologic deficits in these patients.49 Reported patient deaths were associated with progression of cancer, stroke, and/or pneumonia. However, one must remember that most of these patients had severe morbidities owing to pulmonary or systemic noncancer-

related diseases or were at risk for death owing to the progression of their cancer. Some follow-ups after treatment were very short, patient selection criteria varied, and at least four different radio frequency instruments and treatment protocols were followed. Therefore, treatment efficacy cannot be determined and treatment protocols cannot be recommended at this time. However, several pilot clinical series mainly testing safety and therapeutic efficacy are just beginning; therefore, more definitive knowledge will be available about the usefulness and reliability of this treatment approach in the next few years. Prospective phase II and III clinical protocols will have to include well-defined patient selection and treatment end point criteria to make comparisons and treatment recommendations.

Current Clinical RF-ITT Instruments: Lessons from Instrument Design The geometric configurations of the radio frequency treatment probes have been dictated by the following: (1) the general shape and volume of the target cancers, (2) the need to encompass all of the target tissue within the electric current, (3) the requirement to maintain uniform electric current and heat generation within the target volume during the treatment interval, (4) the need to minimize

FIGURE 15-3. At the level of light microscopy, normal rat liver cells (A) are similar to the slightly shrunken, hyperchromatic “heat fixed” cells of the central thermal coagulum (C). Red blood cells in liver sinusoids to the left in image C have ruptured and lost their hemoglobin, but the hemoglobin has been thermally denatured and fixed in situ in the more central portion of the thermal coagulum (right). However, transmission electron microscopy reveals the distinct architecture of normal liver cells (B) to be obliterated by the granular aggregates of coagulated nuclear contents and membranes (arrows), cytoplasmic organelles, and cytosolic contents of the cells from the central thermal coagulum (D). The intact red blood cells (arrowheads) still contain their hemoglobin in the normal liver (B), whereas membrane fragments (arrowheads) are all that are left of red blood cells in a sinusoid lumen in the central thermal coagulum (D). (A and C, 630 original magnification; stained with hematoxylin and eosin. B and D, 1,000 original magnification; stained with lead citrate and uranyl acetate)

80 / Advanced Therapy in Thoracic Surgery TABLE 6-2. Studies of Treatments with Radio Frequency Interstitial Thermal Therapy Study

Patient Characteristics

Electrode Configuration

Response/Follow-Up Time

Libby et al, 198318

Pt with primary lung cancer

Died of disease/2 mo

Dupuy et al, 200040

Pt 1: 45-yr-old male, recurrent primary adenocarcinoma; Pt 2: 66-yr-old female, primary adenocarcinoma; Pt 3: 58-yr-old female, metastatic breast carcinoma

Interwoven wire in tumor Cooled parallel array

Zagoria et al, 200145

52-yr-old man, metastatic renal cell carcinoma 69-yr-old male, metastatic adenocarcinoma 73-yr-old male, primary adenocarcinoma

Highland et al, 200246 Kishi et al, 200247

Rose et al, 200250

Marchand et al, 200248 Vaughan et al, 200253

“Radio frequency probe” Pulsed, cooled parallel array Radial rayed electrodes

Pt 1: 52-yr-old female with Radial rayed metastatic rectal adenocarcinoma; electrodes Pt 2: 66-yr-old male with metastatic 6 cm squamous carcinoma from esophagus; Pt 3: 59-yr-old female with 2 primary nonsmall cell carcinomas 64-yr-old man with metastatic Radial rayed squamous cell carcinoma electrodes 70-yr-old man with multiple NA adenocarcinoma in both lungs with history of easy bruising

Steinke et al, 200252

Female, metastatic leiomyosarcoma

Nishida et al, 200249

6 pts: 4 with metastatic carcinomas, 2 with metachronous lung cancer

Schaefer et al, 200351 73-yr-old male with peripheral squamous cell carcinoma Herrera et al, 200351 33 tumors in 18 pts: metastatic adenocarcinoma (n = 8), metastatic sarcoma, primary (n = 5)

Complications/Comments

RF-ITT 60 min at 42
C; “viable cancer cells present in primary at autopsy” Pt 1: ?residual disease at 3 mo, 1/3 pneumothorax, retreated with RF-ITT; 3/3 post-treatment elevation Pt 2: received external beam in temperature, irradiation after RF-ITT, died of 3/3 mild pleurisy, unknown causes 10 wk after 1/3 pneumonia treatment completed, autopsy refused; Pt 3: NED (PET) 3 mo after RF-ITT 16 mo NED (CT scan) “Tiny” pneumothorax, pleural cutaneous fistula that spontaneously closed NED 12 mo (CT scans) No complications, 3–4 cm “denatured” lung around tumor ?disease at 2 mo (CT scan) Post-treatment fever, mild pneumothorax mild pleurisy, cancer debulked for painful hypertrophic pulmonary osteoarthropathy with lower leg edema; partial response of symptoms, leg edema, and Tc 99m MDP–positive lesions around knees NED at 21, 18, and 10 mo, Prospective study to see if gas respectively microemboli were formed during RF-ITT; they were found but pts had no CNS symptoms; no discussion about cancers

Recurrence at 12 mo (CT scans) NA

No complications, cavitation in mass

Massive intrapulmonary and intrapleural hemorrhage 2 h into RF treatment; angiography did not reveal site of hemorrhage; Pt had been taking clopidogrel, a potent platelet aggregation inhibitor; 8 d post-treatment pt had MI, and 23 d later pt died of aspiration pneumonia Radial array 4d Histopathology of lung cancer, and tumor electrode removed 4 d after RF-ITT confirmed complete with central thermal coagulation lethal thermal injury (fixation) of tumor Radial array 5 pts NED 195–653 d after Mild pneumothorax in four pts; the pt electrode RF, 1 pt alive with disease alive with disease had no enlargement (CT scans) of treated tumor but did have progression of other pulmonary tumors at 287 d Radial array 1 mo 1 mo after procedure, pt had stroke; electrode autopsy showed complete necrosis of tumor Radial array Average: 6 mo; range: 7/13 percutaneous procedure–related electrode; approach: 1–10 mo (CT and PET scans) pneumothorax, 1/18 delayed minithoracotomy pneumothorax, 4/18 (n = 5), pneumonitis/pneumonia, 9/18 small percutaneous pleural effusion, 1/18 transient renal failure treatment (n = 13) Pts with tumors < 5 cm (n = 12): 1 complete response, 7 partial responses, 5 alive and NED, 3 alive with disease, 4 died of disease Pts with tumors > 5 cm (n = 6): 1 alive and NED, 1 alive with disease, 4 died of disease.

CNS = central nervous system; CT = computed tomography; MI = myocardial infarction; NA = not available; PET = positron emission tomography; pt = patient; RF-ITT = radio frequency interstitial thermal therapy; Tc 99m MDP = technetium 99m Tc medronate.

Radio Frequency Ablation of Thoracic Malignancies / 81

peripheral tissue damage around the cancer, and (5) the need to prevent distant thermal injuries (burns) associated with the delivery trochars and reference electrodes.7,8,11,27,40,53 Currently, three different delivery probes are being tested in humans for applications in the lung. Their basic designs, first applied and tested in liver lesions, include arrays of multiple, parallel, internally cooled needle electrodes that can deliver continuous or pulsed current (Radionics, Inc., Burlington, MA) and two instruments composed of radial antenna arrays of thin metal tines deployed within the target tissue (RITA Medical Systems, Inc., Mountain View, CA, and Boston Scientific/ RadioTherapeutics, Inc., Mountain View, CA). The deployed tines expand to assume either flared, conical (RITA) or umbrella-shaped (RadioTherapeutics) antennas.4,5,21 The parallel needle electrodes in the Radionics instrument are cooled to prevent desiccation, formation of water vapor bubbles, and carbonization in tissues adjacent to the needle. These pathophysiologic changes are responsible for an early, sudden increase of tissue impedance that signals a marked decrease in electric current conduction, thus decreasing the electric field and treatment volumes. The diameters of the treatment lesions have increased from about 3 to 7 cm upon the use of the cooled parallel needle electrodes.26 More recently, the Radionics instrument has been modified to deliver pulsed radio frequency as well as continuous radio frequency currents.27 All these modifications are used to cool the tissue to allow larger electric fields to be created farther from the electrodes. Attempts to obtain larger lesions have included infusion of small amounts of saline solution around the application electrode during RF-ITT.53–55 The saline solution maintains a “wet,” conductive environment that allows the persistence and enlargement of the electric field around the electrode. Larger thermal lesions have been produced in livers and lungs of experimental animals receiving the infusion when compared with lesions in animals with no infusion. However, when tested in rabbit lungs, treatment-related complications were more frequent in the infused group (55.6%) than in the noninfused group (20%). These observations suggest that saline infusion during pulmonary RF-ITT may have deleterious effects because the saline might leak into air spaces away from the desired treatment volume and prevent careful control of the thermal lesion size and extent. The electric fields produced by the radial arrays of ray electrodes (antennas) extend from the tine tips as well as the exposed ray tines themselves to fill oval to umbrellashaped treatment volumes. Thermal lesion size is controlled by using different-sized electrode arrays, multiple placements and deployments of the electrodes within and at the periphery of the cancers, and repeated applications of radio frequency energy.

Automatic feedback systems are needed to control the thermal lesion size and extent to vital structures and to make sure the proper tissue temperatures for coagulation are obtained. The feedback systems being used currently involve a sudden increase in impedance (and decrease of electric conductivity) owing to tissue desiccation in the Radionics and RadioTherapeutics instruments, or tissue temperature elevations to 90
C recorded by thermistors embedded in the electrode tips of the RITA electrode. Once the selected thresholds are reached, the power is turned off automatically, although most machines can be switched to a manual mode if needed. Currently most of the above instruments produce acceptable therapeutic thermal lesions over several minutes depending on the physical properties of the tissues and the configurations and placements of the electrodes.

Anatomic and Pathologic Considerations of RF-ITT: Observations from Preclinical and Clinical Experiences The more complete preclinical animal studies of RF-ITT performed in surviving animals with experimental tumors generally indicate good treatment responses with eradication or partial eradication of the cancers.55,56 However, survival follow-up including diagnostic imaging and pathologic studies of RF-ITT lesions in lungs from normal and tumor-bearing animals reveal that important factors in the acute and survival treatment effects of RF-ITT are (1) the functional anatomy of the lungs, (2) the location of the thermal lesion, (3) the proximity of other tissues and organs to the heating volume, (4) the electric properties of the air-filled lung tissues surrounding the solid tumors, and (5) modifications of radio frequency–delivery probes and treatment environments.40,54,55,57 Large blood vessels and bronchi enter into the hila of the lungs and gradually decrease in size as they branch into the lobes, segments, and peripheral pulmonary parenchyma.58,59 Pathologic and imaging studies in rabbits treated with CT-guided percutaneous RF-ITT showed that small and large pneumothoraxes were associated with both central and peripheral thermal lesions.52,55–57The small pneumothoraxes, which were not treated, produced no symptoms, but the large ones were associated with considerable morbidity in the animals. To date no massive pneumothorax has been reported in human patients. Thermal injury and persistent fibrous scarring of lung parenchyma and pleura of adjacent lobes and thoracic walls have been found in surviving animals and patients. The injuries were detected clinically by patient complaints of pleuritic pain, diagnostic images showing acute and

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chronic inflammatory changes in the pleura, and pathologic findings of pleuritis and pleural fibrosis at autopsy. Gross and microscopic pathologic evaluations of RFITT lesions in normal pigs demonstrate the role of anatomy in the production of the complications of RFITT in the lung.42 Radial array electrodes were introduced into the lungs through thoracotomy incisions without continuous image guidance and followed for intervals up to 28 days. Upon removal, the lungs were fixed by perfusion though the bronchi with 10% buffered formalin. Pulmonary hemorrhage and vascular thrombosis within and around the thermal lesions, pulmonary infarction, and chronic pulmonary atelectasis distal to the thermal lesions were related to specific anatomic structures. Pathologically, the acute pig thermal lesions were similar to those seen in the rabbits by other investigators with a central, light-colored, thermal coagulum and a peripheral red rim of hemorrhage, thrombosis, hyperhemia, and hemostasis (Figure 6-4).54,55,57 At 3 days after treatment, the red rim and central coagulum was prominent. In some lesions the distal portion of the red rim was partially obscured by segmental pulmonary hemorrhage distal to thrombus-occluded pulmonary arteries and veins (Figures 6-5 and 6-6). By 7 days the boundary between the thermal lesion and the surrounding normal tissues was formed of inflammatory infiltrates, wound organization, and granulation tissue formation, with these healing reactions originating from the viable tissues surrounding the lesions (Figures 6-7 and 6-8). A wedge-shaped hemorrhagic pulmonary infarction was associated with occlusive thrombosis of a segmental artery and early fibrosis originating from the pleura (Figure 6-9). At 28 days portions of unorganized thermal coagulum persisted in the center of fibrous scar tissue that comprised the now-smaller thermal lesion. Chronic postobstructive atelectasis distal to some thermal lesions was associated with necrosis, fragmentation, and collapse of bronchial cartilage buried in fibrous scar tissue within the thermal lesion (Figure 6-10). Comparisons of the geometry and distributions of the thermal lesions in the normal pig indicated that the radio frequency thermal lesion boundaries can extend across adjacent pleural surfaces and spaces to involve adjacent organs and tissues (see Figure 6-7). The size and configuration of the lesions suggest that both electric field volumes and heat diffusion are factors in the formation of these extended lesions. Similar thermal complications have been reported in RF-ITT of the liver and adjacent abdominal organs.4,5 Vascular thrombosis was associated with transmural thermal coagulation and necrosis of segmental blood vessel walls as well as direct thermal coagulation of intraluminal red blood cells in smaller vessels in the treatment lesions. The segmental and subsegmental vascular thromboses in

the pig lesions were resolved by organization. The vascular lumens were obstructed by scar tissue and/or contained small tortuous vessels characteristic of recanalization. I have observed that in some pigs, intraoperative fluoroscopy showed deflection of the electrode tines by the walls of larger bronchi necessitating repeated placement of the electrodes; this may account for the excessive tearing of blood vessel walls, pleura, and parietal pleura with resultant local hemorrhage and thrombosis. The pig lesions were not made with continuous image guidance, which probably increased the incidence of these complications in the animals. These findings suggest that the placement of RFITT electrodes could be significantly influenced or compromised by the location of the target tumor adjacent to the rigid walls of the larger hilar bronchi. The pathophysiologic consequences of occlusive thrombosis and tearing of relatively large segmental blood vessels such as pulmonary infarction could prove to be a major limiting factor in the RF-ITT treatment of more centrally placed lung cancers. The segmental and subsegmental atelectasis extending distal to the thermal lesion was present in some but not all of the RF-ITT lesions in the pig. The collapsed bronchial walls had been weakened by transmural necrosis of the cartilage and soft tissues owing to direct thermal coagulation within the thermal lesion. The bronchial lumens were filled with cartilage fragments embedded in fibrous scar tissue (see Figure 6-10). The resultant atelectasis seen at 28 days formed narrow, wedge-shaped, fibrotic lesions containing residual collapsed alveoli and bronchioles in the lung periphery. Again, the induction of bronchial wall collapse and atelectasis could be limiting factors for RFITT of lung tumors, especially for those patients with severely compromised pulmonary function. Careful consideration of the potential presence of a larger segmental bronchus within a tumor could be a major determinant for radio frequency probe placement and treatment. Clinical and experimental studies in RF-ITT reveal the sparing of a thin layer of lung tissue around some large arteries with flowing blood and around bronchi.4,5,42,54 The blood and air flow could be important sources of heat dissipation by convection. These observations suggest that cooling the air and increasing air flow during ITT could be tested as a method to control thermal effect. As stated before, electric impedance of tissues is an important determinant in the formation of the electric fields and extent of tissue coagulation in RF-ITT.4,5,11,60,61 It is especially relevant for pulmonary cancers and could potentially be manipulated for designing specific treatments in the lung. Lung parenchyma is filled with air and has a greater electric impedance and lower electric conductivity than the solid/necrotic tissues of most lung cancers. The lung tissue surrounding the tumor can act as an electric insulator and tends to confine a significant

Radio Frequency Ablation of Thoracic Malignancies / 83

portion of the radio frequency field within the tumor. However, no systematic studies have been done to test this concept and its impact on lung RF-ITT. Also, the clinician must remember that the differences of tissue electric properties of pulmonary tissues preclude using treatment parameters derived from RF-ITT applications in the solid tissues of the liver or kidney lesions.

Conclusions RF-ITT has been shown to produce relatively predictable thermal coagulation lesions for the interstitial thermal therapy of lung tumors in animals and humans. Several observations indicate that many factors characteristic of lung

anatomy, physiology, and physical (electric and thermal) tissue properties might either help or hinder the success of RF-ITT. Electrode-delivery systems first designed and validated in the solid tissues of the liver and kidney may have to be modified to maximize the safety and efficacy of RFITT in the lung. Patient selection criteria and treatment goals need to be defined to better match the patient with the treatment. Palliation and debulking of cancer loads in patients with lung metastases may be more acceptable approaches than attempting to cure primary lung cancer. Although there are many challenges, supportive collaboration of clinicians and engineers in this era of technologic advances promises to lead to a better understanding of the application of radio frequency in the treatment of cancers.

FIGURE 6-4. Acute thermal lesion in normal pig lung, resulting from radio frequency interstitial thermal therapy using a radial array radio frequency electrode. A, A distinct red band of thermal damage surrounds the light tan central coagulum. The dips in the red band outer boundary adjacent to large bronchi suggest variation in heating owing to air-flow convection cooling. Pulmonary hemorrhage blends with the outer boundary of the red band in the distal portion of this lung. B, Thermally coagulated, desiccated red blood adjacent to the large bronchus marks the edge of the hole made by the trochar of the electrode. The irregular empty spaces in the blood were formed by expanding, superheated steam formed by water vaporization of the tissues. The lung tissue surrounding this site is thermally coagulated or “fixed.” The probe site in this section corresponds to the central red spot just distal to the large bronchus in the gross specimen in image A. C, The outer boundary of the red thermal damage band (arrows) corresponds to the upper left quadrant of the gross specimen. D, Thrombi and thermally coagulated blood occlude subsegmental pulmonary arteries at the interface of the distal light tan coagulum and the inner boundary of the red damage zone. Notice that the normal lung parenchyma (upper third of image C) and the thermally coagulated lung (upper third of image D) of the central coagulum appear similar owing to heat “fixation” of the lung in the coagulum. (B–D, 30 original magnification; stained with hematoxylin and eosin.)

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FIGURE 6-5. Three days after radio frequency interstitial thermal therapy. A, The proximal red damage and slightly hemorrhagic coagulation zone extends to the pleura in the proximal lesion (left) and blends with pulmonary hemorrhage extending into the distal lung (right). B, A composite image of the histologic sections encompassing the lesion in A emphasizes the red damage zone and the patches of thermally coagulated lung in the center. The blood in the center may have trickled in from hemorrhage in the red zone or may relate to incomplete coagulation of blood vessels in some portions of the lesion. C, The central, lightly colored coagulum and the surrounding red damage zone can be seen from the pleural surface. D, Light microscopic image of the red zone and pleura reveals local pulmonary and pleural edema and the prominent widening of the alveolar walls by blood-engorged alveolar capillaries. (B, 1 original magnification; D, 250 original magnification; B and D, stained with hematoxylin and eosin).

Radio Frequency Ablation of Thoracic Malignancies / 85

FIGURE 6-7. Seven days after radio frequency interstitial thermal therapy. “Kissing” thermal lesions in adjacent segments. The red damage zone of the thermal lesion extends across the pleural space between two pulmonary segments (arrowheads) and is seen in the gross specimen (A) and a composite image (B) of microscopic sections taken from the specimen shown in image A. A distinct band of inflammatory infiltrates and early granulation tissue formation surrounds the outer portion of the thermal lesion in both segments (light band in image A and dark band in image B). These cells and early wound tissues originated from the viable lung parenchyma adjacent to the thermal lesion. (B, 1 original magnification; stained with hematoxylin and eosin) FIGURE 6-6. Three days after radio frequency interstitial thermal therapy. Comparison of viable lung tissue (A), lytic necrosis in red damage zone (B), and thermally “fixed” lung in the central coagulum (C). The pseudostratified columnar epithelia (arrows) that line the bronchi appear similar in the viable (A) and thermally coagulated tissue (C), but the bronchial epithelium in the red zone is completely necrotic (B). (A–C, 630 original magnification; stained with hematoxylin and eosin)

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FIGURE 6-8. Seven days after radio frequency interstitial thermal therapy. A, Chronic pneumonia forms a wedge-shaped, mottled, pale region in the lung adjacent to the irregularly oblong thermal lesion. The distinct boundary of the pneumonia (white arrows) suggests obstruction of a segmental bronchus as a causal factor. Note the fibrous thickening of the pleura (arrowhead). B, A band of fibrous scar tissue (black arrows) separates the hemorrhagic, necrotic coagulum from the area of pneumonia (30 original magnification; stained with hematoxylin and eosin).

Radio Frequency Ablation of Thoracic Malignancies / 87

FIGURE 6-9. Seven days after radio frequency interstitial thermal therapy. A, A pulmonary infarction is present distal to the thermal lesion. The red damage zone is distinct at the proximal border (arrows) of the treatment lesion but blends into the infarction in the distal portion of the lesion. B, This image is a composite of tissue sections taken perpendicular to the cut surface shown in image A through the center of the bronchus. A large pulmonary artery (arrowheads) is torn in an area with changes consistent with holes made by the electrode trochar and proximal tines. Bands of inflammatory cell infiltrates (arrows) separate the superior thermal lesion from viable lung tissue and extend from the pleura into the necrotic tissue of the infarction. C, A higher magnification of the image shown in B demonstrates the outer layer of edematous pleura and subjacent zones of granulation tissue and inflammatory infiltrates invading from the pleura into the necrotic, hemorrhagic lung tissue and the fibrous pulmonary septa (arrows). (B, 1 original magnification; C, 80 original magnification; B and C, stained with hematoxylin and eosin)

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FIGURE 6-10. Twenty-eight days after radio frequency interstitial thermal therapy. A, Lightly colored, fibrous scar tissue surrounds the persistent, dark, central thermal coagulum. This scar tissue defines the outer boundary of the healing thermal lesion. The pulmonary tissue distal to the oval treatment lesion is mottled and firm (arrows). B, A composite image of histologic sections of the entire lesion seen in image A demonstrates the thermal lesion surrounded by cellular scar tissue and a distal tail of atelectatic lung corresponding to the mottled tissue in image A. Active organization at the edge of the necrotic center is marked by a dense infiltrate of inflammatory cells (arrows). C, A higher magnification of the distal coagulum and adjacent fibrous scar shows occlusion of a bronchial lumen (arrowheads) by organizing necrotic tissue and fragments of necrotic cartilage embedded in fibrous scar tissue (arrows). The irregular open space of the upper portion of the bronchus is an artifact produced by tissue tearing during sectioning. D, The air spaces are collapsed but not scarred in this higher magnification of the chronic atelectasis seen in images A and B. The atelectasis probably is related to the bronchial occlusion demonstrated in image C. (B, 1 original magnification; C, 30 original magnification; D, 250 original magnification; B–D, stained with hematoxylin and eosin)

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15. Valvano JW. Tissue thermal properties and perfusion. In: Welch AJ, van Gemert MJC , editors. Optical-thermal response of laser-irradiated tissue. New York: Plenum Press; 1995. p. 445–88. 16. Valvano JW, Pearce J. Temperature measurements. In: Welch AJ, van Gemert MJC , editors. Optical-thermal response of laser-irradiated tissue. New York: Plenum Press;

30. Thomsen S. Identification of lethal thermal injury at the time of phototherapy. In: Muller G, Roggan A, editors. Laser induced interstitial thermal therapy. Bellingham (WA): SPIE International Society of Optical Engineers; 1995. p. 459–67. 31. Thomsen S. Mapping of thermal injury in biologic tissues using quantitative pathologic techniques. In: Ryan T, Wong T, editors. Thermal treatment of tissue with image guidance. Vol 3594. Bellingham (WA): SPIE International Society of Optical Engineering; 1999. p. 82–95.

90 / Advanced Therapy in Thoracic Surgery 32. Thomsen S, Ryan TP, Freeman LJ, DiFancesco MW. Influence of different anatomies on healing of interstitial thermal lesions in goat and pig breast. In: Ryan T, editor. Thermal treatment of tissue: energy delivery and assessment. Vol 4247. Bellingham (WA): SPIE International Society of Optical Engineering; 2001. p. 69–75. 33. Bancroft JD, Cook HC. Manual of histological techniques and their diagnostic application. New York: Churchill Livingston; 1994. 34. Bancroft JD, Stevens A. Theory and practice of histological techniques. New York: Churchill Livingstone; 1996. 35. Dail DH. Tissue sampling. In: Dail DH, Hammar SP, editors. Pulmonary pathology. New York: Springer Verlag; 1994. p. 1–20. 36. Pearse AGE. Histochemistry. Vol 1. New York: Churchill Livingston; 1991. 37. Pearse AGE. Histochemistry. Vol 2. New York: Churchill Livingston; 1991. 38. Pearse AGE. Histochemistry. Vol 3. New York: Churchill Livingston; 1995. 39. Morrison P, Joles F, Charous D, et al. MRI of laser-induced interstitial thermal injury in an in vivo amimal liver model with histologic correlation. J Magn Reson Imaging 1998;8:57–63. 40. Dupuy DE, Zagoria RJ, Akerle W, et al. Percutaneous ablation of malignancies in the lung. AJR Am J Roentgenol 2000;174:57–9. 41. Chung AH. Thermal dosimetry of a focussed ultrasound beam in vivo by magnetic resonance imaging. Med Phys 1999;26:2017–26. 42. Putnam JB, Thomsen S, Siegenthaler M. Therapeutic implications of heat-induced lung injury. In: Ryan T, editor. Matching the energy source to the clinical need. Vol CR-75. Bellingham (WA): SPIE International Society of Optical Engineering; 2000. p. 139–160. 43. Chapman WC, Debelak JP, Pinson CW, et al. Hepatic cryoablation but not radiofrequency ablation, results in lung inflammation. Ann Surg 2000;231:752–61. 44. Herrera LJ, Fernando HC, Perry Y, et al. Radiofrequency ablation of pulmonary malignant tumors in nonsurgical candidates. J Thorac Cardiovasc Surg 2003;125:929–37.

48. Marchand B, Perol M, Roche EDL, et al. Percutaneous radiofrequency ablation of a lung metastasis: delayed cavitation with no infection. J Comput Assist Tomogr 2002;26:1032–4. 49. Nishida T, Inoue K, Kawata Y, et al. Percutaneous radiofrequency ablation of lung neoplasms: a minimally invasive strategy for inoperable patients. J Am Coll Surg 2002;195:426–7. 50. Rose SC, Fotoohi M, Levin DL, Harrell JH. Cerebral microembolization during radiofrequency ablation of lung malignancies. J Vasc Interv Radiol 2002;13:1051–4. 51. Schaefer O, Lohrmann C, Langer M. CT-guided radiofrequency ablation of a bronchogenic carcinoma. Br J Radiol 2003;76:268–70. 52. Steinke K, Habicht J, Thomsen S, et al. CT-guided radiofrequency ablation of a pulmonary metastasis followed by surgical resection. Cardiovasc Interv Radiol 2002;25:543–46. 53. Vaughn C, Mychaskiw G II, Sewell P. Massive hemorrhage during radiofrequency ablation of a pulmonary neoplasm. Anesth Analg 2002;94:1149–51. 54. Goldberg SN, Ahmed M, Gazelle GS, et al. Radio-frequency thermal ablation with NaCl solution injection: effect of electrical conductivity on tissue heating and coagulationphantom and porcine liver study. Radiology 2001;219:157–65. 55. Lee JM, Kim SW, Li CA, et al. Saline-enhanced radiofrequency thermal ablation of the lung: a feasibility study in rabbits. Korean J Radiol 2002;3:245–53. 56. Miao Y, Ni Y, Bosmans H, et al. Radiofrequency ablation for eradication of pulmonary tumor in rabbits. J Surg Res 2001;99:265–71. 57. Miao Y, Ni Y, Bosmans H, et al. Radiofrequency ablation for eradication of renal tumor in a rabbit model by using a cooled-tip electrode technique. Ann Surg Oncol 2001;8:651–7. 58. Goldberg SN, Gazelle GS, Compton CC, McLoud TC. Radiofrequency tissue ablation in the rabbit lung: efficacy and complications. Acad Radiol 1995;2:776–84. 59. Wang N-S. Anatomy (respiratory organs). In: Dail DH, Hammar SP, editors. Pulmonary pathology. 2nd ed. New York: Springer-Verlag; 1994. p. 21–44.

45. Zagoria RJ, Chen M, Kavanagh PV, et al. Radiofrequency ablation of lung metastases from renal cell carcinoma. J Urol 2001;166:1827–8.

60. Nagaishi C, Nagasawa N, Yamashita M, et al. Functional anatomy and histology of the lung. In: Dial D, Hammar SP, editors. Pulmonary pathology. Baltimore: University Park Press; 1972. p. 1–295.

46. Highland AM, Mack P, Breen DJ. Radiofrequency thermal ablation of a metastatic lung nodule. Eur Radiol 2002;12:166–70.

61. Ogan K, Jacomides L, Dolmatch B, et al. Percutaneous radiofrequency ablation of renal tumors: technique, limitations and morbidity. Urology 2002;60:954–8.

47. Kishi K, Nakamura H, Sudo A, et al. Tumor debulking by radiofrequency associated with pulmonary carcinoma. Lung Cancer 2002;38:317–20.

62. De W, Hulse JE, Walsh EP, Saul JP. Factors influencing impedance during radiofrequency ablation in humans. Chin Med J 1995;108:450–5.

CHAPTER 7

LASER BRONCHOSCOPY ROBERT JAMES CERFOLIO, MD, FACS, FCCP

cially true for patients with endobronchial obstruction, is described. Patient characteristics that are favorable or unfavorable for each treatment strategy are listed. Patients who are best served by the different types of laser are compared and contrasted with patients who are better served by laser’s main alternatives—stents, chemotherapy, external beam radiotherapy, and brachytherapy. Although many view these modalities as competitors, we believe that it is best to view them as allies. When all of these treatments are properly used together they lead to excellent palliation of the blocked, bloody, or narrowed airway. The true strength of these diverse treatment strategies is maximized when patients receive a combination of techniques.

Laser bronchoscopy is a relatively new procedure. Although it was first described only three decades ago, its clinical use has become widespread worldwide. Interestingly, it is often used with a relatively old procedure—rigid bronchoscopy, which has been around for over 100 years. Laser bronchoscopy is a powerful and versatile cog in the armamentarium available to thoracic surgeons, general surgeons, and pulmonologists. Several new lasers developed in industry have come to fruition in the medical arena. Some have become powerful clinical tools for the practicing surgeon. As further scientific discoveries are made, the advancements made in the field of lasers will probably continue to be applied to the field of medicine, thus ensuring laser bronchoscopy’s future as bright and dynamic. In the 1970s and 1980s laser bronchoscopy really only meant carbon dioxide (CO2) lasers. Now there is a vast array of instruments that guide and direct a whole host of different types of lasers. The lasers that are used most often clinically, however, via the bronchoscope, include the CO2 laser, the yttrium-aluminum-garnet (YAG) laser, and lasers for photodynamic therapy. The YAG laser can be a KTP laser or a neodymium (Nd) laser. This chapter focuses on these. In the following pages we briefly discuss the history of laser bronchoscopy, the different types of lasers that are currently available, and their basic mechanism of action. We describe the advantages and disadvantages of each type of laser. The technique of rigid bronchoscopy, which remains our preferred way to transfer any laser’s energy to tissue in the airway, is also described. The most common complications and pitfalls of laser bronchoscopy are discussed along with their treatments. Patient selection, which is a critical component for clinical success in any arena but which is espe-

History of Rigid Bronchoscopy The art of rigid bronchoscopy, an important precursor for the development of laser bronchoscopy, was forged by an otolaryngologist and not by a general or thoracic surgeon. In 1897, Gustav Killian reported the first case report of rigid bronchoscopy.1 In that report, Killian retrieved “a pork bone” from a patient’s airway using an esophagoscope. With this report, the age of rigid bronchoscopy was born. By the early 1900s, many more case reports were published concerning the use of rigid bronchoscopy. Chevalier Jackson distinguished himself as a pioneer and leader in this art.2 He not only championed the clinical art of how to perform rigid bronchoscopy, but he also helped design and develop the scope itself. Despite the fact that almost 100 years have passed since Jackson’s initial work, the rigid bronchoscope we use today is amazingly similar to the one he “perfected” in the early 1900s. The only real advancements have been in the light source and in the 91

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optics of flexible bronchoscopy, but little has been done to improve the scope itself.

History of Laser Bronchoscopy The first reported case of laser bronchoscopy was by Strong in 1972. He used the only laser then clinically available, the CO2 laser. Over the next decade CO2 laser emerged as a safe and effective tool to treat laryngeal narrowing or tumors in the upper airway. Although the CO2 laser was, and still is, a very useful tool for these types of lesions, it is housed in a cumbersome device. The laser was harnessed to the rigid scope via a long tube that housed a series of mirrors. These mirrors deflected the beam of light, which finally emerged from this large, bulky machine. The rigid scope allowed the surgeon to ventilate and oxygenate the patient through one arm of the scope while visualizing and lasering the intended lesion in the airway through another. In 1973 Strong and colleagues reported results with 15 patients who had undergone over 70 CO2 laser bronchoscopies.3 Perhaps most important to this report is that he reported few complications. This publication proved the safety of shining a powerful beam of light, through a narrow steel tube inserted in a patient’s airway, despite the presence of oxygen. It proved that the laser was safe in the operating room in proximity to tanks that were filled with highly flammable gaseous anesthetics. This landmark paper laid the groundwork and allowed others to adopt the use of laser bronchoscopy in the clinical setting and to help further refine this art. After these initial endeavors, further research led to the development of flexible scopes. With the development of these scopes came the realization that a more flexible laser system was needed in order to be able to treat more distal aspect of the tracheobronchial tree. Lasers become more powerful, smaller, more compact, and portable. The fibers used to introduce them into the airway become smaller and more bendable. This allowed the surgeon to treat lesions past the main stem bronchi— into lobar and even into subsegmental bronchii. Although the rigid bronchoscope with the CO2 laser is still extremely useful, it is limited by its bulky design. It is limited to treating pathology in the larynx, upper airway, the trachea, main stem bronchi, or in the proximal lower lobe bronchi. The CO2 laser is restricted by the rigid scope’s size and by its nonbendable nature. The scope was too big to enter distal parts of the tracheobronchial tree in most patients. Even when rigid scopes became smaller, the CO 2 laser was still limited to the areas described above. Lesions in the superior segment of the lower lobes and most of the left upper lobe were not accessible.

Types of Lasers The lasers that are clinically used today are introduced into the airway via the rigid or flexible bronchoscope. These lasers are the CO2 and Nd-YAG lasers, described above, and lasers that are used for photodynamic therapy, which include an argon laser (Coherent), a KTP-YAG laser (Laserscope), and a diode laser (Diomed) (Figures 7-1–7-3). Obvious advantages and disadvantages are visible from the photographs. Some machines, such as the Coherent, are larger than others and less portable. Others, like the KTP laser, require a cooling system, so they are also more difficult to move. Some, like the Diomed, do not require any optics and are easy to move.

FIGURE 7-1. The Coherent Laser is not portable and is about 4 feet high and 6 feet long.

FIGURE 7-2. The Laserscope Laser is portable but requires a water line and is about 6 feet high and 2 feet wide.

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Advantages and Disadvantages of Different Lasers

FIGURE 7-3. The Diomed Laser is portable and needs only a wall outlet. It is about 1 foot high and 8 inches wide.

Mechanism of Action Lasers are potentially dangerous. Any physician who is going to use a laser must know a little about their mechanism of action in order to operate one safely. Moreover, all operating room personnel must be familiar with laser safety concerns. Because of the possibility of fire, accidental injur y to hospital personnel, and other medical–legal issues, most laser surgeons and supporting staff are required to attend a course to obtain laser certification. The word laser is an acronym for light amplification of stimulated emission of radiation. This means that lasers generate a narrow beam of light that contains energy. The amount of energy is variable and depends on the wavelength of light it generates. The power of the light can be measured in a variety of ways. There are multiple factors that determine how much of this energy is actually transferred to the intended treated area and the surrounding tissue. The surgeon needs to know the options available to him or her and their implications for potential tissue destruction or injury.

Each laser has unique properties. Not only is the power different for the different types of lasers, but the hardware it utilizes is also quite different. If one is planning on developing a laser center, the initial concerns of cost, space, and safety and other logistical concerns are crucial for proper building and planning. These logistical characteristics of the laser are as important as their clinical features. The first laser used in the clinical arena is the CO2 laser. Its physical design is one of its inherent weaknesses. It is bulky and requires an articulating arm that houses a series of mirrors that deflect light. The machine is portable, but is quite large. The second laser used in the clinical arena is the NdYAG laser. It is smaller and more flexible than the CO2 laser and hence is able to get to smaller aspects of the airway. It can go anywhere the flexible bronchoscope can go. It also has the ability to vary its power, and in general it features a greater depth of penetration. The third type of clinically useful lasering system is the kind used for photodynamic therapy (see Figures 7-1–73). Several different types of lasers can be used to perform photodynamic therapy. The differences in these systems revolve around their size, portability, and power.

Rigid Bronchoscopy Advantages and Disadvantages Although some lasers can be used through the flexible fiberoptic bronchoscope, our preference for most patients with an obstructed airway remains the rigid bronchoscope for several reasons. The rigid bronchoscope affords a larger lumen. This allows one to easily and safely evacuate blood. Although significant bleeding is a very uncommon complication of laser bronchoscopy in experienced hands, it can occur. When it does it can be an anxietyprovoking problem with significant morbidity. The risk of death is higher in the patient who is awake undergoing flexible laser bronchoscopy than it is in the patient under general anesthesia with a rigid scope in the airway. The rigid scope allows one to use large bore suckers. Large pieces of tumors and blood clots can be easily extracted. Although this particular advantage should be rarely actualized (because significant bleeding is uncommon) the more readily seen advantage is the ability to quickly debride the airway with shorter procedure times. Large bore suckers do not fit down a flexible scope. These suckers evacuate blood, clots, and large chunks of tissue that can fall down the airway and obstruct a significant part of the airway. Many of these pieces are too large to be removed with a flexible scope. Smaller fragments can be

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removed, but often it requires one to withdraw the entire scope from the airway and hope the fragment did not fall into the back of the pharynx. The final and perhaps most important advantage of rigid bronchoscopy is that the flexible scope can be and should be used through the rigid scope. In this way all of the advantages and safety features of the rigid scope are maintained and all of the advantages of the flexible scope are kept as well. The disadvantage of rigid bronchoscopy is that it usually requires the patient to receive a general anesthesia. Although rigid bronchoscopy can be performed without muscle paralysis and without general anesthesia, it is most commonly performed in our institution with a shortacting depolarizing agent and a gas anesthetic. Many of the patients who require laser bronchoscopy have stage IV lung cancer. They are weak and debilitated from their metastatic cancer and by previous radiotherapy and chemotherapy. The laser bronchoscopic procedure is usually only palliative. However, with careful management, anesthetic complications are very rare. We have had no serious anesthetic complications in more than 900 rigid bronchoscopies. Another potential disadvantage is cost. Most rigid bronchoscopy is done in the operating room with an anesthesiologist present, and thus it is more costly. However, if it delivers an open airway quicker and safer than other modalities, these costs may be offset. A common perception of rigid bronchoscopy is that it is more difficult to perform. Although this is probably true, like any other procedure it becomes relatively straightforward with experience. Some physicians, especially pulmonologists, may feel uncomfortable with rigid bronchoscopy because it was not a large part of their training. But for those who try it and stick with it, after about 10 to 15 procedures they often begin to prefer it for its debridement of the airway. Another potential problem, though rare, is that some patients simply cannot have a

rigid scope placed. The surgeon needs to know when to stop trying to place the rigid scope and abandon the technique. Patient characteristics that make rigid bronchoscopy difficult include having a small mouth; large teeth (often with caps on the upper teeth); a short, fat neck; a history of radiation to the head and neck; and difficulty extending the neck. In these situations, or when performing a procedure on the subglottic apparatus in any patient, laryngoscopy should be available and employed when needed. In our opinion, the surgical team that is going to perform rigid bronchoscopy should always have a formal laryngoscope with the appropriate attachments available to secure the scope to a table. Figures 7-4 demonstrates how a laryngoscope should be anchored to a Mayo table. Since the art of rigid bronchoscopy is fading and since we believe it is the preferred way to do laser bronchoscopy, we briefly review the technique.

Rigid Bronchoscopy Technique The patient should be brought to a suite where all the potentially needed and appropriate equipment is available. Most bronchoscopy suites either on the floor or in the operating room area should have overhead monitors so that everyone can see what is happening inside the airway. This allows the nurses to better assist; they know what the airway looks like and what the problem is. It also enables the anesthesiologists to better understand the anatomy and to anticipate any potential problems. Rooms that are in the operating room area may offer an advantage for the very rare patient who requires an emergency thoracotomy because of bleeding. The patient’s head should be at the end of the table. The table should have a separate head section that can be flexed, extended, or removed. The neck should be extended, and the degree to which a patient can flex and extend the neck and open the mouth should be assessed

FIGURE 7-4. Intraoperative pictures demonstrate how a laryngoscope is anchored to an overhanging table and how a flexible fiberoptic bronchoscope can be easily inserted through the laryngoscope.

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prior to induction. If the patient has teeth in the upper palate a tooth guard should be placed over them to protect them from injury (as shown in Figure 7-5). In general, there are two ways to introduce the scope. We describe the classic way, which is preferred, first. This classic technique entails placing the rigid bronchoscope between the thumb and index finger of the nondominant hand. The thumb acts as a fulcrum at all times so that the patient’s teeth and the upper palate are spared any undue pressure. The scope is slowly introduced into the mouth. The assistant can help by pulling the left cheek outward with his or her index finger so the lip is not pinched. The bevel end of the scope should be anterior (pointing towards the ceiling). The key is to stay in the midline from this point on. The median furrow of the tongue acts as a vector and leads one to the midline of the oropharynx. Once the oropharynx is identified, the tip of the scope usually has to be gently rotated. The scope is advanced— again using the left thumb and fingers as a fulcrum so that all pressure is exerted against them and not against the patient’s upper teeth. The epiglottis should then come into view. The hypopharynx should then be carefully inspected. Once this is done the beveled part of the scope is used to lift up the epiglottis anteriorly. The glottic opening and the vocal cords should then come into full view. They too should be examined. Many patients with bronchogenic malignancy, who usually are smokers, also have concomitant head and neck cancers. The scope is then turned about 90° to 120° clockwise. Once the upper airway is intubated by the rigid scope, the scope should again be rotated slowly so that the bevel part is anterior. If jet ventilation is used as is our preference (allowing the end of the scope to stay open—instruments can be easily and quickly passed through it and carbon dioxide is ventilated), it should now be hooked up to the side of the scope. The other way to place the rigid scope is using the anesthesiologist’s handheld laryngoscope (Figure 7-6). This instrument is used to suspend or expose the tip of

FIGURE 7-5. A tooth guard is placed on the teeth in the upper palate.

the epiglottis; the rigid scope can then be inserted almost like an endotracheal tube. Once the tip is under the epiglottis the surgeon removes the hand-held laryngoscope and looks through the rigid scope and introduces it as described above (Figures 7-7 and 7-8). This technique,

FIGURE 7-6. A hand-held laryngoscope is used to expose the tip of the epiglottis that is suspended, and the rigid scope is easily introduced into the upper airway.

FIGURE 7-7. The surgeon then looks through the rigid scope to evaluate the vocal chords and the rest of the upper airway.

FIGURE 7-8. The scope is gently rotated and inserted into the proximal trachea. The surgeon’s fingers should serve as a fulcrum so that there is no pressure on the upper teeth.

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although technically easier, eliminates the ability to perform a full examine of the upper airway. Once the scope is in place (Figure 7-9), the flexible scope can be placed down the rigid scope.

Lasering Tumors in the Airway Each laser imparts its energy differently to the tumor. Some impale the tumor, others direct the powerful beam of light onto its surface, and some touch the tumor. Most CO2 lasers have an aiming beam that shines a red light onto the desired target. This targeting light tells the surgeon where the beam is going to go. The surgeon is then able to deliver the laser to the tumor’s surface via a foot pedal. The laser can be delivered in either short bursts or with a continuous firing. The latter is more dangerous, but if the tumor is large and the visibility is good little energy should be imparted to surrounding tissue. The goal is to minimize the amount of lasering to the surrounding normal tissue while maximizing the amount of energy directed onto or into the cancer. The desired amount of power can be dialed into the machine. The surgeon looks through the lens of the CO2 laser that

is fastened onto the end of the rigid bronchoscope and he or she works usually while sitting. A smoke evacuator should also be applied to the end of the scope. The YAG laser is delivered via a malleable cable that is snaked through the working chamber of a flexible scope. This allows one to laser while standing and the action can be viewed on an overhead monitor. The YAG laser also has an aiming beam, but unlike the CO2 laser it has a cooling mechanism that forces air out of the end of the laser. The blowing air can distort one’s vision at times because blood can be stirred up while lasering and it can smear the end of the scope. Like the CO 2 laser, the desired amount of power can be set on a YAG laser and a foot pedal is used to deliver it. Photodynamic therapy, which can be delivered by various lasers, uses a nonthermal method of killing tumor cells. CO2 and YAG deliver heat and hence the risk of an airway fire is real. Patients who undergo photodynamic therapy are given an intravenous chemical (Photofrin, Birmingham, AL). This chemical is picked up by most cells in the body but over the course of 48 to 72 hours is leached out of these cells, except for those in the skin, those in the reticuloendothelial system, and all types of cancer cells. The surgeon then brings the patient to the operating room and selects a diffuser to help impart the laser’s energy to the tumor. These diffusers come in several lengths (1.0, 2.5, 5, and 10 cm). These diffusers are flexible and, like the YAG laser system, are placed down the working port of a flexible bronchoscope. If the tumor is soft and large the diffuser can be impaled directly into the tumor. If the tumor is sessile or hard it can be placed against the tumor. We refer to the latter technique as the juxtaposing technique and the former as the impaling technique. The laser is activated, activating the Photofrin that is in high concentration in the tumor and causing a nonthermal injury to the cancer. The activation releases free oxygen radicals, which leads to ischemic necrosis and cellular death. Dead tissue is debrided the next day to help open the airway. Debridement bronchoscopy is usually unnecessary when tumors of the esophagus are treated.

Patient Selection

FIGURE 7-9. The scope is in place and a flexible fiberoptic bronchoscope or other working instruments can be easily inserted through while jet ventilation is used through a side hole.

For our review of laser bronchoscopy to be clinically complete, we must discuss where it fits into the treatment algorithm of these patients. Most have stage IV lung cancer or metastatic endobronchial metastases. These patients have a very poor life expectancy, so the goal of the treatment is palliation and improvement of quality of life. Most patients with malignant pathology in their airway are best served by a combination of treatments available to palliate their symptoms. Few patients are best

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served by laser bronchoscopy alone. In this section we briefly describe some of the characteristics that may make one treatment better than another for the airway blocked with tumor. In general surgical resection is the best way to palliate an airway; we focus on the patient who is not a surgical candidate. Usually surgery is not advised for patients with stage IV lung cancer, as it affords little to no benefit. A much less common scenario is that the patient has early lung cancer but has underlying comorbidities that make the risks of surgery greater than the benefit. In general, direct endoscopic therapy is the preferred treatment when the patient has an occluded airway. It is our treatment of choice when there is hemoptysis from a bleeding endobronchial lesion or when the patient is significantly short of breath and the lesion is blocking a lobe or greater and the distal airway is patent or recruitable. Direct endoscopic therapy is hallmarked by laser bronchoscopy, but it also includes shavers and rotary blades. Photodynamic therapy, which will be discussed below, has a special role for the patient who suffers from recurrent significant hemoptysis. It offers immediate control of bleeding and usually allows one to core out and remove the lesion and open the distal airway. Photodynamic Therapy We prefer photodynamic therapy for patients who have vascular tumors. This is especially true of metastatic lesions to the airways, such as melanoma and renal cell carcinoma. We also prefer photodynamic therapy when we are unable to visualize the distal tree behind the tumor, because photodynamic therapy almost eliminates the risk of perforation. Although the perforation risk is also extremely low with CO2 and YAG lasers, when the distal area cannot be visualized, it is possible, since the view of the anatomy is often distorted. We have found photodynamic therapy to be extremely helpful in opening up large parts of the airway that is occluded by large bloody lesions. It has become our treatment of choice in patients who have occlusion of either main stem bronchi or of the bronchus intermedius. However, CO2 or YAG laser with a core-out therapy can be just as effective. The only other advantages of photodynamic therapy are deeper penetration of up to 8 to 10 millimeters and, in our experience, a lower risk of significant bleeding during the procedure. Some data show that photodynamic therapy may continue to work via an inflammatory response after the treatment, unlike CO2 or YAG laser treatment. Of course, the disadvantage of photodynamic therapy is that it requires the use of a chemical (Photofrin). This chemical makes patients light sensitive; patients must avoid direct exposure to sunlight for up to 1 month.

Radiation Therapy If the airway has extrinsic compression from metastatic N1 regional lymph nodes narrowing it, then a treatment aimed at shrinking those nodes should be chosen. Direct endoscopic therapy does not offer this capability. If the nodes actually erode into the airway, initial treatment should be laser bronchoscopy to open the narrowed airway and remove the tip of the invading node. Then radiotherapy can be used to treat the rest of the N1 node. Brachytherapy or external beam radiotherapy are options. Brachytherapy is best applied, in our opinion, when the endoluminal component of the mass has been fully treated but there are recurrent or new multiple areas of metastatic N1 nodes compressing several areas of the airway and the patient has already had the maximum amount of external beam radiation allowed. Brachytherapy is contraindicated when the patient has an edematous narrowed airway, when photodynamic therapy has been performed in the previous weeks, or if there is a perforated airway or a fistula between the airway and esophagus. As alluded to above, external beam radiotherapy is a mainstay treatment for nonsmall cell lung cancer and can also be effective. However, in most patients sent to us for laser surgery, it has already been maximized. The usual maximum dosage to the chest is around 60 Gy, although in isolated cases dosages up to 72 Gy have been delivered. This does not take into account some of the new hyperfractionated methods of delivering external beam radiation. Most patients with tumor in their airway have stage IV bronchogenic cancer and have already had several rounds of chemotherapy and radiation completed several months prior. However, if the patient has bulky primary tumor or metastatic lymph nodes that are compressing, narrowing, or occluding the airway then external radiotherapy is an ideal treatment if it has not yet been tried and the maximum allowable dose has not been achieved. Often patients can receive more radiotherapy; old radiation records need to be reviewed along with a survey of the exact areas treated. Chemotherapy Chemotherapy is another effective, commonly used palliative treatment strategy. It is reserved for the patient with a good performance status who has stage IIIa, stage IIIb, or stage IV cancer. There may also be a role for it in early lung cancer, and several randomized trials are currently studying this issue. One prospective randomized trial, referred to as the S9900 trial, by the American College of Surgeons is evaluating the effectiveness of chemotherapeutics agents in stage Ib, IIa, and IIb disease prior to surgical resection. This topic is outside of the realm of this chapter.

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Chemotherapy is also used for the patient with small cell cancer. Chemotherapy can be useful in patients with tumor in the airway, but it is slow to open the airway and is rarely useful by itself. It may be useful in patients with endoluminal cancer either as a bridge to surgery, to theoretically eliminate micrometastases, or to downstage the tumor prior to resection. In patients with stage IV disease, chemotherapy such as Taxol may be used as a radiosensitizing agent when concurrent radiotherapy is planned. Overall, it is best employed in the patient with cancer in the airway who also has metastatic stage IV disease with disease outside the chest and who has a good performance status. However, chemotherapy by itself rarely will open an airway. Some other treatment plan is usually needed to help palliate the airway problem and often laser bronchoscopy is most efficient. Patients with small cell cancer often have mediastinal or hilar lymph nodes that are engorged with cancer. These nodes frequently impinge on and extrinsically compress the airway and chemotherapy can help relieve this problem. Laser bronchoscopy has no role if the airway is only compressed and there is no endoluminal component to the narrowing. Stents Stents are also an important part of the armamentarium for the physician treating these patients. Stents come in many different sizes, shapes, and types. In general stents are also best suited for the patient with malignancy who has an extrinsically narrowed airway and who has already completed radiotherapy or for the patient with a malignant fistulous connection to the esophagus. Because most stents employed today are metal, and thus permanent and difficult to remove after several weeks, our preference is to reserve these types of stents for malignant disease and when other modalities have been exhausted. Their role in the algorithm is almost always after radiotherapy, chemotherapy, and several types of endoluminal treatments have been given and to palliate a perforated airway or to help keep one open. Both covered and noncovered stents are available. We reserve the former usually for malignant tracheoesophageal fistula. Although these stents may be superior because they prevent tumor ingrowth, they may also increase secretions or increase one’s inability to clear secretions. The covered metal stents grow into the surrounding tissue and after several weeks cannot be extracted. Granulation tissue can form at the distal or proximal ends of the stent and can therefore cause a problem of narrowing further down or higher up the airway. If the problem is marched down the airway, past the carina, and into distal lobar or segmental branches or if it goes up to the vocal chords, it is usually more diffi-

cult to treat than the original tumor. For this reason we do not prefer stents for benign disease.

Results As reported in several series, the results of laser bronchoscopy are excellent. The goal of any endoluminal procedure is to open the airway and relieve the patient’s dyspnea or hemoptysis. The clinical reality is that laser bronchoscopy achieves this goal quicker than external beam radiation, chemotherapy, and brachytherapy. No current prospective randomized trial shows this, but a large amount of data already exists that show the efficacy, safety, and swift results of laser bronchoscopy. The real benefit of a prospective randomized trail, though difficult to perform, would be to compare the different types of lasers, their costs, and long-term results.

Clinical Applicability The type of lasers selected by the surgeon or pulmonologist is dependent on several features: probably foremost is the comfort of the operating clinician. Some clinicians are extremely comfortable with one form of laser over another and will use it almost exclusively. Although there are benefits to becoming very proficient with one type of laser, it is best to have all the available lasers in one’s armamentarium, allowing one to select the one that is ideal for the patient. Other factors that the operating technician has to decide on are the type of anesthetic to use (general or local), the type of bronchoscopy needed (rigid with flexible or flexible alone), and the power of the laser. As described above, we prefer general anesthesia and rigid bronchoscopy.

Lasers in Benign Disease Lasers are also useful for certain benign diseases that narrow the airway. Although tracheal resection remain the mainstay of treatment for benign short segment tracheal or main stem lesions, the laser can be useful in isolated cases. Although the specifics are beyond the scope of this chapter, it has been shown that crosshatching an area of stenosis in the 3, 6, 9, or 12 o’clock position followed by dilation with the rigid bronchoscope or balloon can be very effective. The real complication of this procedure, in our opinion, is that it may lead to worsening of the inflammatory response. This can make a surgical resection more difficult later and sometimes leads to more exuberant stenosis. The stenosis can recur quicker and tighter and it also can occur at the distal or proximal end of the original stricture. The application of a variety of topical chemicals has been used to try to prevent restenosis after laser and dilation.

Laser Bronchoscopy / 99

Complications and Treatments The most common complications of laser bronchoscopy are bleeding, airway fire, airway perforation, and injury to operating room personnel. In general, these complications are extremely uncommon; when an experienced team works together and has good communication between the surgeon, laser nurse, anesthesiologist, and person operating the jet ventilator, major intraoperative complications are almost non-existent. Patient selection is also critical, and experienced selection helps eliminate some of these complications. For example, some tumors in the airway, such as melanoma and renal cell carcinoma, which not infrequently metastasize to the airway, are associated with angiogeneis. These tumors can be associated with significant bleeding when targeted with a CO2 or YAG laser. Therefore, in our treatment protocol they are treated by photodynamic therapy first and cored out via rigid bronchoscopy second. Airway fires, the most dreaded and dramatic complication usually occurs because the oxygen source is still on while firing the CO2 or YAG lasers. If a fire in the airway does occur several steps should be taken immediately. The source of oxygen should be extinguished and removed, cold saline should be instilled, systemic steroids and antibiotics should be administered, and the intended procedure terminated or quickly finished depending on the degree of the fire, the level of injury, and the patient’s clinical status. The next most devastating and feared complication is perforation of the bronchus or trachea. Although this rare complication can be disastrous, it may not be recognized or diagnosed until several days after the procedure is completed. Perforation during laser bronchoscopy can occur because the laser inadvertently fired, usually against the membranous weakened wall of the posterior trachea or in the anterior cartilaginous part of the trachea that has tracheal malacia. It probably is most common, however, during aggressive dilation. The ideal treatment is contingent on early recognition and repair. If the patient has malignant disease and the procedure was meant to be palliative, usually repair is most appropriately performed by the placement of a stent. Perforation can occur with any laser, but it is very unlikely with photodynamic therapy unless aggressive debridement or dilating is being performed. It is also rare with CO2 and YAG lasers, but the former is less powerful. Perforations can occur with any laser, and the key is prevention. Prevention requires excellent visibility, the use of settings of no greater than 20 watts for YAG laser, 10 to 20 watts for CO2 laser, and 0.6 to 1.0 watts for photodynamic therapy. This complication is extremely unusual, but when it does occur, early recognition is crit-

ical. If the injury is not diagnosed immediately, the diagnosis should be suspected by the presence of a new pneumothorax or pneumomediastinum on the postoperative chest radiograph x-ray that should be performed all on patients in the recovery room after a laser procedure. Another feared and devastating complication from laser or rigid bronchoscopy is bleeding. The treatment for the bleeding is contingent on what the bleeding is from and the rate of bleeding. Very brisk bleeding from the pulmonary artery can be fatal. If the bleeding is from a bronchial artery, one possible treatment is to immediately block off that side of the airway, suck the blood out of the other side and control the bleeding either by urgent thoracotomy (rarely indicated) or urgent radiologic embolization. Embolization is reserved for arterial bleeding usually from an intercostal artery. Usually embolization is not needed because local measures performed in the operating room through the scope are successful. When significant bleeding comes from the tumor or if there is excessive bleeding at the time of laser bronchoscopy, several steps can be done to help control this dangerous and scary problem. Although massive bleeding is rare, an aggressive endoscopist will often have significant bleeding; in the awake patient and without a rigid bronchoscope this can lead to a fatal result. This is another reason to favor general anesthesia and rigid bronchoscopy. The management of this problem is described at length elsewhere and is only briefly summarized here. Lavage with epinephrine or ice-cold saline is the first step and usually is all that is needed. We usually start with epinephrine diluted 1 to 100, flushing 10 cc down the flexible scope placed through the rigid scope. This alone almost always stops the bleeding if it is from the tumor itself. The key to managing this problem is to first remove the blood from the unaffected side or segment. This allows one to adequately oxygenate the patient. The scope must be suctioned clean prior to shooting epinephrine down it, and the scope’s suction channel must also be cleaned. In this way the vasoconstrictive agent is applied directly to the bleeding site, and blood in the scope is not shot over it. The epinephrine usually causes these small vessels to stop bleeding. Another excellent way to prevent bleeding is to remove the entire tumor in total—another advantage to rigid bronchoscopy. When one is performing flexible fiberoptic bronchoscopy, only small pieces of tumor can be removed and bleeding is more difficult to treat because large bore suckers cannot be used. The final major potential complication of laser bronchoscopy is injury to hospital personnel or patient from the laser itself. Laser fibers can break, or the laser may not

100 / Advanced Therapy in Thoracic Surgery

be put on standby, or it may be accidentally fired. A beam of light that accidentally travels into the back of one’s retina can cause severe permanent injury to one’s vision. For this reason, all persons in the operating room should use protective eyewear. It is the surgeon’s responsibility to ensure everyone is given the opportunity to wear protective eyewear if they so desire.

Conclusion Laser bronchoscopy is an extremely effective and safe procedure in properly selected patients and in experienced centers. There are many different types of lasers and several different ways to deliver the powerful energy harnessed in this concentrated beam of light to pathology in the tracheobronchial tree. Laser bronchoscopy quickly opens the airway in patients with endoluminal occlusion from cancer, and it also has a small but important role in patients with benign lesions. In a patient who has cancer invading the airway that is blocking significant segments or lobes of healthy distal lung, it affords the surgeon the chance to quickly, safely, and efficiently recruit that lung. It leads to immediate relief of dyspnea and hemoptysis and opens the otherwise narrowed, blocked, or bloody airway. It is best used as an adjunct to radiation and chemotherapy. It is least successful when the distal airway is extrinsically compressed by stricture or malignant peribronchial lymph nodes are compressing it. With careful patient selection and intraoperative techniques, rigid bronchoscopy and laser therapy lead to excellent palliation of patients already weakened by stage IV malignancy. Intraoperative complications, despite the potential hazards of laser use near flammable materials, are rare.

References 1. Becker HD, Gustav Killian. A biographical sketch. J Bronchol 1995;2:77–83. 2. Jackson C. The life of Chevalier Jackson: an autobiography. New York: Macmillan; 1938. 3. Strong Ms, Jako GJ, Polayni T, et al. Laser surgery in the aerodigestive tract. Am J Surg 1973;126:529–33. 4. Beamis JF. History of the rigid bronchoscope. In: Bollinger CT, Mathur PN, editors. Interventional bronchoscopy. Progress in respiratory research. Basel: Karger; 2000. p. 2–15. 5. Beamis JF, Rebeiz EE, Vergos KV, et al. Endoscopic laser therapy for obstructing tracheobronchial lesions. Ann Otol Rhinol Laryngol 1991;100:413–9. 6. Dumon JF. Technique of safe laser surgery. Lasers Med Sci 1990;5:171–80. 7. Fisher JC. The power density of a surgical laser beam: its meaning and measurement. Lasers Surg Med 1983;2:301–15. 8. Perrin G, Colt HG, Martin C, et al. Safety of interventional rigid bronchoscopy using intravenous anesthesia and spontaneous assisted ventilation. A prospective study. Chest 1992;102:1526–30. 9. Personne C, Colchen A, Leroy M, et al. Indications and techniques for endoscopic laser resections in bronchology. J Cardiovasc Surg 1986;91:710–5. 10. Rontal M, Rontal E, Wenokur ME, et al. Anesthetic management for tracheobronchial laser surgery. Ann Otol Rhinol Laryngol 1986;95:556–60. 11. Strong MS, Jako GJ. Laser surgery in the larynx. Early clinical experience with continuous CO 2 laser. Ann Otol 1972;81:791–8. 12. Toty L, Personne C, Colchen A, et al. Bronchoscopic management of tracheal lesions using the neodymium yttrium aluminum garnet laser. Thorax 1981;36:175–8. 13. Unger M. Neodymium: YAG laser therapy for malignant and benign endobronchial obstructions. Line Chest Med 1985;2:276–90. 14. Duhamel, DR, Harrell JH II. Laser bronchoscopy. Chest Surg Clin N Am 2001;11:769–91.

CHAPTER 8

SURGICAL MANAGEMENT OF SMALL CELL LUNG CANCER FRANCES A. SHEPHERD, MD, FRCPC

Twenty to 25% of all primary bronchogenic carcinomas are of the small cell subtype. However, since dissemination to regional lymph nodes and/or distant metastatic sites can be identified in ≥ 90% of patients at the time of initial presentation,1 these tumors represent ≤ 5% of cases in most surgical series. Furthermore, extrathoracic micrometastases are likely present even in patients with apparently “limited”-stage or operable tumors, which explains why almost all surgical series from the prechemotherapy era reported 5-year survival rates approaching zero for patients with small cell carcinoma.2,3 One of the most important early studies of surgery for small cell lung cancer was the prospective randomized trial of surgery versus radiation conducted by the Medical Research Council of Great Britain.4,5 Seventy-one patients were randomized to have surgery and 73 to receive thoracic irradiation (30 Gy or more over 20–40 d). The median survivals for patients in the surgical and radiotherapy arms were 199 and 300 days, respectively (Figure 8-1). At 5 years, only one surgical and three radiotherapy patients were still alive (p = .04), and at 10 years, only the three patients in the radiotherapy arm remained alive. Although it was concluded from this study that radical radiotherapy was preferable to surgery, clearly, neither of the treatment policies was really effective. The investigators stated that it would be improbable that any advance in therapy could exert a significant effect on the death rate from this disease in the absence of successful smoking-prevention programs. How true these words are, even today! Following this study, trials of combined modality therapy with preoperative radiotherapy followed by surgery were undertaken for patients with small cell lung cancer, but few patients achieved long-term survival.6–8

The observation in the 1970s that patients with small cell lung cancer were dying from systemic metastases led to the hypothesis that the addition of chemotherapy to local radiotherapy might improve survival. Bergsagel and colleagues from the Princess Margaret Hospital in Toronto, ON, were the first to demonstrate a modest survival advantage with the addition of low-dose cyclophosphamide.9 The British Medical Research Council Lung Cancer Working Party also showed that adding low-dose cyclophosphamide and CCNU (1-[2chloroethyl]-3 cyclohexyl-1-nitrosourea) to radiotherapy resulted in a significant prolongation of progression-free, but not overall, survival.10

FIGURE 8-1. Survival in the two treatment series (all patients). Adapted from Working Party on the Evaluation of Different Methods of Therapy in Carcinoma of the Bronchus.4 p. 979. 101

102 / Advanced Therapy in Thoracic Surgery

At the same time, other investigators were applying the same adjuvant chemotherapy principles to surgical patients. In 1982 Shields and colleagues reviewed the results of four Veterans Administration Surgical Adjuvant Group (VASOG) adjuvant chemotherapy studies and undertook a separate analysis of the 148 patients (4.7%) in those trials who had small cell lung cancer. 11 No survival advantage was seen when single-agent nitrogen mustard or single-agent cyclophosphamide was administered after surgery. However, a small survival advantage was seen for patients in the chemotherapy arm of a three-arm trial in which patients were randomized to receive prolonged intermittent courses of CCNU and hydroxyurea, or no further therapy (Figure 8-2). Shields and colleagues also showed the importance of the TNM (tumor, node, metastasis) staging system in small cell lung cancer patients that has long been recognized to have prognostic significance for nonsmall cell A

HN2, Control,

N = 28 N = 27

Cyloxan Trial

80

Cyloxan, N = 27 Control, N = 20

60

40

B

20

0 0

1/2

1

2

3

4

5

Completed Postoperative Years

C

100

80

60

40

20

CCNU + Hydroxyurea Treated, N = 11 Control, N = 18

Patients Still Living (%)

Treated (CTX), N=6 Treated (CTX, MTX), N = 9 Control, N=3

100

Patients Still Living (%)

Patients Still Living (%)

100

lung cancer.12 Sixty percent of patients with T1N0M0 tumors were alive at 5 years, whereas there were almost no 5-year survivors among the patients who presented either with T2–3 tumors or with mediastinal lymph node involvement (Figure 8-3). Patients with small stage II tumors had an intermediate survival of approximately 30%. These observations suggested that there might be a small subpopulation of patients with small cell lung cancer for whom it might be appropriate to consider a surgical approach. In support of this, Shore and Paneth reported an overall 5-year survival rate of 25% in their retrospective review of 40 patients with small cell lung cancer who underwent potentially curative resection between 1959 and 1972. Four of 10 patients (40%) without nodal involvement achieved long-term survival compared with 9 of 26 patients (35%) who had hilar or mediastinal nodal involvement.13 Small cell lung cancer usually presents with a central mass associated with hilar and mediastinal adenopathy. Lennox and colleagues observed that patients who had large proximal tumors and required a pneumonectomy were less likely to achieve long-term survival. Their 2and 5-year survival rates for patients who required only a lobectomy were 32% and 18%, compared with 14.4%

0 0

80

1/2

1

2

3

4

5

Completed Postrandomization Years 60

40

20

0 0

1/2

1

2

3

4

Completed Postrandomization Years

5

FIGURE 8-2. A, Survival of treated and control patients with undifferentiated small cell carcinoma in the nitrogen mustard (HN2) and cyclophosphamide (Cytoxan) adjuvant chemotherapy Veterans Administration Surgical Adjuvant Group (VASOG) lung trials. B, Survival of treated and control patients with undifferentiated small cell carcinoma in the prolonged intermittent cyclochemotherapy VASOG lung trials. C, Survival of treated and control patients with undifferentiated small cell carcinoma in the CCNU and hydroxyurea adjuvant chemotherapy VASOG lung trials. Adapted from Shields TW et al.12 p. 481.

Surgical Management of Small Cell Lung Cancer / 103

100

T1N0M0, N = 26

Patients Still Living (%)

T1N1M0, N = 16 T1N0M0, N = 23

80

T2N0M0, N = 39 T3 or N2, N = 28

60

40

20

0 0

1

2

3

4

5

Follow-Up Year FIGURE 8-3. Survival, computed by the life table method, from postoperative day 30 (early trials) or from randomization (recent trials) by TNM classification for patients with undifferentiated small cell carcinoma who had undergone a “curative” resection in the Veterans Administration Surgical Adjuvant Group lung trials. Adapted from Shields TW et al.12 p. 481.

and 7.2% for pneumonectomy patients.14 Only rarely does small cell lung cancer present as a solitary pulmonary nodule. In the VASOG review of solitary pulmonary nodules, only 15 patients (4%) were found to have small cell pathology, and 11 were able to undergo surgery.15 Five and 10-year survival rates for those 11 patients were 36.4% and 18.2%, respectively. Since most of these patients underwent surger y before the chemotherapy era, it may be assumed that approximately one-third were cured by their surgery alone as measured by survival at the 5-year mark. This historical review shows clearly that local treatment—surgery, radiation, or both—is inadequate therapy for small cell lung cancer. If surgery is to play a role, it must be in the context of a combined modality treatment program with systemic chemotherapy.

Rationale for Surgery Improved Control at the Primary Site Response rates of 80% or more are achieved with current chemotherapy and radiotherapy combinations for small cell lung cancer, and complete clinical response is seen in approximately 50% of patients with limited-stage disease who are treated with both modalities.16 However, most patients relapse shortly after discontinuing treatment, and the 2-year survival rate is ≤ 20% in most series. For patients with limited disease, the most frequent site of failure is the primary tumor and the hilar or mediastinal lymph nodes. In total, up to 50% of patients fail at the primary site, and for half of those patients, the primary

site may be the first or only area of failure. These clinical observations have also been confirmed in autopsy series.17 Two meta-analyses of thoracic radiotherapy for small cell lung cancer have been published.18,19 The survival data for almost 2,000 patients in 16 trials were available, and data on local control rates were available for nine studies. Both meta-analyses showed that thoracic irradiation resulted in a reduction in local relapse rates from 47.9% to 23.3% (p < .0001).18 They also demonstrated a small but significant survival benefit for patients who received radiotherapy.18,19 Based on the results of these meta-analyses, the standard therapy for patients with limited small cell lung cancer now consists of combination chemotherapy and thoracic irradiation with or without prophylactic cranial irradiation. Median survival > 20 months and 5-year survival rates of approximately 20% have been reported.16,20 However, even the most successful combined modality treatment programs report isolated initial relapse at the primary site in 20 to 25% of patients and a cumulative risk of local recurrence of 50%.20 This high local failure rate led several investigators to question whether surgical resection might result in improved local control. They postulated that contol of bulk disease in the chest by surgery and eradication of low-volume micrometastatic disease by systemic chemotherapy would result in an increased cure rate. Small studies from several centers suggested that this might, indeed, be the case. The University of Toronto Lung Oncology Group reported only two local recurrences in 35 patients treated with combined modality therapy that included surgical resection. 2 1 Similar results were reported by Comis and colleagues, who observed no local recurrences in 16 patients who underwent adjuvant surgical resection after induction chemotherapy.22 Mixed Histology Tumors Small cell lung cancer is found in combination with other histologies such as adenocarcinoma or squamous cell carcinoma in approximately 5 to 10% of cases. 23 Investigators for the Eastern Cooperative Oncology Group reported that mixed histology tumors were more likely to present as peripheral lesions on chest radiographs, although other clinical characteristics were similar to those of pure small cell lung cancer.24 Surgical series of small cell lung cancer report higher percentages of mixed histology tumors. The University of Toronto Lung Oncology Group reported mixed histology in 14 of 79 patients (17.7%) who underwent initial surgery followed by adjuvant chemotherapy, and in 3 of 40 patients (7.5%) who had surgical resections after induction chemotherapy.25 Nonsmall cell lung cancers are less sensitive to chemotherapy and are not likely to be

104 / Advanced Therapy in Thoracic Surgery

controlled by systemic treatment. Thus, it may be appropriate to consider a combined modality treatment program for patients with mixed histology tumors if they meet standard surgical criteria and have no evidence of extrathoracic spread. Late Recurrence after Successful Treatment Several reviews have now suggested that long-term survivors of small cell lung cancer are at high risk of developing second primary tumors, in particular, second primary lung cancers.26–30 Although the patient population at risk for these second tumors is low because of the low cure rate for small cell lung cancer, clinicians must be aware that a new lesion on chest radiograph may not represent a relapse but, rather, a new tumor of different histology. Histologic or cytologic confirmation of the type of malignancy should be obtained, and if nonsmall cell lung cancer pathology is found, further work-up should be directed at determining operability since surgical resection has the potential to be curative for some patients.

Adjuvant Chemotherapy following Surgery The favorable results reported by Shields and colleagues in their review of the VASOG trials led several investigators to administer combination chemotherapy to all patients following complete resection of small cell lung cancer.11 A summary of 10 retrospective reviews of adjuvant chemotherapy after surgery is shown in Table 8-1.12,31–42 Frequently surgery was undertaken for patients in these series because a preoperative diagnosis of small cell lung cancer had not been made. For some, it had not been possible to obtain adequate tissue for any malignant diagnosis, and for others a preoperative diagnosis of

nonsmall cell lung cancer had been made. Some of those latter patients were subsequently found to have mixed histology tumors, whereas others had pure small cell tumors that had been incorrectly diagnosed preoperatively. Maassen and Greschuchna reported that only 18 of 24 patients had a correct histologic diagnosis of small cell lung cancer preoperatively.36 Similarly, the University of Toronto Group found that a correct preoperative diagnosis of small cell cancer had been reached in only 18 of 63 patients.37 Postoperatively, small cell lung cancer was found in 54 patients and mixed histology tumors in 9. Most of the series in Table 8-1 included patients seen over ≥ 10 years, and, frequently, multiple chemotherapy protocols were employed. However, with the exception of the early trials reported by Shields and Hayata and colleagues,12,31 all patients were treated with combinations of drugs that would be considered adequate even today. The duration of chemotherapy treatment was also variable and ranged from a single course of postoperative therapy to multiple courses for up to 18 months. Most groups administered approximately six cycles of treatment. Some centers also administered thoracic radiotherapy as well as prophylactic cranial irradiation. In view of the variability in radiation treatment and incomplete reporting in several series, no conclusions can be drawn concerning the advisability of trimodality therapy. The patients in the reviews summarized in Table 10-1 differ from limited-stage small cell lung cancer patients overall in that they all underwent pretreatment surgical resection and, therefore, detailed pathologic staging is available. The results clearly show that the TNM staging system is highly prognostic for patients with limited small cell lung cancer. In every study the best survival was achieved by patients who had pathologic stage I tumors, and the poorest survival was seen for patients with pathologic stage III tumors (Figure 8-4).39 Survival for patients

TABLE 8-1. Survival by Pathologic Stage for Patients Treated with Adjuvant Chemotherapy after Surgery Study

Stage I

Stage II

No. of Patients Survival (%) Hayata et al, 197831 Shields et al, 198212 Meyer et al, 1983,32 198433 Wada et al, 198534 Osterlind et al, 198635 Maassen and Greschuchna, 198636 Shepherd et al, 198837 Karrer et al, 1990,38 Ulsperger et al, 199139 Macchiarini et al, 199140 Hara et al, 199141 Davis et al, 199342 NA = not available. *Stages I and II combined.

Stage III

No. of Patients Survival (%)

Total

No. of Patients Survival (%)

No. of Patients Survival (%)

27 49 6 5 18 41 19 63

26 51 ≥ 50 37* 22 34 48 61

6 55 4 5 8 19 24 54

17 20 50 NA NA 21 24 35

39 28 10 7 10 64 20 40

0 3 0 33 NA 11 24 35

72 132 30 17 36 124 63 157

11 (5 yr) 28 (5 yr) NA (5 yr) 32 25 (3.5 yr) 20 (3 yr) 31 (5 yr) NA (4 yr)

26 13 11

52 64 50

NA 10 16

NA 42 35

15 (T3N0) 14 5

13 10.7 21

42 37 32

36 (5 yr) NA (5 yr) 36 (5 yr)

Surgical Management of Small Cell Lung Cancer / 105

Likelihood of Survival (%)

100

Stage I (18 Cases) Stage II (24 Cases) Stage III (20 Cases)

80

60

40

20

Stage I vs II p = .134 Stage I vs III p = .038

0 0

1

2

3

4

5

Time (yr) FIGURE 8-4. A comparison of survival by stage for patients treated with adjuvant chemotherapy after surgical resection for small cell lung cancer. Adapted from Shepherd FA et al.37 p. 832.

with stage I cancer ranged from 22% at 3.5 years in the Danish series to 61% at 4 years in the International Society of Chemotherapy Lung Cancer Study Group (LCSG). 35 On average, it would appear that approximately 50% of patients with pathologic stage I small cell lung cancer may be cured when surgery is followed by combination chemotherapy. In the early trials, almost no patients with stage III tumors achieved long-term survival. In the later reviews, in which more aggressive combination chemotherapy regimens were employed, long-term survival ranged from 11% to 35%.36,38,39,43 In all series the survival of stage II patients was between that of patients with stages I and III cancer. In fact, stage for stage, the survival rates are very similar to those seen after surgical resection of nonsmall cell lung cancer. All of the studies that used intensive combination chemotherapy reported survival rates that appear to be superior to those seen in patients following surgery without adjuvant chemotherapy. Since it is likely that the improved survival is attributable to the postoperative chemotherapy treatment and not to improvements in surgical techniques or supportive care, it seems appropriate to recommend that chemotherapy be given to all patients who have undergone resection for limited small cell lung cancer. The short-term toxicity of such treatment is usually quite manageable and reversible, and long-term toxicity is minimal. Since survival does not seem to be superior for patients who received 12 to 18 months of postoperative treatment,34,35 four to six cycles are likely adequate. Whether fewer cycles may also be adequate is unknown. In the study reported by Hara and

colleagues,41 11 patients treated prior to 1981 received only one postoperative course of combination chemotherapy, and 26 patients treated from 1982 to 1989 received two courses followed by consolidation radiotherapy. Although the 5-year survival rates for patients with stage I and II tumors were excellent, only 10.7% of patients with stage III tumors were alive at 5 years. These results appear to be somewhat poorer than those achieved by other groups who administered more courses of adjuvant chemotherapy, although firm conclusions cannot be drawn from these retrospective analyses. Littlewood and colleagues treated two young patients with pneumonectomy followed by a single course of very-high-dose chemotherapy and autologus bone marrow transplantation.44 Both patients relapsed, at 118 and 80 weeks after treatment. It would appear, therefore, that a brief course (maximum six treatment cycles) of standard-dose combination chemotherapy should be the treatment of choice for patients. It is not possible to state with certainty whether it is necessary to administer adjuvant chemotherapy to all patients. Shah and colleagues reported 43.3% actual 5year survival for 28 patients who underwent complete surgical resection without postoperative chemotherapy.45 More than half the patients in this study had peripheral tumors, and their survival was better than that of the patients who had central tumors. However, peripheral stage I nonsmall cell lung cancer is uncommon, as has been shown by the VASOG study of solitary pulmonary nodules in which only 15 of 309 patients were found to have small cell cancer.15 In the VASOG study, 5- and 10year survivals were 36.4% and 18.2%, respectively. The details of postoperative therapy, if any, for these patients were not provided, but it is likely that they did not receive aggressive combination chemotherapy. The 5-year survival rate is less than that reported by Shah and colleagues,45 and one can only speculate whether superior survival might have been achieved with the addition of combination chemotherapy. It is not possible to draw firm conclusions concerning the contribution of the surgery to the overall survival of these patients. It must be remembered that these surgical series included only a select subgroup within limited disease from which patients with adverse prognostic factors, such as supraclavicular adenopathy, bulky primary tumors with superior vena caval obstruction, and/or pleural effusions, were specifically excluded. If surgery does play a role in the treatment of small cell lung cancer, it does so by improving control at the primary site. Relapse patterns were reported in only seven of the trials reviewed,32,37,40–44 but the results from those studies suggest that surgery does contribute to local control since isolated local relapse was seen in only 8 of

106 / Advanced Therapy in Thoracic Surgery

the 201 patients in those studies (Table 8-2). It is still possible, however, that this high rate of local control was due only to the fact that the patients in these series had fewer locally advanced tumors and that the local control rate might have been equivalent with a combination of systemic chemotherapy and thoracic irradiation.

Prospective Trials of Induction Chemotherapy followed by Surgical Resection Phase II Trials The encouraging results achieved with initial surgery followed by adjuvant chemotherapy led several groups to undertake prospective studies of chemotherapy followed by surgery for limited small cell lung cancer. 46–56 The results of nine prospective phase II trials are summarized in Table 8-3.46–54 In all studies, patients received multiple courses (range 2–6) of combination chemotherapy that included agents that are currently considered to be active against small cell lung cancer (cyclophosphamide, doxorubicin, vincristine, etoposide, and cisplatin). The overall TABLE 8-2. Pattern of Relapse for Patients Treated with Surgery followed by Adjuvant Chemotherapy Study

No. of Patients

No. of Patients with Relapse Local Only

Meyer et al, 198332 Friess et al, 198543 Littlewood et al, 198744 Shepherd et al, 198837 Macchiarini et al, 199140 Hara et al, 199141 Davis et al, 199342 Total

10 15 2 63 42 37 32 201

0 1 1 2 2 2 0 8

Distant Local and Only Distant 1 5 1 26 24 NA 15 72

0 1 0 5 0 0 2 8

NA = not available.

response rate was ≥ 82% in all studies except that of Baker and colleagues,49 in which only two preoperative courses of chemotherapy were given. This perhaps suggests that a longer course of induction chemotherapy is advisable, although in the small study reported by Benfield and colleagues, 88% of patients responded to treatment and 100% were able to undergo complete surgical resection after only two courses of chemotherapy.51 On average, approximately 60% of patients in these trials were considered to have responded adequately enough for surgical exploration, and of those ≥ 80% could be resected completely. When calculated from the total number of patients who entered the studies, however, the overall complete surgical resection rate was only about 50%. Not all studies reported surgical toxicity, but it does not appear that the postoperative death or complication rates were significantly increased by the preoperative chemotherapy. Only three postoperative deaths were reported, 5 0 , 5 2 , 5 4 all in patients who had required a complete pneumonectomy. Other postoperative complications included infection, bronchopleural fistula formation, and reversible supraventricular tachycardias. The complete pathologic response rate was considerably lower than the clinical response rate, ranging from 4 to 37%,48,50 and on average was approximately 10%. It is of interest that this complete pathologic response rate is similar to rates reported in studies of induction chemotherapy followed by surgery for patients with stage III nonsmall cell lung cancer.57 All investigators reported that survival was strongly dependant on TNM stage (Figure 8-5). Patients with stage I (T1–2N0) tumors had the best prognosis, with 5year survival rates that approached 70% for completely resected patients. Patients with stage II and III tumors fared less well, but all series reported a small number of patients with stage IIIA tumors (N2) who achieved longterm survival and appeared to be cured by their

TABLE 8-3. Prospective Phase II Trials of Induction Chemotherapy followed by Surgery* Study Prager et al, 198446 Williams et al, 198747 Johnson et al, 198748 Baker et al, 198749 Shepherd et al, 198750 Benfield et al, 198951 Zatopek et al, 199152 Hara et al, 199153 Eberhardt et al, 199754

No.of Patients 39 38 24 37 72 8 25 17 46

Clinical Stage Chemotherapy I II III 2 NA 3 NA 21 NA 10 4 6

12 NA 7 NA 16 5 1 6 2

25 NA 14 NA 35 3 24 7 38

CR/PR (ORR%)

Thoracotomies/CSR(%)

CAOE
2–4 CAE
3 5/26 (82) CAO
6 ± EP CAE
2 1/19 (54) CAO
6 ± EP CAEO
2 5/2 (88) COPE
3 10/14 (96) Various 4/10 (82) EP 15/28 (93)

13/21 (87) 25/21 (55) NA (100) 20/20 (54) 27/30 (80) 8/8 (100) 14/10 (40) 17/17 (100) 32/23 (50)

Complete Pathologic Response(%)

11/8 (21) 2 (5) 4 (11) 23/15 (63) 9 (38) 2 (5) 38/33 (46) 3 (4) 0 (0) 5 (20) NA 11 (24)

A = doxorubicin (Adriamycin); C = cyclophosphamide; CR = complete response; CSR = complete surgical resection; E = etoposide; NA = not available; O = vincristine (Oncovin); ORR = overall response rate; P = cisplatin (Platinol); PR = partial response. *For limited small cell lung cancer.

Surgical Management of Small Cell Lung Cancer / 107

110

Stage I (n = 7)

Likelihood of Survival (%)

100

Stage II (n = 8) Stage III (n = 22)

90

>>

p = .037 p = .448

>

tumors are added to those who relapsed locally, the real local failure rate rises to ≥ 25% of the surgical patients. p = .008

80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

Time (yr) FIGURE 8-5. Comparison of survival by pathologic stage for 38 patients with small cell lung cancer treated with adjuvant surgical therapy after chemotherapy. Adapted from Shepherd FA et al.50 p. 177.

combined-modality treatment program. The median survival for the entire group of patients who entered the trials (including those who did not procede to thoracotomy) was reported for only six studies and ranged from 13 to 33 months.47,48,50,51,52,54 Several authors reported a higher cure rate for patients who required only a lobectomy, 4 7 , 5 4 although this was not confirmed by all authors.46,48 Patients who achieved a complete pathologic response had the best survival. Williams and colleagues reported that all patients who had pathologic complete responses (5) were cured of their tumors compared with only 20% of patients who were operable but had gross or microscopic evidence of residual cancer.47 Local relapse rates ranged from 0 to 40% of completely resected patients.46,49 Most series reported local failure rates that ranged from 10 to 20% for patients who were able to undergo successful resection (Table 8-4). 46–48,50–53,55,56,58 However, if the 15% of patients who had unresectable

The Lung Cancer Study Group Randomized Trial It has been recognized by all of the above investigators that the favorable survival rate achieved in these trials might be due to patient selection. The Toronto group emphasized the importance of selection bias after their review of all patients with limited-stage small cell lung cancer treated at their institutions over a 10-year period.59 They reported a significant survival advantage for patients who had no clinical evidence of mediastinal node involvement or pleural effusion. This group, which would be typical of patients who might be considered for surgery protocols, had a 20% cure rate with standard chemotherapy and radiation alone as opposed to no long-term survival for patients with more advanced tumors. In an attempt to determine whether the addition of surgery to combination chemotherapy and radiotherapy could prolong survival and improve the cure rate for patients with limited small cell lung cancer, the LCSG initiated a prospective, randomized trial of adjuvant surgical resection in 1983.58 Most patients with limitedstage tumors were eligible for this trial, even those with clinically evident mediastinal lymph node involvement. Induction chemotherapy initially consisted of cyclophosphamide, doxorubicin, vincristine, and etoposide but was changed to cyclophosphamide, doxorubicin, and vincristine in the later phase. In the absence of toxicity or progressive disease, patients received five preoperative cycles of chemotherapy. They were then restaged and assessed medically to determine their suitability for thoracotomy, and eligible patients were randomized to have either surgical resection followed by thoracic radiotherapy, 50 Gy delivered over 5 weeks, and prophylactic cranial irradiation, 30 Gy over three weeks; or to the radiotherapy alone (same regimen). Three hundred forty patients entered the trial. Although the clinical response

TABLE 8-4. Pattern of Relapse for Patients Treated with Induction Chemotherapy followed by Surgery* Study Prager et al, 198446 Williams et al, 198747 Johnson et al, 198748 Shepherd et al, 198750 Benfield et al, 198951 Zatopek et al, 199152 Hara et al, 199153 Yamada et al, 199155 Muller et al, 199256 Total

Thoracotomies/Complete Resection 11/8 25/21 23/15 38/33 8/8 14/10 17/17 20/18 48/45 204/175

*Excluding patients who did not have complete surgical resection at the time of thoracotomy.

Relapse Pattern None

Local Only

Distant Only

Local and Distant

4 12 2 10 2 5 10 13 26 106

0 3 3 3 0 0 3 3 4 19

4 6 7 20 6 5 7 7 15 70

0 0 3 0 0 0 0 0 0 6

108 / Advanced Therapy in Thoracic Surgery

rate to chemotherapy was 68% (28% complete response, 37% partial response), only 144 (42%) of patients were randomized: 68 to receive surgery and radiotherapy and 76 to receive radiotherapy alone. Of the 68 patients who were randomized to receive surgery, 6 did not undergo thoracotomy; however, 8 patients in the nonsurgical arm received off-study surgery, so a total of 70 thoracotomies were performed. Fifty-eight patients had some resection of tumor (83%), but only 54 had a pathologic complete resection (77%). Complete pathologic response was documented for 18% of patients who underwent surgery. Nonsmall cell pathology was found in 11% of patients. The median survival from enrolment for all patients was 14 months, and for the randomized patients was 18 months, with no difference seen between the groups in either median or long-term survival (Figure 8-6). Because only half of the randomized patients in this study underwent surgical resection, it is not possible to compare survival based on pathologic stage or TNM subgroup. The Toronto Group were the first to draw attention to the discrepancy between clinical and pathologic staging for patients with small cell lung cancer25,50, they showed that clinical staging could not identify subgroups of patients with different prognoses (Figure 87). In the LCSG trial, in which patients were staged care-

100

Thoracotomy (n = 68)

fully at the time of surgery, clinical and surgical TNM stages after chemotherapy were the same in only 20 patients (29%), and most frequently patients moved into a more advanced stage. 58 For the surgical group, no difference in resectability was identified for patients in any T or N subgroup, although there seemed to be a trend toward unresectability for patients with T3 tumors (p = .08). All pathologic T and N subsets in the surgical patients had similar survival. Why was survival not improved by surgery, and how should the results of this important LCSG trial be interpreted? The survival curves shown in Figure 8-6 were generated on an “intent to treat” basis, which is, of course, mandatory for any prospective randomized trial. It should be noted, however, that 10% of the patients did not receive protocol-specified therapy. Six patients randomized to surgery declined operation, and, of perhaps even greater significance, eight patients in the nonsurgical arm underwent thoracotomy and surgical resection. In such a small study, a 10% protocol violation of this nature may have masked a small but significant survival advantage between the treatment arms. Another question to be asked is why complete surgical resection was possible for only three-quarters of the patients subjected to thoracotomy. Although the combination of cyclophosphamide, doxorubicin, and vincristine was considered standard therapy at the time, a disappointingly low response rate of only 65% was seen in this study. With newer regimens that incorporate

Radiation Alone (n = 78)

110

Stage I (n = 69) Stage II (n = 27)

100

Stage III (n = 23)

90 60

Likelihood of Survival (%)

Patients Surviving (%)

80

40

20

0

80 70 60 50 40 30 20 10

0

6

12

18

24

30

36 0 0

1

2

3

4

5

Time (mo) FIGURE 8-6. A comparison of survival for patients randomized to thoractomy and radiation or radiation alone. Adapted from Shields TW, editor. General thoracic surgery. 4th ed. Baltimore: Williams & Wilkins; 1994.

Time (yr) FIGURE 8-7. A comparison of survival by pretreatment clinical stage for 119 patients who underwent surgery for limited small cell lung cancer. Adapted from Shepherd FA et al.25 p. 385.

Surgical Management of Small Cell Lung Cancer / 109

Salvage Surgery There are few treatment options for patients with small cell cancer who do not respond to initial therapy or who

relapse after a primary response. Typically, only brief periods of palliation or prolongation of survival are achieved with second-line chemotherapy or radiation. This has led some investigators to evaluate whether surgery might be useful as salvage therapy for certain patients with limited small cell lung cancer. Yamada and colleagues operated on nine patients: two who had failed to respond to chemotherapy, six who had achieved partial response, and one complete responder.55 Four patients achieved long-term disease-free survival that ranged from 3 to 11+ years. The Toronto Group performed salvage operations on 28 patients, only 18 of whom were found on pathologic examinations to have pure small cell tumors.60 Overall median survival of the 28 patients was 105 weeks, but only two patients with pure small cell cancer survived beyond 5 years (Figure 8-8). In view of these results, surgery cannot be recommended for patients with pure small cell tumors who fail to respond or who relapse after initial standard therapy. Mixed histology tumors are reported more frequently in surgical series.25,61 In the series of salvage operations reported by the Toronto Group, 10 patients had mixed histology or nonsmall cell tumors, and their median survival was 108 weeks.60 Four of the 10 patients (three with stage I tumors) achieved long-term survival after operation. Because a small number of patients with tumors with mixed histologic type cancers may be cured by surgical treatment, consideration should be given to a second biopsy for patients who have localized, resistant small cell lung cancer. Several authors have now reported that long-term survivors of small cell lung cancer are at increased risk of developing second primary tumors.26–30 In fact, a long-

110

Survival from Date of Diagnosis (Median 105 wk)

100

Likelihood of Survival (%)

etoposide and cisplatin and concurrent radiotherapy administered early in the course of the disease, response rates of 90% or more are standard.16,20 One might speculate, therefore, that a more complete response to chemotherapy might have resulted in a higher complete surgical resection rate. Seventeen percent of patients underwent “open and closed” procedures with no attempt at surgical resection. For some patients the residual tumor was clearly unresectable at the time of thoracotomy. However, for other patients the decision not to proceed to resection was based on scar tissue formation at the area of the primary tumor and in the mediastinum. Response to chemotherapy is often accompanied by an intense local scirrhous reaction that makes surgical resection more difficult. Tumors that may initially appear to be unresectable because of fibrosis may, in fact, be resected safely with careful dissection of the tumor bed and mediastinum. Because this was an international multi-institutional study, each individual surgeon operated on just a few patients. Had this been a larger study, it is possible that the overall resectability rate might have been higher. This is suggested by the observation that the resectability rate was higher for LCSG surgeons than it was in other centers who joined the trial at a later date. This may have been due to their greater experience in operating on both patients with small cell and those with nonsmall cell cancer after induction chemotherapy. Finally, patient selection undoubtedly played a large role in the ultimate results of this trial. All patients with limited disease were eligible to enter this study, with the exception of those who had supraclavicular lymph node involvement and those with pleural or pericardial effusions. Therefore, the majority of patients had stage III tumors. It has long be recognized that surgery has very little role to play in the management of stage III patients with nonsmall cell lung cancer, and this trial suggests that the same is true for patients with small cell lung cancer since many, if not most, patients with limited small cell lung cancer have mediastinal node involvement (often bulky) at the time of initial diagnosis. Nonetheless, it still remains possible that patients with early-stage disease (T1–2N0 and, perhaps, nonbulky stage II) may benefit from a combined modality approach that includes surgery. Because so few patients fall into this subgroup (likely ≤ 10%), it will probably never be possible to undertake a prospective, randomized trial to prove or disprove that surgery is appropriate in this setting.

Survival from Date of Surgery

90

(Median 74 wk)

80 70 60 13

50 40

7 5

30

5

20 10 0 0

1

2

3

4

5

Time (yr) FIGURE 8-8. Survival of 28 patients who underwent operations for small cell lung cancer. Adapted from Shepherd FA et al.60 p. 196.

110 / Advanced Therapy in Thoracic Surgery

term survivor is more likely to have a second primary malignancy than a relapse of the small cell lung cancer, and many of these new tumors arise in the lung. In the University of Toronto series, eight patients underwent surgical resection at the time of “relapse” following a long disease-free interval after initial treatment for small cell lung cancer. Two were found to have nonsmall cell tumors, and both achieved long-term survival after surgery. It is recommended, therefore, that a biopsy should be undertaken for long-term survivors of small cell lung cancer who develop a new lung lesion. If nonsmall cell pathology is documented, the patient should be staged completely, and surgery should be considered if the standard medical and surgical criteria for resection that would be applied to all patients with nonsmall cell tumors are met.

tified at diagnosis, the initial treatment should be chemotherapy to control the small cell component of the disease, and surgery should be considered for the nonsmall cell component. For patients who demonstrate an unexpectedly poor response to chemotherapy, and for those who experience localized late relapse after treatment for pure small cell tumors, a repeat biopsy should be performed. Surgery may be considered if nonsmall cell pathology is confirmed.

Summary

3. Mountain C. Clinical biology of small cell carcinoma: relationship to surgical therapy. Semin Oncol 1978;5:272–9.

Combined modality therapy with surger y and chemotherapy is feasible; the toxicity is manageable and postoperative morbidity and mortality rates acceptable. Patient selection is important, and the results of the LCSG trial indicate that surgical resection does not benefit the majority of patients with limited small cell lung cancer. The chances of long-term survival and cure are strongly correlated with pathologic TNM subgroups, and consideration of surgery for patients with small cell lung cancer should be limited to those with stage I and perhaps stage II cancer. Therefore, before surgery is undertaken, patients should undergo full staging of the mediastinum, including mediastinoscopy. Surgery may be considered for patients with T1–2N0 small cell tumors, and whether it is offered as the initial treatment or after induction chemotherapy does not seem to be important, as has been shown by Wada and colleagues and the University of Toronto Group.28,34 If a small cell tumor is identified unexpectedly at the time of thoracotomy, complete resection and mediastinal lymph node resection should be undertaken if possible. Chemotherapy is recommended postoperatively for all patients, even those with pathologic stage I tumors. Surgery likely has very little role to play for most patients with stage II tumors and virtually no role for those with stage III tumors. Even though chemotherapy can result in dramatic shrinkage of bulky mediastinal tumors, the addition of surgical resection does not contribute significantly to long-term survival for the majority of patients, as has been shown conclusively by the LCSG trial. The final group of patients who may benefit from surgical resection are those with combined small cell and nonsmall cell tumors. If a mixed histology cancer is iden-

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4. Working Party on the Evaluation of Different Methods of Therapy in Carcinoma of the Bronchus. Comparative trial of surgery and radiotherapy for the primary treatment of small celled, or oat-celled carcinoma of the bronchus. Lancet 1966;2:979–86. 5. Fox W, Scadding JG. Medical research council comparative trial of surgery and radiotherapy for primary treatment of small celled or oat-celled carcinoma of the bronchus. Tenyear follow-up. Lancet 1973;2:63–5. 6. Bates M, Levison V, Hurt R, Sutton M. Treatment of oat-cell carcinoma of bronchus by pre-operative radiotherapy and surgery. Lancet 1975;1:1134–5. 7. Levison V. Pre-operative radiotherapy and surgery in the treatment of oat-cell carcinoma of the bronchus. Clin Radiol 1980;31:345–8. 8. Sherman DM, Neptune W, Weichselbaum R, et al. An aggressive approach to marginally resectable lung cancer. Cancer 1978;41:2040–5. 9. Bergsagel DE, Jenkin RDT, Pringle JF. Lung cancer: clinical trial of radiotherapy alone versus radiotherapy plus cyclophosphamide. Cancer 1972;30:321. 10. Medical Research Council Lung Cancer Working Party. Radiotherapy alone or with chemotherapy in the treatment of small cell carcinoma of the lung. Br J Cancer 1979;40:1–10. 11. Shields TW, Humphrey EW, Eastridge CE, Keehn RJ. Adjuvant cancer chemotherapy after resection of carcinoma of the lung. Cancer 1977;40:2057–62. 12. Shields TW, Higgins GA, Matthews MG, Keehn RJ. Surgical resection in the management of small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1982;84:481–8. 13. Shore DF, Paneth M. Survival after resection of small cell carcinoma of the bronchus. Thorax 1987;35:819–22.

Surgical Management of Small Cell Lung Cancer / 111 14. Lennox SC, Flavell G, Pollock DJ, et al. Results of resection for oat-cell carcinoma of the lung. Lancet 1968;2:925–7. 15. Higgins GS, Shields TW, Keehn RJ. The solidary pulmonary nodule. Ten-year follow-up of Veterans Administration–Armed Forces Co-operative study. Arch Surg 1975;110:570–5. 16. Shepherd FA. The role of chemotherapy in the treatment of small cell lung cancer. Chest Surg Clin N Am 1997;7:113–33. 17. Elliott JA, Osterlind K, Hirsch FR, Hansen HH. Metastatic patterns in small cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients. J Clin Oncol 1987;5:246–54. 18. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10:890–5. 19. Pingnon J-P, Arriagada R, Ihde D, et al. A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med 1992;327:1618–24. 20. Murray N, Coy P, Pater J, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small cell lung cancer. J Clin Oncol 1993;11:336–44. 21. Shepherd FA, Ginsberg RJ, Evans WK, et al. Reduction in local recurrence and improved survival in surgically treated patients with small cell lung cancer. J Thorac Cardiovasc Surg 1983;86:498–504.

30. Osterlind K, Hansen HH, Hansen M, et al. Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small cell lung cancer. J Clin Oncol 1986;4:1044–52. 31. Hayata Y, Funatsu H, Suemasu K, et al. Surgical indications for small cell carcinoma of the lung. Jpn J Clin Oncol 1978;8:93–100. 32. Meyer J, Comis RL, Ginsberg SJ, et al. The prospect of disease control by surgery combined with chemotherapy in stage I and stage II small cell carcinoma of the lung. Ann Thorac Surg 1983;36:37–43. 33. Meyer JA, Gullo JJ, Ikins PM, et al. Adverse prognostic effect of N2 disease in treated small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1984;88:495–501. 34. Wada H, Yokomise H, Tanaka F, et al. Surgical treatment of small cell carcinoma of the lung: advantage of preoperative chemotherapy. Lung Cancer 1995;13:45–56. 35. Osterlind K, Hansen M, Hansen HH, Dombernowsky P. Influence of surgical resection prior to chemotherapy on the long-term results in small cell lung cancer. A study of 150 operable patients. Eur J Cancer Clin Oncol 1986;22:589–93. 36. Maassen W, Greschuchna D. Small cell carcinoma of the lung—to operate or not? Surgical experience and results. Thorac Cardiovasc Surg 1986;34:71–6. 37. Shepherd FA, Evans WK, Feld R, et al. Adjuvant chemotherapy following surgical resection for small cell carcinoma of the lung. J Clin Oncol 1988;6:832–8.

22. Comis R, Meyer J, Ginsberg S, et al. The impact of TNM stage on results with chemotherapy and adjuvant surgery in small cell lung cancer [abstract C-844]. Proc Am Soc Clin Oncol 1984;3:226.

38. Karrer K, Denck H, Karnicka-Mlodkowska H, et al. The importance of surgery as the first step in multi-modality treatment of small cell bronchial carcinoma. Int J Clin Pharmacol Res 1990;10:257–63.

23. Hirsch FR, Osterlind K, Hansen H. The prognostic significance of histopathologic subtyping of small cell carcinoma of the lung according to the classification of the World Health Organization. Cancer 1983;52:2144–50.

39. Ulsperger E, Karrer K, Denck H. ISC-lung cancer study group. Multi-modality treatment for small cell bronchial carcinoma. Eur J Cardiothorac Surg 1991;5:306–10.

24. Magnum MD, Greco FA, Hainsworth JD, et al. Combined small cell and non-small cell lung cancer. J Clin Oncol 1989;7:607–12. 25. Shepherd FA, Ginsberg RJ, Feld R, et al. Surgical treatment for limited small cell lung cancer. J Thorac Cardiovasc Surg 1991;101:385–93. 26. Heyne KH, Lippman SM, Lee JJ, et al. The incidence of second primary tumors in long-term survivors of small cell lung cancer. J Clin Oncol 1992;10:1519–24.

40. Macchiarini P, Hardin M, Basolo F, et al. Surgery plus adjuvant chemotherapy for T1–3N0M0 small cell lung cancer. Am J Clin Oncol 1991;14:218–24. 41. Hara N, Ichinose Y, Kuda T, et al. Long-term survivors in resected and non-resected small cell lung cancer. Oncology 1991;48:441–7. 42. Davis S, Crino L, Tonato M, et al. A prospective analysis of chemotherapy following surgical resection of clinical stage I–II small cell lung cancer. Am J Clin Oncol 1993;16:93–5.

27. Tucker MA, Murray N, Shaw EG, et al. Second cancers related to smoking and treatment for small cell lung cancer. J Natl Cancer Inst 1997;89:1782–8.

43. Friess GG, McCracken JD, Troxell ML, et al. Effects of initial resection of small cell carcinoma of the lung: a review of Southwest Oncology Group study 7628. J Clin Oncol 1985;3:964–8.

28. Sagman U, Lishner M, Maki E, et al. Second primary malignancies following diagnosis of small cell lung cancer. J Clin Oncol 1992;10:1525–33.

44. Littlewood TH, Smith AP, Bentley DP. Treatment of small cell lung cancer by pneumonectomy and single course high dose chemotherapy. Thorax 1987;42:315–6.

29. Ihde DC, Tucker MA. Second primary malignancies in small cell lung cancer: a major consequence of modest success. J Clin Oncol 1992;10:1511–3.

45. Shah SS, Thompson J, Goldstraw P. Results of operation without adjuvant therapy in the treatment of small cell lung cancer. Ann Thorac Surg 1992;54:498–501.

112 / Advanced Therapy in Thoracic Surgery 46. Prager RL, Foster JM, Hainsworth JD, et al. The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation. Ann Thorac Surg 1984;38:622–7.

of a stage oriented multimodality treatment including surgery for selected subgroups of limited disease small cell lung cancer [abstract 235]. Lung Cancer 1997;18 Suppl 1:61.

47. Williams CJ, McMillan I, Lea R, et al. Surgery after initial chemotherapy for localized small cell carcinoma of the lung. J Clin Oncol 1987;5:1579–88.

55. Yamada K, Saijo N, Kojima A, et al. A retrospective analysis of patients receiving surgery after chemotherapy for small cell lung cancer. Jpn J Clin Oncol 1991;21:39–45.

48. Johnson DH, Einhorn LH, Mandelbaum I, et al. Post chemotherapy resection of residual tumor in limited stage small cell lung cancer. Chest 1987;92:241–6.

56. Muller LC, Salzer GM, Huber H, et al. Multi modal therapy of small cell lung cancer in TNM stages I–IIIa. Ann Thorac Surg 1992;54:493–7.

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51. Benfield GFA, Matthews HR, Watson DCT, et al. Chemotherapy plus adjuvant surgery for local small cell lung cancer. Eur J Surg Oncol 1989;15:341–4. 52. Zatopek N, Holoye P, Ellerbroek NA, et al. Resectability of small cell lung cancer following induction chemotherapy in patients with limited disease (stage II–IIIb). Am J Clin Oncol 1991;14:427–32. 53. Hara N, Ohta M, Ichinose Y, et al. Influence of surgical resection before and after chemotherapy on survival in small cell lung cancer. J Surg Oncol 1991;47:53–61. 54. Eberhardt W, Wilke H, Stamatis G, et al. Preliminary results

59. Shepherd FA, Ginsberg RJ, Haddad R, et al. Importance of clinical staging in limited small cell lung cancer: a valuable system to separate prognostic subgroups. J Clin Oncol 1993;8:1592–7. 60. Shepherd FA, Ginsberg RJ, Patterson GA, et al. Is there ever a role for salvage operations in limited small cell lung cancer? J Thorac Cardiovasc Surg 1991;101:196–200. 61. Mangum MD, Greco FA, Hainsworth JD, et al. Combined small cell and non-small cell lung cancer. J Clin Oncol 1989;7:607–12.

CHAPTER 9

GENE THERAPY AND THORACIC SURGERY ROBERT I. GARVER JR, MD

Gene Therapy Basics

Gene therapy can be broadly defined as the administration of nucleic acids that direct the production of a new protein within targeted cells. By this definition, oligonucleotide therapeutics are not considered gene therapy since these short deoxyribonucleic acid (DNA) sequences do not, themselves, direct new protein production. In addition, lytic viruses that only contain viral genes and function as cytolytic therapy are not considered gene therapy for the discussion here. Specific proteins have been identified that play a critical role in the initiation or regulation of many clinical entities affecting the thorax. Since gene therapy has the potential for modifying proteins critical to a given disease state, the rationale for developing this modality is intuitively obvious. As technologies developed in the past 10 to 15 years enabled a relatively large number of basic “proof of concept” gene therapy studies in preclinical models, many proponents of gene therapy made overreaching predictions of success in the clinical utility of present-day gene therapy. It is now widely appreciated that gene therapy has not yet fulfilled these prophecies of rapid success, owing largely to the limitations of current gene-delivery technologies. This chapter endeavors to achieve two specific objectives: (1) to provide an understanding of the most common gene therapy technologies, with some appreciation for the limitations that need to be overcome for improved efficacy, and (2) to review specific gene therapy approaches directed toward clinical problems facing the thoracic surgeon, including lung cancer, mesothelioma, and lung transplantation.

Choice and Engineering of the Therapeutic Gene Although messenger ribonucleic acid (RNA) has been used as the nucleic acid in a handful of preclinical gene therapy studies, the vast majority of gene therapy strategies employ the administration of DNA. The primary DNA components required for the production of the new protein within the host cells include the transcription regulatory sequence (also known as the promoter) and the contiguous coding sequence, a combination variably designated as the transgene, expression cassette, or therapeutic gene (Figure 9-1). Several commonly used transcription regulatory sequences continuously direct relatively high levels of coding sequence transcription

Transgene

FIGURE 9-1. Transgene components. The typical transgene employed for gene therapy is a deoxyribonucleic acid containing a promoter (transcription regulatory sequence) that directs the production of transcripts from the contiguous coding sequence. Variations in types of promoters and coding sequence options are indicated in the figure text. 113

114 / Advanced Therapy in Thoracic Surgery

and are commonly referred to as constitutive promoters. It is also possible, depending on the host cell target, to select a transcription regulatory sequence that will only be active in specific tissues such as hepatocytes or prostate cells. The selection of such tissue-specific regulatory sequences obviously can be exploited as a means of targeting the new protein production to specific sites or tissues, a strategy sometimes referred to as transcription targeting. Almost any coding sequence can be used in a gene therapy context, but experience over the past decade has defined several different thematic approaches (Table 9-1). The initial gene therapy approaches focused primarily on protein replacement/augmentation for heritable protein deficiencies such as
1-antitrypsin deficiency or cystic fibrosis. More recently, the administration of transgenes encoding for angiogenic factors that stimulate new vasculature (eg, VEGF) has received significant attention based on potential efficacy observed in small numbers of patients. Gene therapy approaches for neoplastic diseases relevant to thoracic surgical practice have spawned several other strategies that seek to destroy the tumor cells, directly or indirectly. Direct antineoplastic genetic therapy approaches include toxin therapies in which the cancer cells are modified to produce a toxin (eg, diphtheria toxin) or a protein that converts a prodrug into a toxin (herpes simplex virus thymidine kinase [HSVTK]). Another direct antineoplastic strategy is the production of a protein that can dominantly suppress the effects of mutated oncogenes/tumor suppressor genes that perpetuate the neoplastic phenotype (eg, the introduction of wild-type TP53 into neoplastic cells with mutated or deleted TP53). Indirect antineoplastic strategies include the introduction of genes that direct the production of immunomodulatory agents with the aim of increasing the immune response directed against the neoplastic cells (eg, granulocyte-macrophage colony–stimulating factor). Standard genetic engineering technologies have been exploited to further improve the native coding sequences. For example, fusion genes have been made so that the protein produced in transduced cells may be bifunctional, or targeted to a specific cellular compartment. The portion of the gene coding for an enzyme active site can be mutated to code for “superenzymes” that are more efficient than the normal gene product. Vectors The fundamental requirement for any gene therapy strategy is a delivery system, that is, a vector, that effectively delivers the therapeutic nucleic acid. The vectors can be used to facilitate gene delivery in two contexts. The first approach, ex vivo gene therapy, refers to a process wherein the target tissue is removed from the individual,

TABLE 9-1. Thematic Gene Therapy Approaches Theme

Common Targets

Coding Sequence Example

Protein augmentation Direct toxins Indirect toxins

Heritable protein deficiencies Neoplasia Neoplasia

Dominant suppression Immunopotentiation

Neoplasia Neoplasia

Angiogenesis

Vascular disease, neoplasia Neoplasia

Radiosensitizers


1-Antitrypsin Diphtheria toxin A Herpes simplex virus thymidine kinase (HSVTK) TP53 Granulocyte-macrophage colony–stimulating factor VEGF Cytosine deaminase

exposed to the gene therapy vector in a tissue culture context, and at some point thereafter reintroduced into the host. Ex vivo gene therapy can be accomplished by every gene therapy vector system and has been shown to be quite safe. This gene therapy paradigm is obviously limited to those clinical situations in which the genetically modified cells are replaced within the host so as to direct an immune response or produce a deficient protein. The second gene delivery approach is in vivo gene therapy, which refers to the administration of the gene therapy vector directly into the host/patient. As is intuitively obvious, the vector requirements here are more stringent than in ex vivo gene therapy, because vector toxicity, host cell inactivation of the vector, and achievement of therapeutically meaningful delivery of the vector and its gene to the targeted tissue are all important barriers to success. The ideal gene therapy vector is one that efficiently transfers the functional, therapeutic DNA into all cells of a target tissue following intravenous administration, an ideal that can be designated as a targetable-injectable vector. This targetable-injectable vector system is also nontoxic and easily manufactured and stored. In the very brief review of currently available vector systems, the reader will appreciate that the ideal vector has not yet been developed, and the significant limitations of available vector systems is the greatest impediment to clinical efficacy attained by gene therapy. viral vector systems A variety of viruses have been modified for gene therapy applications (Figure 9-2). In most cases portions of the viral genome have been deleted so as to render the virus replication defective as well as provide space for the addition of the therapeutic transgene. At the time of this writing, three viral vector systems have played a dominant role in both preclinical and in human clinical trials: retroviruses, adenoviruses, and adeno-associated viruses (Table 9-2).

Gene Therapy and Thoracic Surgery / 115

Retroviruses are RNA viruses that release the viral genome into the host cell cytoplasm with reverse transcriptase so that a DNA copy is made in the infected cell (viral cDNA); subsequently, the viral cDNA is integrated into the host cell genome. (For a recent, comprehensive review of retroviral vector design, see Hu and Pathak’s article.1) Recombinant retrovirus was the first widely used viral vector system, and the initial successes of this vector system catalyzed early gene therapy development. The advantages of the retroviral vectors include (1) that the transgene is integrated into the host cell genome and thereby transmitted to progeny cells, and (2) the low toxicity of the virus. Disadvantages of retroviruses that have limited their use in clinical trials include (1) a low efficiency of in vivo infection that limits use to ex vivo infection of target tissues that are then replaced within the organism, which is obviously not applicable for many clinical applications; (2) the time-dependent silencing of transgene expression that occurs over several weeks; and (3) the difficulties in developing a targeted recombinant virus capable of infecting specific cell types. The major safety concern of this system is the theoretic possibility that the transgene flanked by the viral promoter sequences could insert into a critical portion of a host cell genome and transform the cell. Wild-type adenoviruses are DNA viruses that, in a simplistic sense, convert infected cells into virusproducing cells for a short period of time prior to lytic cell death caused by the viral proteins. The recombinant adenoviruses are replication defective so that infected cells are not lysed. Recombinant adenoviruses possess several important advantages over the retroviral vectors: they can be easily produced in high titers, they do not integrate viral genes into host cell genomes, and they can infect target cells by in vivo administration. In spite of these important advantages, the adenovirus vector system suffers from the following important disadvantages: difficulties in targeting the recombinant adenovirus infection to the target cells; a reduction of the hepatic tropism, which is responsible for life-threatening toxicity when large amounts of recombinant adenovirus are systemically administered; and a transient expression of the transgene, in part the consequence of the fact that it does not integrate into the host cell genome. These weak points of the adenoviral vector system are being addressed by a number of investigators. Significant

progress has been made, but more work needs to be done. (For a recent, comprehensive review of adenoviral vectors, see the article by Hitt and Graham.2) Adeno-associated viruses (AAVs) are DNA viruses that integrate at a specific site in the host genome, although the integration specificity appears to be less stringent with recombinant AAVs. The AAV vector systems have been largely relegated to ex vivo applications (eg, bone marrow stem cell infection) because these viruses are difficult to manufacture in the large, hightiter lots required for most in vivo applications. (See the A

Transgene Viral Genes Deleted Portion of Viral Genome Viral Coat Proteins that Bind Extracellular Receptors

B

Transgene

FIGURE 9-2. Gene therapy vectors. A, Viral vectors. The bar represents a recombinant viral genome, which typically has a portion of the native sequence deleted that both renders the virus replication defective and provides space for the therapeutic transgene. The viral coat contains receptors that mediate binding to the cell surface and internalization of the intact viral genome. B, Nonviral vectors. Typically, the viral transgene, shown as the bar inside, is the only protein coding sequence that is introduced into cells by this approach. Most nonviral vector systems do not contain exterior binding proteins for the facilitation of cell binding and entry so that the transgene enters the cell via receptor-independent endocytosis, which is often associated with enzymatic destruction of some transgenes.

TABLE 9-2. Recombinant Viruses Commonly Used for Gene Therapy Studies Parental Virus Retrovirus Adeno-associated virus Adenovirus

Transgene Integrated into Host Genome

In Vivo Administration Potential

Human Toxicity

Yes Yes No

Low Low High

Low Low Potentially high

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article by Gao and colleagues for a recent, comprehensive review of AAV vectors.3) In spite of these limitations, AAVs have recently been shown to have potential utility in hemophilia. nonviral vector systems A large number of nonviral vector systems have been employed for basic studies of gene transfer (see Figure 16–2), but the majority of these methods are too toxic or impractical for clinical applications. The clinically relevant methods use one or more compounds that condense the DNA and facilitate target cell entry. (For a comprehensive review of nonviral vectors, see Nishikawa and Huang’s article.4) Cationic lipids have been the most widely used class of nonviral vectors. These positively charged lipids form a complex with the negatively charged DNA to condense the DNA and serve to mask the negative charges that otherwise repel the DNA from cell membranes that are also slightly negative in charge. The lipids interact with the cell membranes by a receptorindependent mechanism, resulting in cytoplasmic entry by endocytosis. Cationic lipids have been combined with other condensing agents as well as targeting moieties as a means of improving efficacy and attempting to target the delivery to specific cell types. The advantages of cationic lipids over the viral vectors include (1) the elimination of many biohazard concerns associated with recombinant virus systems, and (2) the potentially greater uniformity, longer shelf-life, and easier storage than the viral agents. However, the central limitation of the lipid-based vectors is the markedly lower gene-transduction efficiency compared with that of the viral systems, in part the consequence of host cell destruction of the therapeutic DNA that gains entry into the cytoplasm by receptorindependent pathways. Some specific formulations have been developed that can improve the efficiency, but a large gap in efficiency remains between cationic lipids and viral vectors. practical implications of the limitations posed by available gene therapy vector systems In the context of pathophysiologic states addressed by thoracic surgeons, the shortcomings of currently available vectors both limit the utility of intrathoracic gene therapy and dictate the means of administration. All intrathoracic gene therapy strategies have required direct, local administration of the vector at the target. For example, the TP53 gene therapy for nonsmall cell lung cancer (NSCLC) has used intratumoral injections containing the vectors with the wild-type TP53 expression cassette. This means of vector administration results in limited distribution of the vector within the target tissue site, although efficacy can be better than expected owing to “bystander effects.”

Bystander Effects If one accepts the premise that gene therapy works by modifying the genetic makeup of cells one cell at a time, then the corollary of this expectation is that the majority of cells within a target tissue must be transduced with the therapeutic gene for efficacy. In a variety of contexts, preclinical animal models have shown that some gene therapy strategies overcome this apparent limitation of gene therapy by a bystander effect. The bystander effect simply refers to the transduced cells exerting therapeutically desirable effects on surrounding, nontransduced cells that have not been genetically modified (Figure 9-3). The existence of the bystander effect was first described with the HSVTK system, in which cells modified to express the viral thymidine kinase convert the antiviral drug ganciclovir into its toxic form, which subsequently kills the cell. In preclinical studies it was found that the proportion of cells killed greatly exceeded the proportion of cells actually modified to contain the HSVTK protein. Mixing experiments, in which HSVTK-containing cells were mixed with naive cells, confirmed that ganciclovir sensitivity had apparently spread to neighboring cells that had not been genetically modified. It was subsequently shown that the HSVTK bystander effect was largely the consequence of the modified ganciclovir produced within the genetically modified cells disseminating to neighboring cells by intercellular junctional communications.5 Other bystander effects for other transgenes have been identified, although the mechanisms are not all as completely understood.

New Gene Recipient

FIGURE 9-3. Bystander effect. Shown is a schematic representation of nine cells, but only the cell in the center of this group has received the intact viral transgene represented by the bar in the nucleus. However, all of the neighboring cells are killed with the single genetically modified cell as a consequence of the bystander effect. Several bystander effects have been described that work by different mechanisms.

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Summary The initial gene therapy experience has identified genetic strategies that can be effective in modifying target tissues in a clinically meaningful way, based on preclinical animal models. These “proof of principle” studies have helped identify gene products that play essential roles in a variety of pathophysiologic states. It should be clear from the previous sections that the greatest barrier to broad, clinical use of gene therapy for any clinical situation, including intrathoracic diseases, is the development of better vector systems. Incremental improvements have been made in the extant vector systems, such as the development of some rudimentary targeting methodologies that can direct the vector away from some tissues that may sustain vector damage (eg, hepatocytes) and toward the desired target. However, it can be argued that the vector field has not produced any vector systems that are not simply modifications of existing vectors in more than a decade. Once the vector barrier is overcome, gene therapy will become a mainstream therapeutic modality—but for the present, it remains one with narrow applications that can be addressed with the limited vector technology we have today.

Intrathoracic Gene Therapy Relevant to Thoracic Surgical Problems The remainder of this chapter highlights selected gene therapy strategies that have been most extensively studied for intrathoracic conditions encountered by the thoracic surgeon. Lung cancer and mesothelioma are the two conditions relevant here that have been subjected to the majority of gene therapy investigations, although a few studies have addressed aspects of lung transplantation. Preclinical Studies of Lung Cancer Gene Therapy There are two overriding rationales for the interest in exploring the feasibility and efficacy of gene therapy for lung cancer. First, novel therapy development is highly appropriate for this common neoplasm that has an unacceptably low disease-free survival. Second, the past two decades have led to the identification of common somatic mutations that have been shown to play a key role in the initiation and perpetuation of the transformed respiratory epithelium that comprises lung cancer. The identification of these mutations has provided targets for gene therapy, and, in fact, some of the gene therapy experiments have demonstrated the critical role that some mutations play in perpetuation of the transformed state. Table 9-3 lists strategies and specific transgenes that have been employed in preclinical gene therapy studies

for lung cancer. Given the propensity for small cell lung cancer (SCLC) to undergo widespread metastasis and the current lack of a targetable-injectable vector system, the interest in pursuing gene therapy for this category of lung cancer has been relatively limited. The efforts for SCLC have been primarily restricted to using tissuespecific promoters to direct HSVTK expression within the neoplastic cells. There have been no clinical trials of gene therapy for SCLC. The preclinical studies of gene therapy listed in Table 9-3 illustrate that considerably more effort has been expended in exploring gene therapy for NSCLC. Various HSVTK strategies have been employed that use tissuespecific promoters or fusion proteins, for example. Although NSCLC has not been a favorite target of immunotherapy studies, several studies have employed cytokines, immunogenic proteins (MDA7), or cofactors that promote immune responses. Radiosensitization and antiangiogenesis strategies have also been exploited in a limited number of studies. As Table 16-3 shows, the largest effort has been directed toward the addition of genes encoding proteins that counteract a variety of oncogenes, antioncogenes, or other proteins that are essential in maintaining the neoplastic phenotype, a process that is broadly defined here as dominant suppression. In most of these studies, the successful production of the transgene protein leads to the death of the neoplastic cell. TABLE 9-3. Examples of Preclinical Gene Therapy Strategies for Lung Cancer Cancer

Gene Therapy Strategy Example

Small cell lung cancer

Indirect toxin

Nonsmall cell lung cancer

Indirect toxin Immunopotentiation

Dominant suppression

Radiosensitizer Angiogenesis GRP = ; MYC-MAX = .

GRP promoter-directed HSVTK 26 Neuron-specific, enolase-directed HSVTK 27 MYC-MAX-directed HSVTK 28 Multiple HSVTK 29 HGPRT 30 IL2 31 IL1/IL3 32 CD4L33 MDA7 34 TP53 10 p16INK4a35 RB2/p13036 k-ras ribozyme37 p2738 cyclin D antisense39 E1A40 c-erb2 antisense41 IGFB-342 Na+/I+43 flt–receptor decoy 44

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Clinical Studies of Lung Cancer The tumor suppressor (antioncogene) gene TP53 encodes a protein that serves as a critical transcriptional regulator of many other genes that modulate cell growth/division and apoptosis (as reviewed in Malkin’s article6). One of the most important TP53 functions relevant to cancer therapy is its function as a genomic quality-control monitor, whereby damaged DNA is detected early in the course of the cell cycle. Normally functioning TP53 halts the progression of the cell cycle in those cells with damaged DNA and initiates either a process of DNA repair or the onset of apoptosis. Since many chemotherapies, as well as radiotherapy, act by inducing DNA damage in the malignant cells, those cells with mutated or absent TP53 protein might be expected to demonstrate resistance to the therapy as they continue to complete cell cycles in the absence of the TP53 checkpoint. This expectation has been confirmed experimentally and has led to a broad interest in the development of therapies that can compensate for the loss of TP53 function. Not surprisingly, gene therapy has been investigated as one means of correcting the somatic mutations of TP53 in neoplastic cells. In the context of intrathoracic disease, NSCLC has been most extensively studied in both preclinical and clinical studies of TP53 gene therapy. Since neoplastic cells have multiple somatic mutations in addition to those associated with TP53, it was not intuitively obvious that the correction of the TP53 protein alone by the addition of a wild-type TP53 gene would be sufficient to change the cell phenotype. However, extensive experimentation with multiple neoplastic cell types, including NSCLC, has firmly established that addition of wild-type TP53 into neoplastic cells with defective/absent TP53 generally induces those cells to undergo apoptotic cell death.7 In other words, these experiments showed that it was not necessary to address the multiple other mutations in oncogenes and other growth regulatory genes that are commonly present in concert with TP53 mutations for TP53 gene therapy to trigger neoplastic cell death. Since approximately 50% of NSCLCs contain a defective or absent p53 gene product, Dr. Jack Roth and colleagues pioneered studies that examined the effects of transducing wild-type TP53 genes into NSCLC with defective or absent TP53. Initial studies established that NSCLC cell lines with mutated or deleted TP53—but not those with wild-type TP53—were killed by the addition of the normal TP53 gene. 8 Other in vitro studies by several groups have also shown that TP53 gene therapy can also function to both chemosensitize and radiosensitize NSCLC cells that are defective in TP53.9 However, many expected that TP53 gene therapy was little more than an in vitro laboratory phenomenon, where condi-

tions allowed a large majority of the cells to receive the wild-type TP53 gene. Since there was no apparent mechanism for a TP53 bystander effect, it was not clear that TP53 gene therapy would be efficacious in vivo, where only a minority of cells would receive the new gene because of the current vector limitations. Importantly, subsequent animal studies established that the intratumoral administration of wild-type TP53 into engrafted NSCLC with mutant/absent TP53 by either retroviral or adenoviral vectors resulted in a marked reduction in tumor nodule growth.10 The preclinical efficacy in the tumor nodules could only be explained by some type of bystander effect. There is some data suggesting that TP53 gene therapy may exert a bystander effect via antiangiogenic effects, but this is not yet completely understood.11,12 The success of the preclinical studies has been followed by an initial phase I clinical study in which wild-type TP53 carried within an adenoviral vector was administered via intratumoral injection into inoperable NSCLC with mutated/absent TP53. In this doseescalation trial that included 25 evaluable patients, 23 of 25 received multiple intratumoral injections with minimal toxicity. Two of 25 patients had a partial response (PR), 16 of 25 had stable disease over 2 to 14 months, and the remainder progressed. 1 3 Toxicity associated with the gene therapy was minimal. A subsequent phase I trial by the same group assessed the safety of using adenoviral-mediated TP53 gene therapy in conjunction with chemotherapy. In this trial 24 patients received cisplatin, followed 3 days later by an intratumoral administration of TP53. Two of 24 patients had a PR, and 17 of 24 had stable disease; again, toxicity was minimal.14 A phase II trial by a different group also examined adenoviral-mediated TP53 gene therapy in combination with chemotherapy. In this trial 25 patients received an intratumoral TP53 gene in combination with one of two chemotherapy regimens (carboplatin plus paclitaxel, or cisplatin plus vinorelbine) given to patients with advanced-stage disease. Response rates and median survivals in patients receiving either chemotherapy regimen with the TP53 gene therapy were not significantly improved relative to the controls who received the chemotherapy alone.15 A second phase II trial has been reported by the Swisher and colleagues in abstract form that examined TP53 gene therapy in combination with radiotherapy.16 In this trial, subjects receiving radiotherapy concomitantly received intratumoral injections of Ad-p53 on days 1, 18, and 32. There were 13 evaluable patients: 5 of 13 had a complete response and 2 of 13 a PR, but 19% of the patients also experienced grade 3/4 toxicities. It is worth noting here that one small, earlier phase I study examined the safety of administering a recombi-

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nant adenovirus with a -galactosidase gene that functions as a marker without any known therapeutic effect into NSCLC. 17 In this trial of six patients, the virus administration was well tolerated and, surprisingly, four of six patients had PRs in the treated tumors. This result raises a question about the mechanism responsible for the responses seen in some of the adenovirus-p53 trials that may involve effects related to the adenoviral vector as well as the p53 gene product resulting from the successful gene transfer in the treated lung cancers. In summary, TP53 gene therapy has certainly substantiated the importance of mutated TP53 in the maintenance of the neoplastic phenotype. Since many carcinomas contain a multitude of somatic mutations in genes relevant to cell growth, it was particularly noteworthy that the preclinical studies of TP53 gene therapy have identified mutant TP53 as a key target for future therapies—whether they be gene therapy or other modalities. The limited clinical studies have generally shown that the adenoviral delivery of wild-type TP53 is well tolerated, although the studies of concomitant radiotherapy and Ad-p53 did reveal significant toxicity that might temper further increases in the amount of gene therapy vector administered. The efficacy suggested by these early studies of very few patients has been quite modest, and certainly the data do not yet support the widespread use of TP53 gene therapy in NSCLC. However, as pointed out in earlier sections, it seems highly probable that the development of better vector systems could dramatically improve the efficacy of TP53 gene therapy for NSCLC, as well as reducing toxicity associated with the adenoviral vector system. It should also be noted that approximately 50% of NSCLCs involve wild-type TP53 and are therefore not expected to derive any benefit from TP53 gene therapy, no matter how ideal a future vector system may be. Mesothelioma Malignant mesothelioma of the pleural space is a relatively rare neoplasm that responds poorly to conventional therapy. The team of Albelda and Kaiser has pioneered efforts to develop a gene therapy approach for this problematic neoplasm. Their efforts have focused on a toxic gene therapy strategy employing an HSVTK-plusganciclovir system.18 As was briefly alluded to earlier, the HSVTK gene encodes for the viral thymidine kinase that, in and of itself, is not toxic to cells. However, cells containing the HSVTK protein phosphorylate antiherpetic drugs such as ganciclovir into a nucleotide analog that kills the host cell. The HSVTK-plus-ganciclovir system has been widely examined in preclinical and clinical gene therapy investigations for three reasons: (1) the protein encoded by the HSVTK gene is not, itself, toxic, so nonspecific gene transfer (into untargeted cells) does

not lead to problems, (2) the drugs used in conjunction with HSVTK are already approved and available for human use, and (3) the toxicity is conferred only when ganciclovir is present, and in the event of undesirable toxicity, further problems could be greatly mitigated by simply withholding further ganciclovir infusions. In preclinical studies of HSVTK gene therapy for mesothelioma, investigators employed an animal model in which human mesothelioma was engrafted into the peritoneal cavities of immunosuppressed mice or the pleural space of rats.19 Multiple intraperitoneal administrations of adenovirus with an HSVTK transgene resulted in significant reductions in tumor burden and survival advantage compared with those of controls. These promising findings led to a phase I trial of adenoviral-mediated HSVTK gene therapy that was administered via thoracoscopic injection into the tumor mass. The results of this phase I trial of 20 evaluable patients revealed some transient side effects, but only 11 of 20 had demonstrable gene transfer in spite of the direct thoracoscopic administration of the adenoviral vector into the tumor masses, a result that underscores the limitations of available vector systems.20 In this initial phase I report, investigators were unable to identify tumor reduction in any of the patients, although a minority of the patients appeared to have stable disease. An extension of this trial is currently underway. A novel alternative form of the HSVTK-plusganciclovir approach has been developed by Schwarzenberger and colleagues.21 In their strategy an ovarian carcinoma cell line designated PAI-STK is genetically modified to permanently express the HSVTK protein. In preclinical animal studies of ovarian cancer as well as mesothelioma, it was observed that these PAI-STK cells preferentially adhere to the neoplastic cells within the host by an unclear mechanism, and subsequently lead to the killing of the neoplastic cells when ganciclovir is administered, presumably by the bystander mechanism. The results of the first phase I trial of this strategy for mesothelioma have reported that the intrapleural infusion of the PAI-STK cells were well tolerated up to the maximal infused dose (3  10 9 cells). 22 Some scintigraphic data suggested that the PAI-STK cells did home to areas of mesothelioma within the pleural space. In this study there was no report of efficacy. In summary, the current status of gene therapy for mesothelioma is similar to that for NSCLC, in that some small clinical trials have shown that the gene therapy approaches used have been relatively safe. However, the currently published trials of gene therapy for mesothelioma have not shown any significant clinical efficacy. The formidable challenge for mesothelioma gene therapy is the development of a gene-delivery system that will trans-

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duce the therapeutic gene into more than that portion of the tumor that resides at the edge of the pleural effusion space into which the vectors have been administered. Lung Transplantation A small number of preclinical studies have started addressing lung allografts as targets of gene therapy. These proof of principle investigations have sought to examine the feasibility of modifying allograft cells as a means of mitigating acute rejection, although other longer-term objectives may also be achieved by similar means. One important aspect of lung allografts is the opportunity to infuse the vasculature or the bronchial tree in an isolated fashion for extended periods of time without the concern of vector effects beyond the lung, as would be the case in an intact host. Rat lungs have been excised, and either naked plasmid DNA or cationic lipid complexes of plasmid containing marker genes have been instilled into the bronchial tree. 23,24 In these studies successful gene transfer and subsequent gene expression were documented. One study infused Brown Norway rat lungs with an adenoviral vector containing a transgene for CTLA-4Ig protein that greatly mitigates acute rejection in the rat allograft lung transplant model system.25 The lungs were subsequently engrafted into allogeneic Lewis rat recipients, and lungs that had been treated with the vector had a significant reduction in the histologic grade of rejection. Certainly the handful of gene therapy studies directed toward lung transplantation have not clearly defined the optimal target genes and strategies necessary for a therapeutically meaningful intervention, but they are likely to stimulate further studies. The author thanks Dr. Paul Reynolds for his thoughtful review of this chapter. This work was supported in part by a VA Merit Review awarded to Robert I. Garver Jr.

References 1. Hu WS, Pathak VK. Design of retroviral vectors and helper cells for gene therapy. Pharmacol Rev 2000;52:493–511. 2. Hitt MM, Graham FL. Adenovirus vectors for human gene therapy [review]. Adv Virus Res 2000;55:479–505. 3. Gao GP, Wilson JM, Wivel NA. Production of recombinant adeno-associated virus. Adv Virus Res 2000;55:529–43.

6. Malkin D. The role of p53 in human cancer [review]. J Neurooncol 2001;51:231–43. 7. Baker SJ, Markowitz S, Fearon ER, et al. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990;249:912–5. 8. Fujiwara T, Grimm EA, Mukhopadhyay T, et al. A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res 1993;53:4129–33. 9. Fujiwara T, Grimm EA, Mukhopadhyay T, et al. Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res 1994;54:2287–91. 10. Fujiwara T, Cai D, Georges RN, et al. Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst 1994;86:1458–62. 11. Rizk NP, Chang MY, Kouri CE, et al. The evaluation of adenoviral p53-mediated bystander effect in gene therapy of cancer. Cancer Gene Ther 1999;6:291–301. 12. Nishiszaki M, Fujiwara T, Tanida T, et al. Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect. Clin Cancer Res 1999;5:1015–23. 13. Swisher SG, Roth JA, Nemunaitis J, et al. Adenovirusmediated p53 gene transfer in advanced non-small cell lung cancer. J Natl Cancer Inst 1999;91:763–71. 14. Nemunaitis J, Swisher SG, Timmons T, et al. Adenovirusmediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small cell lung cancer. J Clin Oncol 2000;18:609–22. 15. Schuler M, Hermann R, DeGreve JL, et al. Adenovirusmediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small cell lung cancer: results of a multicenter phase II study. J Clin Oncol 2001;19:1750–8. 16. Swisher S, Roth JA, Komaki R, et al. A phase II trial of adenoviral mediated p53 gene transfer (IRPR/INGN 201) in conjunction with radiation therapy in patients with localized non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol 2000;19:461a. 17. Tursz T, Cesne AL, Baldeyrou P, et al. Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients. J Natl Cancer Inst 1996;88:1857–63.

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Gene Therapy and Thoracic Surgery / 121 20. Sterman DH, Treat J, Litzky LA, et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998;9:1083–92. 21. Schwarzenberger P, Lei D, Freeman SM, et al. Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol 1998;19:333–7. 22. Harrison LHJ, Schwarzenberger PO, Byrne PS, et al. Gene modified PA1-STK cells home to tumor sites in patients with malignant pleural mesothelioma. Ann Thorac Surg 2000;70:407–11. 23. Nagahiro I, Mora BN, Boasquevisque CH, et al. Toxicity of cationic liposome-DNA complex in lung isografts. Transplantation 2000;69:1802–5. 24. D’Ovidio F, Daddi N, Suda T, et al. Efficient naked plasmid cotransfection of lung grafts by extended lung/plasmid exposure time. Ann Thorac Surg 2001;71:1817–23. 25. Ugurlu MM, Griffin MD, O’Brien T, et al. The effects of CTLA-4Ig on acute lung allorgraft rejection: a comparison of intrabronchial gene therapy with systemic administration of protein. Transplantation 2001;71:1867–71. 26. Morimoto E, Inase N, Mlyake S, et al. Adenovirus-mediated suicide gene transfer to small cell lung carcinoma using a tumor-specific promoter. Anticancer Res 2001;21:329–31. 27. Tanaka M, Inase N, Miyake S, et al. Neuron specific enolase promoter for suicide gene therapy in small cell lung carcinoma. Anticancer Res 2001;21:291–4. 28. Nishino K, Osaki T, Kumagai T, et al. Adenovirus-mediated gene therapy specific for small cell lung cancer cells using Myc-Max binding motif. Int J Cancer 2001;91:851–6. 29. Smith MJ, Rousculp MD, Goldsmith KT, et al. Surfactant protein A–directed toxin gene kills lung cancer cells in vitro. Hum Gene Ther 1994;5:29–35. 30. Trudeau C, Yuan S, Galipeau J, et al. A novel parasite-derived suicide gene for cancer gene therapy with specificity for lung cancer cells. Hum Gene Ther 2001;12:1673–80. 31. Tan Y, Xu M, Wang W, et al. IL-2 gene therapy of advanced lung cancer patients. Anticancer Res 1996;16:1993–8. 32. Esandi MC, van Someren GD, Bout A, et al. IL-1/IL-3 gene therapy of non-small cell lung cancer (NSCLC) in rats using “cracked” adenoproducer cells. Gene Ther 1998;5:778–88.

33. Noguchi M, Imaizumi K, Kawabe T, et al. Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-gamma gene into lung cancer. Cancer Gene Ther 2001;8:421–9. 34. Saeki T, Mhashilkar A, Chada S, et al. Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in nonsmall cell lung cancer cell in vitro. Gene Ther 2000;7:2051–7. 35. Lee JH, Lee CT, Yoo CG, et al. The inhibitory effect of adenovirus-mediated P16INK4a gene transfer on the proliferation of lung cancer cell line. Anticancer Res 1998;18:3257–61. 36. Claudio PP, Howard CM, Pacilio C, et al. Mutation in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Cancer Res 2000;60:372–82. 37. Zhang YA, Nemunaitis J, Scanlon KJ, et al. Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice. Gene Ther 2000;7:2041–50. 38. Park KH, Seol JY, Yoo CG, et al. Adenovirus expressing p27(Kip 1) induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts. Lung Cancer 2001;31:149–55. 39. Schrump DS, Chen A, Consoli U. Inhibition of lung cancer proliferation by antisense cyclin. Cancer Gene Ther 1996;3:131–5. 40. Chang JY, Xia W, Shao R, et al. Inhibition of intratracheal lung cancer development by systemic delivery of E1A. Oncogene 1996;13:1405–12. 41. Casalini P, Menard S, Malandrin SM, et al. Inhibition of tumorigenicity in lung adenocarcinoma cells by c-erB-2 antisense expression. Int J Cancer 1997;72:631–6. 42. Hochscheid R, Jaquest G, Wegmann B. Transfection of human insulin-like growth factor–binding protein 3 gene inhibits cell growth and tumorigenicity: a cell culture model for lung cancer. J Endocrinol 2000;166:553–63. 43. Boland A, Ricard M, Opolon P, et al. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. Cancer Res 2000;60:3484–92. 44. Kong HL, Hecht D, Song W, et al. Regional suppression of tumor growth by in vivo transfer of cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum Gene Ther 1998;9:823–33.

CHAPTER 10

DATABASES AND CLINICAL OUTCOMES: THE GENERAL THORACIC SURGERY DATABASE JOSEPH C. CLEVELAND JR, MD JOHN D. MITCHELL, MD FREDERICK L. GROVER, MD Quality improvement in cardiac care during the past three decades has made substantial progress. Multiinstitutional databases have been developed specifically to monitor outcomes in cardiac surgery. The leaders in this effort include the Department of Veterans Affairs (VA) National Cardiac Database, the Society of Thoracic Surgeons (STS) National Database, the Northern New England (NNE) Database, and the New York State Database. Historically, a primary focus of these databases was to collect and track cardiac surgical outcomes, with the specific aim that feedback to participating programs could improve outcomes. Secondarily, these databases also provide enormously powerful multi-institutional data from which clinical questions can be effectively answered. 1,2 Continued challenges include measuring other outcomes and extending these databases to other areas in cardiothoracic surgery including congenital heart surgery and general thoracic surgery. These models have been rigorously developed for cardiac surgery and should be easily adaptable for other areas of surgery for monitoring and improving quality of care. The purpose of this chapter is to review the status of the General Thoracic Surgery Database and to provide an overall perspective of the existing models of cardiac surgical databases.

surgical databases to risk adjust outcomes and to establish a process of quality improvement in cardiac surgery. Although these two databases evolved from the same paradigm, they differ substantially. The VA database (Continuous Improvement in Cardiac Surgery Program) involves mandatory reporting. The purpose of this database is to screen quality of outcomes, provide quality improvement, and determine the viability of cardiac surgery programs. Conversely, the STS National Adult Cardiac Surgery Database is a voluntary, surgeon-driven process. This latter database is primarily aimed toward providing internal assessments of quality of cardiac surgical care and local, institutional guidance in quality improvement. In 1972 the VA established the Cardiac Surgery Consultants Committee to monitor cardiac surgical outcomes within the nationwide VA system. This committee originally used unadjusted raw mortality statistics to evaluate volume and death rates among VA medical centers. The committee realized that raw death statistics represented an unappealing and inadequate method to determine the quality of cardiac care between the participating centers. Thus, in 1987 the VA Cardiac Surgery Consultants Committee implemented riskadjusted methodology to appropriately track cardiac surgical outcomes. The obvious benefits of risk adjusting data include that a more fair and accurate assessment of quality of care can be achieved, and it prevents surgeons from denying operations to patients deemed “high risk” with the perception that one or two excess deaths in high-risk patients could adversely affect raw mortality results. To implement this risk-adjusted mortality, a data

Historical Perspective: The Development of the VA and STS Databases Beginning in 1987 and 1989, respectively, the VA Department and the STS developed national cardiac 122

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form was developed that captures variables relative to coronary artery bypass grafting (CABG), valvular surgery, and great vessel surgery. The primary end point for analysis is 30-day surgical death. The definition of 30-day surgical death includes any death from any cause within 30 days after surgery, or death occurring after 30 days that is a direct result of a perioperative complication. Multivariate logistic regression analysis was employed to identify significant risk factors and to determine the odds ratios that were initially predictive of death and complications for CABG only and valve-CABG procedures. Semiannually, masked confidential reports are distributed to each VA center performing cardiac surgery for local quality improvement. Thus, since 1990 risk-adjusted outcomes have been used within the VA system to provide local selfassessment and quality outcomes purposes. The STS initiated the development of a voluntary, national, adult cardiac surgery database in 1989. The motivation for the development of this database included the desire for surgeons to conscientiously review their surgical results, and to allay the growing concerns of various public (Health Care Financing Administration) and private entities regarding the results of cardiac surgery. Under the leadership of Fred Edwards, MD, chair of the adult cardiac surgery database committee, the statistical methodology and risk adjustment in the STS Database used Bayes’ theorem. Subsequently, in 1995 this riskadjustment modeling was changed to multivariate analysis. During the period from 1990 to 1997, the STS National Cardiac Surgical Database was maintained with Summit Medical Inc., which warehoused the data and developed the software package for the database. In 1997 the STS executive leadership decided to license multiple software vendors and to move the data storage and analysis to the Duke Clinical Research Institute. This move has enabled easier data analysis and queries of the database for research purposes. A copy of the current STS software with core STS data elements and definitions is available at . Biannual reports are generated for participants in the STS database, and these reports graphically display the observed-to-expected ratios of death and major complications for the participating center, its region, and the nation. Both the STS and VA databases have been used for 10 to 12 years. Although many similarities exist with regard to sharing common risk factors and similar odds ratios for outcomes, distinct differences are also present. The VA is composed of a 99% male population with a high incidence of comorbidities, and many VA patients lack insurance. Also, as noted previously, the VA database involves mandatory reporting. Although the VA database is used for oversight and the authority exists to close

programs with poor outcomes, this occurrence rarely happens. The review of programs in the VA system includes outside consultants who offer constructive advice rather than providing a punitive construct. In contrast, the STS database is voluntary, with over 450 centers currently participating. Both databases report outcomes every 6 months, and both databases have measured processes of care such as internal mammary artery use and length of stay.

Challenges Facing Both the STS and VA Databases Recent changes in patient confidentiality and data reporting will require creative solutions. Currently, the STS database strips all patient identifiers and scrambles the surgery and birth dates. However, it is unknown what impact the laws of the new Health Insurance Portability and Accountability Act (HIPAA) of 1996 will exert over the collection and reporting of patient data. It is hoped that reason will prevail and that these federal regulations imposed upon the STS database will not be overly onerous or difficult. The second major challenge facing the STS database is the cost of maintaining the database. In the past, hospitals shared the cost of data managers (usually nurses), the software, and data storage and analysis. As hospitals are forced to justify costs and minimize expenses, they are shifting more of the cost burden to the individual cardiothoracic surgical practices. The current cost of software in the STS is approximately $9,000 (US), and the cost of data storage is roughly $2,000 (US). This cost is not insignificant, and it discourages universal participation in the database. Clearly, at a time when increasing scrutiny exists regarding surgical outcomes, cardiothoracic surgeons need to offer a unified front in supporting the efforts of the database. Software and data analysis are provided in the VA system. Clearly, these issues will also play a role in the implementation and development of the General Thoracic Surgical Database.

Extrapolating from Current Databases to the General Thoracic Surgery Database For the past several years, the STS has been developing a General Thoracic Surgery Database. This is taking considerable effort and is being led by David Harpole, MD, and Bill Putnam, MD, in conjunction with the General Thoracic Committee and the General Thoracic Surgery Club. This database has been developed to be a simple one with only two pages of data elements, including a small administrative section; a demographic

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section; and data elements involving preoperative risk factors, operative details, and postoperative events such as pulmonary, cardiovascular, gastrointestinal, and other organ system morbidities, infections, and bleeding. In addition, air leak data is collected and, obviously, mortality data at 30 days. Included are tracheal/bronchial, pulmonary, esophagogastric, chest wall, diaphragm, mediastinum, neck and pleural, pericardial, vascular, and cardiac procedures as they pertain to general thoracic procedures. In addition, in patients with carcinoma, the final pathology and TNM status are captured. In July 2002 the STS offered this database to interested surgeons, the cost of which was quite reasonable, with the software package included in the annual fees of $750 to $1,250 (US) depending on the number of active surgeons performing these procedures per center or group. Data on patients operated on during the calendar year 2002 were sent to the Duke Clinical Research Institute (the data warehousing and analysis center for the general thoracic and adult cardiac databases) for analysis and reports. The data forms and definitions are available on the STS Web page (). It is envisioned that this database will continue to be expanded over time and will serve as a quality-improvement tool for those performing general thoracic surgery in a similar fashion to the way that the adult cardiac surgery and congenital databases are useful for those performing cardiac surgery. It is also expected that, pending HIPAA regulations, provisions will be made for long-term follow-up of these patients. The STS has also developed a minimal data set for congenital heart procedures, with an expected data harvest and analysis for the fall of 2002. This follows a long period of planning under the leadership of Constantine Mavroudis, MD, who is charged with developing the congenital heart database, including major international collaboration on defining congenital cardiac surgical procedures and diseases. In addition, data from this basic congenital cardiac database will be analyzed by the Duke Clinical Research Institute for the STS, with reports being generated and distributed to the congenital heart surgery members. There is also a more complex, complete data set available for the large centers desiring detailed information. Remarkably, both the VA and STS databases during their existence have demonstrated a very significant reduction in risk-adjusted operative mortality approaching 25 to 30% (Figures 10-1 and 10-2).2This has occurred in spite of patient risk factors increasing throughout the 1990s. Similar reductions in mortality following the implementation of analysis of outcome data and their distribution to surgeons and their colleagues have occurred in northern

New England, where they noted a 24% reduction in deaths following the institution of round-robin site visits for feedback of outcome data and training in quality improvement. 3 New York State has also reported a similar reduction in risk-adjusted operative mortality. Of great interest is the fact that for three of these databases (those of the STS, VA, and northern New England), there has been no public reporting of data, just internal dissemination of these data to those providing the care.

FIGURE 10-1. Unadjusted and adjusted operative mortality rates between April 1987 and September 1991.

FIGURE 10-2. Ratio of observed-to-expected mortalities between 1990 and 1999.

References 1. Mavroudis C, Jacobs J. Congenital Heart Surgery Nomenclature and Database Project: overview and minimum dataset. Ann Thorac Surg 2000;69:1–387. 2. Grover FL, Cleveland JC Jr, Shroyer AL. Quality improvement in cardiac care. Arch Surg 2002;137:28–36. 3. O’Connor GT, Plume SK, Olmstead EM, et al for the Northern New England Cardiovascular Disease Study Group. A regional intervention to improve the in-hospital mortality associated with coronary bypass grafting surgery. JAMA 1996;275:841–846.

CHAPTER 11

PRIMARY AND SECONDARY CHEST WALL TUMORS L. PENFIELD FABER, MD

The incidence of fibrous dysplasia is approximately the same as that of osteochondroma, whereas chondroma and bone cysts account for approximately 10 to 25% of benign lesions of bone.4

Chest wall tumors are neoplasms in the bones or soft tissues of the thoracic cage. Primary tumors of the chest wall develop in the bones or soft tissues of the thorax. Bony tumors include chondroid, osseous, giant cell, and marrow-derived tumors. Soft tissue tumors include those of a fibrous, fibrohistiocytic, adipose, neurologic, and muscular character. Secondary chest wall tumors include tumors that arise from an adjacent organ that invade the chest wall, and tumors that have metastasized to the bones or soft tissue of the chest from a distant site. Malignant tumors arising from the lung are the most common of these, followed by breast cancer and malignant tumors of the pleura. Hedblom reviewed and reported on 213 tumors of the chest wall collected from the literature between 1898 and 1921 and updated his collected series to 313 cases in 1933.1 The majority of these cases, unlike findings in other series, involved primary chest wall malignancies, and Hedblom was among the first to pathologically categorize the various primary tumors of the thoracic wall. Primary chest wall tumors are a heterogeneous group of tumors of bone and soft tissue (Table 11-1). Altogether, they comprise only 1 to 2% of all primary tumors of the body.2 Primary malignant chest wall tumors account for approximately 4% of all new cancers diagnosed annually. Malignant tumors of the soft tissues are slightly more common than malignant tumors of bone, and soft tissue sarcoma is the most common primary chest wall malignancy.3 The most common benign tumors of chest wall bone, in decreasing order of frequency, are osteochondroma and fibrous dysplasia, chondroma, aneurysmal bone cyst, and eosinophilic granuloma. Osteochondroma constitutes approximately 30 to 50% of benign bony lesions.

TABLE 11-1. Primary Tumors of the Chest Wall Tissue Involvement Benign tumors of bone Bone Cartilage Fibrous Vascular Marrow Osteoclast Benign tumors of soft tissue Fibrous Adipose Nerve Muscle Malignant tumors of bone Bone Cartilage Fibrous Vascular Marrow Cellular

Malignant tumors of soft tissue Fibrous Fibrohistiocytic Adipose Nerve Muscle

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Tumor Osteoid osteoma Enchondroma Osteochondroma Fibrous dysplasia Hemangioma Eosinophilic granuloma Giant cell tumor Aneurysmal bone cyst Fibroma Lipoma Schwann cell Neurofibroma Angioleiomyoma Osteosarcoma Chondrosarcoma Malignant fibrous histiocytoma Hemangiosarcoma Plasmacytoma Ewing’s sarcoma Askin’s tumor (peripheral neuroectodermal tumor) Desmoid Fibrosarcoma Malignant fibrous histiocytoma Liposarcoma Neurofibrosarcoma Schwann cell sarcoma Rhabdomyosarcoma

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The most common malignant tumors of the bony thorax, in decreasing order of frequency, include chondrosarcoma, Ewing’s sarcoma, osteosarcoma, and solitary plasmacytoma. Chondrosarcoma is the single most common malignant tumor of the chest wall. Myeloma of the bony chest wall must be considered a systemic disease and not a primary lesion. Solitary plasmacytoma, although commonly associated with the development of multimyeloma, is defined as a primary lesion and is less frequently identified. The most common benign lesions of thoracic soft tissue are fibroma, hemangiomas, lipomas, and giant cell tumors. Malignant fibrous histiocytomas, desmoid tumors, liposarcomas, and fibrosarcomas are the most common malignant soft tumors of the chest wall. Primary soft tissue sarcomas of the thoracic wall are more common than malignant tumors of the bony thorax, and when considered as a group constitute the most common form of chest wall malignancy. Secondary chest wall tumors are most commonly lung cancer, breast cancer, and metastatic disease.

Clinical Presentation Approximately one-half of malignant tumors of the bony chest wall occur in the ribs, with the remainder presenting in the scapula, sternum, and clavicle. Malignant tumors of the ribs are frequently found in the anterior aspect of the upper seven ribs, but there is an equal distribution of benign rib tumors throughout the thorax. 5 Specific tumors are found in particular areas of the bony thorax; the chondroma and endochondroma often arise anteriorly in the costal cartilages or sternum. The chondrosarcoma most often occurs anteriorly at the costochondral junction. Benign and soft tissue malignancies of the chest wall occur in all locations with equal frequency. In Dahlin and Unni’s series, 96% of sternal tumors were malignant, with the most common types being chondrosarcoma, plasmacytoma, and osteogenic sarcoma.6 Chest wall tumors occur in all age groups. Ewing’s sarcoma occurs in younger patients, and plasmacytoma presents in the elderly. Chondrosarcoma commonly occurs in adults. A male-to-female ratio of 2 to 1 occurs for malignant chest wall tumors, whereas desmoid tumors are more common in females. Burt reported that only 2% of malignant chest wall tumors were asymptomatic.3 Fifty percent of patients presented with a painless mass, whereas 33% had a painful mass and 15% had pain without a mass being present. Pain is not necessarily a predictor of malignancy; in Hedblom’s series, pain was present in 40% of benign chondromas.1 Benign osteoma presents with severe pain relieved only by medication. Asymptomatic lesions are more often benign, and most of these

are detected on chest radiographs. Soft tissue sarcomas present as a painless mass, but tumors of bone and cartilage, both benign and malignant, present with pain. Generalized symptoms of fever, malaise, and fatigue can be presenting complaints associated with eosinophilic granuloma and Ewing’s sarcoma. Rapidly growing tumors are more likely to be malignant. It is difficult to differentiate a benign from a malignant chest wall tumor by physical examination. Bony tumors are fixed to the chest wall; soft tissue tumors may also be fixed, but others are quite mobile. Both malignant and benign lesions can be tender to palpation.

Diagnosis The chest radiograph is the initial study to be obtained. Comparison with prior films is important to evaluate the rate of growth. Computed tomography (CT) defines the extent of pleural, mediastinal, and soft tissue involvement (Figure 11-1). Metastatic disease to the lung is readily identified, and the radiologic characteristics of the tumor can assist in the clinical diagnosis. Magnetic resonance imaging (MRI) has become extremely valuable in evaluating chest wall tumors (Figure 11-2). It precisely defines the anatomic extent of the tumor, as well as showing adjacent organ involvement. A significant advantage of MRI is that multiplanar imaging with high-contrast resolution defines anatomic planes for planned resection. Differential signal intensity evaluates adjacent vascular structures and becomes critical in the assessment of the upper chest with involvement of the brachial plexus and subclavian vessels. The MRI is supplemental to the CT, and both studies assist in the planning of extensive and difficult chest wall resections. Positron emission tomography (PET) is useful to define metastatic disease when a secondary chest wall tumor is present. This particularly applies to lung and breast cancer. PET is not particularly helpful in defining the extent of a primary chest wall tumor.

FIGURE 11-1. Computed tomography scan illustrating the involvement of ribs, sternum, and mediastinum by a chondrosarcoma.

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histologic diagnosis in 90% of patients.8 A core needle biopsy can be used to establish the diagnosis in easily palpated soft tissue tumors, but can be more difficult to use with bony lesions. A needle aspiration biopsy can confirm the diagnosis for secondary chest wall neoplasms with clinically obvious metastatic disease. Needle aspiration biopsy is not recommended for primary chest wall tumors, as histologic definition is not precise.

Treatment

FIGURE 11-2. Magnetic resonance image showing a desmoid tumor of the shoulder (arrow). Other cuts reveal involvement of the brachial plexus and adjacent vessels.

Whether excisional, incisional, or needle biopsy is more appropriate for diagnosis is somewhat controversial. Graeber and colleagues recommend excisional biopsy to achieve the removal of an entire mass, obtain adequate tissue, and permit early adjuvant therapy.7 However, this approach does not take into consideration the careful planning of a wide resection and reconstruction that frequently requires a multidisciplinary approach. Plasmacytoma, Ewing’s sarcoma, and embryonal rhabdomyosarcoma are best treated with chemotherapy and/or radiation, and incisional biopsies are preferred. Primary chest wall tumors 2 to 3 cm in diameter are diagnosed and treated by excisional biopsy. A 2 cm margin of resection is usually adequate for the smaller lesion. This type of resection permits solid wound closure with simple approximation techniques, and rarely is prosthetic reconstruction required.2 A large lesion, 5 cm or greater, requires definitive diagnosis before resection and planned reconstruction. Incisional biopsy is carried out, and the biopsy site is planned so that it will be completely encompassed by a definitive resection. Minimal dissection is carried out to avoid seeding of the tumor in adjacent tissue planes. Preoperative localization of bone lesions may be required to be certain that the correct rib is removed. Knowing the exact histology prior to a major chest wall resection may permit consideration for preoperative therapy, fully informed patient consent, and plastic and neurosurgical assistance when required. Walsh and colleagues are strong advocates of the trephine or “tru-cut” needle biopsy and observed a correct

Although individual treatment must be tailored to each specific tumor, certain general principles apply. Benign tumors of the soft tissue and bones are usually smaller and are initially treated with excisional biopsy. The margin of resection usually approximates 2 cm, and recurrence is not a significant problem. Chondromas do have a propensity for local recurrence, and if this clinical diagnosis is entertained, resection is adequate. Wide resection is indicated for primary malignant chest wall neoplasms. King and colleagues evaluated the extent of resection in relation to long-term survival in patients with malignant chest wall tumors.9 When a 4 cm or greater margin of resection was obtained, 56% of patients were free of recurrent cancer at 5 years, whereas only 29% of patients who had undergone resection with a 2 cm margin were free of cancer. A 2 cm margin of resection can be adequate for secondary chest wall neoplasms. High-grade tumors of the ribs, such as Ewing’s sarcoma, malignant fibrous histiocytoma, and osteogenic sarcoma, require the removal of the entire involved rib and a portion of the rib above and below. Ewing’s sarcoma is appropriately treated with chemotherapy prior to local control by surgical excision or radiation, and plasmacytoma is best treated by radiation. When suspected clinically, both of these tumors require diagnosis by incisional biopsy prior to treatment. Malignant tumors of the sternum, clavicle, and scapula require resection of the entire bone and enough surrounding tissue to provide an adequate margin. In all cases of malignant chest wall tumors, any attached structures such as pleura, lung, pericardium, or chest wall muscles must be included with the specimen. Surgical resection is indicated for secondary malignant tumors of the chest wall, particularly lung cancer invading the chest wall, for which 2 to 3 cm of rib margin are usually adequate for long-term control. Resection of recurrent breast cancer is indicated for wound hygiene and palliation, with the major objective being a healed chest wall. Resection of metastatic neoplasms to the chest wall can be considered when successful control of the primary has been achieved.

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Benign Bony Tumors Fibrous Dysplasia Fibrous dysplasia is a common lesion of the chest wall, accounting for 20 to 30% of rib tumors.5,10 This lesion occurs equally in males and females and is common in the second and third decades of life. It usually presents as a painless mass involving the bony chest wall; most lesions are solitary, but multiple areas are seen occasionally. Fibrous dysplasia usually is a painless mass identified on a routine chest radiograph, but it can be painful in association with a pathologic fracture or an expansion and stretching of the periosteum. Patients with multiple lesions show abnormal skin pigmentation and precocious puberty (Albright’s syndrome). The radiographic appearance is that of a lytic lesion involving one or more ribs (Figure 11-3). There fre-

FIGURE 11-3. A, Chest radiograph depicting a chest wall mass. B, Computed tomography scan showing classic appearance of fibrous dysplasia with cortical thinning.

quently is an expansion of the rib with significant thinning of the cortex, and the medullary aspect of the rib has a homogeneous ground-glass appearance. Pathologic fracture is a frequent cause of diagnosis precipitating radiologic evaluation. The gross appearance of the affected rib identifies a central fibrous area with a shell of expanded cortex on the surface (Figure 11-4). Malignant transformation into osteosarcoma or fibrous sarcoma is exceedingly rare and is not an indication for excision of this lesion.11 Excision of fibrous dysplasia is indicated for pain or uncertainty of the diagnosis. In cases in which the diagnosis is questioned, incisional or excisional biopsy is indicated. Recurrence after complete excision is rare. Osteochondroma Osteochondroma is among the most common benign neoplasms of the chest wall. The rib is the common location for these tumors, which usually begin in childhood and continue to grow until skeletal maturation is attained. Patients with osteochondromas are usually < 30 years of age, and males are more commonly affected than females. A chest radiograph is usually diagnostic with the finding of a pedunculated or sessile bony excrescence on the surface of the rib, with the medulla of the bone continuous with the medulla of the lesion. A thin cartilaginous cap is present with areas of scattered calcification. Multiple lesions suggest a diagnosis of familial osteochondromatosis. Treatment for the osteochondroma is complete excision, and recurrence is rare. Malignant transformation of these lesions is suggested by pain and continued growth after closure of the epiphyseal plate.5 Malignancy of these lesions is rare and is estimated to occur in < 1%. Malignant transformation can occur in 20% of these lesions in cases of familial osteochondromas or multiple exostoses. The malignant tumor is well differentiated, and local recurrence is unusual if complete resection is accomplished.

FIGURE 11-4. Resected rib of fibrous dysplasia. Cortical thinning is noted. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756.

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Chondromas Chondromas constitute approximately 15 to 20% of all benign tumors of the chest wall. They may occur in the medulla as an enchondroma (Figure 11-5) or less frequently on the periosteum as a periosteal chondroma, but most commonly from costal cartilage. They usually present anteriorly at the costal chondral junction and are a slowly enlarging painless mass. Pain can also be present. Chondromas occur in all age groups, most frequently between the ages of 10 and 30 years. Males and females are affected equally. On radiographs, the chondroma appears as a small lytic area in the bone with sclerotic margins. The lytic areas are typically round or oval, and a rib lesion is expansile with thinning of the cortex. There is no reliable imaging technique to distinguish a low-grade chondrosarcoma from a chondroma. Histologic differentiation between a low-grade chondrosarcoma and a cellular chondroma can also be difficult. Because of this problem, en bloc resection is recommended with wide margins. All tumors arising from the costal cartilages should be considered malignant and treated with wide excision. Inadequate resection frequently results in local recurrence of the malignant form.

occurs in 10 to 20% of instances of eosinophilic granuloma, and there is a strong predilection in males. If there is localized chest pain, chest radiography is required to determine whether there is an expansile lesion of the rib (Figure 11-6). Malignancy cannot be

Eosinophilic Granuloma Eosinophilic granuloma is a part of the spectrum of Langerhans cell histiocytosis, a diffuse infiltrative process of antigen-presenting macrophages together with a variable accompaniment of eosinophils, lymphocytes, and plasma cells. Eosinophilic granuloma is limited to bone, whereas other forms of the disease are systemic. In infants it presents as an infiltration of lymph nodes, liver, spleen, and bone marrow (Letterer-Siwe disease). Hand-SchullerChristian disease presents with bone involvement accompanied by diabetes insipidus. Isolated rib involvement

FIGURE 11-5. Anterior chest wall enchondroma (arrow).

FIGURE 11-6. A, Radiograph of the rib illustrates eosinophilic granuloma (arrow). B, Computed tomography scan depicts the lesion (arrows). C, Resected rib specimen.

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ruled out by the radiologic appearance, and excisional biopsy is performed to establish the diagnosis and provide a cure if the lesion is solitary.5 Radiation therapy can be effective for multiple lesions or tumors in areas that are difficult to resect. Aneurysmal Bone Cysts Bone cysts account for < 1% of chest wall tumors (Figure 11-7). They commonly occur in the ribs and usually are associated with a pathologic fracture (Figure 11-8). A chest radiograph can be diagnostic if it shows a demarcated lytic lesion surrounded by a thin shell of periosteum. Callus formation may be present if there has been a previous fracture. The lesion is usually asymptomatic unless fracture has occurred. Simple excision is indicated for associated pain or when there is a question of metastatic cancer. Osteoid Osteoma Osteoid osteoma is a rare benign tumor of the rib or vertebral body. The presentation is usually sharp pain that requires radiography; films demonstrate a small, radiolucent area surrounded by a marked area of sclerosis. A bone scan illustrates intense uptake in the center of

the lesion, with less dense activity surrounding the central nidus. Surgical resection is recommended for pain, and local recurrence is rare after complete excision. Lesions of the scapula and sternum can be treated with exposure of the nidus by cortical shaving and curetting of the nidus. Hemangioma Hemangiomas present in the vertebral body or ribs and are pain free. The tumor can arise in the soft tissue and protrude into the thorax or develop in a rib with a sclerotic-reticular pattern (Figure 11-9). 12 Increased blood flow through the rib causes absorption, and adjacent slow flow causes deposition of new bone. The lesion presents as linear areas of bone deposition and lucency. Diagnosis is usually made by radiography and CT, and excision is not required except in cases of fracture or cosmetic deformity. Low-grade malignant hemangioendothelioma presents with soft tissue involvement outside the rib; in this instance, excision is recommended. Clear margins must be obtained as there is a significant incidence of local recurrence with this lesion.13 Other benign bony lesions of the chest wall include osteoblastoma, ossifying fibroma, nonossifying fibroma, ossifying lipoma, and giant cell tumors. These lesions can usually be diagnosed by precise radiologic interpretation and do not require excision unless there is associated pathologic fracture or a question of malignancy.

Malignant Bony Tumors

FIGURE 11-7. Resected bone cyst.

FIGURE 11-8. Bone cyst with rib fracture (arrow).

Chondrosarcoma Chondrosarcoma is the most common primary malignant neoplasm of the chest wall and commonly presents anteriorly, arising from either the costochondral arches or the sternum. It is also the most common primary malignant tumor of the sternum. It most commonly affects males and is found in people 20 to 40 years old. McAfee and colleagues reported that 12.5% of patients with chondrosarcomas reported a previous history of chest wall trauma in the location of the tumor. 1 4 Chondrosarcomas also develop as a result of malignant degeneration of a benign chondroma or osteochondroma and are categorized as secondary chondrosarcomas. These lesions are usually of low-grade malignancy, appear at an earlier age, and have a better prognosis than the standard primary chondrosarcoma. The tumor usually presents as a slowly enlarging, painful mass located on the anterior chest wall or sternum. The mass is hard, slightly tender, and fixed firmly to the chest wall (Figure 11-10). The radiographic appearance defines a lobulated mass arising in the medullary portion of the bone with radiolucency and stippled calcification.

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FIGURE 11-10. Chondrosarcoma of the left anterior chest wall (arrows). Note the prior incisional biopsy site.

FIGURE 11-9. A, Bone scan showing activity in a rib hemangioma. B, Resected specimen of a rib hemangioma. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756.

Margins of the tumor are ill defined, and there is frequent destruction of adjacent bony cortex. A CT scan is essential for identifying extension of surrounding tissues and for planning the resection.15 Associated pathologic fractures are uncommon (Figure 11-11). Approximately 10% of these lesions present with synchronous metastatic disease; CT is performed to detect nodules in the lung, and a bone scan is used to identify other distant lesions. These tumors grow outwardly into the soft tissue of the chest wall and also into the pleural space. Lesions > 4 cm are more likely to be malignant, and, as it is extremely difficult to differentiate low-grade chondrosarcomas from benign chondromas, all tumors arising from the costal cartilages should be treated with wide excision. Graeber and colleague recommend surgical excision of all lesions suspected of being chondrosarcomas or chondromas and state that incisional biopsy is not indicated owing to sampling error.7 However, it is our experience at the Rush University Medical Center that in lesions > 5 cm that will require prosthetic reconstruction in association with muscle flap repair, incisional biopsy is mandatory to define the histology. A generous portion of tissue is always obtained, and in our experience biopsy is consistently correlated with final pathologic diagnosis. Incisional biopsy of the larger tumor permits a wellplanned multidisciplinary approach. The outcome of surgical therapy depends on the ability to perform a complete resection with minimum margins of 4 cm. Five-year survival rates range from 67 to 89% in several series. 1 4 McAfee and colleagues reported a 96% 10-year survival rate for chondrosarcomas,14 and Burt reported a 5-year survival rate of 64%.3 Adverse prognostic factors include metastasis at initial presentation, age > 50 years, incomplete resection, and local recurrence. Prognosis has also been reported to be affected by a high histologic grade of the tumor and areas of differentiation within the tumor.16 The natural history of untreated chondrosarcoma is one of hematogenous spread to the lungs, and local

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FIGURE 11-11. A, Computed tomography scan illustrating an anterior chest wall chondrosarcoma. Note the patchy calcification. B, Resected specimen included cartilages and ribs. C, Reconstruction with GORE-TEX (W. L. Gore and Associates, Flagstaff, AZ). D, Photomicrograph showing histologic appearance of a chondrosarcoma (
800 original magnification; hematoxylin and eosin stain).

recurrence significantly decreases survival and also increases the risk of distant metastasis. There is no effective chemotherapy for chondrosarcoma. Radiation therapy is ineffective as the primary treatment. McNaney and colleagues have reported some success with combination photon and neutron radiation.17 Postoperative radiation is mandatory if operative margins are microscopically positive for tumor. Ewing’s Sarcoma Ewing’s sarcoma constitutes 6 to 10% of all malignant chest wall tumors and is the most common primary chest wall tumor in children. It is more common in males than females, and white people are more commonly affected than are those of African descent. Ewing’s sarcoma usually presents as a painful, palpable mass, and pain is the presenting symptom in 90% of patients.18 Systemic manifestations include fever, malaise, and weight loss. These symptoms in association with pain and the classic appearance on radiographs are diagnostic.

Chest wall Ewing’s sarcomas frequently present in the ribs but also arise from the scapula, sternum, and clavicle.19 Gross metastatic disease is present at the time of diagnosis in 20 to 30% of patients, and common sites of metastatic disease include the lungs, bone, and bone marrow. Malignant pleural effusion is a common form of metastatic presentation with primary Ewing’s sarcoma of the chest wall. Radiographs reveal destruction of bone with lytic and blastic areas, and elevation of the periosteum with multiple layers of subperiosteal bone formation creates the classic “onion skin” appearance (Figure 11-12). The surface of the bone may contain radiating ossified spicules, as are commonly seen in osteosarcoma. Pathologic fractures are uncommon. CT and MRI scans are important in evaluating soft tissue, lung, and mediastinal involvement, and a bone scan is necessary to rule out bone metastasis. Excisional biopsy is recommended for diagnosis, and the biopsy should be performed in a manner that will allow for definitive resection.

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FIGURE 11-12. A, Reversed anteroposterior radiograph showing Ewing’s tumor. B, Computed tomography scan illustrating Ewing’s sarcoma (arrow).

The distinction between the peripheral neuroectodermal tumor (PNET) and Ewing’s tumor remains controversial. Until recently the criteria for diagnosis were based on histochemistry and electron microscopy. Chromosomal karyotypes have shown that peripheral/ectodermal tumor and Ewing’s tumor usually show the same translocation (t[11;22][q24;q12]). This translocation results in the transcription of new ribonucleic acid, which includes a conserved region of the ets oncogene that may be an important determinant of the tumor’s behavior in response to therapy. Some investigators regard these tumors as the same entity, as defined chromosomally. However, the PNET occurs in a different location and an older age group and responds to therapy less frequently, which suggests that these tumors are separate entities.

The question arises whether initial resection is the procedure of choice for chest wall lesions when the diagnosis of Ewing’s sarcoma is suspected. Shamberger and colleagues reported that initial resection resulted in a negative pathologic margin in 6 of 16 patients, whereas resection after chemotherapy resulted in negative margins in 17 of 24 patients (p = .05).20 Patients undergoing initial resection usually require eventual radiation, and lung damage can occur with high doses of radiation therapy. Radiation to the heart can add toxicity to the damage caused by necessary chemotherapeutic agents. Initial chemotherapy downsizes the tumor and margins of involvement are better defined, resulting in negative microscopic margins. When the diagnosis is established by incisional biopsy, the initial form of therapy is chemotherapy, consisting of vincristine, dactinomycin, cyclophosphamide, and doxorubicin. Ifosfamide and etoposide have also been effective. Following chemotherapy, if there is no evidence of metastatic disease, local control is provided by surgical resection or radiation therapy. If surgical excision of the lesion has been the primary procedure, then adjuvant chemotherapy and radiation are indicated. Chemotherapy aids in eradicating metastatic disease and decreases the soft tissue component of the primary tumor. It is necessary to use the CT scan as a guide for surgical resection to ensure a complete resection. Shamberger and colleagues reported an event-free survival rate at 5 years of 57% for chest wall Ewing’s sarcoma using multimodality therapy.20 Fizazi and colleagues reported a 50% overall 5-year survival rate in nonpelvic Ewing’s tumors.21 Other series have reported 5-year survival rates of approximately 50%.18,22 Most clinical studies evaluating the use of radiation alone for local control support a tumor dose of 6,000 cGy. Pulmonary fibrosis and restricted lung disease may follow intensive chest radiation, and local recurrence following chemotherapy and radiation can occur in as many as 45% of patients. 23 Surgical resection after chemotherapy provides optimal local control. Local occurrence occurs more frequently when the original tumor is > 8 cm, and both local recurrence and metastatic disease carry a poor prognosis.18 Second-line chemotherapy may be considered, and isolated pulmonary metastasis may respond to surgical resection. Additional surgery or radiation, if not already given, can be considered for local recurrence. Askin’s Tumor Askin’s tumor or PNET belongs to a heterogeneous group of tumors, including primitive round cell sarcomas of bone, neuroectodermal tumors, and typical and atypical Ewing’s sarcoma. 24 PNET shares an identical chromosomal translocation with Ewing’s sarcoma.18

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Askin’s tumors occur mainly in children and young adults; they frequently present in the posterior chest wall and are often thought to be a posterior chest wall tumor (Figure 11-13). Depending on the location, the diagnosis can be made with percutaneous needle biopsy. A trephine specimen is advantageous. Preoperative chemotherapy is recommended, followed by wide surgical resection for local control (similar to the treatment of Ewing’s sarcoma). Positive resection margins are treated with radiation therapy. Osteosarcoma Osteosarcomas represent 5 to 10% of primary malignant tumors of the chest, and occurrence is noted in the second and third decades of life, as well as in the elderly.25 The clinical presentation is that of a painful, rapidly enlarging mass.

FIGURE 11-13. A, Apical and posterior chest wall tumor as seen on a radiograph. B, Computed tomography scan shows the extent of this Askin’s tumor. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756.

Radiographs may show calcified spicules extending from the bone cortex, which produce the classic “sunburst” appearance. However, the sunburst appearance is noted in other diseases of bone and is probably seen in only 25% of osteosarcoma lesions.5 Cortical bone destruction with irregular margins that merges into adjacent normal bone with lytic or blastic changes is usually apparent (Figure 11-14). CT is required to evaluate the extent of involvement and also the presence of metastatic lesions to the lung (Figure 11-15). Diagnosis can be achieved in the soft tissue component of the lesion by trephine needle biopsy or incisional biopsy.

FIGURE 11-14. A, Posterior osteogenic sarcoma. B, Radiograph of resected osteogenic sarcoma. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756.

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Patients with osteosarcoma may have metastatic disease at the time of initial diagnosis; Burt reported that 34% of 41 patients with primary osteogenic sarcoma of the chest wall had metastasis at the time of diagnosis.3 The lungs are the site of metastatic disease most commonly, and as metastatic disease appears in > 50% of these patients, osteosarcoma can be considered a systemic disease. One can extrapolate the success of treating extremity bony sarcomas with preoperative chemotherapy into the treatment of the chest wall osteosarcoma. Combination therapies of doxorubicin, cisplatin, methotrexate, and ifosfamide have all been considered. Chemotherapy is followed by radical chest wall resection. Preoperative chemotherapy provides an opportunity to assess the effectiveness of administered drugs. If the tumor is > 90% necrotic at the time of excision, prognosis is excellent. Minimal necrosis indicates tumor resistance to the drugs and therefore a poor long-term prognosis.26 Postoperative chemotherapy has demonstrated improvement in long-term survival for extremity sarcomas,27 but in Burt’s series, there was no improvement in survival in patients receiving adjuvant chemotherapy compared with patients treated with surgery alone.3 Current therapy for chest wall osteosarcoma is preoperative chemotherapy followed by radical chest wall resection. Positive microscopic margins are treated with postoperative radiation therapy. Pulmonary metastases that occur or persist after postoperative chemotherapy may be treated with surgical excision using staged thoracotomies or sternotomy and multiple bilateral wedge resections. Ipsilateral lung metastasis can be resected at the time of surgery for a primary chest wall osteosarcoma.

FIGURE 11-15. A, Computed tomography scan shows osteogenic sarcoma of sternum. Other cuts indicated extensive sternal involvement. B, Resected specimen of total sternectomy. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756.

Plasmacytoma Plasmacytoma is a plasma cell tumor that is referred to as multiple myeloma if it occurs in two or more locations. The two entities are different manifestations of the same disease process. Approximately 20% of all solitary plasmacytomas occur in the chest wall, with the most common location being the ribs, followed by the clavicle, sternum, and scapula. 1 9 Males are affected twice as frequently as females, and the tumor most commonly occurs in the fifth through seventh decades. The most common presenting symptom is pain without a palpable mass. A radiograph demonstrates an expansile osteolytic lesion with poorly defined borders and soft tissue extension (Figure 11-16). The cortex of the rib is thinned, and pathologic fracture is common. The diagnosis is usually established by surgical excisional biopsy. If the diagnosis is suspected clinically, a trephine needle biopsy or incisional biopsy can be carried out. When the diagnosis is established, other tests

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wide excision for this lesion is not indicated. Radiation therapy yields a 90% local control rate.19 Following local control with radiation, multiple myeloma develops in 45 to 50% of patients. Patients must be followed carefully with periodic evaluation after treatment for a solitary plasmacytoma. The 5-year survival rate for patients with this disease is approximately 20 to 30%.7,29

Benign Soft Tissue Tumors of the Chest Wall Lipoma Lipoma is a benign tumor of fat and occurs superficially as well as deeper; it can protrude through the intercostal space into the thoracic cavity. Subcutaneous lipomas are nontender, well circumscribed, and mobile. They are distributed equally throughout the chest wall and are painless and usually asymptomatic. These lesions are frequently noted incidentally on a routine chest radiograph, and a CT scan shows the typical density of fat. The differential diagnosis lies between lipoma and the rarer liposarcoma. These lesions are well circumscribed, thinly encapsulated tumors of mature adipose tissue (Figure 11-17). Surgical excision is indicated for cosmetic purposes or if malignancy cannot be ruled out. Usually, the diagnosis is strongly suspected, and only local excision is required.

FIGURE 11-16. A, Radiograph showing a solitary plasmacytoma of the chest wall. B, Computed tomography scan of the same lesion.

must be obtained including serum and urine electrophoresis, serum ionized calcium level, bone marrow aspiration, and a complete blood count. A patient with a true solitary plasmacytoma usually has a normal calcium level and is not anemic. Monoclonality of one of the immunoglobulins with normal levels of other circulating immunoglobulins suggests that the plasmacytoma is truly solitary. Radiation is the primary treatment for solitary plasmacytoma.28 The role of surgery is to make the diagnosis, and

Neurofibroma Neurofibromas are commonly multiple and occur as part of the complex of von Recklinghausen’s disease, a familial disorder characterized by these growths that can occur in any part of the body. The disease may be transmitted as an autosomal dominant trait as a result of a gene mutation on chromosome 17, but 50% of cases are sporadic. In addition to multiple neurofibromas, the disease is characterized by café au lait spots of the skin and meningiomas. A chest radiograph demonstrates a mass, and frequently there is associated rib notching (Figure 11-18). In the chest they frequently arise from interthoracic nerves but can occur in bone without nerve sheath involvement. The lesions are usually benign, but malignant degeneration occurs in 5 to 40% of cases.30 Surgical excision is recommended for symptoms of pain or for rapid enlargement. Related to the neurofibroma is the Schwann cell tumor or neurilemoma. This lesion is usually solitary and occurs on a nerve with clear demarcation. The ribs can be involved (Figure 11-19). Excisional biopsy and resection are recommended for diagnosis and treatment. It may be difficult to differentiate the malignant form of this tumor from the benign form. This tumor can be a low-grade malignancy, which is associated with a high recurrence rate. Mitoses

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associated with questionable margins of resection indicate the need for postoperative radiation therapy. Elastofibroma Dorsi Elastofibroma dorsi is a rare tumor that is most commonly found in the lateral chest wall in close proximity to the scapula (Figure 11-20). It occurs in elderly patients and is frequently bilateral.31 The tumor consists of a firm capsule with spindle cell proliferation and adherence to the scapula. It most likely represents a reaction of soft tissue to trauma or movement of the scapula. Local excision after trephine needle biopsy and diagnosis is indicated for persistent pain.

desmoid tumors. Some soft tissue sarcomas are lowgrade malignancies, whereas others are of high-grade malignancy and exhibit different patterns of local growth, metastasis, and recurrence after treatment. Males are affected more frequently than females by a ratio of 2

Malignant Soft Tissue Tumors of the Chest Wall Tumors in the category of malignant soft tissue tumors are essentially all sarcomas and include malignant fibrous histiocytoma, rhabdomyosarcomas, liposarcomas, and

FIGURE 11-17. A, Computed tomography scan depicts a chest wall lipoma protruding over the rib. B, Resected specimen of the chest wall lipoma.

FIGURE 11-18. A, Lateral chest radiograph depicting a neurofibroma. B, Resected specimen with attached ribs. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756.

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FIGURE 11-20. A, Computed tomography scan showing an elastofibroma dorsi (arrow) attached to scapula. B, Magnetic resonance image showing the same lesion (arrow). FIGURE 11-19. A, Computed tomography scan showing a lateral chest wall Schwann cell tumor with rib invasion. B, Resected specimen attached to ribs.

to 1, and the mean age of diagnosis is approximately 40 years. Leiomyosarcomas occur more frequently in females; in Gordon and colleagues’ report, there was a bimodal age distribution with peaks at the third and sixth decades.29 Rhabdomyosarcomas are most prevalent in children and young adults, whereas liposarcomas occur in patients aged 50 to 60 years.

A common symptom of malignant soft tissue tumors is a nonpainful mass. Pain occurs in approximately 10% of patients, and an equal number report pain without evidence of a mass. High-dose radiation therapy can induce soft tissue sarcomas after an interval of 5 to 10 years.29 High-grade malignant fibrous histiocytoma is a common sarcoma occurring after radiation. Findings on chest films can include bone invasion, metastatic disease to the lung, and intrathoracic involvement. CT and MRI provide accurate images of the

Primary and Secondary Chest Wall Tumors / 139 FIGURE 11-21. A, Magnetic resonance image showing sarcoma of the shoulder (arrows). B, Computed tomography scan depicting the soft tissue sarcoma. Reprinted with permission from Faber LP, Somers J, Templeton AC. Chest wall tumors. Curr Probl Surg 1995;32:661–756. C, Computed tomography scans depicting synovial sarcoma invading the chest wall and sternum. Continued on the next page.

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contact with this pseudocapsule must be avoided during resection as it often contains microscopic disease. These tumors often spread along the walls of blood vessels, nerve sheaths, and fascial planes. Malignant fibrous histiocytoma can spread into the marrow and, indeed, the entire affected rib (Figure 11-22), and portions of the rib above and below need to be resected if the chest wall is invaded by this histologic variant. Malignant fibrous histiocytoma shows a histologic pattern of spindle cells with rounded pleomorphic nucleoli arranged in a cartwheel pattern. It is thought to arise from tissue histiocytes. Fever and leukocytosis can be associated, and this tumor can be radiation induced.35 Surgical therapy is wide excision. Positive resection margins should be treated with postoperative radiation. Chemotherapy is usually ineffective. Five-year survival rates approximate 35%. FIGURE 11-21 continued. D, Resected specimen includes the sternum, anterior chest wall, and ribs.

tumor, adjacent thorax, and tissue planes (Figure 11-21). These studies are mandatory for appropriate planning of resection. Incisional biopsy or trephine needle biopsy should be used to make the diagnosis, except in those situations in which the tumor is small enough that complete primary resection with a wide margin can be accomplished by excisional biopsy. Soft tissue sarcomas are classified by type and grade. Typing of a soft tissue tumor is based on the closest match to a differentiated normal cell. Grading uses criteria of mitotic rate, nuclear and cellular pleomorphism, and nucleus-to-cytoplasm ratio. High-grade tumors tend to have more necrosis present. Separation into the different types of tumor is made using histologic and histochemical criteria. Major prognostic indicators for primary soft tissue sarcomas include tumor grade, the presence of distant metastasis, and positive surgical resection margins. The 5year survival rate for low-grade chest wall soft tissue sarcomas after complete resection varies between 85 to 90%, whereas the 5-year survival rate for high-grade lesions is approximately 40 to 50%.29,32,33 Other histopathology influencing survival is controversial. Histopathology did not influence survival in a series of high-grade extremity sarcomas studied at the National Cancer Institute. 34 However, analysis of another series of high-grade tumors revealed that the muscular type had decreased survival when compared with high-grade tumors of the fibrous type.29 Size of the tumor and age of the patient at presentation have not been found to influence survival. Surgical excision with a wide margin is the mainstay of treatment for soft tissue sarcomas of the chest wall. A pseudocapsule frequently surrounds the tumor, and

FIGURE 11-22. A, Computed tomography scan showing malignant fibrous histiocytoma with rib invasion. B, Magnetic resonance image reveals no evidence of invasion into the spinal cord.

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Rhabdomyosarcoma is associated with striated muscle tissue and histochemical analysis shows myoglobin, desmin, and actin. Therapy is wide resection with aggressive adjuvant radiation and multidrug chemotherapy. Five-year survival rates approximate 70%.36 Large masses should be treated with preoperative chemotherapy and radiation, and adjuvant chemotherapy after resection. Liposarcomas are defined as tumors containing lipoblasts, which are large cells with pleomorphic nuclei containing large vacuoles of neutral fat. Most of these tumors are low grade, and wide surgical excision is necessary for control. Local recurrence can be effectively treated with repeat resection as radiation therapy is not particularly effective for this neoplasm. Five-year survival rates can approximate 80%, as reported by Graeber and colleagues.25 Metastasis occurs more frequently with high-grade than with low-grade soft tissue sarcomas, and frequently smaller lesions cannot be detected on a normal chest radiograph. CT of the chest is always indicated when dealing with these sarcomas. In Gordon and colleagues’ series, 51% of high-grade lesions had either synchronous or metachronous metastasis compared with only 10% of low-grade lesions.29 Radiation therapy has shown some benefit in extremity soft tissue sarcomas and decreases the necessity for a radical surgical procedure.37 This treatment can be considered for larger chest wall sarcomas. The role of adjuvant chemotherapy for high-grade lesions is controversial. Chang and colleagues reported a prolonged disease-free survival in patients with extremity sarcomas who received adjuvant chemotherapy with doxorubicin and cyclophosphamide.38 Other studies of chest wall and truncal sarcomas have not demonstrated a clear improvement in survival with the use of adjuvant chemotherapy. 32 Adjuvant therapy does improve the survival of patients with rhabdomyosarcoma. Long-term follow-up of patients who have had a malignant soft tissue tumor is required to detect local recurrence and possible metastatic disease to the lungs. Desmoid Tumor Microscopically, desmoid tumor appears rather benign, with a network of spindle-shaped cells and dense connective tissue. There are no mitotic figures and little, if any, pleomorphism. These findings led to a mistaken impression that this is a benign tumor of “aggressive fibromatosis.”5 This tumor does invade adjacent structures, recur locally, and invade nerves; therefore, it must be considered a low-grade sarcoma. The tumor is more common in females and may be hormonally regulated. This theory is supported by the presence of estrogen receptors in tumor nuclei and by reports of regression of these tumors with the use of

antiestrogen agents such as tamoxifen. They occur in the second through fifth decades, and approximately 40% of all desmoid tumors occur in the chest wall and shoulder region.39 The usual presentation of the desmoid tumor is a painless or slightly tender, poorly circumscribed mass (Figure 11-23). In the shoulder region, they invade tissue surrounding the brachial plexus and can encapsulate vessels of the arm and neck with significant shoulder pain and motor weakness. Diagnosis requires incisional biopsy to obtain adequate tissue for pathologic analysis, and differentiation from a benign lesion can be difficult. Use of MRI assists in defining tissue involvement and the planning of the resection. Metastatic work-up is not required as these tumors do not metastasize. Grossly, the desmoid tumor presents as a vascular scar tissue extending for several centimeters. Margins are poorly demarcated, and it is difficult to define the margin of extension into adjacent muscle and fascial planes. Treatment of the desmoid tumor is wide excision with evidence of microscopically clean margins. The major problem in treating these tumors is local recurrence. Brodsky and colleagues reported on 32 patients with

FIGURE 11-23. A, Anterior chest wall desmoid tumor (arrow) arising in a previous sternotomy incision. B, Resected specimen includes a portion of the inferior sternum and adjacent cartilages and soft tissues.

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chest wall desmoid tumors treated by wide surgical resection, and the 5-year disease-free survival rate was 71% with a 5-year local recurrence rate of 29%.40 Radiation is effective for a recurrent desmoid tumor and requires an effective dose of 5,000 to 6,000 cGy. Desmoid tumors involving the great vessels of the neck or brachial plexus require careful surgical enucleation followed by high-dose radiation.5 Baliski and colleagues reported the successful use of neoadjuvant chemotherapy and radiation for 13 patients with desmoid tumor, 6 of whom were patients with local recurrence. 41 Doxorubicin and 3,000 cGy were given preoperatively, and surgical resection was accomplished 6 weeks later. Eleven patients were disease free at a median of 71 months. This option can be considered for large tumors or recurrent disease.

Secondary Chest Wall Tumors Breast Cancer Isolated local relapse of breast cancer can be considered an indication for chest wall resection. Patients with this condition are plagued by chest wall pain, local infection, purulent discharge with frequent dressing change, and bleeding. Significant palliation and long-term control can be achieved by resection of these lesions. Local recurrence occurs in an area compromised by prior radiation, and the capability for primary healing is retarded. A lesion readily becomes ulcerated with bacterial contamination, and sclerotic blood vessels and deep tissues result in continuing necrosis and tumor growth. A multidisciplinary approach is required for these lesions: the medical oncologist rules out the presence of significant metastatic disease, the plastic surgeon carefully plans the use of muscle flaps for reconstruction, and the thoracic surgeon prepares for the extent of resection. Needle biopsy can be used to confirm the presence of recurrent breast cancer but is not required if the patient demands the removal of the disfiguring chest wall ulceration. En bloc resection of the chest wall is accomplished with 4 cm clinical margins and usually incorporates portions of one rib above and one rib below the lesion. The defect is closed with prosthetic material and covered with healthy, vascularized muscular flaps. Faneyte and colleagues reported a 58% 5-year survival rate in 30 patients who had chest wall resection for breast cancer.42 Review of the literature reveals survival rates ranging from 34 to 58% for resection of recurrent breast cancer performed with curative intent. Downey and colleagues reported on 38 women with chest wall resection for locally recurrent breast cancer without perioperative mortality, and survival rates were 41% at 3 years and 18% at 5 years.43 Synchronous lymph node metastasis was a poor prognostic indicator.

Lung Cancer Primary lung cancer invades the chest wall in approximately 8% of patients. Invasion of the parietal pleura or chest wall constitutes a subgroup of patients with T3 tumors in whom en bloc resection of the chest wall and lung provides satisfactor y 5-year survival rates (Figure 11-24). Resection margins of 2 to 3 mm of normal chest wall are adequate to achieve satisfactory results. The pathologic presence of N1 and N2 positive lymph nodes lessens the long-term survival. Shah and Goldstraw and Piehler and colleagues reported that histologic type, tumor size, depth of chest wall invasion, and extent of resection do not correlate with survival.44,45 Survival after resection for nonsmall cell lung cancer invading the chest wall approximates 35%. The low survival rate in patients with N2 disease emphasizes the need for accurate preoperative staging, which includes mediastinoscopy and PET scanning. Metastatic Tumors Metastatic cancers to the chest wall can be considered for resection. Criteria for this type of resection include the

FIGURE 11-24. A, Computed tomography scan depicting primary lung cancer invading the lateral chest wall. B, Resected lung tissue with adjacent chest wall.

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following: complete resection can be achieved, metastatic disease is localized to the area to be resected, there is no better medical therapy, the primary tumor site has been controlled, and the patient can tolerate the operation. PET and CT of the chest and abdomen are necessary to rule out the presence of other metastatic deposits. Solitary metastatic cancers to the chest wall include renal cell carcinoma, colon cancer, and thyroid cancer (Figure 11-25). Survival is variable following chest wall resection for metastatic lesions, but significant palliation can be achieved, and long-term control is possible.46 The development of a sternal mass following resection of a prior distant malignancy should be considered a metastatic lesion. Diagnosis is usually established via needle biopsy, and appropriate planning for resection can be carried out.47

nostic studies. Careful consideration as to methods of biopsy is required, and following histologic confirmation of the lesion, medical oncologists provide recommendations for neoadjuvant or adjuvant therapy. Surgical resection requires careful planning and is usually accomplished with a plastic surgeon to achieve appropriate reconstruction. Although histology can be a prognostic factor for long-term survival, the sine qua non of a successful result following resection of a chest wall tumor is a pathologic complete resection. Morbidity and mortality are low with this approach for these neoplasms.

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Conclusion

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FIGURE 11-25. A, Isolated metastatic renal cell cancer to the sternum. B, Resected specimen includes a portion of the sternum and adjacent cartilages.

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35. Weiss SW, Enzinger IM. Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer 1978;41:2250–61.

20. Shamberger RC, LaQuaglia MD, Krailo MD, et al. Ewing’s sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 2000;119:1154–61. 21. Fizazi K, Dohollou N, Blay JY, et al. Ewing’s family of tumors in adults: multivariate analysis of survival and longterm results of multimodality therapy in 182 patients. J Clin Oncol 1998;16:3736–43. 22. Jaffe N. Chemotherapy for malignant bone tumors. Orthop Clin N Am 1989;20:487–503. 23. Miser JS, Kinsella TJ. Ewing’s sarcoma and the differentiated sarcomas. In: Pizzo PA, Poplack DG, editors. Principles and practices of pediatric oncology. Philadelphia: JB Lippincott; 1989. p. 347–54. 24. Askin FB, Rosai J, Sibley RK, et al. Malignant small cell tumor of the thoracopulmonary region in childhood. Cancer 1979;43:2438–51. 25. Graeber GM, Snyder RJ, Fleming AW, et al. Initial and long term results in the management of primary chest wall neoplasms. Ann Thorac Surg 1982;34:664–73. 26. Raymond AK, Chawla SP, Carracoch, et al. Osteosarcoma chemotherapy effect: a prognostic factor. Semin Diagn Pathol 1987;4:212–8. 27. Eilber F, Guiliano A, Eckhardt J, et al. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987;5:21–6. 28. Holland J, Trenkner DA, Wasserman TH, Fineberg B. Plasmacytoma: treatment results and conversion to myeloma. Cancer 1992;69:1513–7. 29. Gordon MS, Hajdu SI, Baines MD, Burt ME. Soft tissue sarcomas of the chest wall. J Thorac Cardiovasc Surg 1991;101:843–54. 30. Lee CW, Shulman K, Morecki R, et al. Malignant degenera-

36. Saenz NC, Ghovimi F, Gerald W, et al. Chest wall rhabdomyosarcoma. Cancer 1997;80:1513–7. 37. Tepper JE, Suit HD. Radiation therapy alone for sarcoma of the soft tissue. Cancer 1985;56:475–9. 38. Chang AE, Kinsella T, Glatstein E, et al. Adjuvant chemotherapy for patients with high-grade soft tissue sarcomas of the extremity. J Clin Oncol 1988;6:1491–7. 39. Posner MC, Shiu MH, Newsome JL, et al. The desmoid tumor: not a benign disease. Arch Surg 1989;124:191–6. 40. Brodsky JT, Gordon MS, Hajdu SI, Burt M. Desmoid tumors of the chest wall. J Thorac Cardiovasc Surg 1992;104:900–4. 41. Baliski CR, Temple WJ, Arthur K, Schakar NS. Desmoid tumors: a novel approach for local control. J Surg Oncol 2002;80:96–9. 42. Faneyte JF, Rutgers EJT, Zoetmulder FAN. Chest wall resection in the treatment of locally recurrent breast carcinoma. Cancer 1997;80:886–91. 43. Downey RJ, Rusch V, Hsu FI. Chest wall resection for locally recurrent breast cancer: is it worthwhile? J Thorac Cardiovasc Surg 2000;119:420–8. 44. Shah SS, Goldstraw P. Combined pulmonary and thoracic wall resection for Stage III lung cancer. Thorax 1995;50:782–7. 45. Piehler JM, Pairolero PC, Weiland LH, et al. Bronchogenic carcinoma with chest wall invasion: factors affecting survival following en-bloc resection. Ann Thorac Surg 1982;38:684–90. 46. Warzelham J, Stoelben E, Imdahl A, Hasse J. Results in surgery for primary and metastatic chest wall tumors. Eur J Cardiothorac Surg 2001;19:584–8. 47. Downey RJ, Huvos AG, Martin N. Primary and secondary malignancies of the sternum. Semin Thorac Cardiovasc Surg 1999;11:293–6.

CHAPTER 12

MANAGEMENT OF CHEST WALL DEFORMITIES ALEXANDER A. FOKIN, MD, PHD, FRANCIS ROBICSEK, MD, PHD

Etiology We consider the overgrowth of costal cartilages to be the main factor in the development of both depressive and protrusive deformities.3 If these abnormally elongated cartilages push the sternum inward, pectus excavatum develops; if they push it outward, the result is a carinatum deformity (Figure 12-2).

The most common congenital abnormalities of the anterior chest wall may be divided into four main categories: pectus excavatum, pectus carinatum, Poland’s syndrome, and sternal clefts (Figure 12-1). The first two groups are deformities without tissue defects, whereas sternal clefts are tissue defects without deformities and Poland’s syndrome is a combination of both deformity and tissue defect.

Classification and Assessment Numerous classifications have been suggested for pectus excavatum. Some authors have compared the shape of the deformity to items such as cups or saucers. Other groupings include symmetric and asymmetric varieties of the concavity and/or rotation of the sternum, usually toward the right side.1,2 Quantitative assessment of a pectus deformity may be done most easily by measuring the distance on lateral chest radiographs between the sternum and vertebral column at the manubriosternal junction and at the gladiolus-xiphoid articulation. The normal ratio between these two measurements is around 1.0, which decreases to 0.5 in moderate depressions and even lower in severe depressions.4 The use of computed tomography (CT) allows the accurate measurement of the “pectus index,” that is, the ratio of the transverse diameter of the chest to the anteroposterior diameter at the maximal depression (with ≤ 3.25 for a normal chest and up to 7.4 for severe deformity). 5 The measurement of the volume of the concavity, moire photography, profile determinations, and calculation of the degree of asymmetry, flatness, depression, sternal rotation, and so on, have also been used to measure the severity of pectus excavatum, as well as to evaluate postoperative improvement.6

Pectus Excavatum Pectus excavatum is the most frequently seen anterior chest wall deformity, characterized by depression of the sternal body and adjacent costal cartilages, and a corresponding narrowing of the sternovertebral space. It accounts for about 90% of all chest wall deformities and occurs in 1 of 300 to 400 live births, with a male-tofemale ratio of 2:1 to 4:1. 1 Pectus excavatum is also known as funnel chest and chondrosternal depression. It is usually already recognizable during the first year of life and progresses as the child grows. Although the majority of cases are sporadic, a family history of some form of chest wall deformity has been reported in 37% of patients.2 The deformity may also be a part of different syndromes such as Marfan syndrome or other connective tissue disorders. Pectus excavatum was first described in 1594 by Bauhinus. The term “funnel chest” (“Trichterbrust”) was coined in 1882 by Wilheim Ebstein, and the first attempt to repair this anomaly was by Ludwig Meyer in 1911.1 The contemporary principles of the surgical correction of pectus excavatum were laid down by Ravitch in the early 1950s.1 145

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FIGURE 12-1. Classification of chest wall deformities.

Circulatory Involvement The degree of cardiopulmonary impairment in patients with pectus excavatum and its possible improvement after surgery remains controversial. Sternal depression may displace the heart to the left and rotate it clockwise. An area of relative lucency on the right side of the heart is usually seen on chest radiographs. On lateral radiographs the retrosternal space is absent and the sternovertebral distance is decreased. A sternal imprint on the anterior wall of the right ventricle and compression of the right ventricular outflow tract have been observed. A relative decrease in stroke volume during exercise has been reported and was attributed to impaired ventricular filling. The increase in right and left ventricular volumes after surgical correction suggests the relief of cardiac compression by the operation. Systolic ejection murmurs are frequently identified in these patients and could be explained by the proximity of the sternum to the

FIGURE 12-2. Mechanical model showing how elongation of costal cartilages produces either pectus excavatum (depression) or pectus carinatum (protrusion).

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pulmonary artery. Mitral valve prolapse (ranging from 18 to 65%) is frequently seen in patients with pectus excavatum and may be caused by anterior compression of the heart and deformation of the mitral annulus or ventricular chamber.7 Abnormalities in conduction and arrythmias may also be present. Because of the significant functional reserve of the otherwise-normal heart, patients with pectus excavatum may be asymptomatic, especially at rest. However, there are numerous case reports of a marked improvement (eg, relief from palpitations or arrythmias) after surgical correction of pectus excavatum, as well as increased stamina and exercise tolerance in patients who were considered functionally “normal” before the procedure.1,2 Respiratory Involvement The reduction of the thoracic volume in pectus excavatum occasionally leads to respiratory embarassment. There is also an increased incidence of asthma. Results of pulmonary function studies usually linger in low normal values; however, there is an increase in oxygen uptake, especially in symptomatic patients during exercise, which suggests an increased respiratory work effort. Paradoxically, some degree of additional impairment of pulmonary function has been demonstrated after repair of pectus excavatum, with a decrease in the vital capacity during the first 2 months after correction, probably owing to increased rigidity of the anterior chest wall. Usually, there is a recovery to preoperative levels by the end of the first year after surgery. Workload studies, however, have shown improvement in exercise tolerance following repair. Maximum voluntary ventilation, maximum oxygen consumption, and exercise tolerance have also improved after pectus excavatum repair.1,7 Bronchomalacia may also be associated with pectus excavatum, either coincidentally or caused by compression of the mediastinum. The site of involvement is most commonly the left main stem bronchus. Collapse of the bronchus owing to weakened cartilaginous support or extrinsic compression can cause a harsh, low-pitched, and monophonic wheeze. There is usually also a left mediastinal shift, atelectasis of the left lung, and recurrent pulmonary infection. Children who wheeze persistently should undergo flexible bronchoscopy to confirm the closure of the lumen of the affected bronchus before surgical correction of pectus excavatum is contemplated. Elevation of the sternum during correction of funnel chest has shown limited effect on tracheobronchomalacia. Combining pectus repair with suspension of the aorta and pulmonary artery may further improve the outcome. Aortopexy by raising the anterior wall of the trachea is a recommended treatment of tracheomalacia. In cases of bronchomalacia, pulmonary arteriopexy has

been also proposed to correct the collapse of the left main bronchus. Suspension of the bronchial wall to the ligamentum arteriosum has also been suggested. The benefits of bronchopexy may last long enough to allow the airways to grow and stabilize so that they no longer produce symptoms.8 Scoliosis Postural disorders (eg, bowed neck, stooped shoulders) are often seen (up to 40%) in patients with pectus excavatum, especially if they have an asthenic habitus. Pectus excavatum is associated with scoliosis in up to 40 to 50% of patients. The thoracic curvature is usually between the fourth and ninth thoracic vertebrae, with an average angle of 15
. Only about 18% of patients with pectus excavatum have severe enough scoliosis to require specific treatment.9,10 Pectus Excavatum and Marfan Syndrome Marfan syndrome is a dominant, inherited disorder of the connective tissue that may affect the skeletal and cardiovascular systems as well as the eyes. It occurs in 4 to 8 of every 100,000 live births. As many as two-thirds of patients with Marfan syndrome have pectus excavatum deformity. Scoliosis, with a high likelihood of progression during the patient’s lifetime, is also common. Although the presence of the pectus deformity is less evident in early childhood in patients without Marfan syndrome, when it occurs in patients with Marfan syndrome, it is more progressive and more severe. All tall children that exhibit pectus excavatum, and long, slender, hyperextensible limbs, should be screened for Marfan syndrome. Patients with murmurs audible in the aortic position with dilatation of the aortic root and mitral valve disease and a family history of chest wall deformities should consult a geneticist. If cardiac surgery is contemplated, repair of the chest wall deformity should be done simultaneously with surgical intervention. The recurrence of the deformity after surgical repair (attributed to premature correction without internal support) is much higher in patients with Marfan syndrome (up to 40%) and usually takes place within 3 years after initial repair; therefore, follow-up examinations should span a long enough period to detect complications.11 Pectus excavatum repair in patients with Marfan syndrome should be delayed, if possible, until skeletal maturity is nearly complete. Psychological Effects The psychological effects of pectus excavatum should not be underestimated. Most patients are shy, self-conscious introverts who try to conceal the deformity with posture and clothing. Children, often exposed to mockery, avoid

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swimming pools, beaches, and outdoor activities. Adolescents and young adults are reluctant to undress in the presence of others. In females, asymmetry of the breasts can further aggravate the issue. Parents, who, themselves, may also have the anomaly, are especially protective of their children and do not want them to endure the same unpleasant experiences they may have gone through. After the surgery, in most patients attention is focused more on the esthetic correction rather than on the relief of clinical symptoms. Timing of Surgery The younger the patient, the easier the correction is for the patient and for the surgeon. Some argue that 5 to 7 years old is the best time for surgery; however, depending on the severity of the deformity, accompanying disorders, and clinical symptoms, it can be done earlier. We disagree with the view that repair of pectus excavatum should be delayed because of the danger of developing “aquired Jeune’s syndrome”—a condition of arrested growth of the chest wall owing to overly radical cartilage removal.12 Surgery can be done at any age, but it has to be done well.13 Operative Indications and Surgical Correction The aim of surgical intervention is multifold: (1) to allow normal growth of the thoracic cage, (2) to prevent or treat pulmonary and cardiac dysfunction, and (3) to alleviate psychological problems. Procedures described for surgical correction of pectus excavatum vary from the conservative, cosmetic, silicone implants to the radical, sternal “turnover” technique.13 The first step of “conventional” repair includes bilateral resection of the deformed costal cartilages, transverse osteotomy at the upper end of the sternal depression, and correction of the same by bending the sternum forward. The second step, securing and maintaining the sternum in its corrected position, may use one of many recommended methods. The techniques used for this purpose, based on the type of sternal support used, may be divided into two groups:procedures that do not use special support and those that apply various types of sternal support. The latter group may be further subdivided depending on whether external or internal support is employed. Sternal support may be applied either anterior or posterior to the sternum using various plates, bars, and splints made of metal and other materials, bioabsorbable struts, Kirschner wires, autogenous bone and cartilage, and so on. The most commonly used techniques involve the posterior support of the corrected deformity.14 There are some other techniques that do not fall into these categories, such as the sternal turnover operation, various cosmetic silicone implants, and muscle flaps to

camouflage the deformity, as well as “minimally invasive” techniques with or without endoscopy. The long-term effectiveness of most has not yet been confirmed. Our Recommended Operative Technique Over the years we have successfully used Marlex mesh (Bard, Inc, Cranston, RI) as a support to maintain the sternum in a corrected position.15 This technique, which we developed in the 1970s, employs the advantage of posterior support and does not carry the threat of dislodgment or require a second operation for its removal. The mesh also allows tissue ingrowth and creates a solid and stable anterior chest wall. With the patient under endotracheal anesthesia, a slightly upward convex transverse incision is made over the deformity in accordance with Langer’s lines. In female patients special care is taken not to interfere with the growing breasts. In severe cases in which the deformity involves the manubrium as well as the upper ribs, a midline vertical incision may be used, although it is less cosmetic. The skin and the subcutaneous tissues are mobilized but not separated and are retracted in a single flap. The dissection is extended up to the level at which the deformed cartilages start their depressed course. Using a cautery, the pectoralis major muscles are detached bilaterally from the sternum and then retracted, exposing the costal cartilages. The deformed cartilages (usually IV–VII) are resected subperichondrially on both sides, proportionally to the degree of their depression. A shorter segment is resected from the upper cartilages, and progressively longer portions are removed as the procedure moves downward. To ensure growth and regeneration, care is taken not to damage the growth plates at the junction of the cartilage and the bony rib. Leaving the posterior lamina intact, a wedge-shaped transverse sternal osteotomy is made below the manubrium at the level at which the sternal depression begins. The osteotomy is made in line with an intercostal space, rather than at the chondrosternal junction. The xiphoid process is detached from the sternum. The lower tip of the sternum is raised, the loose mediastinal tissue is dissected bluntly, and the intercostal bundles are bilaterally detached from the sternum close to its edges, leaving the mammary vessels intact. The sternum is now bent forward at the line of the transverse sternotomy. In the course of this manueuver, it is often necessary to break the posterior lamina. To stabilize and maintain the sternum in this corrected position, a sheet of Marlex mesh is cut to the size of the previously existing depression and placed under the sternum. The edges of the mesh are sutured tight, like a drum, to the distal ends of the divided costal cartilages and to the xiphoid with nonabsorbable heavy sutures (Figure 12-3). The substernal

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such as atelectasis. Epidural analgesia not only effectively reduces the pain, it also lowers the necessary dosage of medications. The epidural catheter may be placed preoperatively with its tip positioned at the level of the second or third thoracic vertebra. Simultaneous Pectus Repair and Cardiac Surgery Chest deformities may present numerous technical problems in cardic surgery, including exposure, positioning of the sternal retractor, harvesting the internal thoracic artery, and cannulation. Compression by the depressed sternum may also impair cardiovascular function. Inability to close the chest in patients with pectus excavatum after replacement of the aortic valve and ascending aorta, owing to the increased right atrial pressure and decreased cardiac output, has been reported. These possible events make simultaneous repair of pectus excavatum and the cardiac anomaly advisable.16 One-stage pectus and intracardiac repair through the midline approach is feasible, does not increase morbidity, and avoids the need for a second operation through adhesions. Complications Atelectasis, pneumothorax, wound infection, seroma, and keloid are rare and may be handled accordingly. Bleeding from the injured internal thoracic artery may occur and requires urgent intervention. If the proper technique is applied, true recurrence FIGURE 12-3. Repair of pectus excavatum: transverse wedge sternotomy, subperichondrial resection of the deformed cartilages, and posterior support of the corrected sternum by Marlex mesh sutured taut underneath it. Inset, Cross-sectional view.

space is connected with the right pleural cavity and drained through a water-sealed intercostal catheter for 24 to 48 hours. In our experience connecting the retrosternal space with the right pleural cavity, although it may appear unnecesary, ensures optimal drainage of the operative area, greatly reduces the occurence of wound complications, and ensures undisturbed wound healing. The procedure is completed by uniting the previously detached edges of the pectoralis muscles presternally (Figure 12-4). The skin is closed with an intracutaneous running suture. In cases of asymmetric pectus excavatum, the correction is achieved by an uneven resection of the deformed cartilages and mesh support, as described above. If the sternum is tilted, then it is twisted at the sternotomy site in the opposite direction and secured by a reverse figureof-eight, stainless steel wire suture (Figure 12-5). Respiratory therapy is useful in the immediate postoperative period to prevent pulmonary complications

FIGURE 12-4. Repair of pectus excavatum, cross-sectional view. A, The pectus excavatum deformity. B, Subperichondrial resection of the cartilages, and the detachment of the pectoralis muscles from the sternum. C, Posterior sternal support with Marlex mesh. Pectoralis major muscles are united presternally.

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FIGURE 12-5. Repair of asymmetric pectus excavatum: unevenly resected cartilages, a transverse sternotomy, the sternum detached from the perichondrial connections and its rotation corrected, and the internal thoracic vessels left laterally intact. Inset: Lateral view of a reversed figure-of-eight suture.

after the repair of pectus excavatum should not occur in ≥ 5% of patients.12 Recurrence should not be mistaken for residual deformity, which is usually caused by inadequate cartilage resection. The lack of appropriate support after surgical correction and continued overgrowth of cartilages in connective tissue disorders can cause recurrence. Redo operations are feasible and employ the same principles as the initial operation; however, they are much more difficult and time consuming. There is no obvious correlation between the age at repair and the frequency of recurrence. Innovative cosmetic correction of pectus excavatum with autologous adipose flaps (vs silicone prosthetic implants) during reduction mammoplasty has potential oncologic implications owing to the possibility of developing breast cancer outside the breast boundaries. Flap atrophy may also occur.17

We do not recommend the use of metal supports in the repair of pectus excavatum because of the possibility of migration and the potential for injury to the thoracic or even abdominal organs, and because of the necessity of removing these contraptions 6 to 12 months after their implantation. Chest pain and pleural or pericardial effusion may point to displacement or fracture of the support and indicate its urgent removal. The possibility of heart chamber intrusion (primarily into the right ventricle) with thrombus formation should always be kept in mind and also may necessitate the establishment of a cardiopulmonary bypass.18 Positional asymmetry and disturbed growth of the female breasts may occur in the course of pectus repair if the surgeon misjudges the extent of mammary tissue in children, which can be more medial in girls with funnel chest. When the skin incision is made, a safe distance of 5 cm below the areola (in prepubertal girls) should be maintained in bow-shaped inframammary incisions.19 The extent of the deformity may necessitate a vertical incision; however, this is more prone to keloid formation. “Crosseyed” nipples can be corrected by triangular skin plasty.13 Very rarely the repair of pectus excavatum can lead to thoracic outlet syndrome owing to the additional displacement of the ribs in patients with preexisting positional abnormalities of the first and second ribs. Prior to pectus surgery, minor signs of neurovascular compression caused by latent thoracic outlet syndrome should be documented. In addition, hyperabduction of the arm during surgery should be avoided.20

Pectus Carinatum Pectus carinatum is a protrusion deformity of the anterior chest wall with an abnormal prominence of the sternum and/or adjacent costal cartilages. It is the second most common chest wall anomaly after pectus excavatum. The proportion of occurrence between pectus carinatum and pectus excavatum ranges from 1:13 to 1:4. Pectus carinatum accounts for 5 to 22% of all anterior chest wall deformities. Males are affected two to four times more frequently than females.1,2 Among healthy school-age students, the condition is present in 0.06 to 1.7%.1,21 Most cases of pectus carinatum are sporadic; however, familial incidence has been reported in as many as 26% of cases.2 It can also be part of a syndrome or connective tissue disorder. The basic etiologic mechanism is thought to be overgrowth of the costal cartilages, just as occurs in pectus excavatum, with secondary forward displacement of the sternum.22 Carinatum deformities may be divided into three main groups: (1) keel chest, (2) lateral pectus carinatum, and (3) pouter pigeon breast. Iatrogenic pectus carina-

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tum may be of traumatic or surgical origin.21 Patients may also have advanced congenital heart disease that causes right ventricle enlargement severe enough to create a carinatum deformity. In a category by itself is secondary pectus carinatum owing to severe kyphosis deformity.22 Keel Chest: Classification Keel chest has two varieties. Chondrosternal prominence is the most common variety of pectus carinatum and is characterized by forward displacement of the lower third of the sternal body, with maximum prominence at the sternoxiphoidal junction. The condition has also been referred to as pyramidal chest, sternal kyphosis, chicken breast, sternum cuneiform, piriform chest, and oblique pigeon breast, among others. The chest may also be barrel shaped (often seen in toddlers), with the sternum arching forward at its middle section. In sternum elevatum, the sternoxiphoidal junction is “in line” with the sternal axis, and the maximal prominence is at the tip of the xiphoid process.14,22 The ossification pattern is normal in keel chest. The angle of Louis (the angle between the manubrium and body of the sternum) approaches 180
. The body habitus of most patients is usually asthenic. The deformity is often associated with the bilateral depression of the lower costal cartilages, mistakenly identified by some as Harrison’s grooves. These depressions can be fairly deep and significantly contribute to the reduction of thoracic capacity.21 In our experience keel chest was identified at around 3 years of age in 75% of cases. The next peak of identification was observed at 9 to 11 years and was probably due to a period of accelerated growth. In lateral radiographs the anteroposterior diameter of the chest is increased, the ribs seem to tear away from the sternum, and the retrosternal space is extended. The elongated cardiac silhouette is positioned in the middle mediastinum.21,23 Lateral Pectus Carinatum Lateral pectus carinatum is characterized by marked unilateral protrusion of the costal cartilages, usually from the second rib down. Often there is concomitant rotation of the sternum (30–45
) along its longitudinal axis toward the opposite side. A less frequently encountered variety is the localized prominence of only two cartilages with minimal or no sternal involvement. This condition is always asymmetric. Clinical Features Pain from local trauma to the protruding sternum and discomfort during sleep in the prone position are the

most frequent complaints with pectus carinatum. Significant respiratory symptoms are rare; however, less severe symptoms, such as moderate dyspnea, fatigue, asthmatic signs, and nondescript chest pain, are present in about one-third of these patients. Respiratory insufficiency associated with cor pulmonale may be seen in patients with a combination of severe kyphosis and pectus carinatum. Cardiac symptoms are less common in patients with keel chest than in those with pectus excavatum. The clinical symptoms are rare and may be due to decreased pulmonary reserve, caused by impaired respiratory movements of the thorax with increased residual air and reduced vital capacity. The incidence of scoliosis has been reported in 15 to 37.8% of patients with pectus carinatum, with the single thoracic curve between the fourth and ninth vertebrae, with an average angle of 16
.2,10,24 Psychological Effects The psychological effects of pectus carinatum, in general, are more prevalent than are those of pectus excavatum. Because of the protruding character of the deformity, it is more difficult to hide under clothing. Depressions on both sides of the sternum, if present, further emphasize the protrusion. In cases of lateral pectus carinatum, even a moderate prominence makes the chest appear unsightly. To conceal the protrusion, patients hold themselves slightly bent, which leads to an abnormal posture and further aggravates the deformity. Treatment Various nonoperative methods, such as physiotherapy, the use of plaster of paris, and external compression, are dismissed by the words of Howard: “The remedy for the deformity is operation. Physiotherapy is useless without operation, and retaining apparatus is worse than useless.”1 We prefer to do surgery before children reach school age to prevent psychological trauma and pathologic posture. Also, at this age, it is easier to perform extensive surgical correction. surgical correction of keel chest For the surgical correction of keel chest, a bow-shaped submammary skin incision is made. After the skin and subcutaneous tissues have been mobilized, they are retracted cranially. Deformed cartilages are exposed either one by one or by detaching and laterally retracting the pectoralis major muscle. Subperichondrial resection of the deformed costal cartilages is then performed on both sides. If the protrusion of the cartilages is asymmetric, it is corrected by uneven bilateral resections. Inadequate resections may lead to residual deformity and

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unsatisfactory cosmetic results. Resection of portions of the bony ribs is rarely necessary, even in advanced cases. In chondrosternal prominence where there is angulation at the sternoxiphoidal junction, the xiphoid process is detached and a 2 to 3 cm length of the lower sternum is resected. A transverse sternotomy is performed at the level of the beginning of the abnormal forward curve. The sternum is bent at the level of the sternotomy and pressed posteriorly; it is thus brought into a corrected position (Figure 12-6). It is a good practice after correction of the anomaly to pull the skin edges temporarily together and observe carefully to see whether additional corrective steps need to be made before permanent closure is undertaken. Unless the patient already has a chest tube, the substernal space is drained using a perforated vacuum drain through a separate stab incision through the inferior skin flap.

FIGURE 12-6. Keel chest repair: transverse sternotomy at the beginning of the forward curve, bilateral subperichondrial resection of the deformed cartilages, and the sternum shortened by resection. The xiphoid process is reunited with the sternum. Inset: Lateral view: A, anatomy of the deformity; B and C, steps of correction.

The xiphoid process and rectus muscle are then reattached to the caudal end of the sternum to further secure the sternum in its corrected position. Care should be taken that the latter maneuver is done under tension to ensure traction upon the sternum by the rectus muscles via the xiphoid. The edges of the pectoralis muscle are now united in front of the sternum to further secure its corrected position and to provide a smooth, soft contour to the anterior chest wall. If there is no sternoxiphoidal forward angulation but the xiphoid itself is elevated (sternum elevatum), xiphoid detachment and sternum resection are omitted (Figure 12-7). The wound is then closed layer by layer. A light compression dressing further secures the corrected position of the anterior chest wall.

FIGURE 12-7. Repair of pectus elevatum: bilateral subperichondrial resection of the deformed cartilages. After a transverse sternotomy, the sternum is pushed down. Inset: Lateral view: A, anatomy of the deformity; B and C, steps of correction.

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surgical correction of lateral pectus carinatum The operation for the repair of lateral pectus carinatum has to be tailored to the extent and location of the deformity; it may be very simple or quite extensive. If the anomaly consists only of unilateral overgrowth of a few cartilages, the skin incision is made directly over them, the muscle fibers are separated, and the procedure is limited to subperichondrial removal of the unsightly protuberance. It is advisable, however, to be radical rather than conservative and to resect the neighboring cartilages. If the anomaly also involves the bony portion of the rib, one should not hesitate to remove the bony protrusions as well. If the procedure necessitates more extensive resection of costal cartilages on one side, removal of a short segment of corresponding cartilages on the contralateral side is advised to prevent tilting of the sternum, which may cause recurrence of the anomaly. If pectus carinatum is accompanied by kyphosis, the matter of operative indication and the surgery itself should be a combined undertaking of both a thoracic and an orthopedic surgeon. Simultaneous operations on the anterior chest wall and the spine should be avoided. Pouter Pigeon Breast Pouter pigeon breast is a rare congenital deformity of the chest characterized by a protrusion of the manubriosternal junction, the adjacent ribs, and premature sternal ossification. It is considered to be the second most common type of pectus carinatum, although it is noticeably different in nature from keel chest and lateral pectus carinatum. Most often it occurs as a single anomaly, but it also can be a part of syndromes such as Noonan’s and Turner’s.1,25,26 The condition is also known by the following pseudonyms, among others: arcuate pectus carinatum, chondromanubrial prominence with chondrosternal depression, Currarino-Silverman syndrome.1,2,25,26 In our experience the deformity was spread evenly between males and females.21 There also have been familial cases reported.2,23 clinical features The main clinical feature of pouter pigeon breast is the protrusion of the junction between the manubrium and the body of the sternum, with a reduction in the angle of Louis. The adjacent costal cartilages, usually from II to V, also protrude. Abnormal ossification of the manubr iosternal junction is always present (Figure 12-8A and B). Normally, manubriosternal synchondrosis exists throughout life and is replaced by synostosis only in 10% of the population. All patients with pouter pigeon breast, regardless of age, have a

completely ossified manubriosternal joint. Fusion of the sutures between the four sternal segments (sternebrae) also occurs prematurely. This abnormal ossification may happen as early as 2 years of age and can be confirmed with conventional lateral radiographs. 25,26 The sternum is slightly wider and thicker than normal. In lateral view the anterior chest wall is Z-shaped. The term angulated synostosis of the sternum may best describe the anatomic and morphologic peculiarities of this abnormality. Depression of the lower third of the sternal body is present in about one-third of the patients (Figure 128C), and because of this the condition is frequently mistaken for pectus excavatum, despite being distinctly different in other aspects. Protrusion of the manubrium often creates the illusion of mesosternal depression. The condition is usually symmetric. cardiac abnormalities Several cardiovascular abnormalities may coexist with premature sternal ossification, ventricular septal defect being the most common. Presence of congenital cardiac disease in patients with pouter pigeon breast and abnormal ossification of the sternum has been estimated to be from 18 to 55%.2,23,25,26 This makes the search for occult cardiac lesions advisable in all patients with this deformity. respiratory disorders Abnormal pulmonary function is uncommon, and if it occurs it is less severe in patients with pouter pigeon breast than in those with either pectus excavatum or classic keel chest. However, patients with pouter pigeon breast have restricted compliance of the rib cage owing to ossification of the manubriosternal junction; such compliance is thought to be physiologically necessary for optimal respiratory function. psychological effects Because of the appearance and particularly high location of pouter pigeon breast on the anterior chest wall, patients refuse to wear a deep décolletage. Usually, an awareness of the deformity and the associated negative emotions materialize at around 7 years of age, with full psychological impact at around 10 years of age. classification Determination of the angle of Louis on the lateral chest radiograph allows the objective measurement of the deformity and also assists in the selection of the proper surgical technique (see Figure 12-8). The normal angle of Louis is between 175 and 145
. When the angle reaches 130
(mild deformity), we recommend only follow-up once a year. In patients with an angle of ≤ 130
, we

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FIGURE 12-8. Classification of pouter pigeon breast. A, Normal thoracic cage: the sternum is segmented, the manubriosternal junction is not ossified (synchondrosis), the angle of Louis is normal, and the sagittal diameter of the chest at the angle of Louis (a) and at the lower third of the sternum (b) is normal. B, Pouter pigeon breast deformity without mesosternal depression: there is abnormal ossification at the sternum, the angle of Louis is reduced, and the sagittal diameter at the angle of Louis (a1) is slightly increased and is unchanged at the lower third of the sternum (b1). C, Pouter pigeon breast deformity with mesosternal depression: the angle of Louis is further reduced and the sagittal diameter at the angle of Louis (a2) is greater than usual and decreased at the lower end of the sternum (b2).

recommend surgical correction, especially when the manubrial prominence is accompanied with the depression of the lower sternal body. When sternovertebral distance is reduced, the range of the angle of Louis is usually between 134 and 110
.26 Our preferred patient age for repair is between 5 and 7 years old. If the angle is ≤ 115
, the operation should be done, regardless of the patient’s age. Pouter pigeon breast is usually already noticeable before the age of 3 years and often during the first year of life. Progression occurred with the growth of the child in half of our patients. As the deformity worsens, the angle of Louis decreases, primarily because the manubrium approaches the horizontal line. We found no correlation between the degree of reduction in the angle of Louis and the depression of the lower sternum. operative indications In the implementation and timing of surgical correction of pouter pigeon breast, the following are considered: (1) degree of the deformity, (2) existence of depression of the lower part of the sternum, (3) yearly progression of the deformity, (4) associated cardiac and respiratory abnormalities, and (5) whether the deformity is part of a syndrome.

surgical correction Correction of pouter pigeon breast is performed through a slightly upward convex submammary incision. If the deformity consists only of protrusion at the angle of Louis, the operation may be limited to chiseling the prominent bone off with a wide, flat osteotome and resecting costal cartilages II and III. If depression of the sternal body is also part of the anomaly, besides the above maneuver, additional intervention is necessary. A transverse wedge (1.5–2 cm) osteotomy is performed at the angle of Louis, leaving the posterior lamina intact. To have a good cosmetic result, the angle of Louis should be corrected by at least 30
so that it is not smaller than 140
after the operation.26 The sternum is then freed by detachment of the intercostal bundles bilaterally and by dissecting the loose mediastinal tissues posteriorly. A transverse linear sternotomy is then performed at the level of the mesosternal depression. The depressed sternum is brought into a normal position by breaking it at both osteotomy sites, straightening it, and supporting it with a Marlex mesh “hammock” as described for correction of pectus excavatum (Figure 12-9). The final steps for closure of the wound and drainage are the same as those described for surgical correction of pectus excavatum. Simultaneous correction of cardiac lesions is possible.16 If done well, postoperative complications are rare and the long-term results are good.

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FIGURE 12-10. Full-blown Poland’s syndrome with the absence of the sternocostal part of the pectoralis major muscle, the absence of the pectoralis minor muscle, hypoplasia of the latissimus dorsi, aplasia of ribs III to V, and ipsilateral “mitten hand.” Reprinted with permission from the Society of Thoracic Surgeons.51 FIGURE 12-9. Repair of pouter pigeon breast with mesosternal depression: chiseled manubrial protrusion, wedge-shaped sternotomy of the angle of Louis, and linear sternotomy at the depressed site. Marlex mesh underneath the sternum is stretched and sutured to the distal stumps of the resected costal cartilages. The xiphoid is reattached. Inset: Lateral view: A, anatomy of the deformity; B and C, steps of correction.

Poland’s Syndrome

between the extent of the deformities of the hand, breast, and chest wall. Poland’s syndrome is almost always unilateral, although a single bilateral case has been reported.29 The anomaly was first described in 1826 by L.M. Lallemand and then in 1841 by Alfred Poland. The estimated incidence of Poland’s syndrome is 1 in 30,000 live births. Males are affected more frequently than females by a ration of 3:1 or 2:1. The right side of the body is involved in 60 to 75% of cases.1,2,30

Poland’s syndrome is a rare congenital anomaly characterized by brachysyndactyly, hypoplasia or absence of the breast and/or nipple, hypoplasia of the subcutaneous tissue, absence of the costosternal portion of the pectoralis major muscle, absence of the pectoralis minor muscle, aplasia or deformity of the costal cartilages or ribs II to IV or III to V, and alopecia of the axillary and mammary regions. Concisely, it could be defined as pectoral aplasia-dysdactylia syndrome. The extent and degree of various components of the syndrome are variable, and rarely does one individual manifest all of its features (Figure 12-10). 1,2,27,28 There is no correlation

Etiology Poland’s syndrome is a nongenetic congenital abnormality with a low risk of recurrence (< 1%) in the same family. A report of Poland’s syndrome in one identical twin provides evidence of its sporadic nature.31 However, familial transmission has been reported in approximately 25 cases and could be due to an autosomal dominant gene with low penetrance.27,28,30 The pathogenesis of Poland’s syndrome remains unclear. Currently, the dominant theory is the “subclavian artery blood supply disruption sequence.”32 A meso-

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dermal defect during the sixth and seventh weeks of gestation leads to hypoplasia of the subclavian artery or one of its branches which, in turn, results in the interruption of the embryonic blood supply. The site and amount of obstruction determine the extent of the anomaly. Hypoplasia of the internal thoracic artery causes the absence of the sternocostal portion of the pectoralis major muscle, whereas hypoplasia of branches of the brachial artery leads to hand abnormalities. Clinical Features In all patients with Poland’s syndrome, the sternocostal attachment of the pectoralis major is absent, and in most cases the pectoralis minor is absent as well. The absence of the pectoral muscles, however rarely, causes functional impairment. In some cases the latissimus dorsi, external oblique, and serratus anterior muscles may also be affected. Breast-involvement ranges from mild hypoplasia to complete absence (amastia). The nipple and areola are usually hypoplastic and elevated, lightly pigmented, or even absent (athelia). Supernumerary nipples may also be present. In some cases the entire rib cage is normal, with only the pectoralis muscles absent; however, there is often an ipsilateral depression of the chest wall with hypoplasia of the ribs and cartilages. Usually, ribs II to IV or III to V are involved, with the second rib being the least frequently involved. Aplasia of the anterior portions of one to three ribs with more severe lateral depression may occur in up to 11% of patients.2,28 The sternum may rotate toward the involved side, thus forming an asymmetrical contralateral pectus carinatum.2 Dextrocardia in patients with left-sided Poland’s syndrome has been documented in 17 patients and was combined with rib defects, although it was not associated with other cardiovascular anomalies.33 Lung herniation occurs in 8% of the cases. Conventional anteroposterior radiography usually demonstrates the unilateral hyperlucent lung.1,27,28 Hand involvement in Poland’s syndrome may vary from mild shortness of the middle phalanges with cutaneous webbing to a complete absence of the hand. The reported incidence of hand anomalies in Poland’s syndrome has been reported from 2.5 up to 56%. In turn, in patients with syndactyly, about 10% have Poland’s syndrome.2,34 It may occur that one family member shows isolated pectoral hypoplasia, which is also considered to be Poland’s syndrome, while another member may have the combined hand-pectoral deformity. Cases without involvement of the hand are defined as “partial Poland’s

sequence” and occur with greater frequency than does full-blown Poland’s syndrome.1,2,27,34,35 There is a well-known association between Poland’s syndrome and Möbius’ syndrome, a bilateral congenital facial nerve palsy with paralysis of the abductors of the eye. It has been proposed that premature regression of the primitive trigeminal arteries might be the cause.32 In some patients with Poland’s syndrome, absence of the upper portion of the serratus anterior results from the obstruction of blood flow in the suprascapular arteries and leads to elevation and winging of the scapula (Sprengel’s deformity).32 Klippel-Feil syndrome may also accompany Poland’s syndrome.32 Klippel-Feil syndrome is characterized by a shortness of the neck resulting from fusion of the cervical vertebrae and abnormalities of the brainstem and cerebellum due to a delay in the development of the vertebral arteries. There is also an association between aplasia of the pectoralis major muscle and renal anomalies (eg, unilateral renal agenesis or duplication of the urinary collecting system), which can be accompanied by renal hypertension.1 A relationship exists between congenital malformations and tumors. Cases of Poland’s syndrome associated with leukemia, non-Hodgkin’s lymphoma, leiomyosarcoma, and cervical cancer, for example, have been reported. Poland’s syndrome can also be associated with invasive ductal carcinoma in the hypoplastic breast. Therefore all persons with Poland’s syndrome should be carefully monitored for early detection of cancer.1,36 Operative Indications Surgical intervention for Poland’s syndrome is indicated for the following reasons: (1) ipsilateral concave deformity of the chest wall and the possibility of its progression, (2) lack of adequate protection of the heart and lung, (3) paradoxic movement of the chest wall, and (4) aplasia or hypoplasia of the breast in female patients. Anesthesia In patients with aplasia of ribs and lung hernia, unilateral ventilation of the opposite lung using a double-lumen endotracheal tube is recommended to prevent pulmonary injury.27 Epidural anesthesia is recommended during and after surgery with the end of the catheter at the level of the second or third thoracic vertebra.35 Treatment The surgical treatment of Poland’s syndrome, depending on the age and sex of the patient, may be carried out in one or two stages and involves stabilization and/or reconstruction of the chest wall with simultaneous augmenta-

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tion mammoplasty in females. The latter involves insertion of a breast prosthesis beneath an island pedicle musculocutaneous flap of the latissimus dorsi.27 Whereas in adults the correction should be done in one stage, in children the procedure is usually carried out in two stages: first the depression of the chest is corrected, then in adulthood latissimus dorsi muscle transposition and/or mammoplasty is carried out, when necessary. Surgical repair involves the following: • When there is a large defect in the ribs and lung herniation, stabilization of the chest wall can be achieved by attaching split rib grafts taken subperiosteally from the unaffected side of the chest, using bony allografts

from other parts of the body or a mesh patch to the edges of the defect (Figure 12-11). If a rib graft is used, the medial end of the graft is inserted into an opening created in the side of the sternum and then sutured. Laterally the graft is attached to the freshened surface of the rib stumps. If mesh is used, it should be stretched taut and sutured to the margins of the defect. If both bony grafts and mesh are used, the mesh should be sutured to the rib grafts as well. 1 When the defect involves two ribs, it is possible to split the normal ribs above and below the defect and attach the newly created ends to the stumps of the aplastic ribs (Figure 12-12). In cases where ribs are fused at

FIGURE 12-11. A, Poland’s syndrome with aplasia of ribs III to V and sternal rotation. B, Split rib grafts are harvested from the contralateral side; they are secured medially into created sternal notches and laterally to the ends of the aplastic ribs. Sternal rotation is corrected by an osteotomy and figure-of-eight suture. C, Prosthetic mesh is sutured to edges of the defect and on top of rib grafts.

FIGURE 12-12. A, Poland’s syndrome with aplasia of the anterior portions of two ribs. B, Ribs above and below the defect are split, and their ends reattached to the stumps of the aplastic ribs.

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FIGURE 12-13. A, Repair of Poland’s syndrome with two ribs fused at their sternal ends. B, Separation and reattachment of the lower rib to the sternum at the notch.

their sternal ends, reconstruction can be done by separating them and reattaching them to the sternum (Figure 12-13). • In cases of hypoplastic ribs with ipsilateral chest depression, correction should be accomplished by subperichondrial resection, along with Marlex mesh reinforcement. • Sternal rotation, if present, should be corrected simultaneously with the rib correction and by transverse sternotomy and “reversed” figure-of-eight wire suture. • Hypoplasia of the breast may be remedied using a prosthetic implant and/or musculocutaneous flaps. • The loss of muscle mass and the anterior axillary fold can be corrected by transplantation of a latissimus dorsi musculocutaneous flap. The status of the latissimus dorsi is of paramount importance and influences the surgical approach and results. A hypoplastic latissimus dorsi muscle can be present with a normal-looking posterior axillary fold. Clinical examination is therefore unreliable, and the anatomy of the muscle can only be accurately demonstrated by CT, magnetic resonance imaging, or mediolateral oblique mammography. In cases involving a missing latissimus dorsi muscle, microsurgical transfer of the contralateral latissimus dorsi is an option.27,37,38 In cases involving a hypoplastic latissimus dorsi muscle, there have been reports of reconstruction using a free transfer of an upper gluteal flap or microvascular free abdominal muscle flap using internal thoracic vessels as recipient vessels.38 Complications To prevent displacement of the rib grafts, their medial ends should be embedded into an opening created in the

side of the sternum and they should also be sutured to the prosthetic sheet above it. After covering the rib defect with the autogenous fascia lata, slackening may occur over approximately 6 months, causing the defect to reappear.1 Partial skin necrosis has also been reported when a hypoplastic latissimus dorsi was transplanted.37 The results of Poland’s syndrome repair are generally good. We recommend a first follow-up examination 6 months after surgery, following physical therapy to create a slight hypertrophy of transformed muscle flaps.35

Cleft Sternum Cleft sternum is a partial or complete separation of the lateral sternal bars and is also known as bifid sternum or sternal fissure. It is caused by failed ventral midline fusion of the sternal bands, which normally occurs during the first 3 months in the embryo. Females with cleft sternum outnumber males, especially when the cleft is accompanied by a combination of supraumbilical raphe and facial hemangiomas.1,39,40 Clinical Features Cleft sternum presents as a concave defect of the sternum, which paradoxically deepens upon inspiration and bulges with expiration, coughing, or the Valsalva maneuver. The shape of the defect varies from a narrow U to a broad V, the width of which may vary from 2 to 6 cm. The pulsation of the heart is usually discernable through the thin and sometimes ulcerated skin. Herniation of the lung may occur at the upper edge of the defect. A midline, pigmented raphe reaching from the xiphoid process to the navel is common.41 Presence of an omphalocele or an umbilical hernia is frequent. Intracardiac

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anomalies such as ventricular septal defect or tetralogy of Fallot may also complicate sternal clefts. An association with craniofacial hemangiomas is common. Classification of the anomaly is based on some of the peculiar features, especially on the length of the fissure. The correction of different varieties may require different surgical techniques. There are four main types of sternal clefts. Superior sternal cleft, the most common type of this malformation, involves the manubrium and the upper part of the body of the sternum and usually extends down to the level of the fourth intercostal space (Figure 12-14A). The position of the heart is normal, and the pericardium, pleura, and diaphragm are intact. Subtotal sternal cleft involves the manubrium and most of the sternum, leaving only a narrow cartilaginous bridge (up to 15 mm) at the xiphoid process (Figure 12-14B). In cases of total sternal cleft, the sternal halves are completely separated (Figure 12-14C). This is the least common type of abnormality and may be mistaken for sternal agenesia. Wide diastasis of the rectus abdominis muscle is common. Inferior sternal cleft usually occurs in Cantrell pentalogy, which also includes an omphalocele or omphalocelelike abdominal defect, a crescent-shaped anterior

diaphragmatic defect, and a hole in the pericardium, which allows pericardial-peritoneal communication (Figure 12-14D). Cantrell pentalogy is also often associated with various intracardiac anomalies, such as atrial or ventricular septal defects, tetralogy of Fallot, and left ventricular diverticulum.1,2,28 Clinical Symptoms Clinical symptoms of sternal clefts may be caused by abnormal changes in intrathoracic pressure, displacement of the heart and large vessels, and impairment of venous return. Cyanosis, dyspnea, arrhythmia, and other circulatory difficulties may be present. A chest wall defect can also lead to reduced air exchange and a loss of strength of cough. Tracheal hemangioma can cause bleeding during endotracheal intubation.39–41 Diagnosis is easily established at birth. Prenatal diagnosis is feasible in the last weeks of gestation by ultrasonography. Establishment of diagnosis should initiate a thorough search for associated cardiovascular anomalies, as well as other midline structure malformations. In children with fasciocutaneous vascular lesions, an angiographic examination of the vertebrobasilar system is recommended. 4 2 Congenital aortic abnormalities (aneurysm, coarctation) should be ruled out, especially

FIGURE 12-14. Classification of the main types of sternal clefts. A, Superior sternal cleft. B, Subtotal sternal cleft. C, Total sternal cleft. D, Inferior sternal cleft.

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in patients with hemangiomatosis and supraumbilical raphe. On radiographs of the chest, superior mediastinal widening with an increased distance between sternal ends of the clavicles is noticeable. Operative Indications Sternal clefts should be corrected for several reasons: (1) lack of bony protection of mediastinal structures makes the heart and great vessels vulnerable to trauma; (2) the appearance of a protruding heart is disturbing for both patients and parents; (3) enlargement of the defect, over time, worsens the appearance and makes it more difficult to correct; (4) the presence of a dermopericardial sinus may lead to pericardial infection; (5) paradoxic respiratory movements of the chest induce dyspnea and predispose recurrent respiratory infections; (6) impairment of the venous return affects cardiac function; and (7) umbilical hernia and rectus muscle diastases require correction and can be repaired simultaneously. Surgical planning depends on the age of the patient, the type of the defect, and any accompanying anomalies of the heart. By consensus, operative correction should be carried out during the neonatal period and certainly no later than 2 months of age. At this time the sternal halves may be sutured together without tension and the chest cavity will likely accommodate the thoracic viscera. The maneuver of approximation of the ribs in the midline by applying gentle bilateral pressure on the chest (if the patient can endure it) can be used for “training” and ensure the surgeon that the repair will be well tolerated. The presence of ulcerated and/or infected skin or a skin-to-pericardium sinus should hasten the time of surgical intervention.1,28 Simultaneous repair of cardiac and aortic malformations is feasible.43 At an older age, surgical repair is more difficult because the chest becomes rigid and may require more complex methods of repair. The first successful operation for the anomaly was done by Burton in an 11-week-old child in 1943.44 Surgical repair is accomplished through a vertical midline incision. Midline raphe or ulcerated skin, if present, should be excised. The pericardium is dissected from the skin and sternal bands. The periosteum is incised on the anterior aspect of the sternal halves, elevated, and then turned medial and inward (Figure 1215).45 The sternal halves are approximated and sutured together. Notching of the sternal bars or a V-shaped sternotomy can ease their alignment. 46 In older patients oblique or Z-shaped sliding chondrotomies adjacent to the sternum should be performed to further facilitate the approximation.45 If the cephalad diastasis is wide, it may require the detachment and mobilization of the stern-

oclavicular junctions (Figure 12-16). The sternal bars are then united with nonabsorbable interrupted sutures passed through the remaining periosteum as well as the bone and reinforced with peristernal sutures.1,41 Uniting the sternothyroid, sternohyoid, and sternocleidomastoid muscles from both sides or switching the median sternal attachments of the sternocleidomastoid muscles prevents lung herniation at the base of the neck.41,47 In cases of subtotal sternal clefts, the cartilaginous bridge holding the halves apart should be resected before the bars are united.

FIGURE 12-15. Surgical correction of the superior sternal cleft: creation of the periosteal flaps, sliding chondrotomies, and notching of the sternal bars and midline wedge sternotomy for approximation of the sternal halves.

FIGURE 12-16. Repair of the superior sternal cleft: detachment at the sternoclavicular junction, suturing of the periosteal flaps, crossing and suturing of the medial attachments of the sternocleidomastoid muscles, and union of the sternal halves.

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In cases of total cleft sternum, the trimmed edges of the sternal halves are sutured together. Diastasis of the rectus abdominis muscles, if present, should also be corrected.7 Reconstruction of the defect, especially if it is very wide or in adult patients, may require autologous bone graft or the application of a polytef or Marlex mesh patch or a titanium plate, for example.1,48 The first postoperative day is the most critical owing to the possibility of compression of the heart caused by acute reduction of the mediastinal space. This makes careful monitoring of the patient’s cardiorespiratory status mandatory. Epidural anesthesia is recommended after the operation. Results and Complications Appropriate repair of sternal clefts should result in a solid anterior chest wall of normal shape. Less satisfactory results such as the development of a fissure-like funnel chest deformity are rare and may require additional correction later on. If the correction was not carried out high enough, herniation at the base of the neck may occur. Torticollis can be prevented by the wearing of an orthopedic collar in the early postoperative period.41 Sternal Foramen Sternal foramen or congenital perforation of the sternum is a circular osseous defect (3–18 mm in diameter) usually located in the lower third of the sternal body and is caused by incomplete fusion of a single pair of sternal primordia. The incidence of single, mesosternal midline foramen is about 6 to 8% of the population. Males are affected about twice as often as females.49 Because the anomaly may not be seen on routine radiographs, CT scanning is recommended to demonstrate the presence of this anomaly. As a rule, the condition is asymptomatic. A few lethal complications have been reported owing to secondary damage to the right ventricle or ascending aorta by a sternal biopsy or acupuncture needles used without a guard.50 In forensic investigations sternal foramen could serve as a trait peculiar to the individual in skeletal identification. It also could be mistaken for a gunshot wound by the unaware or misdiagnosed as bone destroyed by osteomyelitis or carcinoma.

2. Shamberger RC. Chest wall deformities. In: Shields TW, LoCicero J III, Ponn RB, editors. General thoracic surgery. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 535–61. 3. Robicsek F, Sanger PW, Taylor FH, Thomas MJ. The surgical treatment of chondrosternal prominence (pectus carinatum). J Thorac Cardiovasc Surg 1963;45:691–701. 4. Welch KJ. Satisfactory surgical correction of pectus excavatum deformity in children. J Thorac Surg 1958;36:697–713. 5. Chuang J-H, Wan Y-L. Evaluation of pectus excavatum with repeated CT scans. Pediatr Radiol 1995;25:654–6. 6. Nakahara K, Ohno K, Monden Y, Kawashima Y. An evaluation of outcome in patients with funnel chest by computed tomogram. In: Wada J, Yokoyama M, editors. Chest wall deformities and their operative treatment. Tokyo: Ad Printing Inc.; 1990, 53–61. 7. Shamberger RC. Cardiopulmonary effects of anterior chest wall deformities. Chest Surg Clin N Am 2000;10:245–52. 8. Kamata S, Usui N, Sawai T, et al. Pectus excavatum repair using costal cartilage graft for patients with tracheobronchomalacia. J Pediatr Surg 2001;36;1650–2. 9. Frick SL. Scoliosis in children with anterior chest wall deformities. Chest Surg Clin N Am 2000;10:427–36. 10. Waters P, Welch K, Micheli LJ, Shamberger R, Hall JE. Scoliosis in children with pectus excavatum and pectus carinatum. J Pediatr Orthop 1989;9:551–6. 11. Arn PH, Scherer LR, Haller A, Pyeritz RE. Outcome of pectus excavatum in patients with Marfan syndrome and in the general population. J Pediatr 1989;115:954–8. 12. Haller JA. Complications of surgery for pectus excavatum. Chest Surg Clin N Am 2000;10:415–26. 13. Robicsek F. Surgical treatment of pectus excavatum. Chest Surg Clin N Am 2000;10:277–96. 14. Robicsek F, Fokin AA. Surgical corrections of pectus excavatum and carinatum. J Cardiovasc Surg 1999;40:725–31. 15. Robicsek F. Marlex mesh support for the correction of very severe and recurrent pectus excavatum. Ann Thorac Surg 1978;26:80–3. 16. Willekes CL, Backer CL, Mavroudis C. A 26-year review of pectus deformity repairs, including simultaneous intracardiac repair. Ann Thorac Surg 1999;67:511–8. 17. Adams WP. Discussion of article by Guimares J, Maia M, Monteiro E, Ferraro A. Aesthetic correction of mild pectus excavatum with autologous tissue during mastopexy. Plast Reconstr Surg 2001;108:757–62.

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27. Urchel HC Jr. Poland’s syndrome. Chest Surg Clin N Am 2000;10:393–403.

42. Pascual-Castroviejo I. The association of extracranial and intracranial vascular malformations in children. Can J Neurol Sci 1985;12:139–48.

28. Landolfo K, Sabiston DC Jr. Disorders of the sternum and the thoracic wall. In: Sabiston DC, Spencer FC, editors. Surgery of the chest. 6th ed. Philadelphia: WB Saunders Company; 1995. p. 494–515.

43. Bové T, Goldstein JP, Viart P, Duevaert RT. Combined repair of upper sternal cleft and tetralogy of Fallot in an infant. Ann Thorac Surg 1997;64:561–2.

29. Karnak I, Tanyel FC, Tuncbilek E, et al. Bilateral Poland anomaly. Am J Med Genet 1998;75:505–7. 30. Freire-Maia N, Chautard EA, Opitz JM, et al. The Poland syndrome: clinical and genealogical data, dermatoglyphic analysis, and incidence. Hum Hered 1973;23:97–104. 31. Stevens DB, Fink BA, Prevel C. Poland’s syndrome in one identical twin. J Pediatr Orthop 2000;20:392–5. 32. Bavinck JNB, Weaver DD. Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies. Am J Med Genet 1986;23:903–18.

44. Burton JF. Method of correction of ectopia cordis. Arch Surg 1947;54:79–84. 45. Sabiston DC. The surgical management of congenital bifid sternum with partial ectopia cordis. J Thorac Surg 1958;35:118–22. 46. Jewette TC, Butsch WL, Hug HR. Congenital bifid sternum. Surgery 1962;52:932–6. 47. Daum R, Hecker WC. Operative correction of total sternum bifida. Thoraxchir Vask Chir 1964;12:333–9. 48. Hazari A, Mercer N, Pawade A, et al. Superior cleft sternum: construction with a titanium plate. Plast Reconstr Surg 1998;101:167–70.

33. Fraser FC, Teebi AS, Walsh S, Pinsky L. Poland sequence with dextrocardia: which comes first? Am J Med Genet 1997;73:194–6.

49. Cooper PD, Stewart JH, McCormick WF. Development and morphology of the sternal foramen. Am J Forensic Med Pathol 1988;9:342–7.

34. Ireland DC, Takayama N, Flatt AE. Poland’s syndrome. J Bone Joint Surg Am 1976;58:52–8.

50. Schratter M, Bijak M, Nissel H, et al. Foramen sternale: minor anomaly—great significance. Fortschr Rontgenstr 1997;166:69–71.

35. Bairov GA, Fokin AA. Surgical treatment of Poland’s syndrome in children. Vestn Khir Im II Grek 1994;152:70–2.

51. Fokin AA, Robicsek F. Poland’s syndrome revisited. Ann Thorac Surg 74:2218–25.

CHAPTER 13

SURGICAL MANAGEMENT OF CONGENITAL LESIONS OF THE LUNG KAREN MICHIKO KLING, MD PAUL M. COLOMBANI, MD Congenital lesions of the lung are a diverse collection of clinical entities that share characteristics due to their common embr yologic background. The tracheobronchial tree develops between gestational weeks four and five with deepening of the laryngotracheal groove and separation from the primitive foregut. Lung development occurs throughout fetal development and has four stages. In the embryonic stage (weeks 0–7) the lung bud separates from the primitive foregut, and in the pseudoglandular phase (weeks 8–16) the remainder of the airways develop into the tracheobronchial tree. Errors in mesodermal and endodermal embryogenesis and in lung bud migration lead to bronchogenic cysts, pulmonary sequestrations, congenital cystic adenomatoid malformations (CCAMs), epithelial foregut cysts, and foregut duplications. Lung development is concluded with the canalicular and terminal sac stages, which involve development and growth of alveoli and their supporting vasculature; these occur between weeks 17 and 24 and between week 25 and term, respectively. The exact time at which development goes awry determines exactly which anomaly or combination of anomalies will occur. The overall occurrence of congenital lung anomalies is rare; there is no evidence of familial or ethnic preponderance although there is a slight predilection (1.3:1) for boys. Most conditions are recognized within the first 6 months of life and are limited to one hemithorax. The most urgent clinical presentation is respiratory distress in the newborn period due to compression of adjacent functional lung, mediastinal shift, pulmonary hypoplasia, or airway obstruction. Older children may present with recurrent infection, hemoptysis, or compression related phenomena such as dysphagia. With the advent of more sophisticated and more prevalent

imaging, anomalies are also found incidentally. The widespread use of antenatal sonography makes this a common “presentation” and allows for early chromosomal analysis and echocardiogram to aid in antenatal care and decision making. A multitude of studies can be obtained to aid in diagnosis; often the only one necessary is a chest roentgenogram or ultrasound that demonstrates a space-occupying lesion. The imaging modalities chosen vary among institutions and are largely dependent on personal preferences, experience, and availability of technologists and specialized pediatric radiologists. Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) more precisely define pulmonary involvement and vascular anatomy, but regardless of the specific diagnosis, most congenital lung anomalies require surgical resection and often anatomical considerations can most accurately be assessed and effectively addressed during surgery. Therefore, additional invasive and costly imaging should be reserved for those cases in which the results may obviate operation or significantly alter the timing of operation or without which safety would be compromised. For infants and children, noninvasive studies may require long periods of immobility that they may not tolerate without general anesthesia. As will be addressed below, assisted ventilation with many of these lung lesions can be detrimental. The surgical congenital lung anomalies include bronchogenic cysts, pulmonary sequestrations, congenital lobar emphysema (CLE), CCAMs, congenital chylothorax, pulmonary lymphangiectasis, pulmonary agenesis, and congenital pulmonary arteriovenous malformations. Surgical resection is usually the treatment and can be limited to the defect itself but more commonly requires segmentectomy or lobectomy. Resection is generally 163

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recommended as soon as thoracotomy and general anesthesia are deemed safe. The urgency depends on the presence and severity of symptoms and the specific diagnosis. Occasionally, incidental diagnoses in asymptomatic adults or those with preclusive medical comorbidities may warrant observation.1 Without comorbidities, thoracotomy and resection of these lesions are extremely well tolerated from a physiologic, pain, and recuperative perspective. Outcome is dependent on associated pulmonary hypoplasia, pulmonary hypertension, fetal hydrops, cardiac compromise, renal anomalies, and syndromic defects. Survival varies from more than 95% in children with isolated lesions to less that 10% in those with associated congenital complications or fetal hydrops. Because of the dismal outcome for those with hydrops, an attempt to intervene through fetal surgery has become one of the newest surgical directives.

Bronchogenic Cyst Bronchogenic cysts arise from anomalous airway buds that contain nonfunctional pulmonary tissue (Figure 13-1). The cyst is lined with ciliated columnar or cuboidal cells with intervening mucous glands and the cyst wall contains both cartilage and smooth muscle. Mucoid material is produced and accumulates within the cyst contributing to its growth. Bronchogenic cysts represent 25% of the congenital bronchopulmonary anomalies and occur equally in male and female infants.2 There are no known associated syndromes or chromosomal abnormalities. Cysts that develop during an embryological phase before the separation of bronchopulmonary and foregut elements may be intimately associated with the esophagus; cysts that occur during the pseudoglandular phase of proximal airway development are situated centrally within the parenchyma or about central air-

FIGURE 13-1. Bronchogenic cyst: Ciliated columnar epithelium with smooth muscle cells in cyst wall. 100
magnification; hematoxylin/eosin stain.

ways. Peripheral lesions develop during the canalicular phase of lung development in which alveoli are being formed. Therefore, bronchogenic cysts occupy many locations (Figure 13-2). Cysts are usually, but not exclusively, situated in lower lobes, are single, and are unilateral; multiple or bilateral cysts may rarely occur. Some report that parenchymal locations are the most common, accounting for up to 70% of bronchogenic cysts. This is not universally accepted, however, and others report a predominance of mediastinal lesions, including cysts along the trachea, carina, proximal main stem bronchi, and paraesophageal area.3,4 In addition, bronchogenic cysts may be located in the neck, airway wall, chest wall, pericardium, pancreas, adrenal gland, and tongue. Cysts are characteristically between one and ten centimeters long and gradually increase in size due to mucus production by the cyst epithelium. Although there are almost always adherent fibrous bands connecting the cysts to adjacent tissue, cysts predominantly have no communication with the tracheobronchial tree, and this is the rule for extrathoracic cysts. Rarely, especially with multiple, peripheral lesions, there will be some patency between cysts and other tracheobronchial structures.5 Two-thirds of children with bronchogenic cysts present early with symptoms while the other third have incidentally noted lesions and are typically older children or even adults. More recently, bronchogenic cysts are being diagnosed on antenatal screening ultrasound. The most common presenting symptom, which is infection, is seen in up to one-half of symptomatic patients. Other complaints may be related to compression of the gastrointestinal tract and symptoms of dysphagia, mediastinal mass with airway compression, hemoptysis, or palpable mass. Infants with multiple, peripheral cysts are

FIGURE 13-2. Bronchogenic cyst: Possible anatomical locations.

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most likely to present in the perinatal period as a result of displacement of normal lung and impaired respiration. If peripheral lesions cause airway obstruction, postobstructive infections or lobar hyperinflation may develop. When airway blockage is more central, significant hyperinflation, mediastinal shift, and cardiopulmonary compromise may occur. A more unusual presentation in which the cyst exists within the airway wall may present with signs and symptoms similar to an airway foreign body; if such a cyst is proximal and enlarges rapidly due to mucus production, inflammation, or hemorrhage, acute airway obstruction may occur. This condition may be hard to diagnose with routine imaging studies as there is no predominant mass. Bronchoscopy may be the only means for diagnosis and treatment of this situation. For the majority of patients, however, symptoms are less severe and less acute; presentation is usually as an older infant or child with complaints of infection or dysphagia. Symptoms of cough, wheezing, fever, or hemoptysis prompt chest roentgenogram, which may demonstrate an unusual opacity or lucency, postobstructive emphysematous changes, or air–fluid level within the cyst (Figure 13-3). A chest radiograph that suggests a mass should be followed by CT scan to verify and localize the mass, determine its resectability, and to eliminate any nonoperative diagnoses such as pneumonias, simple lung abscesses, and certain lymphangiectasis. CT scan should demonstrate a cystic structure with a nonenhancing wall; it may have an air–fluid level (Figures 13-4 and 13-5). A finding of segmental emphysematous change may warrant bronchoscopy to rule out an airway foreign body (especially in the age group in which aspiration is common) or extrinsic airway compression. It may be

difficult to differentiate between bronchogenic cyst and pulmonary abscess, but an indolent clinical course coupled with persistent radiograph findings in the face of abatement of clinical symptoms suggests bronchogenic cyst over infectious etiologies. Those with persistent evidence of systemic infection and pulmonary symptoms may have infection alone or in combination with underlying bronchogenic cysts and would likely benefit from resection with respect to either the infection or cyst. Patients who present with dysphagia should undergo esophagogram, which will sometimes reveal evidence of

FIGURE 13-3. Bronchogenic cyst: Plain radiograph demonstrating a large right-sided bronchogenic cyst.

FIGURE 13-4. Bronchogenic cyst: Computed tomography scan with 2 cm right-sided nonenhancing mass representing a paratracheal bronchogenic cyst.

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FIGURE 13-5. Bronchogenic cyst: Magnetic resonance imaging of sagittal section of the bronchogenic cyst in Figure 13–4.

compression phenomena; then CT scan or ultrasound should be performed to identify the mass responsible and define its anatomy. Routine use of upper gastrointestinal contrast study in the absence of symptoms is not indicated to assess for potential connection with the gastrointestinal tract. This occurs rarely and is easily addressed at the time of operation. The treatment for a bronchogenic cyst is complete surgical excision. Usually this involves simple enucleation, which can be performed via thoracotomy, thoracoscopy, or mediansternotomy, but segmental pulmonary resection may be necessary if the lesion is intraparenchymal. The timing of surgery depends upon the presentation; obviously cases with an element of airway obstruction are urgent. Patients with infections should be treated initially with intravenous antibiotics; those who present with dysphagia or an incidental finding should undergo resection electively. Serious medical comorbidities should be resolved preoperatively unless the airway is an issue, but out of concern for malignancy (reported as early as age 8 years6) even elective resection should not be postponed more than a few months. One should be cognizant of potentially abnormal vascular structures, since distinct congenital lung anomalies can rarely occur simultaneously in the same patient, and the second anomaly may manifest itself as aberrant

pulmonary blood supply. Infected cysts are often surrounded by a bed of dense vascular reactive tissue, which makes anatomical planes difficult to discern and dissect. Those with systemic signs of infection or pneumonia should be treated with antibiotics before surgery. If possible, surgery should be postponed for a few weeks to decrease the postoperative pulmonary sequellae and potentially decrease the acute local inflammatory reaction around the cyst. A pulmonary abscess resistant to antibiotic treatment can be percutaneously drained prior to surgery. If persistent or rapidly recurrent infection is a problem, one may have to proceed with surgery in the face of infection. Even without infection, cysts are fixed intensely via dense fibrous bands to surrounding tracheal, esophageal, and other mediastinal structures that must not be injured. In the rare instance that resection of a cyst wall would cause unacceptable destruction of another structure, the epithelium of any cyst wall which remains can be fulgurated entirely. Although communication with the gastrointestinal tract is unlikely, any potential connection should be traced towards the lumen and inspected to assure that a communication is not present or that it has been properly interrupted leaving patency of the enteric body. Stapling devices or sutures are equally sufficient and attention should be paid not to compromise the lumen. Endobronchial lesions can be excised through a rigid bronchoscope if technically feasible (large patient, proximal airway, small lesion, ability to maintain airway wall integrity) with any remaining cyst wall fulgurated via laser. Those not amenable to endoscopic techniques may be treated via sleeve resection of the airway or segmental resection of that airway and its associated parenchyma. In a very proximal endobronchial cyst that undergoes rapid expansion and causes obstruction, a surgical airway emergency may develop that necessitates rigid bronchoscopy to secure an airway, diagnose, and potentially treat the lesion. With respect to airway management for less emergent endobronchial lesions, because an intralumenal obstruction frequently allows inflation but diminishes excursion of air, infants may have hyperinflation, mediastinal shift, impaired respiratory mechanics, and tracheal deviation making intubation challenging. Therefore, one should be prepared to use flexible or rigid bronchoscopy to establish a patent airway. Positive pressure ventilation should be avoided as this compounds mediastinal shift and may have hemodynamic consequences. If necessary, pressure ventilation should be avoided. It may worsen hyperinflation, mediastinal shift, respiratory mechmain stem intubation of the contralateral bronchus may be used to ventilate one lung until the obstructing lesion can be removed. Bronchogenic cysts diagnosed prenatally should generally be addressed after the infant has been delivered and the diagnosis has been confirmed. It may be

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difficult to differentiate a bronchogenic cyst from other congenital cystic malformations. These other diagnoses may have associated anomalies, which need to be investigated and addressed prior to cyst excision. Cysts should be followed by ultrasound prenatally and if a large cyst causes in utero compromise from mediastinal displacement or hydrops, in utero decompression can be achieved via aspiration or thoracoamniotic shunt placement.7 These cysts do not routinely expand rapidly in utero, so ultrasound monitoring does not have to be done as frequently as for lesions such as CCAM or pleural effusions. There is some debate, but most pediatric surgeons believe for several reasons that asymptomatic children should undergo resection of their bronchogenic cyst in the absence of prohibitive medical comorbidities and risk factors that may rarely warrant observation. Cysts increase in size over time due to mucous production and therefore will ultimately become symptomatic; resection before infectious complications develop is preferable, especially since this may decrease inflammation and make resection technically easier. There is also a malignant potential. Both rhabdomyosarcoma and adenocarcinoma have developed within bronchogenic cysts.8–10 Although malignancy is a rare occurrence, the natural history is difficult to evaluate as most lesions are resected in children. A welldifferentiated papillary adenocarcinoma in a retroperitoneal bronchogenic cyst was found at laparotomy for abdominal pain in a 55-year-old woman.8 Therefore, in asymptomatic adults, because of the malignant potential and presence of the lesion since birth, bronchogenic cysts should be addressed at the time of their discovery. The advent of sophisticated techniques provides an avenue for surveillance and in some situations may justify conservative treatment of adults with small, stable, asymptomatic cysts that are not prone to connection with the tracheobronchial tree.11 Cyst fluid and sometimes cyst wall can be sampled via percutaneous or transbronchial needle aspiration. Recurrence after aspiration, malignant cells, cyst growth, symptoms, an air–fluid level, or an intraparenchymal lesion warrants complete surgical resection. When evaluating the benefits of resection in adults, the patient’s projected longevity and comorbid medical issues should be assessed in conjunction with the proposed surgical procedure (less invasive bronchoscopy or thoracoscopy versus mediansternotomy or thoracotomy) and the probability of developing a malignancy.

vascular supply (Figure 13-6). Several theories exist regarding their development. Sequestrations could result from traction applied to developing lung tissue by elongating systemic arterial channels, which would explain the ultimate anatomical relationship between the pulmonary tissue and systemic blood supply. Sequestrations may also represent other congenital lung anomalies such as CCAMs or bronchogenic cysts that develop an aberrant blood supply. Alternatively, sequestrations may develop from accessory lung buds, which have systemic blood supply separate from the normal pulmonary vasculature. The arterial supply to the sequestration usually emanates from below the diaphragm and is almost always a branch from the abdominal aorta. Sequestrations that develop before the completion of visceral pleura formation exist within normal lung parenchyma and are called intralobar; extralobar sequestrations develop after pleura formation of the normal lung and have their own pleura (Figure 13-7). Pulmonary sequestration accounts for about 30% of bronchopulmonary-foregut anomalies. 4 There is no strong gender preference, although some reports describe a male preference (1.5:1). No known causative genetic defect exists, although at least one report involves two male siblings with sequestrations.12 Associated congenital anomalies occur and with higher frequency in extralobar sequestration; as the bronchopulmonary tree and foregut are closely linked in development, many associated anomalies are other congenital lung bud or upper gastrointestinal defects. Sequestration may be found in conjunction with bronchogenic cysts, esophageal cysts, CCAM, and tracheoesophageal fistulas. Sequestrations are most often unilobar and involve the lower lobes but can involve an entire lung 1 3 or rarely both lungs. Classification into intralobar and extralobar subtypes is not only useful from a pathologic standpoint, but also has clinical application, as each variety has different

Pulmonary Sequestration Pulmonary sequestrations were first described by Pryce in 1946. They are composed of nonfunctional embryonic lung with absent or abnormal communication to the tracheobronchial tree and a predominantly systemic

FIGURE 13-6. Pulmonary sequestration: 50
magnification; hematoxylin/eosin stain.

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FIGURE 13-7. Pulmonary sequestration: Intralobar versus extralobar types.

presenting symptoms and sequellae related to its anatomy and associated congenital defects. The proportion of intralobar versus extralobar sequestration is reported with wide discrepancy with some suggesting a 3:1 preponderance of the intralobar kind and others describing a 2:1 ratio in favor of the extralobar type. Intralobar sequestrations may represent between 30 and 75% of pulmonary sequestrations and have no pleural covering. Their intraparenchymal location and lack of pleural barrier allow some degree of aeration from communication with anomalous tracheobronchial structures or with surrounding alveoli.14 The systemic arterial supply is from the abdominal aorta approximately 85% of the time and traverses the inferior pulmonary ligament to reach the sequestration. The remainder of cases have predominantly thoracic aorta as the tributary or rarely brachiocephalic and coronary sources of arterial supply15; in about 15% of cases there are multiple arteries to the mass. Venous drainage is via the inferior pulmonary veins in left-sided sequestrations and via the vena cava in right-sided cases. On the right side, this pattern of venous drainage and sequestration may create something referred to as a scimitar sign on chest radiograph, in which there is a curved sharp-edged opacification bordering the right heart, which represents the anomalous vein. About 70% of intralobar sequestrations are found on the left side and 80% of cases occur

within the lower lobes, making the left lower posterior and basilar segments the most common locations.15,16 There are infrequent associated anomalies or connections with the gastrointestinal tract in contradistinction with the extralobar variety. Extralobar sequestrations, which may represent between 25 and 60% of sequestrations, are also most common in lower lobes and found predominantly (75–90%) on the left side. Most masses are found between the lower lobe and the diaphragm but can be occasionally found below the diaphragm near the adrenal gland. These sequestrations are surrounded by their own pleura, and most (80%) blood supply is also from the abdominal aorta. The veins drain into the azygous or hemiazygous system. Extralobar sequestrations are more commonly found in boys (3:1), and one-half of these patients have associated congenital anomalies. The associated anomalies include congenital cardiac lesions, pericardial defects, pectus excavatum, pulmonary vascular hypoplasia, cervical vertebral anomalies, esophageal diverticula, intestinal (especially terminal ileal or colonic) duplications, and arteriovenous malformations. A Bochdalek diaphragmatic hernia or diaphragmatic eventration is found in 30% of patients with extralobar sequestrations. The tests and operations prompted by these associated conditions often lead to the diagnosis of extralobar sequestrations incidentally and account for the discovery of extralobar sequestrations in early infancy. 1 5 Since extralobar sequestrations are not connected to the tracheobronchial tree, they do not usually become infected and are often asymptomatic. The lack of tracheobronchial connection also means that these masses are not aerated and diagnosis of intraabdominal sequestrations may be obscured by juxtaposition to a solid intra-abdominal organ. Although sequestrations may occasionally be diagnosed prenatally, this is uncommon because they are not necessarily cystic thoracic masses. Presentation in the newborn period is also uncommon unless there is respiratory distress or the work-up of associated congenital anomalies reveals a sequestration. Respiratory distress develops when there is involvement of an entire lung, impairment of functional lung by displacement, or lung hypoplasia from mass effect in utero. A large sequestration that produces mediastinal shift may impair venous return and have hemodynamic consequences. In addition, the sequestrations’ aberrant vascular supply can act as a high-volume, low-resistance shunt causing overwhelming demands on the heart, leading to congestive failure. Sequestrations that communicate with the gastrointestinal tract represent about 10% of sequestrations and tend to present in the newborn or infant period because of infection. A report describing the presentation

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of sequestrations with gastrointestinal communication reported that 43% were evident by 7 days of life, 30% within the first year, 17% by age 18 years, and 10% as adults.17 Most commonly, however, children present by age 10 years with chronic cough, recurrent pneumonia, or its complications. Pulmonary abscess can cause erosion of vessels, and because of their systemic arterial pressure, hemoptysis or hemothorax can be massive; even fatal hemoptysis has been reported. Sequestrations are discovered incidentally in about 15% of cases on imaging for unrelated issues or during surgery to correct other congenital defects such as diaphragmatic hernia.15 Diagnostic imaging should start with plain chest radiograph, which may demonstrate consolidation (since extralobar sequestrations are not connected to the tracheobronchial tree and are not aerated) or mass effect; sometimes there will be cysts or evidence of lung abscess (Figure 13-8). The diagnosis of sequestration can be confirmed by documenting the aberrant blood supply with ultrasound, MRI, or CT (Figures 13-9 and 13-10). It is important to image below the diaphragm since most arterial supply is from the abdominal aorta. Invasive studies such as aortography are unnecessary; even MRI and CT are not routinely necessary if plain film and ultrasound provide enough evidence of a thoracic mass

with infradiaphragmatic aortic blood supply. Ultrasound is noninvasive and excellent for vascular evaluation; it also does not require the same duration and degree of stillness as magnetic resonance scanning. In young children, advanced imaging may require general anesthesia as well as contrast material; therefore, more complex tests should be used only if additional information is needed

FIGURE 13-8. Pulmonary sequestration: Plain radiograph with hyperlucent area demonstrating a right-sided pulmonary sequestration.

FIGURE 13-9. Pulmonary sequestration: A, Ultrasound identifying the aberrant systemic blood supply originating from the aorta and entering the mass. B, Duplex demonstrates the arterial waveform in this vessel.

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FIGURE 13-10. Pulmonary sequestration: Left-sided pulmonary sequestration with its arterial supply from the abdominal aorta. A, Large vessel within the sequestration in the left hemithorax. B and C, Vessel can be seen originating from the abdominal aorta.

with respect to airway anomalies, associated congenital chest anomalies, or questionable vasculature. Once a diagnosis is made and operation is deemed necessary, many questions can be both effectively evaluated and treated in the operating theater. If communication with the gastrointestinal tract cannot be easily investigated at operation or preoperative knowledge will in some way alter operative management, upper gastrointestinal contrast evaluation should be done. The treatment of pulmonary sequestration is resection. In adults with asymptomatic intralobar sequestrations or extralobar sequestrations with gastrointestinal communication, if the risk of subsequent infection outweighs the risk of operation based on comorbid medical conditions, resection should be done. Although conservative management of asymptomatic sequestrations has been presented in the literature,18 this was posed because some may diminish on imaging studies and it assumes that they will not become symptomatic. Since there is real risk or infection and hemorrhage and potential risk of malignancy, we feel that resection is warranted unless medical comorbidities make this unsafe or the projected survival will not be enhanced. Resection of intralobar sequestrations requires resection of the segment or lobe involved. On occasion, sequestrations can involve the entire lung and will require pneumonectomy. Care must always be taken to identify the arterial supply, and one must be mindful that there can be not only aberrant systemic arterial supply but also hypoplastic and friable pulmonary blood vessels supplying the sequestration. The systemic supply should be sought coursing through the inferior pulmonary ligament coming from the abdominal aorta or coming directly from great thoracic arteries. It can be considerable in size, and inadvertent entry during surgery can cause life-threatening exsanguination. Adhesions due to previous infection make dissection of already unfamiliar anatomy even more difficult and often lead to resection of normal lung parenchyma to accomplish a safe and complete resection. Any communication with the tracheobronchial tree can

be effectively obliterated with staples or sutures to avoid a large postoperative air leak. In addition, with extralobar sequestrations one must consider their possible intraabdominal location and any potential communication with the gastrointestinal tract. Communication is usually associated with extralobar sequestrations, although there have been rare reports involving intralobar sequestrations. The lower esophagus is the most common area for connection (70%) with mid and upper esophagus representing a few percent and the stomach approximately 15%. In a report of 57 patients with gastrointestinal involvement, 75% were on the right side, and one-half of these involved the total right lung; an additional 7% were bilateral.17 There was up to a 25% occurrence of hypoplastic pulmonary arterial supply in addition to anomalous systemic aortic supply, and there was concomitant esophageal irregularity in some cases. With these observations, sequestrations with communication to the gastrointestinal tree (referred to as communicating bronchopulmonary foregut malformations [CBPFM]) were anatomically classified into four groups. 1 9 Type IA sequestrations (16%) are described as those found in conjunction with tracheoesophageal fistula (proximal atresia and distal fistula). In this circumstance, the right main bronchus of a hypoplastic right lung inserts into the esophagus. A pulmonary artery and vein are present but there can be accessory systemic blood supply. The treatment involves reimplanting the right main bronchus into the trachea. Type IB cases are described as having a lobe or segment with its airway connected to the esophagus, and these should be reimplanted into the airway if technically feasible; if technical limitations prohibit this, resection is performed. Type II sequestrations (33% of the series) have the right main bronchus leading to the esophagus but no associated esophageal atresia. Pulmonary vasculature is normoanatomic but may be hypoplastic. If possible, these should have the bronchus reimplanted into the trachea. Forty-six percent of the subjects had type III sequestration, in which lobar or segmental airways communicate with the esophagus

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without esophageal atresia. These usually have systemic arterial supply but may also have atretic pulmonary blood supply. Venous drainage may be pulmonary, azygous, or portal. These cases should undergo resection. In the cases where lobar or segmental airways connect to the esophagus, the corresponding airway is absent in conjunction with the tracheobronchial tree.17 Type IV sequestrations (5%) are described as intralobar sequestrations in which part of the tracheobronchial tree connects to the esophagus. These have systemic blood supply and they should be resected. The outcome of children with pulmonary sequestration is excellent if it is isolated or if the prognosis for any associated congenital conditions is good. The survival for surgical resection has reached almost 100%, even for pneumonectomy; the main complications are postoperative pulmonary infection or leak from gastrointestinal communication. Improvements in imaging and understanding of the vascular abnormalities associated with sequestrations make exsanguination from an aberrant artery preventable. Reflux is also reported to occur frequently in those who have had sequestrations with connection to the gastrointestinal tract at the gastroesophageal junction. Complications occur infrequently and are treatable. The major morbidity comes from pulmonary hypoplasia or associated congenital anomalies, especially cardiac defects or diaphragmatic hernia associated pulmonary hypoplasia. A 75% mortality is reported in the 15% of sequestrations with associated conditions.20

Congenital Lobar Emphysema CLE refers to a hyperinflated segment of histologically normal lung. It occurs rarely and is more common in male than female babies (3:1). In 20% of patients, associated cardiac, rib, and renal anomalies exist. Most often, a single, upper lobe is affected, specifically the left upper lobe; multiple lobes can be involved and 20% are bilateral. Lobar emphysema is caused by expiratory collapse of the airway and air trapping. Air can also enter the parenchyma through pores of Kohn with adjacent lung and thereby keep an area hyperinflated even if the airway is obstructed on inspiration. Constant hyperinflation leads to septal destruction and large emphysematous air sacs. Physiologically, CLE causes symptoms by displacing normal lung, creating mediastinal shift, and decreasing venous return. CLE can be due to not only intrinsic obstruction (foreign body, mucus, or endobronchial lesion) but also extrinsic causes of compression such as masses, enlarged cardiac chambers (15%), lymphadenopathy, or vascular rings, and these etiologies should be entertained during differential diagnosis espe-

cially in a patient presenting after the newborn period. Intrinsic causes, which are more likely to present in infancy, include hypoplasia (Figure 13-11) of airway cartilage (documented in about 35% but perhaps as prevalent as 70%), excess bronchial mucosa, mucous plugging, airway torsion, alveolar fibrosis, alveolar septal destruction, and polyalveolar lobes. Polyalveolar lobes, which may account for up to 30% of congenital hyperinflation syndromes, demonstrate increased numbers of alveoli that accumulate air.21 In up to 50% of cases, the exact cause of hyperinflation is not identified. The timing and acuity of presentation depends on the degree of hyperinflation, rate at which it develops, displacement of normal lung, and mediastinal shift. Presentation can be dramatic, for example, with expiratory obstruction causing a sudden increase in hyperinflation with mediastinal shift and cardiopulmonary collapse. This is most characteristic of CLE from airway hypoplasia with collapse or intrinsic airway obstruction as an etiology. With parenchymal causes of emphysema such as septal destruction or polyalveolar lobes, hyperinflation is from gradual accumulation; therefore, sudden expansion due to expiratory insufficiency does not lead to sudden mediastinal shift phenomena. If the area involved is large, infants may present in the perinatal period when their lungs become aerated and hyperinflation develops. Respiratory distress can be severe if the hyperinflation is sudden, causing mediastinal shift, which exacerbates instability by diminishing the expansion of the contralateral lung and limiting venous return and cardiac output. Infants usually present with respiratory distress or even cyanotic spells within 1 to 2 months of age. Children who present in the newborn period are more likely to have symptoms that worsen quickly and

FIGURE 13-11. Congenital lobar emphysema (CLE): Pathology specimen of airway from surgically resected CLE. The airway is collapsed and cartilage, which should have a uniform circumferential distribution, has a sparse and irregular pattern. 50
magnification; hematoxylin/eosin stain.

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require surgery early on. Fifty percent of babies that undergo resection for CLE are diagnosed within several days of life; the other half may not present for months. Less symptomatic infants and children have a more insidious presentation manifested by failure to thrive, mild tachypnea, unequal breath sounds, shifted position of maximal cardiac impulse, expiratory wheezing, hyperresonance, or tracheal deviation. The presentation can take several months while the degree of collapse reaches a point at which air trapping occurs. Crying spells can significantly exacerbate hyperinflation and mediastinal shift. Prenatal diagnosis is rare because the lungs are not aerated; therefore, the diagnosis is usually made with plain chest film in the newborn period or upon presentation with clinical signs. Chest radiograph will demonstrate a hyperlucent area, surrounding atelectasis, ipsilateral diaphragmatic flattening, and possibly mediastinal and tracheal deviation (Figure 13-12) The lobes are involved in the following distribution: left upper lobe 40%, right middle lobe 35%, right upper lobe 20%, and bilateral 1%. 2 2 Differentiation via radiograph from primary cysts or tension pneumothorax may be difficult but one will see faint outlines of pulmonary vasculature

FIGURE 13-12. Congenital lobar emphysema (CLE): Plain radiograph showing a left-sided CLE with hyperinflation, mediastinal shift, and displacement of the cardiac silhouette towards the right hemithorax. Lung markings are present throughout the left hemithorax and no collapsed lung edge is evident which differentiates this from a tension pneumothorax.

within the affected CLE. Additional imaging is usually unnecessary to diagnose CLE but may be helpful in finding the etiology or differentiating CLE from atypical appearing CCAM or pneumothorax if diagnosis is unclear on plain film. Extrinsic causes of airway obstruction such as a thoracic mass or vascular ring should be investigated using MRI or CT, especially in older patients in whom these etiologies are more likely (Figure 13-13). Bronchoscopy should be performed if suspicion of a foreign body or endobronchial lesion is high. Echocardiography to identify associated cardiac conditions and ultrasound to look for renal anomalies will be positive in 20%. Although not routinely necessar y, a ventilation–perfusion scan, if performed, will show delayed uptake and washout of xenon and decreased blood flow in the emphysematous portion. Pulmonary function tests (they would show slightly decreased flow) are not necessary for preoperative workup of isolated CLE since the remainder of the lung has normal function. There is no associated lung hypoplasia because the hyperinflation develops after delivery and does not cause in utero compression of the developing lung. Occasionally, on CT or ventilation–perfusion scan, additional areas of hyperinflation become evident; these, however, can be seen and addressed at the time of thoracotomy. The treatment strategy for CLE is resection of the affected lobe (Figure 13-14). One must also eliminate any possible extrinsic or intrinsic cause for obstruction and hyperinflation that can masquerade as CLE; if this leads to resolution of air trapping, the diagnosis was not primar y CLE and lobar resection be avoided. Occasionally, a mass or vascular ring causing compression will be apparent as the cause of bronchiolar collapse and can be removed. In addition, rarely, things causing endobronchial obstruction may be amenable to endoscopic removal. For this reason, bronchoscopy should be performed prior to resection to identify any potentially treatable lesions. Since at least one-half the cases of CLE have no known etiology and many others have hypoplastic airway cartilage as a cause, sparing a lobe is rarely possible. Complete resection of the lobe and any additional segments involved is curative and should be prompt. Some feel that babies with mediastinal shift regardless of symptoms should be kept under medical observation until surgical correction. If there is evidence of longstanding stable disease without symptoms (delayed referral perhaps), these children have low likelihood of sudden decompensation and can remain at home until surgery, which should occur within the next couple of weeks. Symptoms, unpredictable course, or unpredictable compliance are indications for admission and surgery as soon as any necessary preoperative treatment is completed. Evaluation for associated cardiac

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FIGURE 13-13. Congenital lobar emphysema: Computed tomography scan showing the hyperlucent, emphysematous segment of left lung.

disease should be done mitigated by the urgency of lung resection. Children with evidence of increasing hyperinflation should definitely be under medical observation and resection should wait only long enough for preoperative preparation. While awaiting surgery, mild respiratory distress should be treated with oxygen and babies should be kept as calm as possible to reduce tachypnea and vigorous crying that may contribute to hyperinflation through deep inspiration. If there is very mild tachypnea and serial chest films do not demonstrate mediastinal shift or increased CLE size, resection can be done at the earliest possible time within that hospitalization. Some babies will present with cardiorespiratory collapse in the perinatal period or have an acute decompensation marked by sudden increase in lobar distension, respiratory and cardiovascular collapse due to hyperinflation, mediastinal shift, and decreased cardiac output. Oxygen should be administered and the baby kept as calm as possible. Since positive pressure ventilation via bag-mask or endotracheal tube increases hyperinflation and may immediately worsen the situation, it is optimal to support the child spontaneously breathing until the surgical team is ready to perform thoracotomy. If the patient cannot maintain parameters compatible with survival, one must obviously intervene and intubate the patient. Tracheal shift may make intubation difficult and once the airway is secured every effort should be made to minimize positive ventilatory pressure. If the infant cannot be maintained with spontaneous ventilation, there are some maneuvers that can be helpful. Highfrequency or jet ventilation may be used to ventilate with

less-positive pressure and if the lobar emphysema occurs on the left, right main stem intubation may allow selective ventilation of the normal lung and decrease hyperinflation and mediastinal shift. Left main stem intubation will be very difficult to accomplish due to normal anatomical considerations augmented by the probable mediastinal shift towards the left in severely impaired children. One can also as a temporizing measure decompress the emphysematous lobe via needle thoracostomy to alleviate the mediastinal shift and hopefully improve cardiovascular status. This will be followed by a large air leak, which will impair ventilation. Again, jet and highfrequency ventilatory modes may afford decreased air leak and one can vary the column of water in the thoracostomy collection chamber. The greater the column of water against which the air leak drains, the higher the inspiratory pressure can get before leaking and losing the capacity to distend normal lung; however, when more pressure is allowed to develop, the lung may become hyperinflated. The same airway considerations apply to elective resections for CLE. Since immediate thoracotomy may be necessary, the surgical team should be in the operating room, gowned and gloved with instruments ready to perform emergent thoracotomy before induction of anesthesia. One must be cognizant of tracheal deviation and have fiberoptic bronchoscopy available for intubation. Intubation should be attempted in an anesthetized but spontaneously breathing patient; when positive pressure becomes necessary, one should use low ventilatory pressures and tolerate slightly suboptimal parameters until the lobe is delivered from the

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Release of the inferior pulmonary ligament may allow a lower lobe to fill the hemithorax more easily after resection of the upper lobe. In a completely asymptomatic patient without radiological evidence of mediastinal shift or a mild and stable degree of hyperinflation, surgery can be performed semi-electively. The development of symptoms or inadequate access to medical care warrants prompt excision. There is no known risk of malignancy and infectious complications are rare, therefore asymptomatic adults without the radiograph indications above should not need resection. The outcome for babies with CLE is excellent, with survival approaching 100%; complications of thoracotomy such as wound infections, pneumonia, or reintubation occur in 5 to 10% of patients, but associated anomalies are responsible for most of the morbidity and any mortality. Even those infants who undergo emergent thoracotomy fare well and have swift physiological improvement. After resection of CLE, the atelectatic lung expands and occupies the entire hemithorax. Children continue to increase the size and number of their alveoli substantially until age 2 to 4 years and do not stop lung growth until about age 8 years. When studied years after resection, lung volumes are equal on both sides and pulmonary function tests postresection document performance at 90% of normal levels without any evidence of functional impairment.2

Congenital Cystic Adenomatoid Malformation FIGURE 13-14. Congenital lobar emphysema: Surgical specimen of emphysematous upper lobe.

chest. If the hyperinflated lobe is on the left, right mainstem intubation may limit hyperinflation of the left side. Thoracotomy and delivery of the entire affected lobe will restore the normal position of the mediastinum and allow ventilatory and cardiovascular parameters to return to normal. Resection of the entire involved lobe and any adjacent hyperinflated tissue is essential to prevent recurrence. Small residual amounts of hyperinflation may appear insignificant at operation, but with removal of the dominant hyperinflated lobe, these areas very rarely can quickly become dramatically hyperinflated and physiologically significant. The vascular anatomy is normal but vessels may be smaller and more friable. After removal of the affected lobe, the remaining lung should be positioned to prevent torsion. This is important with rightsided resections as the right middle lobe is most prone to torsion and it should be sutured to the remaining lobe.

CCAM is a benign lung tumor of dysplastic overgrown bronchioles and results from abnormal pulmonary mesenchymal development. It occurs with equal proportions in male and female infants and is not associated with chromosomal defects or known teratogens. It develops between week 1 and week 6 of gestation and other congenital defects occur in about 25% of affected fetuses. These include intestinal atresias, diaphragmatic hernia, renal agenesis, pectus deformities, and cardiac anomalies. Although within the mass the airways are not canalized, there is continuity with the tracheobronchial tree. The majority of cases involve a portion of only one lobe, and lower lobes are preferentially involved. In the most common type of CCAM (type I) lesions occur with more frequency on the right side; types II and III CCAMs have no predilection for side. CCAM is caused by a defect in the switch from the canalicular phase to the terminal sac phase of lung development and therefore the histological appearance is that of lung tissue at 20 weeks’ gestation (Figure 13-15). 23 On pathological review, overgrown bronchioles that do not form channels are characteristic, and they are lined by cuboidal or columnar epithelial

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cells; occasional elements of skeletal muscle can be found suggesting a hamartomatous condition. The most commonly used classification for CCAM divides the malformations into three types based on the cyst characteristics.24 Type I is macrocystic disease and represents 60 to 70% of CCAM; 50% of type I lesions occur on the left, 35% occur on the right, and between 2 and 14% are bilateral.25,26 This type of CCAM is composed of single or multiple cysts (usually between one and four) that are more than 2 cm. The cyst walls may include smooth muscle cells and are lined with ciliated pseudostratified columnar epithelium. Type II CCAM, which occurs 20% of the time, is commonly called mixed disease and contains adenomatoid material mixed with small and medium-sized cysts of about 1 cm. In this case, alveolar type tissue is found among the cysts that are lined with ciliated cuboidal or columnar epithelium. Congenital anomalies (which occur in up to 70% of type II CCAM) and prematurity (up to 75%) 23 are almost exclusively associated with this type of CCAM, accounting for its poorest prognosis. Type III disease occurs 10% of the time and is referred to as microcystic CCAM. This subtype presents more often in boys. Its appearance on ultrasound is echogenic due to solid components, and this firm mass tends to involve an entire lobe. It is composed of mainly adenomatoid bronchioalveolar-like tissue with minimal amounts of small cysts but there is no normal lung. Some authors classify CCAM into two types.27 The macrocystic type has single or multiple fluid filled cysts greater than 5 mm, and the microcystic type has solid components in combination with cysts less that 5 mm. As with other chest occupying lesions that lead to compression or lung hypoplasia, the most common symptom is respiratory distress. In situations where

FIGURE 13-15. Congenital cystic adenomatoid malformation: Dysplastic overgrown bronchioles of congenital cystic adenomatoid malformation. 12.5
magnification; hematoxylin/eosin stain.

mediastinal displacement has occurred, decreased venous return can lead to cardiac collapse and further diminished function of the contralateral lung. In utero, this mass effect leads to lung hypoplasia and to hydrops; compression of the esophagus can also lead to polyhydramnios. The severity of symptoms depends on the degree of hypoplasia. In the newborn period severe respiratory and cardiovascular symptoms develop from lung hypoplasia and mediastinal shift. In older children, recurrent infection is the most common symptom. With longstanding disease, bronchioalveolar cancer and rhabdosarcoma have been reported. 28 Some infants with prenatal diagnosis are asymptomatic at delivery and may even have radiologic regression or disappearance of the mass. Most have varying degrees of respiratory symptoms at birth. Most diagnoses are made before age 6 months, and 60% are made within the first month. Onehalf of CCAMs will present in the newborn period either with symptoms or as a result of prenatal screening; also, type II CCAM babies will often present with prematurity. The 50% of infants that present after the newborn period fare much better with their milder CCAMs. These children may not have a lesion that causes respiratory distress at rest, but during times of stress, such as with upper respiratory infections, increased activity, or sometimes feeding, they will become symptomatic. At these times they may present with tachypnea or wheezing, and on auscultation may have decreased breath sounds over the affected lobe. Infection can also occur with cough and fever, and a pattern of recurrent infections usually leads to chest roentgenogram. Failure to thrive is another presentation prompting a search for pulmonary afflictions. Sometimes the diagnosis is made incidentally as patients undergo imaging for other reasons. The chest radiograph may reveal the characteristic cystic mass or an infiltrate. It may take recurrent infiltrates in the same lobe to trigger studies such as CT to diagnose an underlying CCAM. CCAM is the most commonly diagnosed congenital lung anomaly because its cystic appearance makes it readily apparent on prenatal ultrasound. Prenatal diagnosis is therefore common and CCAMs are detectable on ultrasound by 12 weeks’ gestation. Ultrasound typically demonstrates a macrocystic, microcystic, or solid lesion and may show displacement of the heart or diaphragm. Polyhydramnios is seen in 65% of cases and is ominous. Hydrops and ascites can be seen in up to 45%. The diagnosis in babies after delivery is usually discovered after the infant has plain chest film for respiratory distress or unequal breath sounds; up to 15% of babies are diagnosed after age 6 months. The chest radiograph will have a mass that may appear typically macrocystic or may appear solid in nature if there is microcystic disease

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(Figure 13-16). The appearance of CCAM on plain chest film may be deceptive; a frequent mimic of CCAM is congenital diaphragmatic hernia, which has a very different treatment algorithm. Placement and visualization of a nasogastric tube in the chest differentiates the two thoracic anomalies. Infants with prenatal diagnosis of CCAM should have confirmation of its persistence, as there are reports that some CCAMs seen on prenatal sonography are no longer apparent on postnatal imaging. Examination with ultrasound or CT helps to assess the amount of involved lung and to differentiate CCAM from mediastinal and other primary lung lesions such as

sequestration, bronchogenic cyst, diaphragmatic hernia, or lymphangiectasis. In the newborn period, an ultrasound to confirm that the mass is a parenchymal CCAM may be the only necessary study (Figure 13-17). It will also indicate whether the lesion is microcystic or macrocystic (Figure 13-18). Although uncommon, vascular abnormalities can occur with cystic adenomatoid malformations and one should look for this on ultrasound. As the age at presentation increases, chest CT becomes more important and effective at deciphering the growing differential of infectious etiologies, malignancies, and foreign bodies. Many surgeons prefer CT imaging

FIGURE 13-16. Congenital cystic adenomatoid malformation (CCAM): Plain radiograph demonstrating multiple cysts in a left-sided CCAM. There is minimal mediastinal displacement. Multiple cysts can appear similar to a congenital diaphragmatic hernia.

FIGURE 13-17. Congenital cystic adenomatoid malformation, multicystic: Ultrasound. Bottom ridge represents the vertebral column. The left side of the image is cephalad.

FIGURE 13-18. Congenital cystic adenomatoid malformation (CCAM): Ultrasound. The vertebral column can be seen traversing the image and a large hypoechoic area represents the normal lung. The two small hypoechoic areas are the CCAM, and the echodense area bordering the left side of the image is the liver.

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because of the axial images and their own familiarity with interpreting this test (Figure 13-19). The treatment for CCAM even in asymptomatic patients is surgical resection before the development of infectious or malignant complications (Figures 13-20 and 13-21). Babies with prenatal diagnoses should be cared for at a tertiary medical center and followed with ultrasound every 2 weeks to watch for the development of hydrops. Hydrops is the most ominous sign of poor outcome, and affected infants have severe lung hypoplasia; in the past almost all babies with hydrops died (up to 70% in utero and 90% that were delivered). Hydrops also precipitates preeclampsia, and premature delivery further

FIGURE 13-19. Congenital cystic adenomatoid malformation, leftsided: Computed tomography scan.

FIGURE 13-20. Congenital cystic adenomatoid malformation: Intraoperative photo.

FIGURE 13-21. Congenital cystic adenomatoid malformation: Specimen.

exacerbates the situation with lung disease of prematurity. Fetal echocardiography should be performed to identify any concomitant cardiac defects and help provide a prognosis. Today, parents have the following options: postnatal care, fetal intervention, or termination for moribund cases. In considering fetal procedures and their risks, it is important to know that even in cases with hydrops, regression of the CCAM can occur in up to 15% of cases. Also, with modern resuscitation, ventilatory techniques, prepartum steroids, and extra corporeal membrane oxygenation (ECMO), fetuses without hydrops or other lethal anomalies have almost 100% survival and fetal intervention cannot be routinely recommended. For this reason, consideration of fetal intervention can effectively be restricted to those with early development of hydrops. Even before the advent of open fetal surgery and fetoscopic techniques, fetal intervention has been available via cyst aspiration and thoracoamniotic shunting and these techniques have been reported as early as 1988.29 Cyst aspiration requires repeat drainage as the thoracic cavity rapidly fills with fluid to occupy the space created by the cyst aspiration27; this is therefore not a good long-term solution. Thoracoamniotic shunting has been successful in a small number of hydropic patients with macrocystic disease who have a dominant cyst amenable to drainage; however, shunt dislodgement or occlusion can be problematic. In a report of thoracoamniotic shunt use in six fetuses with hydrops and macroscopic disease with a predominant large cyst, five of six patients survived and the one death was due to premature rupture of membranes followed by precipitous delivery. This underscores the point that even seemingly less invasive fetal procedures disturb the intrauterine environment and are not without significant risk of premature delivery. 30 Fetal thoracotomy with surgical resection of the CCAM continues to evolve. A review of 134 fetuses with CCAM over a 15-year period confirms the principle that fetal procedures be limited to those with hydrops. Fourteen of the fetuses underwent

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elective abortion and the remaining 120 were analyzed. One hundred and one fetuses were managed expectantly with delivery and any surgical intervention done postnatally; every hydropic fetus died or expired shortly after delivery, and all 76 nonhydrops babies survived, although 4 required ECMO support. This further verifies that nonhydrops fetuses have good prognosis, but hydrops is lethal without prenatal intervention. In the same study, 19 fetuses underwent fetal procedures; 6 fetuses were discussed above regarding thoracoamniotic shunting. The remaining 13 fetuses underwent thoracotomy and lobectomy between gestational weeks 21 and 29 done through a hysterotomy. Survival of the hydrops fetuses after open fetal surgery was 62% and hydrops resolved within 2 weeks, mediastinal shift was gone after 3 weeks, and there was evidence of substantial lung growth. All 5 of 13 deaths were attributable to inability to maintain the pregnancy either during the procedure or in the perioperative period.27 Preterm labor following fetal surgery and pulmonary hypoplasia continue to be responsible for the morbidity and mortality in this technique. These data demonstrate that without hydrops the risk of fetal intervention outweighs the benefit and these infants should be treated after delivery with an attempt to carry the fetus to term. Other authors have confirmed these data.30–33 In cases of the “mirror” syndrome of maternal hyperdynamic state or after placentomegaly develops, there were no survivors of fetal interventions due to inability to sustain the pregnancies. Therefore, fetal intervention is not indicated and in these situations or in the face of concomitant lethal anomalies, some families have opted for termination. If hydrops develops after 32 weeks or if the biophysical profile of an otherwise viable fetus deteriorates (greater than 24 weeks’ gestation without other lethal conditions) early delivery is indicated. Early delivery occurs in up to 50% of CCAMs and is often the result of preterm labor that cannot be treated. Steroids should be given to enhance lung maturity if the fetus is less than 32 weeks’ gestation. The majority of these preterm infants will require immediate intubation and resuscitation. Severely premature infants (less than 29 weeks) will have not only CCAM-related lung hypoplasia, but also lung disease of prematurity to add to their respiratory compromise, and a significant number of these infants will be dependent on such high ventilator settings to sustain marginal respiratory parameters that they will not tolerate thoracotomy. If there is any indication that the CCAM and its mass effect on respiratory mechanics are the predominant cause of respiratory failure, resection should be undertaken immediately and the condition may improve; however, this is not always clear and if the pulmonary insufficiency is mostly related to lung hypoplasia or prematurity, resection will not bring swift

improvement, and positioning or retraction necessary for surgery may be more than the baby can tolerate. In addition, as with in utero CCAMs, these lesions may decrease in size after birth. In very premature, low birth weight babies whose primary lung disease or pulmonary hypertension is the main cause of respiratory failure, resection should be postponed until the infant is fit for thoracotomy under general anesthesia from a respiratory standpoint. In some premature infants clinical reasoning becomes somewhat circular, with resection precluded due to lung disease of prematurity and slow improvement in pulmonary status in part potentially due to the remaining mass. There are some maneuvers to improve respiratory mechanics while waiting for surgery. Placing the child with the symptomatic side down may decrease distension on the affected side by limiting aeration and jet or high-frequency ventilation minimizes hyperinflation and decreases traumatic high airway pressures in premature lungs. Associated life-threatening conditions, especially cardiac conditions, must be addressed, and the congestive cardiac failure must be aggressively treated with inotropes and diuresis. Unfortunately some babies have such significant hypoplasia that they do not improve. ECMO can be used to support infants with severe pulmonary hypoplasia, and surgical resection of the CCAM can even be performed while on ECMO. The infants must weigh more than 2 kg to utilize ECMO and must be fully heparinized. Inability to wean from bypass by approximately 2 weeks indicates pulmonary hypoplasia so severe that the infant is unsalvageable and bypass support is withdrawn. Term or near-term infants with a prenatal diagnosis of CCAM should undergo chest radiograph because there may be regression or even disappearance of the mass. If the mass is not evident on postnatal plain film, ultrasound or CT should be done; if there is still no evidence of a mass, patients are followed with serial ultrasound. Evidence on future exams of a mass warrants excision. Those with a clear lesion on imaging but mild or absent symptoms can undergo resection electively if no mediastinal shift develops over the first 48 hours. Mediastinal shift, tachypnea, oxygen requirement, or ventilator dependence should prompt resection as soon as preoperative preparation can be completed and more urgently if symptoms dictate. Cardiac lesions should be anticipated and sought with echocardiogram, especially with type II lesions, in which associated congenital anomalies are common. Children and adults with asymptomatic or incidentally noted CCAM should undergo resection electively not only because there is documented risk of malignancy,28 but also because infectious complications that would likely develop can thereby be avoided. Technically, resection of CCAM usually requires lobectomy, but in up

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to 15% pneumonectomy may be required. This is more common in type III CCAM as the more diffuse and microscopic nature may make it difficult to separate from surrounding normal lung and because type III disease has a propensity to involve the entire lung. Very rarely, segmental resection of the CCAM is possible along with its tributary tracheobronchial tree. The airways and vessels follow a normal anatomic configuration, although there may be additional systemic arterial supply similar to that in sequestration. Significant anesthetic difficulties regarding airway deviation or hyperinflation are rare and mild compared with CLE, but they must be anticipated. Pulmonary hypoplasia and lung disease of prematurity are the most important factors in determining outcome. There is a tremendous range in survival (11–95%)25 and fetal hydrops portends the poorest prognosis. Uncomplicated macrocystic (type I) CCAM has survival rates of 70 to 95%. Types II and III CCAMs have the poorest prognosis (< 50% survival23) due to frequent associated cardiac defects, severe lung hypoplasia, the incidence of prematurity in type II lesions, and the increased incidence of diffuse lung involvement in type III. In addition, type II CCAM is more frequently associated with in utero hydrops and polyhydramnios, which both independently worsen prognosis. Medical comorbidities not only contribute independent physiological complications but also increase anesthetic risk and sometimes postpone surgical resection. Fetal hydrops is seen in up to 45% of fetuses with CCAM and is a grave prognostic sign; in 68% of these there will be fetal demise, and of the remaining 32% that are delivered, 89% succumb, making the outcome with hydrops almost universally fatal. Polyhydramnios itself is associated with 50% mortality.25 Of all CCAMs diagnosed in the prenatal or newborn period, up to 60% will die because this includes the significant number of cases with fetal hydrops or polyhydramnios with in utero death and those with associated anomalies that die. However, of the infants that survive to delivery, since the remaining group has very low incidence of hydrops and is comprised mainly of the favorable CCAM subtypes, survival of 80 to 100% has been reported. 4,34 Infants without hydrops, associated severe prematurity, or associated anomalies have a survival of up to 90%. Children who have delayed presentation with infection fare the best and have essentially 100% survival. The advent of fetal surgery shows promise in improving the survival for cases of fetal hydrops in which demise was previously almost certain, and the survival for fetuses with hydrops may be as high as 74% with fetal intervention.27 Unfortunately, intraoperative contractions, maternal hyperdynamic state, and preterm delivery still lead to fetal demise up to 25% of the time.27 Cases without evidence of hydrops have a

more favorable prognosis, and regression of the lesion occurs in up to 15%; all nonhydropic fetuses analyzed in the literature survived with postnatal treatment, and fetal surgery cannot be routinely recommended for these cases at this point. The ability to predict more accurately which fetuses will have significant symptoms after birth and, more importantly, development of techniques to prevent surgically induced preterm delivery may expand the indications for this modality.

Pleural Effusion Fluid in the pleural space occurs in 1 in 10,000 newborns and has a male predilection (2:1). There are no known associated teratogens but effusions have been associated with a variety of other anomalies and genetic syndromes including Down syndrome, Turner syndrome, Caffey hyperostosis, Opitz-Frias syndrome, congenital pulmonary lymphangiectasis, esophageal atresia, and extralobar sequestration.35,36 Congenital effusions may be primary (chyle) or secondary (nonimmune hydrops or hypoalbuminemia), and most are found on the right side although effusions can occasionally be bilateral. Primary chylous effusions are of unclear etiology, although some derangement in either increased production or decreased absorption must be involved. Reduced lymphatic drainage may come from inadequate communication between pulmonary lymphatic channels and their main thoracic drainage; this may be a result of congenital absence, birth injury, or obstructing mediastinal mass. Lymphatic abnormalities are not usually found in other organs with the exception of rare associated lymphangiectasis. Congenital effusions can become very large and cause ipsilateral lung hypoplasia due to in utero pulmonary displacement. Situations in which the effusion causes mediastinal shift may lead to hydrops by impairing venous return and cardiac output. Many infants will have prenatal diagnosis and will have respiratory distress at birth. Most other infants present within the first several days of life with varying degrees of respiratory distress. Infants with mild symptoms present with decreased breath sounds on the affected side, and plain chest film quickly identifies the effusion as an opacified hemithorax and caudad displacement of the ipsilateral diaphragm. Primary pleural effusions may demonstrate downward displacement of the ipsilateral diaphragm but secondary effusions will not and this helps to distinguish between the two. The appearance of the pleural fluid may by deceiving, as chylous effusions may appear clear if the patient has no enteral fat intake. A cell count demonstrating more than 60% lymphocytes supports chylothorax; triglycerides are usually greater than 200 mg/dL,

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specific gravity is usually greater than 1.012, protein levels are about 40 g/L, and glucose has serum levels.37 Pleural effusions can be detected on prenatal ultrasound by 16 weeks’ gestation; their discovery should prompt investigation of fetal heart function (as an etiology for secondary effusion or for associated anomalies), thoracic masses, and chromosomal abnormalities, and serial ultrasound should be performed every 2 weeks to watch for development of hydrops. If there is evidence of hydrops, aspiration should be performed as often as necessary to control the hydrops. Pleuroamniotic (thoracoamniotic) shunt placement may obviate multiple aspirations. These shunts often become occluded or dislodged, so continual sonographic monitoring and drain replacement must be done to assure proper drainage. Early delivery is not recommended unless refractory hydrops develops or if gestation is greater than 32 weeks. Pleural effusions may also resolve over time in utero especially in cases of small unilateral collections, but this is uncommon. For large primary effusions without hydrops in which respiratory compromise at delivery is a concern, aspiration shortly before delivery should be done. Unless there has been prenatal drainage, most infants with sizeable pleural effusion will need to be intubated and one should also be prepared to perform emergent thoracentesis. Intubation should be the standard with respiratory distress, bilateral effusions, or for any premature baby with effusions. Infants who are relatively asymptomatic (mild tachypnea, minimal oxygen requirements) should be followed with serial chest roentgenogram; resolution of mild effusions may occur as intrapleural pressures change or with treatment of associated conditions (ie, diuresis and inotropic support). Worsening of symptoms (ventilator dependence, significant tachypnea, mediastinal shift, or cardiovascular compromise) in patients who do not respond to medical treatment mandates drainage. Initially, this may be done via aspiration, which may need to be repeated every few days. If multiple aspirations become necessary, a drainage tube can be placed. Secondary effusions will subside with treatment of their causative conditions. Primary, chylous effusions may be more recalcitrant. Chylothorax due to surgical injury heals quite readily with decompression and dietary measures; therefore, we infer that lymphatic injuries resulting from birth trauma may respond similarly. If there is a mass obstructing lymphatic drainage, its removal will enhance normal drainage and the effusion should resolve. Cases without known etiology or those in which congenital lymphatic defects are suspected may be the most difficult to treat. An elemental diet can be given orally as long as improvement in the effusion is noted and protein losses are not causing malnutrition. Persistent accumulation requires

parenteral nutrition to minimize lymph volume and to support the protein losses in the effusion. It is essential to remember that T cells and thereby immunity are also decreased because of these lymphatic losses. These management strategies are usually successful but if drainage does not improve for more than 2 weeks, surgical ligation of the thoracic duct proximal and distal to the leak should be performed38 and can be accomplished via open thoracotomy or thoracoscopic techniques. Preoperatively, a fat-laden meal may increase drainage and help identify the leak; alternatively, 1% isosulfan blue dye can be used. Preoperative lymphoscintigraphy in such small patients is usually nonspecific and rarely helpful. Surgical ligation is usually successful; the addition of fibrin glue may fortify the repair but is unproven. There are reports of microvascular lymphatic repair in thoracic duct injuries; however, there are no reports documenting efficacy of repair in the miniscule lymphatics specific to congenital chylothorax or in the neonatal age group. In the event of surgical failure, an unidentifiable duct leak, or a diffuse leak, pleuroperitoneal shunting can be done for decompression. As with many congenital thoracic problems, the outcome is dependent on associated factors such as fetal hydrops, prematurity, cardiac disease, pulmonary hypoplasia, and associated genetic syndromes. The outlook after in utero diagnosis is poor, with 50% mortality. Hydrops carries the gravest prognosis with 95% mortality; babies with polyhydramnios (42%) also have bad outcome and bilateral cases often suffer fetal demise. The infants that survive to term represent cases with favorable prognosis without hydrops, bilaterality, or polyhydramnios. The overall survival, therefore, for babies born with congenital pleural effusions is 75%, and babies born without associated anomalies have an 85% survival.

Congenital Pulmonary Lymphangiectasis Congenital pulmonary lymphangiectasis or lymphangiectasia is a condition in which dilated lymphatics occupy the bronchovascular space, the pleura, and the interlobular septa. During the fifth month of gestation, pulmonary interstitial connective tissue fails to diminish and lymphatic channels become occluded; this leads to the formation of diffusely dilated cystic lymphatics.39 The condition is very rare and found twice as often in boys as girls. It can occur in conjunction with lymphedema and there have been associations with congenital cardiac diseases and Noonan, Ullrich-Turner, and Down syndromes. 4 0 Conditions which increase lymphatic volume and circulation exacerbate lymphatic dilation. Primary congenital lymphangiectasis can be distin-

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guished from a secondary form of the disease by its presentation in the neonatal age group and the dismal clinical course. Many fetuses are stillborn, and any infants that come to term present with severe respiratory failure and pleural effusion. Plain chest film demonstrates effusion with diffuse granular parenchyma, prominent interstitial markings, and variable hyperinflation in one or both lungs.41 Aspiration of pleural fluid will yield lymph and sometimes biopsy is necessary to confirm the diagnosis. Treatment is supportive with drainage of pleural effusions, low-fat high-protein diet, and medium-chain triglyceride supplementation aimed at limiting the volume of lymphatic flow and thereby the distension of the lymphatics. Heart and lung transplantation has been performed but has not shown encouraging results with respect to this disease entity.39 Unfortunately, despite these measures, outcome is often fatal early on due to the significant pulmonary hypoplasia.

Pulmonary Lymphangiomatosis Pulmonary lymphangiomatosis is a condition in which there exist multiple lymphangiomas within the lung parenchyma as well as concomitant lymphatic disorders in up to 75% of patients. 39 The exact developmental abnormality that leads to the appearance of these lymphangiomas is unknown, but there is increased proliferation of interconnected lymphatic channels within the mediastinum and lung parenchyma with surrounding parenchyma that is normal in architecture. Histologically, there may be isolated lymphangiomas or a more diffuse pattern that, although invasive in appearance, consists of mature cells and is benign. The condition is very rare and the occurrence is equal between sexes. Lesions are bilateral and generally located in the mediastinum, pleura, chest wall, parenchyma, or bone. Lymphangiomatosis usually presents late in childhood with symptoms of wheezing or respiratory distress. It can also manifest as chylous pleural effusions, chylopericardium, chylous ascites, chyloptysis, protein losses, lymphopenia, and even disseminated intravascular coagulopathy. Chest radiograph will demonstrate bilateral interstitial infiltrates, pleural effusions, and pericardial effusions, and pulmonary function tests may show both an obstructive and restrictive pattern. On CT imaging, the pulmonary septa are thickened and the mediastinum and perihilar regions can be encased. Lymphangiography will reveal many lymphangiomata associated with the thoracic duct, lung, and bone. The combination of chylothorax and lytic bone lesions is suggestive of pulmonary lymphangiomatosis.39 Biopsy is diagnostic and special endothelial stains such as factor VIII–related antigen and CD31 varieties help identify this lesion.39 Over time these lesions

continue to grow relentlessly and cause compression phenomena. Treatment is palliative and again methods to decrease lymphatic volume and chylous effusions should be employed. Surgical resection is plagued by high recurrence, as complete excision without sacrifice of essential structures is infrequently possible. Sclerotherapy with doxycycline is often employed to palliate the effusions and attempt to minimize protein losses. This difficult-totreat condition is mostly fatal.

Pulmonary Hemangiomatosis Pulmonary hemangiomatosis is a locally invasive but benign vascular tumor of the lung parenchyma. Capillary proliferation of thin-walled vessels in the pulmonary interstitium is characteristic on histopathological review. The condition is very rare with few reported cases. Patients present with respiratory distress or pulmonary hypertension, and there can be an associated consumptive coagulopathy (Kasabach-Merritt syndrome) or hemolytic anemia. Treatment is supportive including pulmonary toilet, treatment of concurrent infections, and nutritional optimization. Additional modalities that have been employed in attempts to eradicate the disease or halt its progression include steroids, cytotoxic agents, radiation, laser ablation, embolization or resection of localized disease, and cryotherapy. Unfortunately, none have had great results and come at the expense of many significant side effects or invasive procedures. Most recently, interferon- has been used with encouraging results; although there can be hemodynamic effects in the first 48 hours, side effects are otherwise minimal.42 The mechanism of interferon action is probably as an antiangiogenesis agent via inhibition of proliferating smooth muscle, endothelium, and fibroblasts. Lung transplantation has been employed in a few cases that progressed to unrecoverable pulmonary failure.43 Previously this condition was considered universally fatal, but the advent of antiangiogenesis therapies and lung transplantation for unresponsive cases may warrant cautious optimism.

Primary Pulmonary Hypoplasia and Agenesis Pulmonary hypoplasia exists in varying degrees and may be primary or secondary; in its most severe form it is called pulmonary agenesis and there is an absence of parenchymal and bronchial structures on one side. Secondary pulmonary hypoplasia is caused by conditions that mechanically restrict lung development by occupying the thoracic cavity, by limiting development of the thorax (thoracic dystrophies), or by impeding amniotic fluid return (renal impairment or neuromuscular dys-

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function of diaphragmatic excursion). These lesions are as common as the above-mentioned etiologies. Primary hypoplasia and agenesis are very rare and thought to be due to failure at various stages of development in bronchial budding from the trachea. There does not seem to be a gender preference. A multitude of associated congenital anomalies have been associated with primary pulmonary hypoplasia and agenesis, namely intracardiac defects, esophageal atresia, and genitourinary anomalies. Primary hypoplasia may be unilateral or bilateral and both sides are affected equally; agenesis only slightly more often affects the left side and is unilateral although it may be associated with contralateral hypoplasia. In the cases of agenesis, up to 50% have associated anomalies and in most cases patients with concomitant congenital defects have a right-sided agenesis. Agenesis is extremely rare, with a worldwide experience of only several hundred cases. Some infants are asymptomatic and diagnosed via work-up of another congenital condition or on routine physical exam that demonstrates decreased breath sounds on the affected side with possible mediastinal and tracheal displacement. Older children may also have evidence of chest asymmetry or scoliosis. Some present with an antenatal diagnosis or as a result of incidental findings on unrelated imaging studies. Patients who present with respiratory failure do so in a continuum of severity from exercise induced dyspnea or wheezing, to marked tachypnea and cyanosis. For unclear reasons, infectious complications represent the predominant presentation, although there is no anatomic basis for postobstructive phenomena. It is postulated that the airway has decreased clearance mechanisms.2 The diagnosis is apparent on plain film and shows an empty hemithorax with contralateral lung hypertrophy displacing the mediastinum to the affected side so that it occupies some of the empty hemithorax. Vertebral anomalies are also common.44 This can be differentiated from a tension pneumothorax as the mediastinal structures are deviated toward the hypoplastic side instead of being pushed to the contralateral side by air pressure. Since it is not possible to discern exactly the anatomy of the airway on plain film, it is possible that severe atelectasis from a variety of causes, especially main stem occlusion, could appear similarly. Confirmation that the bronchus is absent must be obtained via bronchoscopy, which is the most sensitive test. Ultrasound, CT, or MRI will also provide this information but are unnecessary as bronchoscopy is mandatory and conclusive in any child who can tolerate the procedure. In the event that there is unacceptable anesthetic or surgical risk (ie, respiratory compromise from infection, coagulopathy, or associated cardiac disease), imaging studies that obviate general

anesthesia may be used as confirmator y studies. Historically, bronchography was performed with contrast but posed significant risk to the contralateral lung. Its use has been obviated by the techniques discussed above. Although the treatment of pulmonary agenesis will not be altered by these confirmatory studies, it is important to treat any other causes of lung collapse that are revealed and in this way bronchoscopy may be therapeutic as well. Patients who undergo echocardiography or cardiac catheterization for cardiac disease will demonstrate a pathognomonic absence of the ipsilateral pulmonary artery. The treatment of primary hypoplasia and agenesis centers on exceptional pulmonary toilet and prevention of infection in the solitary lung. Infections of a single lung are life threatening and must be immediately and aggressively treated with antibiotics, chest physiotherapy, nutritional support, and appropriate bronchodilators. Surgical intervention is generally limited to bronchoscopic confirmation of the agenesis (a normal trachea and contralateral bronchus will be seen without evidence of the ipsilateral structures), maintenance of the contra lateral bronchus, or correction of the many associated anomalies. The aim is to limit or consolidate procedures to minimize general anesthesia and to optimize lung performance. The greatest difficulty is with procedures that necessitate displacement of the solitary lung as in tracheoseophageal fistula repair. Cardiopulmonary bypass can be used for support although these procedures can usually be accomplished by an experienced team without the use of bypass. Any alternative to intrathoracic procedures should obviously be considered and an example with respect to tracheoesophageal fistula ligation would be transabdominal occlusion of the gastroesophageal junction via ligature with concomitant gastrostomy (D. J. Y. Dunn, personal communication). Although most patients who have hypoplasia related to thoracic dystrophy die due to insurmountable congenital conditions, a few may benefit from thoracoplasty to distract and enlarge the thorax. The use of lung transplantation is not reported for pulmonary agenesis.2 In the past, up to one-half of the children born with pulmonary agenesis died before age 5 years from complications of pulmonary infection or associated anomalies4,45; the increased incidence of additional congenital defects in right-sided agenesis compounds the difficulty. Recently, with the advent of more powerful antibiotics, sophisticated modes of ventilation, and improvements in the treatment of cardiac disease, survival seems to be improving.

Surgical Management of Congenital Lesions of the Lung / 183

Alveolar Capillary Dysplasia Alveolar capillary dysplasia occurs when there is aberrant development of pulmonary capillaries coupled with abnormal pulmonary lobules. The pneumocytes and vessels are separated by an increased distance, and there may be a misalignment or absence of pulmonary veins within the pulmonary intralobular septa. Special stains for CD34 and collagen type IV also support this diagnosis. Although there has been one report of a familial case, it is most often sporadic.46 Its occurrence is very rare and uniformly fatal although not necessarily immediately. Infants have severe persistent pulmonary hypertension. Definitive diagnosis of alveolar capillary dysplasia is made upon histopathologic review of the lung biopsy, and its utility is in providing prognostic information for the family, as there is no successful treatment. Infants are usually treated as if they have primary pulmonary hypertension before the diagnosis of alveolar capillary dysplasia is established. This is done using standard measures of alkalinization, sophisticated ventilatory modes, nitric oxide, and even ECMO. Although intravenous prostacyclin and inhaled nitric oxide have both been shown to decrease pulmonary vascular hypertension and increase oxygen saturation, no known modality of treatment has been shown to effect survival in alveolar capillary dysplasia.47 The treatment is usually pursued until the infant succumbs to refractory pulmonary hypertension, and only after postmortem examination is the diagnosis made. Alternatively, in a child showing no improvement despite maximal therapy, if a biopsy is performed and establishes a diagnosis of alveolar capillary dysplasia the family can be counseled and care terminated due to the known fatal outcome of this disease.

Pulmonary Arteriovenous Fistula Pulmonary arteriovenous fistulas consist of single or multiple fistulas between pulmonary arterial and venous channels. There are two types of congenital pulmonary arteriovenous fistulas. The capillary form is associated with Rendu-Osler-Weber syndrome in 60% of cases and consists of multiple capillary telangiectasias; it is inherited in an autosomal dominant pattern and has variable penetrance. The cavernous type involves one or more branches of the pulmonary artery feeding a cavernous angioma.48 Pulmonary fistulas are extremely rare and less than 20 case reports of newborn cases exist in the literature.48 Only 15% of cases are diagnosed in infancy, and patients present with a continuum of respiratory distress symptoms. These range from mild symptoms to clubbing, polycythemia, cyanosis, and sometimes cardiac failure from intrapulmonary shunting. The severity of symptoms depends upon the size and number of vessels

involved in the fistula process. Peripheral arteriolar involvement has inconsequential respiratory and hemodynamic effect whereas with more central involvement of larger vessels or more numerous involvement of small vessels, symptoms may be life threatening. Multiple episodes of pulmonary hemorrhage are common in the capillary form. Infectious cerebral issues have also been described and are thought secondary to emboli that escape the natural alveolar filter of the lung by traversing the fistulas. The diagnosis is made from a combination of clinical and radiographic tests. Arterial blood gases will reveal varying degrees of right-to-left shunting and ventilation perfusion studies will be abnormal. Increased vascular markings or an interstitial infiltrate are characteristic but nonspecific findings on plain chest film. A CT scan revealing a confluence of vessels and high attenuation in the lung parenchyma is suggestive of arteriovenous fistulas, and this can be confirmed via echocardiography, nuclear medicine study, or pulmonary angiogram. In echocardiography with agitated microbubbles, the bubbles to which the capillary alveolar filter is a natural barrier travel through the fistulas and into the left heart. Albumin labeled with radioactive tracer similarly is normally caught in this natural filter and appears in the lung parenchyma; appearance in the systemic circulation indicates a shunt is present and the area within the parenchyma without tracer demonstrates where the shunt has bypassed the normal pulmonary deposition. Pulmonary angiography demonstrating a capillary network of abnormally shaped vessels not only confirms the diagnosis but is also an avenue for treatment via embolization. Embolization is very successful for focal lesions and results immediately in physiologic improvement of arterial blood oxygen saturation.48 Situations involving diffuse disease or embolization failures or situations in which new fistulas open after successful embolization are best treated with resection, which is curative. The use of interferon has been proposed to control the growth and proliferation of these arteriovenous fistulas, but there is no evidence yet that it is successful. Interferon may have application in situations in which disease too diffuse for surgical resection.

Conclusions Congenital lung bud anomalies represent a diverse group of conditions related by their common developmental lineage. Their often parallel embryological maturation leads to similarities among these entities as well as their occasional synchronous presentation. The physiological significance of space-occupying fetal thoracic lesions is their impairment of the developing lung and their ability to impair cardiac performance through mediastinal shift.

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Surgical resection of congenital lung lesions can be curative, but outcome is ultimately dependent upon the underlying pulmonary capacity and associated congenital anomalies. Fetal surgery has become a feasible alternative in the treatment of infants with some congenital anomalies. At the present time it can only be recommended for treatment of congenital lung lesions causing fetal hydrops in fetuses without evidence of concomitant lethal conditions. Current investigation within this field seeks to identify the optimal timing and optimal candidates for intervention, and its success depends upon the ability to control preterm labor.

Acknowledgments The authors thank Dr. Andrew Campbell, Chief of Ultrasound at St. Christopher’s Hospital for Children and Professor of Pediatric Radiology at Drexel University College of Medicine, for images of congenital lung malformations from his personal teaching files and for his suggestions regarding diagnostic imaging of these anomalies.

References 1. Bromley B, Parad R, Estroff JA, et al. Fetal lung masses: prenatal course and outcome. J Ultrasound Med 1995;14:927–36. 2. Oldham KT. Lung. In: Oldham KT, Colombani PM, Foglia PR, editors. Surgery of infants and children: scientific principles and practice. Philadelphia (PA): Lippincott-Raven Publishers; 1997. p. 935–70. 3. Haller JA, Golladay ES, Pickard LR, et al. Surgical management of lung bud anomalies: lobar emphysema, bronchogenic cyst, cystic adenomatoid malformation, and intralobar pulmonary sequestrations. Ann Thorac Surg 1979;28:33–43. 4. DeLorimer AA. Congenital malformations and neonatal problems of the respiratory tract. In: Welch KJ, Randolph JG, Ravitch MM, et al, editors. Pediatric surgery. Chicago (IL): Year Book Medical Publishers; 1986. p. 631–51. 5. Crawley-Coha T. Congenital lung malformations. In: Wise BV, McKenna C, Garvin G, et al, editors. Nursing care of the general pediatric surgery patient. Gaithersburg (MD): Harmon Aspen Publishers Inc; 2000. p. 176–87. 6. Suen HC, Mathisen DJ, Grillo HD, et al. Surgical management and radiological characteristics of bronchogenic cysts. Ann Thorac Surg 1993;55:467–81. 7. Kitano Y, Flake AW, Crombleholme TM, et al. Open fetal surgery for life-threatening fetal malformations. Semin Perinatol 1999;23:448–61. 8. Sullivan SM, Okada S, Kudo M, et al. A retroperitoneal bronchogenic cyst with malignant change. Pathol Int 1999;49:338–41.

9. Krous HF, Sexauer CL. Embryonal rhabdomyosarcoma arising within a congenital bronchogenic cyst in a child. J Pediatr Surg 1981;16:506–8. 10. Murphy JJ, Blair GK, Fraser GC, et al. Rhabdomyosarcoma arising within congenital pulmonary cysts: report of three cases. J Pediatr Surg 1992;27:1364–7. 11. Bolton JW, Shahian DM. Asymptomatic bronchogenic cysts: what is the best management? Ann Thorac Surg 1992;53:1134–7. 12. Abuhamad A, Bass T, Katz M, et al. Familial recurrence of pulmonary sequeastration. Obstet Gynecol 1996;87:843–5. 13. Jona JZ, Raffensperger JG. Total sequestration of the right lung. J Thorac Cardiovasc Surg 1975;69:361–4. 14. Carter R. Pulmonary sequestration. Ann Thorac Surg 1969;7:68–8. 15. Savic B, Birttel F, Tholen W, et al. Lung sequestration: report of seven cases and review of 540 published cases. Thorax 1979;334:96–101. 16. Buntain WL, Woolley MM, Mahour GH, et al. Pulmonary sequestration in children: a 23-year experience. Surgery 1977;81:413–20. 17. Srikanth MS, Ford EG, Stanley P, et al. Communicating bronchopulmonary foregut malformations: classification and embryogenesis. J Pediatr Surg 1992;27:732–6. 18. MacGillivray TE, Harrison MR, Goldstein RB, et al. Disappearing fetal lung lesions. J Pediatr Surg 1993;28:1321–4. 19. Usui N, Kamata S, Ishikawa S, et al. Bronchial reconstruction for bronchopulmonary foregut malformation: a case report. J Pediatr Surg 1995;30:1495–7. 20. Chan V, Greenough A, Nicolaides K. Antenatal and postnatal treatment of pleural effusion and extra lobar pulmonary sequestration. J Perinatal Medicine 1996;24:335–8. 21. de Lorimier AA. Respiratory problems related to the airway and lung. In: O’Neill AJ, Rowe MI, Grosfeld JL, et al, editors. Pediatric surgery. Volume 1. St. Louis (MO): Mosby; 1998. p. 873–97. 22. Cremin BJ, Movsowitz H. Lobar emphysema in infants. Br J Radiol 1971;44:692–6. 23. Borowitz D, Huday B. Congenital lung malformations. In: Glick PL, Pearl HR, Irish MS, Caty MS, editors. Pediatric surgery secrets. Philadelphia (PA): Hanley and Belfus; 2001. p. 47–52. 24. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol 1977;8:155–71. 25. Thorpe-Beeston JG, Nicolaides KH. Cystic adenomatoid malformation of the lung: prenatal diagnosis and outcome. Prenat Diagn 1994;14:677–88. 26. Miller RK, Sieber WK, Yunis EJ. Congenital cystic adenomatoid malformation of the lung: a report of 17 cases and

Surgical Management of Congenital Lesions of the Lung / 185 review of the literature. Pathol Annu 1980;15:387–402. 27. Adzick NS, Harrison MR, Crombleholme TM. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998;179:884–9. 28. Benjamin DR, Cahill JL. Bronchioalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 1991;95:889–92. 29. Rodeck CH, Firsk NM, Fraser, DI, et al. Long-term in utero drainage of fetal hydrothorax. N Engl J Med 1988;319:1135–8. 30. Adzick NS, Harrison MR, Flake AW, et al. Fetal surgery for cystic adenomatoid malformation of the lung. J Pediatr Surg 1993;28:806–12. 31. Brown MF, Lewis D, Brouillette RM, et al. Successful prenatal management of hydrops, caused by congenital cystic adenomatoid malformation, using serial aspirations. J Pediatar Surg 1995;30:1098–9. 32. Evans MG. Hydrops fetalis and pulmonary sequestration. J Pediatr Surg 1996;31:761–4. 33. Miller JA, Corteville JE, Langer JC. Congenital cystic adenomatoid malformation in the fetus: natural history and predictors of outcome. J Pediatr Surg 1996;31:805–8. 34. Ryckman FC, Rosenkrantz JG. Thoracic surgical problems in infancy and childhood. Surg Clin North Am 1985;65:1423–54. 35. Sanders RC. Structural fetal abnormalities: the total picture. St. Louis (MO): Mosby-Year Book; 1996. 36. Grewal RG, Yip CK. Intralobar pulmonary sequestration and mediastinal bronchogenic cyst. Thorax 1994;49:615–6. 37. Van Aerde J, Campbell AN, Smith JA. Spontaneous chylothorax in newborns. Am J Dis Child 1984;138:961–4. 38. Andersen EA, Hertel J, Pedersen SA, et al. Congenital chylothorax: management by ligature of the thoracic duct. Scand J Thorac Cardiovasc Surg 1984;18:193–4.

39. Faul JL, Berry GJ, Colby TV, et al. Thoracic lymphaniomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med 2000;161:1037–46. 40. Moerman P, Vandenberghe K, Devlieger H, et al. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am J Med Genet 1993;47:54–8. 41. Fanaroff AA, Martin RJ. The respiratory system: respiratory disorders in preterm and term infants. In: Miller MJ, Fanaroff AA, Martin RJ, editors. Neonatal-perinatal medicine: diseases of the fetus and infant. St. Louis (MO): Mosby; 2002. p. 1025–48. 42. White CW. Treatment of hemangiomatosis with recombinant interferon alfa. Semin Hematol 1990;27(3 Suppl 4):15–22. 43. Eltorky MA, Headley AS, Winer-Muram H, et al. Pulmonary capillary hemangiomatosis: a clinicopathologic review. Ann Thorac Surg 1994 57:772–6. 44. Swischuk LE, Richardson CH, Nichols MM, et al. Primary pulmonar y hypoplasia in the neonate. J Pediatr 1979;95:573–7. 45. Booth JB, Berry CL. Unilateral pulmonary agenesis. Arch Dis Child 1967;42:361–74. 46. Boggs S, Harris MC, Hoffman DJ, et al. Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression. J Pediatr 1994;124:125–8. 47. Steinhorn RH, Cox PN, Fineman JR, et al. Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia. J Pediatr 1997;130:417–22. 48. Olgunturk R, Oguz D, Tunaoglu S, et al. Pulmonary arteriovenous fistula in the newborn: a case report of RenduOsler-Weber syndrome and a review of the literature. Turk J Pediatr 2001;43:332–7.

CHAPTER 14

VASCULAR RINGS AND SLINGS RICHARD G. OHYE, MD LAURIE C. WILD, RN, MSN KHALED H. MUTABAGANI, MD, PHD ERIC J. DEVANEY, MD EDWARD L. BOVE, MD artery, while the distal segment involutes. Similarly, the proximal left sixth arch contributes to the proximal left pulmonary artery, and the distal sixth arch becomes the ductus arteriosum (Figure 14-1).

Anomalies of the aortic arch and pulmonary artery have long been recognized. The first report of a vascular ring dates back to 1737 with the description of a double aortic arch by Hommel. Subsequently, in 1794, Bayford linked posterior esophageal compression and dysphagia with an aberrant right subclavian artery. He termed the anomaly lusus naturae or “prank of nature” and the related symptoms as dysphagia lusoria. The term “vascular ring” is credited to Robert Gross, who in 1945 performed the first surgical repair of a double aortic arch in a 1-year-old child with tracheal compression. In 1947, Gross also performed the first innominate artery suspension for innominate artery compression syndrome. Pulmonar y arter y sling was first described by Glaevecke and Doehle in 1897 based on a post-mortem finding in a 7-month-old infant with severe respiratory compromise. Potts reported the first division and reimplantation of an aberrant pulmonary artery in 1954.

FIGURE 14-1. Normal aortic arch development. AO = aorta; DA = ductus arteriosum; LCCA = left common carotid artery; LECA = left external carotid artery; LICA = left internal carotid artery; LSCA = left subclavian artery; PA = pulmonary artery; RCCA = right common carotid artery; RSCA = right subclavian artery.

Embryology By the end of the fourth week of embryonic development, the six aortic or branchial arches have formed between the dorsal aortae and ventral roots. Subsequent involution and migration of the arches results in the anatomically normal or abnormal development of the aorta and its branches. The majority of the first, second, and fifth arches regress. The third arch forms the common carotid artery and proximal internal carotid artery. The right fourth arch forms the proximal right subclavian artery. The left fourth arch contributes to the portion of the aortic arch from left carotid to left subclavian arteries. The proximal portion of the right sixth arch becomes the proximal portion of the right pulmonary

The pulmonary artery is formed from two vascular precursors, as well as through a combination of angiogenesis, the de novo development of new blood vessels, and vasculogenesis, the budding and migration of existing vessels. As stated above, the proximal pulmonary arteries are based upon the sixth arches, whereas the primitive lung buds initially derive their blood supply from the splanchnic plexus. Ultimately, these two segments of the pulmonary artery join and the vascular network with the lung parenchyma forms (Figure 14-2).

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Vascular Rings and Slings / 187

other cardiac defects. Significant associated cardiac anomalies occurred in 21% (12 of 57) of our patients (Table 14-2). The incidence in the literature ranges from 11 to 20%.1,2,5 A right aortic arch is generally associated with a greater incidence of coexisting anomalies. In our series, of the 12 patients with an associated defect, 8 had a right aortic arch, 2 had a double aortic arch, 1 had a right ligamentum, and 1 had a pulmonary artery sling. TABLE 14-2. Associated Cardiac Anomalies FIGURE 14-2. Normal pulmonary artery development. LPA = left pulmonary artery; RPA = right pulmonary artery.

Anomaly

Associated Defect

Right aortic arch

Ventricular septal defect Tetralogy of Fallot Atrial septal defect, branch pulmonic stenosis Coarctation Tetralogy of Fallot Atrioventricular septal defect Ventricular septal defect Interrupted aortic arch, aortopulmonary window

Incidence and Classification The incidence of clinically significant vascular rings is 1 to 2% of all congenital heart defects. These vascular anomalies can be divided into complete vascular rings and partial vascular rings, either of which can cause tracheoesophageal compression. Complete vascular rings can be divided into double aortic arch and right aortic arch with retroesophageal left ligamentum arteriosum. These two categories can be further subdivided based on the specific anatomy (Table 14-1). Incomplete vascular rings include aberrant right subclavian artery, innominate artery compression, and pulmonary artery sling. Other rare variations, which have been described, include left aortic arch with right descending aorta and right ligamentum and left aortic arch with aberrant right subclavian artery and right ligamentum. Fifty-seven patients presented to the C.S. Mott Children’s Hospital at the University of Michigan with the diagnosis of vascular ring or sling during 1988–2001. The prevalence of the various forms of vascular ring at our institution, along with those from selected surgical series, is listed in Table 14-1.1–4 Vascular anomalies can also occur in conjunction with

Double aortic arch Right ligamentum Pulmonary artery sling

Number of Patients 4 2 1 1 1 1 1 1

Clinical Presentation Children with a complete vascular ring generally present within the first weeks to months of life. Typically, children with a double aortic arch present earlier in life than those with a right arch and retroesophageal left ligamentum. In the younger age group, respiratory symptoms predominate, as liquids are generally well tolerated. Respiratory symptoms may include stridor, nonproductive cough, apnea, or frequent respiratory infections. The cough is classically described as “seal bark” or “brassy.” Respiratory symptoms may be exacerbated during feeding, as the food bolus distends the esophagus, impinging upon the soft posterior trachea further narrowing the lumen. These symptoms may mimic asthma, respiratory infection, or reflux, and children with vascular rings may be initially misdiagnosed, leading to a delay in diagnosis.

TABLE 14-1. Distribution of Vascular Anomalies at the C.S. Mott Children’s Hospital, 1988–2001 (n = 57) Anomaly Complete vascular rings Double aortic arch Right dominant Left dominant Codominant Right arch, left ligamentum or ductus Aberrant left subclavian Mirror-image branching Right ligamentum Incomplete vascular rings Innominate artery compression Aberrant right subclavian Pulmonary sling

Prevalence (%) 77 43 74 16 11 55 79 21 2 14 87 13 9

Prevalence Range in Selected Surgical Series1–4 (%) 65–82 38–55 73–81 15–20 3–7 24–45 65–92 8–35 0–3 14–29 80–83 17–20 2–5

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With the transition to solid food, dysphagia becomes more apparent. Occasionally, older children may present with symptoms only of dysphagia. The presentation of a patient with an incomplete vascular ring is variable. Children with innominate artery compression usually present within the first one to two years of life with respiratory symptoms. Although, aberrant right subclavian artery is the most common arch abnormality, occurring in approximately 0.5 to 1% of the population, it rarely causes symptoms. Classically, when symptoms do occur, they present in the seventh and eighth decade, as the aberrant vessel becomes ectatic and calcified, causing dysphagia lusoria due to impingement of the artery on the posterior esophagus. An aberrant right subclavian can cause symptoms in children when they are of an abnormally large caliber or when associated with tracheomalacia, as in the one patient in our series requiring early intervention. However, since an aberrant right subclavian is rarely the cause of respiratory symptoms in children, it is imperative to rule out the other more frequent etiologies. Children with pulmonary artery slings generally present with respiratory symptoms within the first few weeks to months of life. As with complete rings, respiratory symptoms may include stridor, nonproductive cough, apnea, or frequent respiratory infections and may mimic other conditions leading to misdiagnosis.

double aortic arch. The lateral film may reveal tracheal compression. With a pulmonary artery sling, there may be anterior bowing of the right main stem bronchus,or leftward deviation of the distal trachea and carina. Barium Esophagography Historically the diagnostic study of choice, barium esophagography remains a very useful modality. In many cases, the clinical history and barium esophagography are sufficient for surgical intervention. 6 The patterns of external compression on the column of barium are often characteristic of the various arch anomalies. The findings on barium esophagography may also be subtle and can be dependent upon operator experience. The radiologist should therefore be made aware of the suspicion of a vascular ring to improve the sensitivity of the examination. A double aortic arch will show impressions on both sides of the esophagus on the anteroposterior view. The right arch is generally higher than the left (Figure 14-3). The lateral projection reveals posterior compression of the esophagus (Figure 14-4). A right aortic arch with aberrant left subclavian will also show posterior compression of the aorta on the lateral view of a barium

Diagnosis The methods for diagnosing a vascular ring are variable because of the variability in presentation and the spectrum of diagnostic tests available. A child with a presumptive diagnosis of asthma or tracheomalacia may be referred to a pulmonologist and a diagnosis of vascular ring made or suspected initially by chest radiograph and bronchoscopy. In some situations, the diagnosis is made by echocardiography during evaluation for concurrent cardiac defects. Regardless, the diagnosis generally begins with a chest radiograph. Confirmatory studies may include barium esophagography, computed tomography (CT), magnetic resonance imaging (MRI), bronchoscopy, and echocardiography. Tracheograms and cardiac catheterizations, which have been used extensively in the past, are rarely currently indicated. Chest Radiograph The initial evaluation of a child suspected of having a vascular ring should include an anteroposterior and lateral chest radiograph. The study may show unilateral or bilateral hyperinflation, atelectasis, or infiltrate. The anteroposterior view will generally reveal the side of the aortic arch and descending aorta and may suggest a

FIGURE 14-3. Anteroposterior projection of a barium esophagogram in a patient with a double aortic arch. The arrows indicate the typical impression of the higher right and lower left aortic arches.

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FIGURE 14-4. Lateral projection of a barium esophagogram in a patient with a double aortic arch. The arrow indicates the typical posterior compression of the esophagus.

esophagogram. However, the anteroposterior projection will reveal the oblique course of the artery upward from right to left. An aberrant right subclavian artery will again cause posterior compression of the esophagus, while the lateral shows the upward oblique course of the artery from left to right (Figure 14-5). A pulmonary artery sling will cause anterior esophageal compression on the lateral barium esophagogram. Computed Tomography CT is an accurate method of diagnosing and differentiating the various types of vascular anomalies. A limitation is the potential to miss nonenhancing segments, such as the ligamentum arteriosum or an atretic segment of the lesser arch in a double aortic arch. Diagnosis can be made by visualizing the anatomy directly, or by other more subtle clues, such as the “four artery sign.”7 The “four artery sign” consists of finding two dorsal subclavian arteries and two ventral carotid arteries evenly spaced around the trachea, characteristic of a double aortic arch or aberrant right subclavian artery.

FIGURE 14-5. Anteroposterior projection of a barium esophagogram in a patient with an aberrant right subclavian artery. Note the oblique course of the artery indicated by the arrow.

Magnetic Resonance Imaging MRI provides the most detailed views of the vascular anatomy, esophagus, and airways (Figures 14-6 and 14-7). The ability to manipulate the images not only on axial, sagittal, and coronal axes but also in continuous threedimensional planes can be very useful in defining the exact anatomy in difficult cases. In addition, unlike CT scanning, there is no need to expose the patient to ionizing radiation or intravenous contrast. A potential downside of MRI is the duration of the study, which may require sedation in a patient with a compromised airway, whereas spiral CT can be done very rapidly. Although the images can be spectacular, another factor is the cost of MRI, which probably cannot be justified in straightforward cases of vascular ring. Lastly, MRI is not universally available in many parts of the world.

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Bronchoscopy Many patients presenting with respiratory symptoms undergo a bronchoscopy prior to the diagnosis of vascular anomaly. A double aortic arch and a right aortic arch with retroesophageal left ligamentum can reveal external compression of the trachea. Bronchoscopy can be very useful in diagnosing innominate artery compression

syndrome as there is a specific finding of pulsatile compression of the anterior trachea one to two centimeters above the carina. Compression of the pulsatile mass with the bronchoscope resulting in loss of the right upper extremity pulse confirms the diagnosis. The lumen must be reduced by more than 70 to 80% for the innominate artery to be the sole etiology of the respiratory symptoms. Bronchoscopy is mandatory in cases of pulmonary artery sling to evaluate the patient for the presence or extent of associated tracheal stenosis. Bronchoscopy is also useful to rule out other potential causes of respiratory symptoms, such as tracheomalacia, subglottic stenosis, or foreign body. As with any patient with a potentially compromised airway, appropriate care should be taken during bronchoscopic evaluation. Echocardiography Two-dimensional and Doppler echocardiography are also useful in diagnosing vascular anomalies. Both surface and transesophageal techniques have been employed to define the anatomy of the vascular ring, as well as to demonstrate other associated cardiac lesions. At our institution, we have found the echocardiogram to be a useful adjunct. However, significant operator dependence, the inability to assess atretic segments and surrounding structures such as the airways, and the ready availability of other studies has generally relegated echocardiography to being a secondary modality.

FIGURE 14-6. Coronal view of a magnetic resonance image in a patient with a double aortic arch showing the two arches (white arrows) surrounding the trachea and esophagus (black arrow).

Treatment Complete Vascular Rings double aortic arch A double aortic arch occurs when the distal portion of the right dorsal aorta fails to regress (Figure 14-8). The two arches form a complete ring, encircling the trachea

FIGURE 14-7. Coronal view of a magnetic resonance image in a patient with an aberrant right subclavian artery showing the artery (white arrow) originating from the descending aorta and coursing upward from left to right.

FIGURE 14-8. Formation of a double aortic arch. AO = aorta; DA = ductus arteriosum; LCCA = left common carotid artery; Lig. = ligamentum arteriosum; LSCA = left subclavian artery; PA = pulmonary artery; RCCA = right common carotid artery; RSCA = right subclavian artery.

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and esophagus. The right arch is dominant in the majority of the cases, followed by left dominant, with codominant arches being the least common (see Table 30–1). The left and right carotid and subclavian arteries generally arise from their respective arches. The ligamentum arteriosum and descending aorta usually remain on the left. The approach to repair of a double aortic arch is via a left posterolateral thoracotomy. The procedure can easily be accomplished through a limited, muscle-sparing incision through the third or fourth intercostal space. The lung is retracted anteriorly and inferiorly, exposing the posterior mediastinum. The vagus and phrenic nerves are identified and preserved. The pleura is incised from the descending aorta up through the left subclavian artery and retracted with stay sutures. The descending aorta, left subclavian artery, left arch, right arch, and esophagus are all positively identified (Figure 14-9). The ligamentum or ductus arteriosum is circumferentially dissected, doubly ligated, and divided, with care not to injure the recurrent laryngeal nerve. The nondominant arch is then divided between two vascular clamps at the point where brachiocephalic flow is optimally preserved. If there is concern regarding the location for division, the arches can be temporarily occluded at various points, while monitoring pulse and blood pressure in each limb. If there is an atretic segment, the division is done at the point of the atresia. The ends of the divided arch are oversewn with two layers of polypropylene suture. Dissection around the esophagus and trachea in the regions of the ligamentum or ductus and nondominant arch allows for retraction of the vascular structures and lysis of any residual obstructing adhesions.

FIGURE 14-9. Intraoperative view of a double aortic arch. DAo = descending aorta; L = left; R = right.

right aortic arch with left ligamentum arteriosum There are three anatomic variations for a right arch with a left ligamentum, depending embryologically on the segment of the left fourth arch or left dorsal aorta that regresses. This variability determines where the ligamentum arteriosum and left subclavian artery arise. If the left fourth arch regresses between the aorta and left subclavian, a right aortic arch with aberrant left subclavian artery results. The ligamentum arteriosum is retroesophageal, bridging the left pulmonary artery and aberrant left subclavian, forming a complete vascular ring (Figure 14-10). If the left fourth arch regresses after the origin of the left subclavian artery but before the arch reaches the dorsal aorta to communicate with the left sixth arch (which becomes the ductus arteriosum), there is mirror-image branching. The retroesophageal ligamentum arteriosum arises directly from the descending aorta or from a Kommerell’s diverticulum off of the descending aorta, forming the complete ring (Figure 14-11). If

FIGURE 14-10. Formation of a right aortic arch with aberrant left subclavian and retroesophageal left ligamentum arteriosum. AO = aorta; DA = ductus arteriosum; LCCA = left common carotid artery; Lig. = ligamentum arteriosum; LSCA = left subclavian artery; PA = pulmonary artery; RCCA = right common carotid artery; RSCA = right subclavian artery.

FIGURE 14-11. Formation of a right aortic arch with mirror-image branching and retroesophageal left ligamentum arteriosum. AO = aorta; DA = ductus arteriosum; LCCA = left common carotid artery; Lig. = ligamentum arteriosum; LSCA = left subclavian artery; PA = pulmonary artery; RCCA = right common carotid artery; RSCA = right subclavian artery.

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communication is maintained between the left fourth and sixth arches, there is mirror-image branching with the ligamentum arising from the anterior, mirror-image left subclavian and a ring is not formed (Figure 14-12).

and trachea are lysed. Rarely, the Kommerell’s diverticulum has been reported to cause compression even after division of the ligamentum. As such, it may be prudent to resect or suspend the diverticulum posteriorly to the prevertebral fascia, if it is particularly prominent. Incomplete Vascular Rings

FIGURE 14-12. Formation of a right aortic arch with mirror-image branching and left ligamentum arteriosum, which does not form a vascular ring. AO = aorta; DA = ductus arteriosum; LCCA = left common carotid artery; Lig. = ligamentum arteriosum; LSCA = left subclavian artery; PA = pulmonary artery; RCCA = right common carotid artery; RSCA = right subclavian artery.

innominate artery compression In innominate artery compression syndrome, the aortic arch and ligamentum are in their normal leftward position. However, the innominate artery arises partially or totally to the left of midline (Figure 14-14). As the artery courses from left to right anterior to the trachea, it causes tracheal compression. The symptoms of innominate artery compression may be mild to severe. With mild symptoms and minimal tracheal compression on bronchoscopy, children can be observed expectantly as the symptoms may resolve with growth. Indications for surgery include apnea, severe respiratory distress, significant stridor, or recurrent respiratory tract infection.

The surgical approach for a right aortic arch with retroesophageal left ligamentum arteriosum is the same as for a double arch. After positively identifying the descending aorta, pulmonary artery, and aortic arch, the ligamentum is localized (Figure 14-13). The origin of the ligamentum may be directly from the descending aorta, from a Kommerell’s diverticulum off of the descending aorta, or from an aberrant left subclavian artery. The ligamentum is dissected free, ligated in case of patency, and divided with care to avoid injuring the recurrent laryngeal nerve. Any adhesions around the esophagus FIGURE 14-14. Embryological origin of innominate artery compression syndrome. AO = aorta; LCCA = left common carotid artery; LSCA = left subclavian artery; PA = pulmonary artery.

FIGURE 14-13. Intraoperative view of a right aortic arch with aberrant left subclavian and patent left retroesophageal ductus arteriosum rather than the typical ligamentum. L = left.

Several approaches for the correction of innominate artery compression syndrome have been described. These include simple division, division with reimplantation into the right side of the ascending aorta, and suspension to the overlying sternum. Suspension is currently the most widely used technique. This method avoids the risks of cerebral and right arm ischemia. In addition, by not performing a circumferential dissection of the innominate artery, the suspension of the vessel will also pull up on the anterior trachea. While Dr. Gross first described the procedure of suspension through a left anterolateral thoracotomy, adequate exposure is easily obtained through a limited left anterior, right anterior, or right inframammary anterolateral thoracotomy. Once the innominate artery is exposed, no dissection of the artery is undertaken. Pledged polypropylene sutures are passed partial thickness through both the innominate artery and

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the aorta at the origin of the innominate. Temporary distraction on the sutures under bronchoscopic guidance aids in the optimal placement of the sutures in the vessels and overlying sternum. Once satisfactory reestablishment of tracheal patency is confirmed by bronchoscopy, the sutures are brought through the sternum and secured. Rarely is it necessary to divide and reimplant the innominate at a more appropriate location on the arch, except under such extenuating circumstances as concurrent pectus excavatum. left aortic arch with aberrant right subclavian artery An aberrant right subclavian artery occurs when there is regression of the right fourth arch between the right common carotid and right subclavian arteries (Figure 14-15). The right subclavian then arises from the leftward descending aorta, laying posterior to the esophagus as it crosses from left to right. Although the artery can compress the esophagus posteriorly, it is rarely the cause of symptoms in children. Surgical treatment involves simple division via a left posterolateral thoracotomy.

FIGURE 14-15. Formation of a left aortic arch with aberrant right subclavian artery. LCCA = left common carotid artery; LSCA = left subclavian artery; RCCA = right common carotid artery; RSCA = right subclavian artery.

Pulmonary Artery Sling Normally, the right and left sixth aortic arches contribute to the proximal portions of their respective pulmonary arteries. If the proximal left sixth arch involutes and the bud from the left lung migrates rightward to meet the right pulmonary artery, a pulmonary artery sling is formed (Figure 14-16). Pulmonary artery slings are associated with complete tracheal rings and tracheal stenosis in 30 to 40% of patients.8 Origin of the right upper lobe bronchus from the trachea has been reported in frequent association with pulmonary artery sling.3 Initial attempts at the repair of a pulmonary artery sling involved reimplantation after division of the left pulmonary artery (LPA) and translocation of the trachea without cardiopulmonary bypass. These early reports

FIGURE 14-16. Formation of a pulmonary artery sling. LPA = left pulmonary artery; RPA = right pulmonary artery.

had a high incidence of LPA thrombosis. This has led some authors to advocate division of the trachea and translocation of the LPA. This approach would seem sensible if the trachea were being divided in the course of tracheal reconstruction. However, due to the incidence of airway complications with tracheal reconstruction, it is difficult to justify dividing a normal trachea. In addition, anterior compression of the reconstructed trachea has been reported when the LPA is not relocated onto the main pulmonary artery.9 More recently, several authors have once again advocated the reimplantation of the LPA with excellent results.9,10 The procedure is done via a median sternotomy on cardiopulmonary bypass to insure optimal visualization of the repair. Aortic crossclamping is not necessary. The origin of the LPA from the right pulmonary artery (RPA) is located and the LPA mobilized from behind the trachea (Figure 14-17). After the institution of cardiopulmonary bypass, the LPA is divided off of the RPA and the proximal end oversewn. The LPA is then translocated anterior to the trachea and reimplanted into the main pulmonary artery. Any necessary reconstruction of the trachea is done concurrently with bronchoscopic assistance. Many techniques for tracheal reconstruction have been described, the most common of which are resection with primary reanastomosis and sliding tracheoplasty for short segment stenosis and rib cartilage or pericardial patch for long areas of narrowing. Primary reanastomosis and sliding tracheoplasty have the benefit of not requiring any patch material but are not suitable for long-segment stenosis. Rib cartilage has the advantage of structural rigidity during spontaneous negative pressure ventilation. However, in the very small stenotic neonatal airway, particularly when there is early take-off of the right upper lobe bronchus directly from the trachea further diminishing the size of the distal trachea, a pericardial

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approach to these anomalies is the same as for a leftsided ring division, with the caveat that the right recurrent lar yngeal nerve will loop around the right ligamentum.

FIGURE 14-17. Intraoperative view of a pulmonary artery sling. LPA = left pulmonary artery; RPA = right pulmonary artery.

patch may be the best option. Choices for tracheal reconstruction should be tailored to the individual patient. The specific operative details are covered in Chapter 17, “Techniques of Tracheal Resection and Reconstruction Including Tracheal Substitutes and Tracheal Transplantation.”

Special Surgical Considerations Vascular Rings Requiring Right Thoracotomy Over 95% of vascular rings without concurrent cardiac defects can be performed through a left thoracotomy. A right thoracotomy is indicated for the rare cases where there is a right ligamentum arteriosum. A right ligamentum occurs in the setting of a left aortic arch with right descending aorta, where the ligamentum bridges from the descending aorta to the right pulmonary artery forming a complete ring. Right ligamentum arteriosum has also been described with a left aortic arch with aberrant right subclavian artery. In this case, the ligamentum may arise from the aberrant subclavian artery, a diverticulum off of the arch or directly from the left arch to the right pulmonary artery. In addition, a double aortic arch with an atretic segment proximal to the right carotid artery is more easily divided through a right thoracotomy. The

Minimally Invasive Surgery Burke and colleagues have reported the use of videoassisted thoracoscopic surgery (VATS) for the repair of vascular rings.11 Candidates for thoracoscopic division were limited to those patients requiring only the division of nonpatent vascular structures. A Kommerell’s diverticulum compressing the airway was also considered a contraindication. The group reported eight patients with symptomatic vascular rings undergoing VATS division. There were three patients with a double aortic arch with atretic left segment and five patients with a right aortic arch, aberrant left subclavian artery, and left ligamentum arteriosum. At a median follow-up of 5.9 months (range 1.5–9.5), seven of eight (88%) patients had symptomatic improvement. One patient had persistent but improved stridor. There were no operative deaths. Three patients required limited thoracotomy, two for division of patent vascular structures and one for intraoperative bleeding. One patient has a chylothorax necessitating a second VATS procedure for ligation of a lymphatic leak. Robot-assisted, minimally invasive surgical techniques can also be applied to the treatment of vascular rings. We reviewed our experience with five pediatric patients, who underwent robot-assisted vascular ring division utilizing the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA). In this early cohort, patients were limited to those candidates requiring division of a nonpatent vascular structure. A Kommerell’s diverticulum was not considered a contraindication to surgery and was simply tacked to the prevertebral fascia using the robot as in an open procedure. The median age was 6 years (range, 1–10 years) and the lowest weight was 10 kg. All procedures were competed endoscopically. These patients were compared to the 10 most recent vascular ring divisions performed by a traditional open approach. The median length of stay for the da Vinci patients (2 days, range, 2–13 days) was significantly lower than the open cohort (4 days, range, 2–6 days, p < .01). The median operating time for the da Vinci was 116 minutes (range, 70–211) compared to 83 (range, 70–95) for the open technique. While this difference was statistically significant (p = .03), the absolute difference in operating time was only 33 minutes. There was one chylothorax in each group. Currently, this approach is the treatment of choice at our institution for the management of all vascular rings, including those rings with patent vascular structures, for patients over 10 kg.

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Postoperative Management

References

For most vascular rings and pulmonary artery slings not requiring tracheal reconstruction, postoperative management is routine, with early extubation and short inpatient hospitalization. Occasionally, postobstructive atelectasis or pneumonia may require prolonged intubation for ventilatory support and management of secretions and antibiotic therapy. The parents should also be cautioned that, even in cases of a simple vascular ring, the respiratory symptoms frequently do not resolve for 3 to 6 months or more. When concurrent tracheal reconstruction has been performed, the patient is kept intubated, sedated, and paralyzed if necessary, with the endotracheal tube and positive-pressure ventilation serving to stent open the repair for 1 week. Prior to attempted extubation, bronchoscopy is performed to assess the repair and identify any need for removal of granulation tissue or secretions. Occasionally, tracheostomy with or without long-term positive-pressure ventilation is required. If significant portions of the trachea have been resected, hyperextension of the neck is avoided to prevent traction on the anastomosis. This may be accomplished by placing a heavy suture from the chin to the upper chest for the first week postoperatively.

1. van Son JAM, Julsrud PR, Hagler DJ, et al. Surgical treatment of vascular rings: the Mayo clinic experience. Mayo Clin Proc 1993;68:1056–63.

Results Mortality for the repair of a vascular ring is 0.5 to 7.6%, with improved survival occurring in more recent series.1–4 Most deaths are related to other cardiac defects or respiratory infection and failure. Historically, pulmonary artery sling has been associated with LPA thrombosis in up to 90% and death in 50%. However, Backer and colleagues recently reported a series of 16 patients repaired utilizing LPA division and reimplantation, all of whom also required tracheal reconstruction.10 There were no operative mortalities, one late death due to respiratory complications, and 100% LPA patency. The major source of morbidity, as well as mortality, in this and other series is related to tracheal reconstruction.9,10

2. Woods RK, Sharp RJ, Holcomb GW III, et al. Vascular anomalies and tracheoesophageal compression: a single institution’s 25-year experience. Ann Thorac Surg 2001;72:434–9. 3. Backer CL, Mavroudis C. Vascular rings and pulmonary artery sling. In: Mavroudis C, editor. Pediatric cardiac surgery. 2nd ed. St. Louis (MO): Mosby; 1994. 4. Mitchell JH, Austin EH III. Vascular rings, slings and other arch anomalies. In: Kaiser LR, Kron IL, Spray TL, editors. Mastery of cardiothoracic surgery. Philadelphia (PA): Lippincott-Raven; 1998. 5. Backer CL, Ilbawi MN, Idriss FS, et al. Vascular anomalies causing tracheoesophageal compression. J Thorac Cardiovasc Surg 1989;97:712–31. 6. Arciniegas E, Hakimi M, Hertzler JH, et al. Surgical management of congenital vascular rings. J Thorac Cardiovasc Surg 1979;77:721–7. 7. Lowe GM, Donaldson JS, Backer CL. Vascular rings: 10year review of imaging. Radiographics 1991;11:637–46. 8. Berdon WE, Baker DH, Wung JT, et al. Complete cartilagering tracheal stenosis associated with anomalous left pulmonary artery: the ring-sling complex. Radiology 1984;152:57–64. 9. van Son JAM, Hambsch J, Haas GS, et al. Pulmonary artery sling: reimplantation verses antetracheal translocation. Ann Thorac Surg 1999;68:989–94. 10. Backer CL, Mavroudis C, Dunham ME, Holinger LD. Pulmonary artery sling: results with median sternotomy, cardiopulmonary bypass, and reimplantation. Ann Thorac Surg 1999;67:1738–45. 11. Burke RP, Wernovsky G, van der Velde M, et al. Videoassisted thoracoscopic surgery for congenital heart disease. J Thorac Cardiovasc Surg 1995;109:499–508.

CHAPTER 15

THORACIC OUTLET SYNDROME HAROLD C. URSCHEL JR, MD, FACP, FACS, FACC, LLD (HON), DS (HON) AMIT N. PATEL, MD, MS

Anatomic Considerations

Thoracic outlet syndrome is the compression of the subclavian vessels and brachial plexus at the superior aperture of the thorax. It has been previously designated according to etiologies such as scalenus anticus, costoclavicular, hyperabduction, cervical rib, and first rib syndromes. The various syndromes are similar, and the specific compression mechanism is often difficult to identify; however, the first rib seems to be a common denominator against which most compressive factors operate.1–3 The symptoms are neurologic, vascular, or mixed, depending on which component is compressed. Occasionally, the pain is atypical in distribution and severity and is experienced predominantly in the chest wall and parascapular area, simulating angina pectoris.4 Diagnosis of nerve compression can be objectively verified by determining the ulnar nerve conduction velocity.5 In vascular compression, the diagnosis is usually established clinically, rarely requiring the use of angiography. The ulnar nerve conduction velocity (UNCV) test has widened the clinical recognition of this syndrome and has improved diagnosis, selection of treatment, and assessment of therapeutic results.6,7 Physiotherapy to improve posture, strengthen shoulder girdle muscles, and stretch neck muscles is used initially in most cases of thoracic outlet syndrome and is often successful in cases of mild compression.8 Surgical treatment involves removal of the first rib, usually through the transaxillary approach, and is reserved for cases of severe compression that have not responded to medical therapy.

The subclavian vessels and brachial plexus traverse the cervicoaxillary canal to reach the upper extremity. The outer border of the first rib divides this canal into a proximal division composed of the scalene triangle and the space bounded by the clavicle and the first rib—the costoclavicular space. The distal division comprises the axilla. The proximal division is the most critical for neurovascular compression. It is bound superiorly by the clavicle and the subclavius muscle; inferiorly by the first rib; anteromedially by the border of the sternum, the clavipectoral fascia, and the costocoracoid ligament; and posterolaterally by the scalenus medius muscle and the long thoracic nerve. The scalenus anticus, inserting on the scalene tubercle of the first rib, divides the costoclavicular space into two compartments: an anterior compartment containing the subclavian vein and a posterior compartment containing the subclavian artery and brachial plexus. The axilla, which is the outer division of the cervicoaxillary canal, with its underlying structures including the pectoralis minor muscle, the coracoid process, and the head of the humerus, is also an area of potential compression (Figure 15-1).

Compression Factors A variety of factors may cause compression of the neurovascular bundle at the thoracic outlet. The basic factor, which was pointed out by Rosati and Lord, is deranged anatomy to which congenital, traumatic, and atherosclerotic factors may contribute.8 Bony abnormalities are present in approximately 30% of patients, either as cervical rib, bifid first rib, fusion of first and second ribs, clavicular deformities, or previous thoracoplasty (Table 15-1). 196

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FIGURE 15-1. Forces in the thoracic outlet that may compress the neurovascular structures against the first rib.

TABLE 15-1. Etiologic Factors in Thoracic Outlet Syndrome Anatomic Potential sites of neurovascular compression Interscalene triangle Costoclavicular space Subcoracoid area Congenital Cervical rib and its fascial remnants Rudimentary first thoracic rib Scalene muscles Anterior Middle Smallest Adventitious fibrous bands Bifid clavicle Exostosis of first thoracic rib Enlarged transverse process of C7 Omohyoid muscle Anomalous course of transverse cervical artery Brachial plexus post-fixed Flat clavicle Traumatic Fracture of clavicle Dislocation of head of humerus Crushing injury to upper thorax Sudden, unaccustomed muscular efforts involving shoulder girdle muscles Cervical spondylosis and injuries to cervical spine Atherosclerosis

Pathologic changes in the configuration of the cervicoaxillary canal alter the normal functional dynamics and serve as the basis of the clinical maneuvers used in the diagnosis of the thoracic outlet syndrome. Adson or Scalene Test This maneuver, described by Adson in 1951, tightens the anterior and middle scalene muscles, thus decreasing the interscalene space and magnifying any preexisting compression of the subclavian artery and brachial plexus. The patient is instructed to (1) take and hold a deep breath, (2) extend his or her neck fully, and (3) turn his or her face toward the side. Obliteration or diminution in the radial pulse suggests compression.9 Costoclavicular Test—Military Position The shoulders are drawn down and backward. This maneuver narrows the costoclavicular space by approximating the clavicle to the first rib, thus tending to compress the neurovascular bundle. Changes in the radial pulse with production of symptoms indicate compression.

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Hyperabduction Test When the arm is hyperabducted to 180°, the components of the neurovascular bundle are pulled around the pectoralis minor tendon, the coracoid process, and the head of the humerus. If the radial pulse is decreased, compression should be suspected.9 Arm Claudication Test The shoulders are drawn up and backward. The arms are raised to the horizontal position with the elbows flexed 90°. With exercises of the hands, numbness or pain is experienced in the hands and forearms if compression is present.

Signs and Symptoms The symptoms of thoracic outlet syndrome depend on whether the nerves or blood vessels, or both, are compressed at the thoracic outlet. Symptoms of nerve compression that most frequently occur are pain and paresthesia, present in about 95% of patients, and motor weakness, in approximately 10%. Pain and paresthesia are segmental in 75% of cases, 90% occurring in the ulnar nerve distribution.11 Pain is usually insidious in onset and commonly involves the neck, shoulder, arm, and hand. In some patients, the pain is atypical, involving the anterior chest wall or the parascapular area, and is termed pseudoangina because it simulates angina pectoris. These patients have normal coronary arteriograms and decreased ulnar nerve conduction velocities, strongly suggesting the diagnosis of thoracic outlet syndrome. The usual shoulder, arm, and hand symptoms that might have provided the clue for the diagnosis of thoracic outlet syndrome are initially either absent or minimal compared with the severity of the chest pain. Without a high index of suspicion, the diagnosis of thoracic outlet syndrome is frequently overlooked, and many of these patients become “pseudo–cardiac cripples” without an appropriate diagnosis or develop severe psychological depression when told that their coronary arteries are normal and that they have no significant cause for their pain. The two distinct groups of patients with pseudoangina are as follows. Group I patients have symptoms and clinical findings suggesting angina pectoris but have normal coronary arteriograms and significant depression of UNCV. Group II patients have both significant coronary artery disease, as evidenced by 75% or greater stenosis in one or more of the major coronary arteries on coronary arteriography, and thoracic outlet syndrome, as evidenced by depression of the ulnar nerve conduction velocity. A high index of suspicion of thoracic outlet disease in such individuals must be maintained so that

the appropriate methods of diagnosis and management can be exercised. Objective laboratory tests that are important for differentiating these two groups of patients include electrocardiogram, exercise stress tests, coronary arteriograms, electromyogram, UNCV, cineesophagogram, and radiographs of the chest.4 To understand the symptomatic overlap between coronary artery disease and this atypical manifestation of the thoracic outlet syndrome, that is, pseudoangina, it is necessary to review the neuroanatomy, innervation, and pain pathways of the arm, chest wall, and heart. At least two types of pain pathways are present in the arm—the commonly acknowledged C5 to T1 cutaneous “more superficial” fibers, and the T2 to T5 afferent spinal fibers, which travel with the sympathetic nerves and transmit “deeper” painful stimuli from the ulnar median and parascapular distribution, as reported by Kuntz.12 The cell bodies of the two types of afferent neurons are situated in the dorsal root ganglia of the corresponding spinal segments. They synapse in the dorsal gray matter of the spinal cord and the axons of the second order neurons, cross the midline, and ascend in the spinothalamic tract to the brain. Compression of the “superficial” C8 to T1 cutaneous afferent fibers elicits stimuli that are transmitted to the brain and recognized as integumentary pain or paresthesias in the ulnar nerve distribution. In contrast, compression of the predominantly “deeper” sensory fibers elicits impulses that are interpreted by the brain as deep pain originating in the arm or referred to the chest wall. The pseudoangina experienced in thoracic outlet compression shares with angina pectoris the same dermatomal distribution in that the heart, arm, and chest wall have afferent fibers convergent on T2 to T5 spinal cord segments and cell bodies that are located in the corresponding dorsal root ganglia. Referred pain to the chest wall is a component in both pseudoangina and angina pectoris. Due to somatic pain being more common than visceral pain, the brain interprets activity arriving in a given pathway as a pain stimulus in a particular somatic area. Two theories attempt to explain the mechanism of referred pain from the heart or arm stimuli to chest wall. The convergence theory holds that somatic and visceral afferents converge on the same spinothalamic neurons; when the same pathway is stimulated by activity in visceral afferents, the signal reaching the brain is the same and the pain is projected to the somatic area. The facilitation effect theory holds that because of subliminal fringe effects, incoming impulses from visceral structures, such as the heart, lower the threshold of spinothalamic neurons receiving afferents from somatic areas, so minor activity in the pain pathways from the somatic areas—activity that

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would normally die out in the spinal cord—passes on to the brain and is interpreted as somatic pain rather than pain in the viscera, where the stimulus was initiated. Symptoms of vascular compression in thoracic outlet syndrome, much less common than those of neurologic compression, include coldness, weakness, easy fatigability of the arm and hand, and pain that is usually more diffuse in distribution. Raynaud’s phenomenon is occasionally noted. Venous compression is recognized by edema, venous distention, and discoloration of the arm and hand. Thrombosis of the subclavian vein—“effort thrombosis” or Paget-Schroetter syndrome—is infrequently noted but was described by Lang.13 Objective physical findings, in contrast, are more common in patients with primarily vascular rather than neural compression. Loss or diminution of radial pulse and reproduction of symptoms can be elicited with Adson’s test, costoclavicular test (military position), and hyperabduction maneuvers in most patients with vascular compression. Other possible findings are venous distention and edema, trophic changes, Raynaud’s phenomenon, temperature changes, subclavian vein thrombosis, and even arterial occlusion and claudication. In cases of neural compression, the objective neurologic findings, which occur less frequently, consist of hypoesthesia, anesthesia, and occasional muscular weakness or atrophy.

Diagnosis The basic diagnostic considerations of the thoracic outlet syndrome include the history and physical examination, radiographs of the chest and cervical spine, neurologic consultation, electromyography, and UNCV test. On occasion, a cervical myelogram, coronary angiogram, and venograms may be necessary to elicit the diagnosis. Cardinal for the establishment of the thoracic outlet diagnosis in pseudoangina is the elimination of the possibility of significant coronary artery disease by submaximal exercise stress testing and coronary arteriography when indicated. Subsequently, after excluding pulmonary, esophageal, and chest wall causes, the diagnosis of thoracic outlet syndrome must be entertained and established by the appropriate clinical evaluation and the slowing of the UNCV. Nerve Conduction Velocity Motor conduction velocities of the ulnar, median, radial, and musculocutaneous nerves can be reliably measured, as described by Jebsen.7 Caldwell and associates improved and adapted to clinical use the technique of measuring UNCV in evaluating patients with thoracic outlet compression.6 Conduction velocities over proximal and distal segments of the ulnar nerve are determined by

recording the action potentials generated in the hypothenar or first dorsal interosseous muscles. The points of stimulation are the supraclavicular fossa, midupper arm, area below the elbow, and wrist. 1 4 The Meditron 201-AD or the TECA B-3 electromyograph, including the coaxial cable with three-needle or surface electrodes, can be used for this examination. The normal average UNCV values are 72 m/s across the thoracic outlet, 55 m/s around the elbow, 59 m/s in the forearm, and 2.5 to 3.5 m/s at the wrist. In patients with the thoracic outlet syndrome, the average UNCV value is reduced to 53 m/s across the outlet, with a range of 32 to 65 m/s.5 Angiography Simple clinical observations usually suffice to determine the degree of vascular impairment in the upper extremity, and as Lang noted, peripheral angiography is rarely needed.13 Bruits in the supra- or infraclavicular spaces suggest stenoses, and absence of pulse denotes total obstruction. In these instances, retrograde or antegrade arteriograms of the subclavian and brachial arterial systems are indicated to demonstrate localized pathologic changes. Using arteriography or phlebography routinely for demonstrating temporary occlusion of the vessels in different arm positions would seem redundant to an adequate clinical examination in most patients and is associated with some morbidity. The UNCV is usually depressed in patients with vascular compression as well as nerve compression and serves to satisfy the physician and patient with regard to objective testing; moreover, it is less expensive and safer. In instances of venous stenosis or obstruction, as in Paget-Schroetter syndrome, phlebography is indicated to discern the extent of thrombosis to determine the status of collateral venous circulation. Differential Diagnosis Thoracic outlet syndrome should be differentiated from a variety of neurologic, vascular, pulmonary, and esophageal lesions. It is necessary to differentiate it from lesions of the cervical spine, brachial plexus, and peripheral nerves (Table 15-2). Several arterial and venous phenomena can be confused with thoracic outlet syndrome; however, the differentiation can often be made clinically (Table 15-3). In patients with atypical presentations, such as chest pain, a high index of suspicion of thoracic outlet in addition to angina pectoris must be maintained.

Therapy Patients with the thoracic outlet syndrome should receive physiotherapy before operative intervention. Such therapy must be properly performed because many of these

200 / Advanced Therapy in Thoracic Surgery TABLE 15-2. Differential Diagnosis of Nerve Compression Cervical spine Ruptured intervertebral disk Degenerative disease Osteoarthritis Spinal cord tumors Brachial plexus Superior sulcus tumors Trauma: postural palsy Peripheral nerves Entrapment neuropathy Carpal tunnel: median nerve Ulnar nerve: elbow Radial nerve Suprascapular nerve Medical neuropathies Trauma Tumor

TABLE 15-3. Differential Diagnosis of Vascular Compression Arterial Arteriosclerosis Aneurysm Occlusive disease Thromboangiitis obliterans Embolism Functional Raynaud’s disease Reflex vasomotor dystrophy Causalgia Vasculitis, collagen disease, panniculitis Venous Thrombophlebitis Mediastinal venous obstruction Malignant Benign

patients receive the same treatment as persons with “cervical syndrome,” which often exaggerates the symptoms of thoracic outlet compression. Proper physiotherapy for thoracic outlet compression includes heat massages, active neck exercises, scalenus anticus muscle stretching, strengthening of the upper trapezius muscle, and posture instruction. Sagging of the shoulder girdle, common among the middle aged, is a major etiologic factor in this syndrome. Therefore, many of the patients with less severe disease benefit from strengthening of the shoulder girdle and improving posture. More than one-half of the patients seen by surgeons require no surgical procedure and improve significantly with conservative management. Most patients with a UNCV above 60 m/s improve with conservative management; however, most patients with a UNCV below 60 m/s require surgical resection of the first rib and correction of other bony abnormalities. Roos and Owens found that resection of the first rib, with cervical rib when present, is best performed through

the transaxillary approach for complete removal, with decompression of the seventh and eighth cervical and first thoracic nerve roots.15 It can be accomplished without major muscle division, as in the posterior approach advocated by Clagett, or retraction of the brachial plexus, as in the anterior supraclavicular approach suggested by Falconer and Li.16,17 The infraclavicular approach does not allow complete removal of the first rib. The transaxillary approach shortens the postoperative disability and provides better cosmetic results when compared with both the anterior and posterior approaches, particularly because 80% of patients are women.

Transaxillary Resection of First Rib The patient is placed in the lateral position with the involved extremity abducted to 90° by traction straps wrapped carefully around the forearm and attached to an overhead pulley. An appropriate amount of weight, usually 1 to 2 pounds, depending on the build of the patient, is used to maintain this position without undue traction. Traction can be intermittently increased by the anesthesiologist for exposure. The axilla and forearm are prepared and draped. A transverse incision is made below the hairline between the pectoralis major and the latissimus dorsi muscles and dissected to the external intercostal fascia. Care should be taken to prevent injury to the intercostobrachial cutaneous nerve, which passes from the chest wall to the subcutaneous tissue in the center of the operative field. The dissection is extended cephalad next to the external intercostal fascia up to the first rib. Careful dissection of the neurovascular bundle is performed, and its relation to the first rib and both scalene muscles is clearly outlined to avoid injury to these structures. The insertion of the scalenus anticus muscle on the first rib is dissected and the muscle is divided. The first rib is dissected subperiosteally with a periosteal elevator and carefully separated from the underlying pleura to avoid pneumothorax. The rib is then divided at its middle portion. Alligator forceps are used to pull the anterior portion of the rib away from the vein. The costoclavicular ligament is cut, and the rib is divided at its sternal attachment. The anterior venous compartment is thus decompressed. The posterior segment of the rib is then grasped with alligator forceps and retracted away from its bed to facilitate its dissection and separation from the subclavian artery and brachial plexus posteriorly. The scalenus medius muscle should not be cut from the rib but rather stripped with a periosteal elevator to avoid injuring the long thoracic nerve that lies on its posterior margin. The dissection of this rib segment is carried to its articulation with the transverse process of the vertebra and divided. If the dissection is kept in the

Thoracic Outlet Syndrome / 201

subperiosteal plane, no damage occurs to the first thoracic nerve root, which lies immediately under the rib. Complete removal of the neck and head of the first rib is achieved by a long double-action pituitary rongeur. The eighth cervical and first thoracic nerve roots can be visualized clearly at this point. If a cervical rib is present, it is removed at this time and the seventh cervical nerve root can be observed. Only the subcutaneous tissues and skin require closure, because no large muscles have been divided. Intermittent firm traction is required for exposure, and no evidence of brachial plexus stretching or neuritis has been observed when this technique is used. The patient is encouraged to use the arm normally and can be discharged from the hospital between 2 and 3 days after the surgical procedure.3 It is preferable to remove the entire first rib, including its head and neck, to avoid future irritation of the plexus, because a residual portion may cause recurrence of symptoms. The periosteum should be fragmented and destroyed to prevent callus formation and “regeneration” of the rib. Removal of incompletely resected or “regenerated” rib can best be accomplished through the posterior approach.18 For lysis of adhesions of the brachial plexus in symptomatic patients with decreased UNCV following previous complete resection of the first rib, the anterior supraclavicular approach is used. Postoperative pain may become a significant issue in patients with a first rib resection. To overcome this problem we have been using a C8-T1 paravertebral block placed by the anesthesiologist at the end of the procedure. A comparative study demonstrated a significant decrease in postoperative pain scores when a patient received a paravertebral block versus no block.19 Recently, Wolf has described a total thorascopic approach for removal of the first rib in thoracic outlet syndrome.20 This may also reduce postoperative pain. However, outcomes regarding complete removal or regeneration of the rib are yet to be determined.

Results The clinical results of first rib resections in properly selected patients are good in 85%, fair in 10%, and poor in 5%. A good result is indicated by complete relief of symptoms, a fair result by improvement with some residual or recurrent mild symptoms, and a poor result by no change from the preoperative status. Uniform improvement of symptoms is usually obtained in patients with primarily vascular compression. In patients with predominantly nerve compression, however, two groups with different rates of improvement are observed. The first group includes patients with the

classic manifestations of ulnar neuralgia and elicitation of pulse diminution, in whom an average preoperative UNCV is reduced to 53 m/s. Ninety-five percent of patients in this group are improved by first rib resection. In the second group are patients with atypical pain distribution, who may or may not have shown pulse changes by compression tests, and in whom the average preoperative ulnar nerve conduction velocity was only reduced to 60 m/s. Surgical intervention is carried out in such patients as a therapeutic trial after prolonged conservative therapy has failed. Although, many patients in the second group improve, the fair and poor results all occur in these patients. The UNCV and clinical status are highly correlated. Patients with good postoperative results have a preoperative average UNCV of 51 m/s and show return to a normal average of 72 m/s after operation. In those who have fair results, the preoperative UNCV averages 60 m/s and increases to an average of only 63 m/s after operation. In the poor result group, no appreciable change occurs in the postoperative from the preoperative values; in fact, the average conduction time was only 58 m/s.11 No hospital mortality has been directly related to this procedure. Postoperative morbidity after the transaxillary approach includes clinically inconsequential pneumothorax in 15%, hematoma in 1%, and infection in 1%.

Paget-Schroetter Syndrome “Effort” thrombosis of the axillary-subclavian vein— Paget-Schroetter syndrome—usually occurs as a result of unusual or excessive use of the arm in addition to the presence of one or more compressive elements in the thoracic outlet. Sir James Paget in 1875 in London and von Schroetter in 1884 in Vienna described this syndrome of thrombosis of the axillary-subclavian vein, which bears their names.21,22 The word “effort” was added to thrombosis because of the frequent association with exertion producing either direct or indirect compression of the vein. The thrombosis is caused by trauma or unusual occupations requiring repetitive muscular activity as has been observed in professional athletes, linotype operators, painters, and beauticians. Cold and traumatic factors such as carrying skis over the shoulder tend to increase the proclivity for thrombosis. Elements of increased thrombogenicity also increase the incidence of this problem and exacerbate its symptoms on a longterm basis. For years, patients with effort thrombosis were treated with anticoagulants and conservative exercises; if recurrent symptoms developed when they returned to work, they were considered candidates for first rib resection.

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Use of thrombolytic agents with early surgical decompression of the neurovascular compression has reduced morbidity, such as postphlebitic syndrome and the necessity for thrombectomy. Evaluation of 512 patients with Paget-Schroetter syndrome (effort thrombosis of the axillary-subclavian vein) over 35 years emphasizes the necessity of (1) an accurate diagnosis, (2) expeditious thrombolytic therapy, and (3) prompt first rib resection. • Group I (35 patients) was initially treated with anticoagulants only. Twenty-one developed recurring symptoms after returning to work, requiring transaxillary resection of the first rib. Thrombectomy was necessary in eight. • Group II (36 patients) was treated with thrombolytic agents initially, followed promptly by first rib resection. Thrombectomy was necessary in only four. Thirty-one of these patients (95%) showed improvement and returned to work with no further complication. • Group III (384 patients) was evaluated within the first 4 weeks following thrombosis and had excellent results using the group II protocol. No thrombectomy was required, and all veins were open at surgery or recanalized within 6 months. • Group IV (57 patients) was seen after 6 weeks from venous occlusion. Intravascular stents had been inserted in 22 patients. (In only 50% of these was it possible to decrease the amount of clot with thrombolytic infusion, and all veins remained occluded.) After first rib resection, 32 patients recanalized spontaneously and became asymptotic. Of the 25 patients with persistent occlusion, 5 developed severe postphlebitic syndrome, 5 had mild symptoms, 3 required “Roto-Rooter” destruction of the clot with “relief ” of symptoms, and 12 developed adequate collateral circulation. (Bypass grafts were performed in 3 patients occluded before our evaluation.) No deaths were reported in this series.3,23,24 Adam and DeWeese reported long-term results in patients treated conservatively with elevation and Coumadin.25 They noted a 12% incidence of pulmonary embolism. Development of occasional venous distention occurred in 18%, and late residual arm symptoms of swelling, pain, and superficial thrombophlebitis were noted in 68% of the patients—deep venous thrombosis with postphlebitic syndrome. One patient had phlegmasia cerulea dolens. These findings substantiate our observations in group I that a more aggressive operative approach after thrombolytic therapy is indicated, particularly for younger patients in precipitating occupations.

One advantage of urokinase over streptokinase is the direct action of urokinase on the thrombosis distal to the catheter, producing a local thrombolytic effect. Streptokinase produces a systemic effect involving the alteration of serum plasminogen and increasing potential complications. Heparin is given postoperatively until the catheter is removed. A decrease in the need for thrombectomy after use of the thrombolytic agent followed by aggressive surgical intervention is another advantage, as some of the long-term disability is related to morbidity from thrombectomy as well as recurrent thrombosis. The natural history of Paget-Schroetter syndrome suggests moderate morbidity with conservative treatment alone. Bypass with vein or other conduits have limited application. Causes other than thoracic outlet syndrome must be treated individually using the basic principles mentioned. Intermittent obstruction of the subclavian vein can lead to thrombosis, and decompression should be used prophylactically.

Recurrent Thoracic Outlet Syndrome Removal of the first rib offers relief of symptoms in patients with thoracic outlet syndrome not improved by physiotherapy. Ten percent of the surgically treated patients develop variable degrees of shoulder, arm, and hand pain and paresthesias that are usually mild and short-lasting and which usually respond well to a brief course of physiotherapy and muscle relaxants. In 1.6% of patients, however, symptoms persist, become progressively more severe, and often involve a wider area of distribution because of entrapment of the intermediate trunk in addition to the lower trunk and C8 and T1 nerve roots. Symptoms may recur from 1 month to 10 years following initial rib resection. In most instances, recurrence is within the first 3 months. Symptoms consist of aching or burning pain, often associated with paresthesia, involving the neck, shoulder, parascapular area, anterior chest wall, arm, and hand. Vascular lesions are uncommon and consist of causalgia minor and infected false aneurysms. There are two distinct groups of patients requiring reoperation. Pseudorecurrence occurs in patients who never had relief of symptoms after the initial operation. Cases can be separated etiologically as follows: cases in which (1) the second rib was mistakenly resected instead of the first; (2) the first rib was resected leaving a cervical rib; (3) a cervical rib was resected leaving an abnormal first rib; or (4) a second rib was resected leaving a rudimentary first rib. The second group, in whom true recurrence takes place, includes those patients whose symptoms were relieved after the initial operation but who developed recurrence with a significant piece of

Thoracic Outlet Syndrome / 203

the first rib remaining and those patients who had complete resection of the first rib but demonstrated excessive scar formation on the brachial plexus.18 Physiotherapy should be instituted in all patients with symptoms of neurovascular compression following first rib resection. If symptoms persist and conduction velocity remains below normal, reoperation is indicated. Reoperation for recurrent thoracic outlet syndrome is always performed through the posterior thoracoplasty approach to provide better exposure of the nerve roots and brachial plexus, thereby reducing the danger of injury to these structures as well as providing adequate exposure of the subclavian artery and vein. It also provides a wider field for easy resection of any bony abnormalities or fibrous bands and allows extensive neurolysis of the nerve roots and brachial plexus, not always accessible through the limited exposure of the transaxillary approach. The anterior or supraclavicular approach is inadequate for reoperation. The basic elements of reoperation include (1) resection of persistent or recurrent bony remnants of either a cervical or the first rib, (2) neurolysis of the brachial plexus and nerve roots, and (3) dorsal sympathectomy. Sympathectomy removes the T1, T2, and T3 thoracic ganglia. The surgeon should avoid damaging the C8 ganglion—upper aspect of the stellate ganglion—which produces Horner syndrome. This provides relief of major and minor causalgia and alleviates the paresthesias in the supraclavicular and infraclavicular areas. The incidence of postsympathetic syndrome has been negligible in this group of patients. The use of a nerve stimulator to differentiate scar from nerve root is cardinal to avoid damage in reoperation.18 The technique of the operation includes a high thoracoplasty incision, extending from 3 cm above the angle of the scapula, halfway between the angle of the scapula and the spinous processes, and caudad 5 cm from the angle of the scapula. The trapezius and rhomboid muscles are divided the length of the incision. The scapula is retracted from the chest wall by incising the latissimus dorsi over the fourth rib. The posterior superior serratus muscle is divided and the sacrospinalis muscle is retracted medially. The first rib remnant and cervical rib remnant, if present, are located and removed subperiosteally. After the rib remnants have been resected, the regenerated periosteum is removed. Most regenerated ribs occur from the end of an unresected segment of rib rather than from periosteum, although the latter is possible. At the initial operation, therefore, it is important to remove the first rib totally to reduce the incidence of bony regeneration in all patients with primarily nerve compression and pain symptoms.

If excessive scar is present after removal of any bony rib remnant, it may be prudent to perform the sympathectomy initially. This involves resection of a 1-inch segment of the second rib posteriorly to locate the sympathetic ganglion. The first thoracic nerve may be easier to locate beneath rather than through the scar. Neurolysis of the nerve root and brachial plexus is performed, using a nerve stimulator. Neurolysis is carried down to but not into the nerve sheath. It is extended peripherally over the brachial plexus as far as scar persists. Excessive neurolysis is not indicated, and opening of the nerve sheath produces more scar than it relieves. To minimize excessive scar, efforts in the initial operation for thoracic outlet should include complete removal of the first rib, avoidance of hematomas by adequate drainage either by a catheter or by opening the pleura, and avoidance of infection. The subclavian artery and vein are released if symptoms mediate. The scalenus medius muscle is debrided. The dorsal sympathectomy is completed via extrapleural dissection. Meticulous hemostasis is performed, and a large, round Jackson-Pratt catheter drain is placed in the area of the brachial plexus, although not touching it. This drain is brought out through the subscapular space through a stab wound into the axilla. Methylprednisolone acetate (Depo-Medrol) 80 mg is left in the area of the nerve plexus. The patient is not given systemic steroids unless keloid formation has previously been manifested. The wound is closed in layers with interrupted heavy polydiaxanone sutures to provide adequate strength. The arm, kept in a sling, is to be used gently for the first 3 months. Range-of-motion exercises are prescribed to prevent shoulder limitation; however, overactivity is contraindicated to minimize excessive scar formation. When the problem is vascular, involving false or mycotic aneurysms, special techniques for reoperation are used. A bypass graft is interposed from the innominate or carotid artery proximally, through a separate tunnel distally, to the brachial artery. Usually, the saphenous vein is used, although other conduits may be selected. The arteries feeding and leaving the infected aneur ysm are ligated. At a subsequent stage, the aneurysm is resected through a transaxillary approach with no fear of bleeding or ischemia of the arm. Special instruments have been devised to provide adequate resection through the transaxillary or posterior route. These include a modified strengthened pituitary rongeur and a modified Leksell double-action rongeur for first rib removal without danger to the nerve root. The sympathectomy, which may be performed thorascopically in highly scarred patients, relieves chest wall pain that mimics angina pectoris, esophageal disease, or

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even a lung tumor by denervating the deep fibers that travel with the arteries and bone.26 Results of reoperation have been excellent if an accurate diagnosis was established and the proper procedure was executed. Follow-up of over 400 patients has ranged from 6 months to 15 years. All patients improved initially after reoperation; in 79%, improvement was maintained for more than 5 years. Symptoms easily managed with physiotherapy developed in 14%; 7% required a second reoperation, in every instance because of rescarring. No deaths occurred, and only one case of significant infection requiring drainage was recorded. There have been isolated reports of using intra-arterial wall stents for recurrent thoracic outlet syndrome after surgical decompression. Most of these patients have been anticoagulated. However, long-term patency and symptomatology need to be evaluated before widespread use of wall stents.27

References 1. Ranney D. Thoracic outlet: an anatomical redefinition that makes clinical sense. Clin Anat 1996;9:50–2. 2. Urschel HC Jr. The history of surgery for thoracic outlet syndrome. Chest Surg Clin N Am 2000;1:183–8. 3. Urschel HC Jr. The transaxillary approach for treatment of thoracic outlet syndrome. Chest Surg Clin N Am 1999;4:771–80. 4. Urschel HC Jr, Razzuk MA, Hyland JW. Thoracic outlet syndrome masquerading as coronary artery disease. Ann Thorac Surg 1973;16:239–48. 5. Urschel HC Jr, Razzuk MA, Wood RE, et al. Objective diagnosis (ulnar nerve conduction velocity) and current therapy of thoracic outlet syndrome. Ann Thorac Surg 1971;12:608–20. 6. Caldwell JW, Crane CR, Krusen UL. Nerve conduction studies in the diagnosis of the thoracic outlet syndrome. South Med J 1971;64:310. 7. Jebsen RH. Motor conduction velocities in the median and ulnar nerves. Arch Phys Med 1967;48:185. 8. Rosati LM, Lord JW. Neurovascular compression syndromes of the shoulder girdle. Modern Surgical Monographs. New York: Grune & Stratton; 1961. 9. Adson AW. Cervical ribs: symptoms, differential diagnosis for section of the scalenus anticus muscle. J Int Coll Surg 1951;16:546. 10. Jamieson WG, Chinnick B. Thoracic outlet syndrome: fact or fancy? A review of 409 consecutive patients who under-

went operation. Can J Surg 1996;39:321. 11. Urschel HC Jr, Razzuk MA. Neurovascular compression in the thoracic outlet: changing management over 50 years. Ann Surg 1998;228:609–17. 12. Kuntz A. Afferent innervation of peripheral blood vessels through sympathetic trunks. South Med J 1951;44:673. 13. Lang EK. Roentgenographic diagnosis of the neurovascular compression syndromes. Radiology 1962;79:58. 14. Le Forestier N, Moulonguet A, Maisonobe T, et al. True neurogenic thoracic outlet syndrome: electrophysiologic diagnosis in six cases. Muscle Nerve 1998;21:1129. 15. Roos DB, Owens JC. Thoracic outlet syndrome. Arch Surg 1966;93:71. 16. Clagett OT. Presidential address: research and prosearch. J Thorac Cardiovasc Surg 1962;44:153. 17. Falconer MA, Li FWP. Resection of the first rib in costoclavicular compression of the brachial plexus. Lancet 1961;1:59. 18. Urschel HC Jr, Razzuk MA. The failed operation for thoracic outlet syndrome: the difficulty of diagnosis and management. Ann Thorac Surg 1986;42:523–8. 19. Patel AN, Finlay KU, Urschel HC. The effect of a perioperative paravertebral block on pain management after first rib resection. 2002;15:374–5. 20. Ohtusuka T, Wolf RK, Donsker SB. Port-access first-rib resection. Surg Endosc 1999;13:940. 21. Paget J. Clinical lectures and essays. London: Longmans Green; 1875. 22. Von Schroetter L. Erkrankungen der fegasse. In: Nathnogel. Handbuch der Pathologie und Therapie. Vienna: Holder; 1884. 23. Angle N, Gelabert HA. Safety and efficacy of early surgical decompression of the thoracic outlet for Paget-Schroetter syndrome. Ann Vasc Surg 2001;15:37. 24. Urschel HC, Razzuk MA. Paget-Schroetter syndrome: what is the best management? Ann Thorac Surg 2000;69:1663–9. 25. Adams JT, DeWeese JA. Effort thrombosis of the axillary and subclavian veins. J Trauma 1971;11:923. 26. Urschel HC Jr. Dorsal sympathectomy and management of thoracic outlet syndrome with VATS. Ann Thorac Surg 1993;56:717. 27. Cohen GS, Braunstein L. Effort thrombosis: effective treatment with vascular stent after unrelieved venous stenosis following a surgical release procedure. Cardiovasc Intervent Radiol 1996;19:37.

CHAPTER 16

THE MANAGEMENT OF PLEURAL SPACE PROBLEMS ALEX G. LITTLE, MD

Anatomy

tion of this magnitude, it is easy to understand how a seemingly minor perturbation in the system can result in the creation of a large pleural effusion. Normally the pleural space contains less than 5 mL of fluid. Increases in this amount constitute a pleural effusion, which can be classified as an exudate or a transudate.1 A transudative effusion is the result of increased formation or decreased absorption of pleural fluid caused by changes in the Starling forces. An exudative effusion results from inflammatory or malignant alterations or diseases of the pleura itself. The effusion is considered to be exudative if analysis shows at least one of the following criteria: (1) pleural fluid protein divided by serum protein is greater than 0.5; (2) pleural fluid lactate dehydrogenase (LDH) divided by serum LDH is greater than 0.6; and (3) pleural fluid LDH is greater than two-thirds the upper limit of normal for the serum LDH. Transudative effusions meet none of these criteria. Depending on the size of an effusion and the status of the lungs, a range of symptoms may be seen. If the effusion is small or the lungs can accommodate the effusion, the patient may be entirely asymptomatic. When the effusion is larger or the lungs are unable to compensate, symptoms occur related to loss of lung volume and lung compression. These include chest pain, cough, shortness of breath, and dyspnea on exertion. Extreme cases can cause mediastinal shift leading to hemodynamic instability.

The pleura is a serous membrane. The visceral pleura covers the lung parenchyma while the parietal pleura lines the inside of the thoracic cage, both the chest wall and the mediastinum. Both pleural components are composed of a single layer of metabolically active mesothelial cells that can absorb or secrete fluid.

Pathophysiology Fluid movement, or flux, in or out of any anatomic space, including the pleural cavity, is determined by the relationship described by Starling between hydrostatic and oncotic pressures (the Starling forces) on each side of the membrane separating the space from the tissues, by the permeability of the membrane to fluid and macromolecules, and by the efficiency of lymphatic drainage of the space. When equilibrium is reached, the amount of fluid in the anatomic space is constant. Changes in any of these causes fluid movement in or out of the space to occur. When considering the pleural cavity as an anatomic space, this means that potential causes of pleural effusion include (1) increased hydrostatic pressure from heart failure, (2) decreased intravascular oncotic pressure from hypoalbuminemia, (3) decreased intrapleural pressure from atelectasis of the lung, (4) inefficient pleural lymphatic drainage because of obstructing mediastinal tumor, and (5) increased capillary permeability from inflammation of or tumor implants on either the visceral or the parietal pleura. Under normal circumstances, between one and two liters of pleura fluid flow daily from the parietal through the visceral or mediastinal pleura into mediastinal lymphatics and ultimately the systemic venous circulation. With fluid production and absorp-

Malignant Pleural Effusion Malignant pleural effusion complicates the care and worsens the quality of life of many cancer patients. The most typical pathogenetic situation is involvement of parietal or visceral pleura with metastatic deposits. These 205

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metastases leak fluid and blood from weakened capillaries, producing the frequently bloody pleural effusion. In addition, both hypoalbuminemia, caused by cancer cachexia, and metastatic tumor blockage of mediastinal lymphatic pathways can contribute to or even independently cause a malignant pleural effusion. Roughly 40% of clinically significant pleural effusions are caused by malignancy with the most common types being lung cancer, breast cancer, and lymphoma. Obviously, there is a difference in tumor types between men and women. Table 16-1, adapted from Johnson, gives a complete breakdown of the cancers most commonly associated with development of malignant effusions.2 This translates into approximately 100,000 new cases of malignant pleural effusion diagnosed each year in the United States. 3 The frequency with which this entity devastates the quality of the remaining short life of cancer patients mandates appropriate and aggressive management by thoracic oncologists. TABLE 16-1. Etiology of Malignant Pleural Effusion Men Primary Tumor

Women Incidence (%)

Lung Lymphoma or leukemia Gastrointestinal tract Other

49.1 21.1 7.0 21.8

Primary Tumor

Incidence (%)

Breast Female genital tract Lung Lymphoma or leukemia Other

37.4 20.3 15.0 8.0 19.3

Adapted from Johnson ww.2

Diagnosis A malignant pleural effusion is an effusion associated with metastatic pleural nodules or bulky mediastinal disease in lymph nodes. The former etiology is the most common, so the majority of patients have identifiable malignant cells in the fluid. However, this is not always the case. Therefore the effusion is considered malignant if it is associated with metastatic deposits either in the mediastinum or on a pleural surface, regardless of the presence or absence of malignant cells in the pleural fluid. When a pleural effusion develops in the setting of a patient who already is known to have metastatic cancer, diagnosis is usually not a significant issue. If the effusion is not causing symptoms, attention is directed toward therapy to address the systemic disease (ie, chemotherapy). When the effusion is causing the patient enough respiratory embarrassment to require specific local treatment, the diagnosis can be confirmed at the time therapy is begun. A patient without a history of cancer who presents with a new pleural effusion, however, presents a diagnos-

tic challenge. The initial step in the investigation of this initially idiopathic effusion is to investigate potential causes of transudative effusions such as congestive heart failure and causes of exudative effusion such as infection. Once these potential causes of idiopathic effusion have been thoroughly evaluated with the appropriate clinical investigations and eliminated as etiologic possibilities, the next step is either thoracentesis, with both chemical analysis and cytologic evaluation of the fluid, or closed pleural biopsy. The majority of patients will eventually be proved to have malignant effusions. One large study of 414 patients with idiopathic pleural effusion identified malignancy by one of these two methods in 281 (68%) cases.4 The cytologic examination of fluid obtained by thoracentesis was positive for cancer in 163 (58%) of the cancer patient population. Closed pleural biopsy was positive in 121 (43%) of the patients but was diagnostic only 7% of the time when an earlier thoracentesis was nondiagnostic. However, this means that 133 (32%) patients did not have a diagnosis established by either of these interventions. Multiple other reports confirm that up to 27% of patients with effusions of unknown origin remain without a diagnosis after thoracentesis or pleural biopsy.2,3,5,6 Video-assisted thoracic surgery (VATS) is a safe and efficacious diagnostic option when these less invasive maneuvers have been unsuccessful. General anesthesia and one-lung ventilation are required. However, frequently only one access port is needed, so the procedure truly is minimally invasive. With an operating telescope (Figure 16-1) fluid can be aspirated and biopsies taken through the operating port. This translates into minimal postoperative patient discomfort; a chest tube can be placed through the same incision. This intervention permits evacuation of all loculated fluid collections,

FIGURE 16-1. The bottom instrument is a right-angled operating thoracoscope. The camera is attached to the eyepiece and either a suction instrument (top) or biopsy forceps (middle) can be passed through the operating channel of the thoracoscope. This instrument can be used to visually explore the pleural cavity, evacuate loculated fluid pockets, and biopsy pleural, pulmonary, and lymph node lesions through a single, small access incision.

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as well as visualization and biopsy of visceral and parietal pleural nodules that are not identifiable otherwise. One of my patients is an illustrative example. She had an idiopathic effusion; a computed axial tomography scan showed only the effusion. At VATS exploration there were multiple small (less than 3 mm) nodules studding the parietal pleura. Biopsy showed these to be metastatic breast cancer 10 years following contralateral mastectomy. In addition to pleural lesions such as in my patient, suspicious mediastinal and hilar lymph nodes can also be sampled for histologic examination and culture. In multiple clinical reports VATS has been shown to have a sensitivity ranging between 80 to 100% for both benign and malignant disease.5–9 False-negative results are very uncommon, and specificity is generally reported as 100%. In one experience with 161 patients with an idiopathic pleural effusion, 24 of 35 (69%) patients with two or more nondiagnostic thoracenteses were ultimately found by VATS to have either a primary or metastatic pleural malignancy.5 Of another 41 patients from the same study with nondiagnostic closed pleural biopsy, VATS successfully identified a malignant ideology in 27 patients (66%). In this particular investigation, the diagnostic sensitivity of thoracoscopy for malignancy was 95%, specificity was 100%, and the negative predictive value of VATS was 94%. The sensitivity and specificity were both 100% for benign disease. These results were obtained with minor complications, and the average hospital length of stay, which also included performance of and recovery from therapeutic maneuvers, was 10 days. Only one procedure resulted in death. As these experiences show, a VATS or thoracoscopic type of diagnostic intervention in cancer patients is generally both efficacious and well tolerated and associated with minimal morbidity. However, both thoracentesis and closed pleural biopsy are less invasive, can be performed at the bedside, and result in a definitive diagnosis in approximately two-thirds of patients. Therefore, despite reports suggesting the use of VATS as the initial diagnostic step, 8 this approach should generally be reserved for patients in whom thoracentesis or closed biopsy are not diagnostic.9

therapeutic thoracentesis is appropriate. If removal of a clinically significant quantity of pleural fluid produces no change in the patient’s respiratory symptoms, which might be due to lung disease such as emphysema or to primary or secondary lung malignancy, again no treatment is indicated.

Treatment The aggressiveness with which treatment should be pursued is dependent upon the extent to which a malignant pleural effusion produces respiratory symptoms and the patient’s performance status. If the patient does not have respiratory compromise or is in the terminal phase of disease, no specific local treatment is necessarily indicated. When the clinical picture is ambiguous and it is not clear whether the effusion or the underlying lung disease is responsible for the clinical picture, a single

video-assisted thoracic surgery Some patients, up to 30% in some series, fail to respond to chemical pleurodesis with various sclerosants via a chest tube.3,5,10 The result is that the malignant effusion either persists or recurs. This necessitates alternative therapy. VATS exploration and drainage allows evacuation of loculated fluid collections that are not drainable by a routine chest tube. This accomplishment is combined with intraoperative powdered talc insufflation, which ensures an even coverage of all pleural surfaces, thus

thoracostomy and pleurodesis When respiratory symptoms are present or thoracentesis relieves respiratory embarrassment, suggesting that the patient’s quality of life can be improved by reexpansion of compressed lung, then treatment strategies are undertaken. Placement of an intercostal chest tube and instituting tube thoracostomy drainage is the standard first step. This is followed by instillation of a chemical sclerosant through the chest tube to produce pleural inflammation, which will result in fibrous adhesions between the visceral and parietal pleura, establish pleurodesis, and treat the effusion by eliminating the pleural space. Although some physicians proceed quickly to pleurodesis after chest tube placement, I prefer to wait up to 3 days for fluid drainage to decrease below 250 cc/d. This may help to maximize contact between the visceral and parietal pleural surfaces by minimizing the tendency of accumulating fluid to keep them apart. However, a lengthy delay is inappropriate; sclerosis should be attempted within 3 days of chest tube placement regardless of the volume of drainage. Various chemical agents have been used in the past as pleural sclerosant. Presently, talcum powder, either two grams in the powder form or two to five grams mixed with saline to constitute a slurry, is the preferred agent for pleurodesis. There is both experimental evidence10 and clinical experience11 that talc successfully promotes adhesion formation between the two pleural surfaces and results in clinical resolution in more than 90% of patients. I prefer the powder form as it disperses quickly and completely throughout the pleural space following injection with a bulb syringe through the chest tube. When it is installed in slurry form, the chest tube should be clamped for a brief period to allow the slurry to migrate within the pleural space.

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promoting extensive adhesion formation and a successful pleurodesis. With more experience this approach may become appropriate as a primary undertaking to simultaneously satisfy diagnostic and therapeutic goals. At present, a VATS intervention should be withheld until at least one attempt has been made at pleurodesis via a chest tube. However, this approach is effective.8,12,13 In one report of 34 patients, a VATS intervention with talc insufflation was successful in controlling the effusion in 32 of the patients.8 Another prospective investigation compared 85 patients treated with tube thoracostomy drainage and either bleomycin or tetracycline sclerosis with 39 patients treated with talc insufflation after VATS evacuation of all fluid.12 Analyzing patients who survived their malignant disease process, the VATS group had a 95% success rate at 90 days compared with a 70% success rate for the bleomycin-treated patients and a 47% success rate for the tetracycline group. Although some of this difference may be due to the superior efficiency of talc compared with the other agents, these results certainly establish the high success rate that can be obtained with a VATS intervention, even in a significantly compromised patient population. A VATS parietal pleurectomy is the most aggressive therapeutic option available. 1 4 Assuming that this approach has the same effectiveness as an open pleurectomy, this is the most definitive procedure available. However, it is a more extensive surgical undertaking than talc poudrage and can be associated with some blood loss. Given the efficacy of VATS fluid evacuation and talc poudrage in the context of the overall debility and limited life expectancy of this patient population, pleurectomy probably is appropriate for only occasional, carefully selected patients. shunts and catheters Pleuroperitoneal and pleurovenous shunts represent alternative treatment options for select patients.15 These devices are rarely appropriate for initial therapy but are suited for patients when tube thoracostomy or VATS sclerosis either fails completely or achieves only partial success and there are persistent, loculated fluid collections. These devices can be placed under local anesthesia and their effectiveness has been documented.15 However, it is necessary for either the patient or a family member to regularly compress the subcutaneous pump chamber to achieve fluid movement. If this is not done, only minimal spontaneous fluid flow occurs. In contrast to pressure-driven flow through a peritoneovenous shunt for ascites, the absence of an appropriate pressure gradient between the pleural cavity and either the peritoneal cavity or the venous system results in little or no fluid transfer on a spontaneous basis.

Alternatively, indwelling pleural catheter systems may be considered and used to withdraw aliquots of pleural fluid as necessary to relieve symptoms. Their use requires the patient to tolerate an external device and results in loss of protein-rich fluid as the pleural contents are aspirated and discarded. Nonetheless, their use has been shown to be associated with both decreased hospitalization time and less cost than chest tube placement and pleural sclerosis, and this is a legitimate alternative therapeutic option.16

Pleural Space Infections Definitions A parapneumonic effusion is any pleural effusion associated with bacterial pneumonia. Parapneumonic effusions can be classified as simple effusions, complicated effusions, or empyemas. Simple parapneumonic effusions are uninfected, free-flowing fluid collections; complicated parapneumonic effusions are early infected fluid collections, and thoracic empyemas are well-established collections of pus within the pleural cavity.17 Parapneumonic effusion develops in 36 to 57% of patients with pneumonia, although less than 5% of these progress to empyema. Parapneumonic effusion (40 to 60%), prior thoracic surgery (15 to 30%), and thoracic trauma (10%) are responsible for most cases of empyema.18 The morbidity and mortality of patients with parapneumonic effusion is higher than in patients with pneumonia alone due in part to the need for management of the pleural effusion. Prognosis is worse in the elderly, in patients with coexistent cardiac, pulmonary, or renal disease, and in patients with hospital-acquired or culture-positive empyema, especially those involving gram-negative bacteria or multiple pathogens. Clinical Presentation Clinical manifestations vary depending upon the underlying pulmonary process, the responsible organism, the quantity of bacteria and fluid in the pleural space, the stage of the disease, and the host defense mechanisms. The clinical presentation can range from an absence of symptoms to a severe febrile illness with toxemia and shock. In general, it is difficult to distinguish patients with infected pleural effusions from those with sterile parapneumonic effusions on the basis of history and physical examination because of the underlying pulmonary infectious process. Clinical manifestations include fever, dyspnea, chest pain, and cough with mucopurulent sputum. Infected pleural effusions due to aerobic organisms usually manifest acutely, whereas in anaerobic pleuropulmonary infections the time course is usually more protracted. Factors predisposing to aspira-

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tion such as alcoholism, unconsciousness, and periodontal disease are common in patients with anaerobic infections. Occasionally an empyema or a complicated effusion is manifested by failure of response or worsening of the clinical condition despite adequate antibiotic therapy for pneumonia. A sudden expectoration of a large amount of purulent sputum or hemoptysis suggests the development of a bronchopleural fistula (BPF). Physical examination often reveals decreased breaths sounds, dull percussion, and restricted respiratory excursions. Although rales from an associated pneumonia may be heard, the presence of a pleural friction rub is not distinctive. With chronicity, an empyema can erode the chest wall and present as a spontaneously draining subcutaneous abscess known as empyema necessitatis. Other manifestations of chronic empyema include chondritis and osteomyelitis of the ribs, pericarditis, mediastinal and vertebral abscesses, disseminated infection, and multiorgan failure. Anemia and leukocytosis may be present but are nonspecific. In stage 1, or the exudative stage, the pleural fluid is a thin exudate with a white blood count (WBC) less than 1,000 cells/mm3, LDH below 500–1,000 U/L, pH greater than 7.20, and a glucose level greater than 40 mg/dL. This is also called a simple parapneumonic effusion. Stage 2, or the fibrinopurulent or transitional stage, is characterized by infection of the pleural fluid. The fluid is turbid and contains bacteria and cellular debris. The pleural fluid glucose is usually less than 40 mg/dL, the LDH greater than 1,000 U/L, the WBC greater than 5,000/mm3, and the pH less than 7.20. Fibrin is deposited parallel to the pleural surfaces, and as the stage progresses, fibrinopurulent membranes partition the pleural space into two or more loculations. As the fluid thickens, amorphous gelatinous masses adhere to the pleural surfaces compromising lung expansion. This is also termed a complicated parapneumonic effusion. If untreated, the fluid becomes frankly purulent, giving rise to a true empyema. During this stage loculations prevent extension of the infectious process but make evacuation of the pleural cavity by nonsurgical means progressively difficult. In stage 3, the chronic or organizing stage, fibroblasts migrate into the pleural cavity and produce an inelastic membrane called the pleural peel or cortex, entrapping the lung and rendering it essentially functionless. Imaging plain roentgenograms The posterior-anterior and lateral chest radiographs are the best initial diagnostic modalities. When the patient is upright, free pleural fluid first accumulates in the lowest part of the hemithorax, the posterior costophrenic

angles. Lateral decubitus views allow detection of 50 to 100 mL of fluid and the presence of loculation if the fluid fails to layer out along the dependent chest. computed tomography Computed tomography (CT) is of great value in the overall evaluation of parapneumonic effusions and should be done early in the assessment of patients with complex parapneumonic effusion or empyema. CT is helpful in (1) differentiating pleural fluid from peripheral parenchymal infiltrates or pleural thickening, (2) evaluating the parenchymal disease, (3) determining loculation, (4) characterizing the pleural surfaces, and (5) guiding and assessing therapy. Management The therapeutic armamentarium for parapneumonic effusion or empyema includes antibiotic therapy, thoracentesis, tube thoracostomy, radiologic-guided percutaneous catheter drainage, intrapleural fibrinolytic agents, and a variety of surgical drainage procedures including VATS and open thoracotomy.18–23 Table 16-2 depicts an overview of the classification, diagnostic criteria, and treatment options of parapneumonic effusions. The initial diagnostic challenge is to distinguish pleural effusions that will respond to antimicrobial therapy alone from collections that require tube thoracostomy or surgical drainage for their resolution. Uncomplicated parapneumonic effusions usually require no specific therapy. Treatment of the underlying pneumonia is the basis of therapy. Thoracentesis or, rarely, thoracostomy tube drainage of the pleural fluid is appropriate for large fluid collections causing respiratory compromise by compression of the adjacent lung. Once the diagnosis of a complicated parapneumonic effusion or empyema has been established, treatment follows the traditional guidelines for managing any abscess: (1) antibiotic therapy to control the underlying infection, (2) adequate drainage, and (3) obliteration of the dead space. Infected pleural effusions should be approached and treated with the same urgency as an intra-abdominal abscess or as any other collection of pus in any body cavity. antibiotics Early appropriate antimicrobial therapy for pneumonia minimizes the development of parapneumonic effusion and aborts the progression of uncomplicated effusion to complicated effusion or empyema. Antimicrobial agents that are able to penetrate the pleural compartment in sufficient quantities to achieve and exceed the minimal inhibitory concentration include penicillins, cephalosporins, aztreonam, clindamycin, and ciprofloxacin.

210 / Advanced Therapy in Thoracic Surgery TABLE 16-2. Classification and Therapy for Parapneumonic Effusions and Empyema Class

Diagnostic Criteria

Treatment

Insignificant effusion Parapneumonic effusion Borderline complicated

Antibiotics; thoracentesis usually unnecessary Antibiotics plus thoracentesis Antibiotics; tube thoracostomy usually necessary

Simple empyema

Small; < 10 mm fluid on a lateral decubitus film >10 mm thick on lateral decubitis film pH 7.0–7.2 or lactate dehydrogenase value > 1,000 IU/L; glucose level > 40 mg/dL; negative Gram stain and culture pH < 7 or glucose value < 40 mg/dL or positive Gram stain or culture pH < 7 or glucose value < 40 mg/dL or positive Gram stain or culture plus multiple loculi Single loculus of pus or free-flowing fluid

Complex empyema Chronic empyema

Mulitple loculi of pus Thick pleural peel; trapped lung

Simple complicated effusion Complex complicated effusion

Antibiotics and tube thoracostomy Antibiotics plus tube thoracostomy with or without fibrinolytics VATS Tube thoracostomy with or without VATS plus antibiotics VATS or thoracotomy plus antibiotics Decortication plus antibiotics

Modified from Bartlet JG. Empyema. Gorbach S, Bartlett JG, Blacklow NR, editors. Infectious diseases. 2nd ed. Philadelphia (PA): W.B. Saunders; 1992. p. 639–44. VATS = video-assisted thoracic surgery.

Aminoglycosides are less capable of entering the empyema collection and more importantly, they are inactivated by the acidic pH of the pleural fluid environment. The development of an empyema after a penetrating wound to the chest is related to the contamination of the pleural space at the time of the injury. Recent studies indicate that prophylactic antibiotics have a role in the prevention of empyema in patients undergoing closedtube thoracostomy for traumatic hemothorax or pneumothorax. The most important factor, however, in preventing empyema remains the complete evacuation of any hemothorax. Empiric therapy using combinations of agents against aerobes and anaerobes is recommended. A positive Gram stain of pleural fluid is utilized to guide initial antibiotic therapy, which may need to be adjusted according to the patient’s clinical course and the results of the pleural fluid cultures and sensitivities. Often several weeks of therapy are necessary to achieve satisfactory resolution. tube thoracostomy The decision to institute tube thoracostomy is based on the characteristics of the pleural fluid and the absence of multiple loculations demonstrated by plain films or CT scan as illustrated in Figure 16-2. Indications for tube thoracostomy include complicated parapneumonic effusion and empyema as indicated by gross pus in the pleural space, organisms on Gram stain of the pleural fluid or culture, pleural fluid glucose less than 40 mg/dL, LDH greater than 1,000 U/L, or pleural fluid pH below 7.20. If the CT scan of the chest demonstrates a multiloculated effusion, tube thoracostomy is inadequate and the pleural space infection should be approached by either VATS or open thoracotomy. A size 26F to 36F thoracostomy tube is typically utilized. The chest tube must be positioned at the most dependent level and must enter the fluid collection. A

preliminary thoracentesis to localize the fluid collection with certainty helps in selecting the optimal place for chest tube insertion. In the presence of a BPF an additional tube at a higher and more anterior level should be considered. It is also important to use tubing and connections of maximum diameters throughout the whole system as narrowing at any site increases resistance to flow and hampers drainage. Adequate drainage of early complicated parapneumonic effusion is usually achieved with simple tube thoracostomy. Failures occur mainly as a result of incomplete drainage because of loculated or inaccessible collections, improper tube positioning, or high fluid viscosity. Successful drainage by tube thoracostomy of a complicated parapneumonic effusion is associated with rapid clinical and radiologic improvement. If there is no significant improvement over 24 to 48 hours, incomplete drainage or inappropriate antibiotic therapy should be suspected and investigated with repeat CT scan of the chest or review of microbial sensitivities. If CT demonstrates a single remaining loculation, a second chest tube should be inserted or a catheter placed under CT guidance. The chest tubes are left in place until the pleural cavity is obliterated by expansion of the lung, pleural fluid is serous and drainage is less than 50–100 cc/d, infection is controlled, and any BPF is sealed. Fibrinolytic agents or a more extensive surgical procedure such as VATS is required if closed thoracostomy drainage fails to achieve resolution. In patients with an established empyema, when there are no remaining signs of infection and the lung is stuck to the chest wall, the chest tubes are opened to the atmosphere and slowly advanced from the pleural space over a period of several weeks to allow resolution of the infection and obliteration of any residual cavity. Although uncommon, complications associated with tube thoracostomy occur and include subcutaneous

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emphysema, chest wall hematoma, hemothorax, lung laceration, chylothorax, and injury to mediastinal structures, diaphragm, or intra-abdominal viscera. intraplueral fibrinolytic agents Enzymatic debridement of the pleural space using fibrinolytic agents such as streptokinase (SK) or urokinase (UK) facilitates chest tube drainage of loculated or viscous early stage fibrinopurulent collections. SK or UK is administered as a solution of 250,000 U in 100 mL of sterile normal saline via chest tubes or catheters. The chest tubes are clamped, and patients are encouraged to change their positions at regular intervals to enhance distribution of the instilled agent. After 4 to 6 hours, the chest tubes are unclamped and placed back on suction. This procedure can be repeated daily until clinical FIGURE 16-2. A, This chest radiograph shows a right lower lobe pneumonia associated with a pleural effusion. B, Chest computed axial tomography scan also shows the pneumonia and demonstrates that there is only one fluid collection; ie, there are no loculations. Thoracentesis documented bacteria in this parapneumonic effusion, which resolved with appropriate antibiotic coverage and chest tube drainage.

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improvement is achieved, radiographic resolution is obtained, or significant pleural fluid drainage ceases. Success rates for fibrinolytic agents vary between 70 and 90% and are influenced by the appropriate selection of patients. 24 A good outcome is usually obtained in complicated effusions and early empyemas.

Operative Management anesthetic management A double lumen endotracheal tube for contralateral lung ventilation is essential for access during a VATS procedure and helpful for open thoracotomy. The double lumen tube also helps prevent contamination of the dependent lung. Postoperative pain control is essential for unrestricted breathing and coughing, which are necessary to maintain adequate ventilation and clearance of pulmonary secretions. Epidural analgesia is ideally suited for this purpose. Early ambulation with portable suction devices, incentive spirometry, and chest physiotherapy should be instituted routinely. All patients receive heparin subcutaneously or are fitted with sequential compression devices for prophylaxis against deep venous thrombosis. video-assisted thoracic surgery VATS is gaining popularity in the management of patients with complex parapneumonic effusions or early empyema and is competitive with open thoracotomy. Timely management and patient selection are critical for its success. 21,22 VATS is particularly useful during the fibrinopurulent stage of empyema and in the presence of the radiology findings depicted in Figure 16-3, which shows a multilocular process that will not be sufficiently drained with tube thoracostomy alone. At this stage, empyemolysis is achieved with complete breakdown of all loculations and drainage of the gelatinous exudate from the pleural cavity. Early fibrin membranes or thin peels can usually be removed from the visceral pleura to allow lung reexpansion. A unilocular space and full lung expansion must be achieved at the completion of the procedure. Before closure, chest tubes are placed for postoperative drainage of the pleural space. The tubes are removed when there are no remaining signs of infection and drainage is serous and less than 50–100 mL/d. Once the empyema has progressed to the organized state, VATS is often unsuccessful due to the thicker and more adherent pleural peel entrapping the lung and an open procedure becomes mandatory. In borderline cases, VATS can be used as an initial step. Some of these early organizing empyemas can be dealt with by VATS, while in more advanced cases VATS can assist in identifying the

most appropriate site for thoracotomy incision to approach the empyema. thoracotomy Samson and Buford proposed early thoracotomy for evacuation of pleural space infections; however, this time-honored surgical technique is being supplanted by VATS for many patients. Thoracotomy is usually performed during stage 2 and the initial part of stage 3 when the pleural surfaces are covered by amorphous gelatinous fluid collections but a true fibrous peel has not formed. 20 Blunt finger dissection usually suffices to disrupt the fibrinous septations and allows access to all other areas of the pleural cavity. Total elimination of fibrin membranes from the lung, diaphragm, and parietal pleura facilitates immediate and full lung reexpansion. Thoracostomy tubes are placed anteriorly and posteriorly; additional chest tubes or Jackson-Pratt drains may be used to drain more inaccessible areas. The earlier the drainage procedure is performed the better the outcome provided the underlying pulmonary process is adequately addressed and completely resolved with antibiotic therapy. decortication A chronic empyema develops due to (1) delay in diagnosis, (2) inadequate drainage in the acute stage, (3) continuing reinfection from a BPF, (4) retained hemothorax, and (5) specific infections such as tuberculosis and fungal infections. In this situation, a true decortication procedure is required for removal of the cortex of fibrous tissue entrapping and restricting the lung. The major indications for decortication are the formation of a fibrous peel or cortex as a result of chronic empyema, a chronic organized hemothorax, and tuberculosis pleuritis with lung entrapment.23 The goals of therapy are to limit morbidity and mortality, shorten hospital stay, and return pulmonary function to baseline. The principles for successful decortication include the following: (1) removal of the fibrin membranes overlying the visceral pleura to promote complete reexpansion of the collapsed lung, (2) adequate wide exposure, (3) development of a proper plane of cleavage between the peel and the visceral pleura, (4) removal of the firmly attached fibrous cortex by sharp dissection, (5) complete freeing of the lung to achieve circumferential mobilization and reexpansion, (6) closure of BPFs, (7) adequate hemostasis, and (8) wide drainage by placing two or more chest tubes or other drainage devices to assure complete evacuation and obliteration of any potential space.23 These principles are only achievable with an open thoracotomy. I also find it helpful to continue ventilation

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of the entrapped lung during sharp dissection of the pleural peel. This facilitates the surprisingly difficult task of distinguishing the fibrous cortex from true visceral pleura.

FIGURE 16-3. A, This chest radiograph shows complete opacification of the left hemithorax with shift of the mediastinum to the right. The patient was febrile and producing purulent sputum. B, The chest computed axial tomography scan reveals a large effusion that is multiloculated. Video-assisted thoracic surgery was performed for this complex parapneumonic effusion. Fluid was aspirated, fibropurulent material was extracted, and lung adhesions to the chest wall were detached. At the conclusion of the procedure, two chest tubes were placed for continuing drainage of the pleural cavity.

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References 1. Light RW, MacGregor MI, Luchsinger PC, Ball WC. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 1972;77:507–13. 2. Johnson WW. The malignant pleural effusion: a review of cytopathologic diagnosis of 584 specimens from 472 consecutive patients. Cancer 1985;56:905–10. 3. Lynch TE. Management of malignant pleural effusions. Chest 1993;103:385–9. 4. Prakash V. Comparison of needle biopsy with cytologic analysis for evaluation of pleural effusions: analysis of 414 cases. Mayo Clin Prac 1985;60:158–64. 5. Harris RJ, Kavuru MS, Rice TW, et al. The diagnostic and therapeutic utility of thoracoscopy. Chest 1995;108:828–41. 6. Harris RJ, Kavuru MS, Mehta AC, et al. The impact of thoracoscopy on the management of pleural disease. Chest 1995;107:845–52. 7. Colt HG. Thoracoscopy. A prospective study of safety and outcome. Chest 1995;108:324–9. 8. Yim APC, Chun SS, Lee TW, et al. Thoracoscopic management of malignant pleural effusions. Chest 1996;109:1234–8. 9. Marel M, Stastny B, Melinova L, et al. Diagnosis of pleural effusions. Chest 1995;107:1598–603. 10. Bresticker MA, Oba J, LoCicero J, Greene R. Optimal pleurodesis: a comparison study. Ann Thorac Surg 1993;55:364–7. 11. Webb WR, Ozmen V, Moulder PV, et al. Iodized talc pleurodesis for the treatment of pleural effusions. J Thorac Cardiovasc Surg 1992;103:881–6. 12. Hartman DL, Gaither JM, Kesler KA, et al. Comparison of insufflated talc under thoracoscopic guidance with standard tetracycline and bleomycin pleurodesis for control of malignant pleural effusions. J Thorac Cardiovasc Surg 1993;105:743–8.

13. Schulze M, Boehle AS, Kurdow R, et al. Effective treatment of malignant pleural effusion by minimal invasive thoracic surgery. Ann Thorac Surg 2001;71:1809–12. 14 Waller DA, Morritt GN, Forty J. Video-assisted thoracoscopic pleurectomy in the management of malignant pleural effusion. Chest 1995;107:1454–6. 15 Little AG, Kadowaki MH, Ferguson MK, et al. Pleuroperitoneal shunting: alternative therapy for pleural effusions. Ann Surg 1988;208:443–50. 16. Putnam JB, Walsh GL, Swisher SG, et al. Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter. Ann Thorac Surg 2000;69:369–75. 17 Light RW. A new classification of parapneumonic effusions and empyema. Chest 1995;108:299–301. 18. Magovern CJ, Rusch VW. Parapneumonic and posttraumatic pleural 14 space infections. Chest Surg Clin N Am 1994;4:561–82. 19 Light RW. Management of parapneumonic effusions. Chest 1991;100:892–3. 20. LeMense GP, Strange C, Sahn SA. Empyema thoracis therapeutic management and outcome. Chest 1995;107:1532–7. 21. Mackinlay TAA, Lyons GA, Chimondeguy DJ, et al. VATS debridement versus thoracotomy in the treatment of loculated postpneumonia empyema. Ann Thorac Surg 1996;61:1626–30. 22. Landreneau RJ, Keenan RJ, Hazelrigg SR, et al. Thoracoscopy for empyema and hemothorax. Chest 1995;109:18–24. 23. Martella AT, Santos GH. Decortication for chronic postpneumonic empyema. J Am Coll Surg 1995;180:573–6. 24. Lee-Chiong TL, Matthay RA. Current diagnostic and medical management of thoracic empyema. Chest Surg Clin N Am 1996;6:419–37.

CHAPTER 17

TECHNIQUES OF TRACHEAL RESECTION AND RECONSTRUCTION SIMON K. ASHIKU, MD DOUGLAS J. MATHISEN, MD A wide variety of conditions involve the trachea. The most effective treatment for most of these abnormalities is tracheal resection. Over the past 30 years, techniques have evolved that allow for singled-staged operations for lesions in the subglottis, trachea, or carina with excellent results. Even long segments may be resected with the creation of a tension-free anastomoses utilizing “release” techniques. This chapter focuses on the conditions amenable to tracheal resection followed by a more detailed discussion of the diagnostic and operative approaches to these problems.

The upper trachea is supplied principally by branches of the inferior thyroid artery and the lower trachea by branches of the bronchial arteries (Figure 17-1A and B). These vessels enter the trachea via very fine lateral pedicles that lack collateralization (Figure 17-2).5 To prevent devascularization of the suture line, the length of circumferentially dissected trachea must be limited to no more than 1 cm proximal or distal to the transected airway. Dissection along the pretracheal plane and the plane between the trachea and esophagus avoids the lateral vascular pedicles and can be safely performed to mobilize the trachea.6 The recurrent laryngeal nerves ascend in the tracheoesophageal grooves bilaterally and pass medial to the inferior cornua of the thyroid cartilage. They enter the larynx at its junction with the cricoid posteriorly, adjacent to the cricoar ytenoid joints (Figure 17-3). Maintaining a plane of sharp dissection with scissors directly on the trachea is the best way to avoid injury to these nerves. No attempt should be made to locate the recurrent laryngeal nerves in most cases.

Surgical Anatomy The adult trachea averages 11 cm in length from the lower border of the cricoid cartilage to the carinal spur. There is an additional 1.5 to 2 cm of subglottic intralaryngeal airway. There are 18 to 22 cartilaginous rings, with approximately 2 rings per centimeter. 1 The only complete cartilaginous ring in the normal airway is the cricoid cartilage, the remainder of the rings completing only an anterior arch. The normal trachea will remain open even during extremes of coughing, in contrast to a malacic trachea which collapses with cough. The blood supply and connective tissue attachments of the trachea specifically allow vertical movement of the trachea. In a young person, hyperextension brings up to one-half of the trachea into the neck, and flexion devolves the trachea almost entirely into the mediastinum. Therefore, neck flexion is a useful maneuver to relieve tension on tracheal anastomoses. In elderly or kyphotic patients, the decreased extent of neck flexion limits the amount of trachea that can be safely resected without undue tension on the suture line.2–4

Conditions Treated by Tracheal Resection Surgically amenable tracheal lesions may arise from several different etiologies. Those most common abnormalities treated with surgical resection are traumatic, neoplastic, and idiopathic. Postintubation tracheal stenosis following prolonged intubation occurs principally at the level of the endotracheal tube or tracheostomy tube cuffs. Stoma stenosis occurs with tracheostomies and is thought to be due to cicatricial healing of the anterior and lateral tracheal 215

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FIGURE 17-1. Blood supply of the trachea. A, Right anterior view. B, Left anterior view. Reprinted with permission from Salassa JR et al.5

walls that have been eroded at the level of the stoma by excessive leverage applied to the tracheostomy tube. This appears as an A-shaped stenosis bronchoscopically (Figure 17-4). Cuff stenosis resulted formerly from highpressure cuffs and, more recently, from overinflated lowpressure cuffs. The circumferential pressure injury results in circumferential stenosis (Figure 17-5).7,8 Traction on the tracheostomy tube may cause varying degrees of destruction of the the cartilagenous rings between the stoma and point of cuff stenosis, resulting in tracheal malacia. Stenosis in the subglottic region may occur as a result of prolonged intubation with endotracheal tubes, following cricothyroidotomy, or following high placement of a tracheostomy where the tube erodes through the cricoid cartilage.9 Prolonged mechanical ventilation may cause tracheoesophageal fistula. Tracheoesophageal fistula are caused most commonly by pressure necrosis between a nasogastric tube in the esophagus and an inflated balloon cuff in the trachea. Tracheal–innominate artery fistula may arise from either a tracheostomy tube placed too low in the thoracic trachea or from an innominate artery lying high at the sternal notch. The tracheostomy tube subsequently erodes into the vessel at the inferior margin of the stoma.

FIGURE 17-2. Microscopic blood supply of the trachea. Transverse intercartilagenous arteries derived from the lateral longitudinal anastomosis penetrate the soft tissues between each cartilage to supply a rich vascular network beneath the endotracheal mucosa. Reprinted with permission from Society of Thoracic Surgeons; Salassa JR et al.5

Direct external trauma, blunt or penetrating, may result in a tear or complete disruption of the trachea at any level. Inhalational burns are usually maximal in the

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FIGURE 17-3. Position of the recurrent laryngeal nerves in relation to the trachea and larynx. Reprinted with permission from Pearson et al. Thoracic surgery. 1st ed. W.B. Saunders. p. 278.

proximal subglottic region and diminish in more distal airway. In most cases, the tracheal rings are not destroyed.10 Primary tracheal tumors are extremely rare, with an estimated incidence of 2.7 cases per million per year. The large preponderance are malignant. The two most common malignant primary tracheal neoplasms are squamous cell carcinoma and adenoid cystic carcinoma. Squamous cell carcinoma of the trachea is epidemiologically similar to squamous cell carcinoma of the lung, occuring primarily in smokers in their 50s and 60s. It may present confined to the trachea or invading into adjacent mediastinal structures (Figure 17-6). Adenoid cystic carcinoma is a exophytic intratracheal lesion that involves the tracheal wall to variable extents. This mass may compress mediastinal structures without invading them initially. Lymph node metastases occur but less commonly than in squamous cell carcinoma. The most striking characteristic of adenoid cystic carcinoma is its potential for extending long distances submucosally and perineurally.11,12

FIGURE 17-4. Tracheostomy stoma site stenosis. The characteristic A-shaped lumen is evident and results from a primarily anterior and lateral cicatricial process. Reprinted with permission from Sabiston and Spencer. Surgery of the chest. 6th ed. W.B. Saunders. p. 413.

Several neoplasms may secondarily involve the trachea through direct extension. Both bronchogenic and midesophageal carcinomas may erode into the carina. Thyroid carcinomas, on the other hand, typically invade the trachea at the second and third rings, where the thyroid isthmus is adherent to the trachea.13 Idiopathic laryngotracheal stenosis affects the upper trachea and lower larynx. These patients are predominately women. Histologically, the lesions are characterized by cicumferential keloidal type fibrosis with thickening of the lamina propria without cartilaginous destruction.14,15

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Clinical Presentation Despite the disparate etiologies of tracheal stenosis, all patients with compromise of their tracheal lumen present with similar signs and symptoms. Progressive airway obstruction frequently begins with shortness of breath on exertion, then shortness of breath at rest, then wheezing or stridor. Postintubation lesions generally

present with these symptoms 1 to 6 weeks following extubation. Tracheal malacia patients have a characteristic barking cough with an expiratory wheeze, while patients with pure stenosis tend to have stridor on inspiration. Tracheal malignancies, in addition to bearing symptoms of airway obstruction, frequently present with cough and hemoptysis. Extensive tumors may result in hoarseness or dysphagia.

Radiologic Assessment Once a tracheal lesion is suspected, the diagnosis is accomplished by simple radiologic studies.16,17 A standard posteroanterior chest radiograph, centered high on the trachea, will reveal most tracheal stenoses. However, detailed information about the location of the lesion, its longitudinal extent, and the amount of normal trachea available for reconstruction is best demonstrated by logitudinal tomograms of the entire airway (Figure 17-7). This includes lateral projections of the extended neck to provide views of the larynx and upper trachea. These can be supplemented by fluoroscopy to evaluate the functional state of the glottis and delineate areas of malacia.

FIGURE 17-5. Cuff level stenosis. The stenosis here is circumferential and the remaining lumen round. Reprinted with permission from Sabiston and Spencer. Surgery of the chest. 6th ed. W.B. Saunders. p. 413.

FIGURE 17-6. An exophytic squamous cell carcinoma of the trachea. Reprinted with permission from Sabiston and Spencer. Surgery of the chest. 6th ed. W.B. Saunders. p. 407.

FIGURE 17-7. A, Plain pulmonary artery chest radiograph of cuff stenosis. B, A typical tomographic view of the the same lesion. Reprinted with permission from Sabiston. Textbook of surgery. 15th ed. W.B. Saunders. p. 1819.

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In general, the detailed longitudinal image provided by such conventional radiographs is of greater help to the surgeon than the cross-sectional images provided by computerized tomograms. Virtually all the essential information is provided in a single view, giving the surgeon an accurate assessment of the lesions extent. However, computed tomography (CT) is useful for evaluating tumors to identify extraluminal extension and enlarged mediastinal lymph nodes. Recently, the use of high-speed helical CT scanners to acquire images combined with powerful three-dimensional imaging software has created impressive three-dimensional airway reconstructions. It is not clear that any additional useful information is gained over that which can be obtained from the less expensive, linear tomograms. It is important to stress that all of these studies must be performed without an indwelling tracheostomy tube. In cases where a tracheostomy tube has been in place chronically and must be removed for the examinations, there must be a physician competent in tube replacement present in the event the airway is lost.

Bronchoscopy Expert bronchoscopic evaluation is essential to confirm diagnosis and plan operative strategy. Interventional bronchoscopic techniques are usually required to clear the airway for complete preoperative evaluation, passage of endotracheal tube, and prevention of impending airway obstruction and to allow time for thorough preoperative evaluation and preperation. The diagnosis of airway lesions is usually made on the basis of clinical history and radiographic appearence. However, bronchoscopic evaluation is necessary to confirm the diagnosis either by the visual appearance in the case of benign strictures or with biopsies in the case of tumors. Creating an operative strategy also requires a thorough evaluation of the lesion. Careful bronchoscopic measurements determine the length of the lesion and the amount of normal trachea proximal and distal available for reconstruction. Under the best of circumstances, up to 50% of the trachea can be resected and a primary anastomosis performed. Mature surgical judgement is required to determine resectability since many factors such as age, body habitus, amount of cervical trachea and lesion location conspire to limit the amount of trachea that can be safely resected. With benign strictures, special attention must be given to assessing the state of the mucosa. When stents or T-tubes are in place, they must be removed and the mucosa assessed. If extensive mucosal inflammation or ulceration exists, definitive repair should be delayed until mucosal healing occurs.

This may require a short period of decannulation or change to a smaller T-tube. With idiopathic laryngotracheal stenosis, active inflammation extending into the subglottis demands temporizing dilatation and delay of operation while the inflammation subsides. Parenthetically, patients taking systemic corticosteriods should be weaned from them and be off for at least a month before a definitive resection is attempted. Familiarity with the techniques of interventional bronchoscopy are essential for the management of tracheal pathology. The ability to safely dilate a benign stenosis or “core out” an obstructing tumor is required to evaluate the distal airway, allow safe passage of an endotracheal tube, temporarily reestablish a patent airway allowing delay in operation or to emergently manage an airway. Dilating a narrow, fibrotic stricture, such as with postintubation stenosis, is challenging and can result in airway rupture, complete obstruction, or excessive destruction of tracheal mucosa. In these situations, progressively larger Jackson dilators passed through the rigid bronchoscope can be used to effectively dilate the stenosis under direct vision. An assortment of pediatric rigid bronchoscopes and adult rigid bronchoscopes can then be used with increasing sizes using a gentle corkscrew motion. By gradually dilating these tight, rigid structures the risk of complications is minimized.18 Obtructing tracheal tumors are managed first by “core out” using the rigid bronchoscope, forceps, and suction.19 The relatively soft consistency and compressibilty of tumors allows a rigid bronchoscope to be passed beyond even near total obstructions. After the distal airway is assessed, biosy forceps are used to partially debride the tumor to assess consistency and vascularity. Using the tip of the bronchoscope in a corkscrew motion, most tumors can be easily cored out. Forceps are then used to remove tumor fragments. If bleeding ensues, the bronchoscope is advanced distal to the lesion and serves to tamponade the bleeding. Direct application of epinephrine-soaked pledgets can stop persistant oozing. Using the techniques discussed above virtually all lesions can be safely evaluated and managed. 18 It is important, however, to stress a few key points. Patients with critical airway stenosis should be endoscoped in the operating room where rigid bronchoscopy is available and ready for use. Flexible bronchoscopes can precipitate airway obstruction in patients with critical airway stenosis (< 4 mm) by inducing secretions, edema, and bleeding. Without the ability to dilate and control the airway with rigid broncoscopy, death ensues rapidly. Endoscopic removal of malignant or inflammatory lesions is only a temporary measure. It is useful in allowing time for preoperative assessment and for the weaning of cortico-

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steriods. Tracheostomies may be useful in some patients as the only way to secure an airway. When possible, they should be placed through the stenosis, preserving the uninvolved trachea for future reconstruction.

Anesthesia An experienced anesthesiology team working in close cooperation with the surgical team is essential. Replacement of spontaneous breathing with positive pressure ventilation can convert a partially obstructing lesion into a complete obstruction. When maintenance of the airway is a concern, a breathe down with an inhalation agent is employed and paralytics given once the airway is secured.20 Anesthesia is maintained with total intravenous anesthesia (TIVA) using short-acting agents such as remifentanil and propofol. This allows immediate extubation at the completion of the procedure and maintains continuous anesthesia during periods when inhalational agents are interrupted by the procedure. When a thoracotomy incision is used, epidural anesthesia significantly decreases thoracotomy pain. For lower tracheal and carinal resections, endotracheal intubation is accomplished with an extra-long, armored endotracheal tube. Its flexibility allows bronchoscopic placement into one of the main stem bronchi. After transecting the airway, the orotracheal tube is pulled back into the trachea and intermittent ventilation is performed with sterile crossfield equipment. The orotracheal tube is again advanced once the anastomosis is completed. The anesthesiology team should be familiar with the techniques of highfrequency “jet” ventilation. Cardiopulmonary bypass is not helpful and only introduces unnecessary risks.

Simple Tracheal Resection This section describes our technique for uncomplicated resections of the middle and upper trachea. Rigid bronchoscopy with dilation is performed at the time of planned resection, and if the lesion appears amenable to surgery, the patient is intubated, positioned, and prepared for incision. For most relatively short lesions, the patient is placed supine with an inflatable airbag beneath the shoulders with the neck extended. The inflatable bag is important in alleviating tension since it can be deflated to facilitate neck flexion just prior to tying down the anastomosis. The head and neck are supported in a foam “doughnut.” The arms are tucked at the sides and only the neck and upper sternum are prepared and draped. A low collar incision is adequate for most tracheal resections involving the upper trachea. Occasionally, vertical extension with a partial sternal split is required for middle to lower tracheal lesions (Figure 17-8A).

Dissection is carried through the platysma, and subplatysmal flaps are elevated superiorly to the level of the cricoid and inferiorly to the level of the sternal notch. The strap muscles are separated in the midline, and a plane of dissection is established very close to the tracheal wall to avoid injury to the recurrent laryngeal nerves (Figure 17-8B). The pretracheal plane is dissected to the level of the carina. The investing fascia of the innominate artery and the adjacent mediastinal fat is left intact to guard against postoperative tracheoinnominate fistulization. The location and extent of the lesion may sometimes be identified by observation of changes in the tracheal wall as seen in the operative field. Often, however, these changes are subtle, and the limits of the resection must be delineated by the surgeon transilluminating the trachea above and below the lesion with a flexible bronchoscope while the assistant watches the field and marks the limits of the lesion with fine sutures. The trachea is sharply dissected circumferentially at the most distal extent of the lesion, with the dissection plane maintained on the tracheal wall. Sterile ventilating tubing is then positioned under the ether screen and fastened to the drapes. The endotracheal tube is withdrawn into the upper trachea, the trachea divided at the most distal extent of the lesion, and bilateral 2-0 Vicryl traction sutures placed such that they are anchored around a tracheal ring about 1 cm below the distal transection site. A cuffed, armored Tovell tube is promptly passed into the distal tracheal segment and attached to the sterile connecting tubing, and crosstable ventilation commenced (Figure 17-8C). The diseased segment of trachea is sharply dissected from the esophagus and transected at the most proximal extent of the lesion and passed out of the field. The patient’s neck is then flexed and the anastomosis tested for tension. Using the traction sutures, the proximal and distal segments can be brought towards one another. When they come together without tension, the anastomosis can be created. If the limits of flexion and safe dissection have been reached and anastomotic tension still exists, then one proceeds with release procedures (see below). It is simplest to anticipate the need for release procedures and perform them prior to dividing the trachea, but this is not always possible. When the surgeon is satisfied that the anastomosis will not be under tension, interrupted 4-0 Vicryl anastomotic sutures are placed (but not tied) such that the knots will be on the outside, beginning posteriorly in the midline and proceeding around either side to the front (Figure 17-8D). The sutures are placed 5 to 6 mm from the cut edge of the trachea and 4 mm apart. They should encircle a tracheal ring on either side of the anastomosis to help prevent dehiscence. Frequently, the Tovell tube

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FIGURE 17-8. Resection of a simple midtracheal stenosis. See text for description. Reprinted with permission from Grillo HC. Surgery of the trachea. Curr Prob Surg 1970;7:3–59.

must be withdrawn for short periods to allow accurate placement of the more difficult sutures or for suctioning blood from the distal airway. Before placing the anterior sutures, the Tovell tube is permanently removed from the distal tracheal segment and the translaryngeal endotracheal tube advanced carefully beyond the anastomosis. Prior to tying down the anastomotic sutures, the inflatable airbag beneath the shoulders is deflated, the 2-0 traction sutures are tied, and any last few degrees of neck flexion that may be required are instituted. The anastomotic sutures are then tied from anterior to posterior. The integrity of the suture line is tested under saline with the cuff deflated or placed proximal to the anastomosis. If the field has not been irradiated, we do not employ

tissue flaps to cover the anastomosis. A closed suction drain is left in the pretracheal space. After closing in layers, a #2 suture is placed through the skin and fascia overlying the angle of Louis and then through the soft tissue in the submental area. This suture is tied without slack, but not under tension, in order to avoid sudden neck extension for the first 5 to 7 postoperative days. Extubation is performed in the operating room if at all possible, and this is facilitated by the avoidance of paralytic agents in the anesthetic. We have rarely been sufficiently worried about a tracheal anatomosis to place a tracheostomy, and in these cases we position the tracheostomy at least two rings away from the anastomosis and protect the anastomosis with the thyroid gland or

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strap muscles. In situations where postoperative intubation is thought to be necessary, a small uncuffed endotracheal tube is left in place initially and a stitch placed on the trachea to mark the site for tracheostomy should it become necessary. This allows limited dissection and accurate placement in a reoperative field. It is best to wait a few days before placing a tracheostomy to allow skin flaps and other tissue layers to seal before exposing them to airway secretions. This also allows for postsurgical airway edema to resolve before committing to a tracheostomy tube. For tumors, the approach is modified in a number of ways. Considerable experience is required to make the judgment of whether a tumor can be safely resected with sufficient tissue to provide a clear margin and yet allow successful primary reconstruction of the airway. This can be particularly difficult in patients with adenoid cystic carcinoma in whom frozen sections may show microscopic tumor at grossly clear resection margins. When extension of resection to the more distal trachea is required, an upper sternal split may be extended into the right fourth interspace. The plane of dissection in tumor cases must be kept away from the involved portion of trachea in order to ensure an adequate radial margin. This endangers the recurrent laryngeal nerves more than in resections for benign disease. If a recurrent nerve is involved by tumor, the nerve is sacrificed. Paratracheal lymph nodes are removed en bloc with the specimen when possible, but extensive lymph node dissection cannot be done for fear of destroying the blood supply to the remaining trachea. Postoperative radiation therapy is recommended in all cases of bronchogenic or adenoid cystic carcinoma, unless contraindicated by performance status or anastomotic complications.11

Laryngotracheal Resection In cases where an upper tracheal lesion involves the cricoid, occuring most commonly in idiopathic laryngotracheal stenosis or tumor, a laryngotracheal resection will be necessary. In idiopathic laryngotracheal stenosis the lesion typically involves the cricoid on its anterior and lateral luminal surface. The operative procedure must be tailored to address the particular anatomical involvement encountered (Figure 17-9). The recurrent laryngeal nerves are protected by bevelling off the cricoid anteriorly and laterally while preserving the posterior plate.21,22 The extent of anterior cricoid resection ranges from complete, with a line of transection through the cricothyroid membrane to none at all, depending on the extent of involvement. Tracheal resection depends on the distal extent of lesion (Figure 17-10A and B). The trachea is appropriately tailored so that the proximal trachea

coapts well with the cut edge of the lar ynx (Figure 17-10C and D). 2-0 Vicryl “traction sutures” are placed in the midlateral position both proximally and distally. Interrupted 4-0 Vicryl sutures were used to fashion the anastomosis. The midline of the thyroid cartilage is approximated to the midline of tracheal “prow.” 2-0 Vicryl traction sutures are tied followed by individual 4-0 Vicryl anastomotic sutures (Figure 17-10E and F). This operation is modified in patients in whom the stenosis affects the mucosa overlying the cricoid plate. Sparing the posterior cricoid plate preserves the recurrent laryngeal nerves. The line of mucosal division is performed high on the posterior cricoid plate to excise involved mucosa and submucosa (Figure 17-11). Mucosal resection stops short of the superior border of the cricoid plate, immediately below the arytenoid cartilages. The rostrum or “prow” of the proximal tracheal cartilage is shaped as described above, but posteriorly a broad-based flap of membranous wall is fashioned, which is advanced to resurface the denuded posterior criciod plate. The posterior portion of the anastomosis is made with interrupted 4-0 Vicryl sutures placed only through the full thickness of mucosa and submucosa of the posterior wall of the larynx, and then through the full thickness of the membranous wall of the trachea (Figure 17-12), inverted so that the suture knots lay external to the lumen. Four sutures are placed through the cartilaginous portion of the inferior margin of the cricoid plate and the outer portion of the membranous wall of the trachea below the proximal edge of the flap in order to fix the membranous wall to the inferior edge of the cricoid plate. When the lesion extends proximally toward the conus elasticus, it is necessary to accept some residual narrowing because of the height of the anastomosis.

Lower Tracheal and Carinal Resections While isolated benign strictures of the lower trachea and carina are seen, the most common lesions requiring surgery are tumors. Therefore, the principles of surgical oncology must be strictly applied to most of these resections. Patients with bronchogenic carcinoma and N2 disease should be considered to have unresectable disease, and surgery should only be performed in a protocol setting.23–26 Mediastinoscopy is performed on the day of proposed surgery not only to assess nodal status and resectability, but to facilitate the resection and reconstruction by mobilizing the pretracheal plane while visualizing the recurrent laryngeal nerve. Scarring of the pretracheal plane from prior mediastinoscopy limits airway mobility, complicates reconstruction, and increases the likelihood of injury to the left recurrent

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FIGURE 17-9. Upper airway stenosis. A, High tracheal stenosis, easily treated by segmental resection and tracheotracheal anastomosis. B, Stenosis that reaches to the lower border of the cricoid cartilage. C, Stenosis of the lower subglottic larynx and upper trachea. The extent of the lesion anteriorly is so great that correction requires removal of the anterior portion of the cricoid cartilage. D, Stenosis that reaches to the glottis. There is no subglottic space to which an effective anastomosis can be made. Reprinted with permission from Grillo HC. Primary reconstruction of airway after subglottic laryngeal and upper tracheal stenosis resection. Ann Thorac Surg 1982;33:3–18.

FIGURE 17-10. Operative repair of anterolateral stenosis of the subglottic larynx and upper trachea. A, Anteroposterior view. B, Lateral view, showing the extent of disease involvement and the ultimate lines of transection. C and D, Larynx and trachea after removal of the specimen. Recurrent nerves have been left intact. Mucous membrane of larynx has been transected sharply at same level of division as cartilage. E and F, Anteroposterior and lateral views of reconstruction. Reprinted with permission from Grillo HC. Primary reconstruction of airway after subglottic laryngeal and upper tracheal stenosis resection. Ann Thorac Surg 1982;33:3–18.

laryngeal nerve. Scar tissue also may be difficult to distinguish from tumor. A standard right posterolateral thoracotomy in the fourth interspace creates excellent exposure of the lower trachea and carina and allows for most resections through a single incision. When tumor extension down

the left main bronchus precludes carinal reconstruction following complete resection, median sternotomy, bilateral thoracotomies, or extended clam-shell incision should be used since they permit sleeve pneumonectomy. Segmental resection of lesions that involve only the lower trachea and not the carina, present less of a chal-

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FIGURE 17-11. Techniques of posterior membranous tracheal wall flap with cricoid resurfacing. Reprinted with permission from Grillo HC. Laryngotracheal resection and reconstruction for subglottic stenosis. Ann Thorac Surg 1992;53:54–63.

lenge than carinal resections. Only carinal resections will be discussed since the techniques are applicable to both forms of excisions and reconstructions. Once the right lung is collapsed and retracted anteriorly, the pleura overlying the carina is incised and the carina exposed. Division of the azygos vein facilitates exposure. The carina should be circumferentially freed by dissecting on the airway and avoiding the left recurrent laryngeal nerve. Dissection should be kept to a minimum and skeletonization of the airway limited to only the diseased segment to be resected. Likewise, a balance must be struck between achieving adequate lymphadenectomy and maintaining tracheobronchial blood supply. Tapes are placed around the trachea and both main stem bronchi. The inferior pulmonary ligament is released to allow greater mobility of the right lung and equipment for crossfield sterile ventilation prepared. The order of dividing the airway structures varies, but commonly the trachea is divided first. Preoperative bronchoscopic assessment by the surgeon directs the tracheal division to just proximal to the tumor. An adequate margin can then be taken under direct visualization in the form of a complete ring sent separately for intraoperative frozen section. The endotracheal tube is then removed to allow division of both main stem bronchi under direct endobronchial visualization. Adequate margins are taken of both distal bronchi and sent separately for frozen section. Only the left main stem bronchus is reintubated, main-

taining collapse of the right lung. If mediastinoscopy was not performed, then airway mobilization should be accomplished in the anterior plane up to the neck proximally and down the left main stem distally. Additional airway mobility can be obtained by hilar mobilization as described below. Placement of 2-0 Vicryl lateral traction sutures in the trachea and both bronchi allows for easy handling of these structures during the reconstruction phase. The optimal mode of carinal reconstruction depends largely on the extent of resection. In the series from Massachusetts General Hospital reported by Mitchell and colleagues, 15 different modes of reconstruction were employed. The three most common methods, arranged in order of frequency, were (1) end-to-end anastomosis of trachea to left main stem with reimplantation of right into trachea, (2) end-to-end anastomosis of trachea to right main stem with reimplantation of left into the bronchus intermedius, and (3) anastomosis of trachea to reapproximated left and right main stem creating a “neocarina” (Figure 17-12).25 The “neocarina” method is the most simple but can be used in only limited resections since cephalad movement of the “neocarina” is limited by the aortic arch, requiring

FIGURE 17-12. Carinal reconstruction postresection. The three most common methods, arranged in order of frequency. A, End-to-end anastomosis of trachea to left main stem with reimplantation of right into trachea. B, End-to-end anastomosis of trachea to right main stem with reimplantation of left into the bronchus intermedius. C, Anastomosis of trachea to reapproximated left and right main stem creating a “neocarina.”

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generous caudal displacement of the trachea. For this reason, end-to-end anastomosis of trachea to the left main stem with reimplantation of the right into the trachea is more commonly employed. A right hilar release maneuver facilitates this procedure. More extensive resections require end-to-end anastomosis of trachea to right main stem with reimplantation of left into the bronchus intermedius. This obviates the need for extensive left main stem mobility. When there is extensive endobronchial involvement, excessive lung destruction, or invasion of hilar vessels, then carinal (sleeve) pneumonectomy is necessary. Experienced intraoperative judgment is required to determine the ideal approach. The anastamosis is fashioned with interrupted simple 4-0 Vicryl sutures placed with knots tied outside the lumen. Once reconstructed, the anastomoses are tested for air tightness to 40 cm of water. All suture lines are circumferentially wrapped with pedicled flaps of pericardial fat or a broad-based pleural flap. In high-risk patients, especially those who have undergone prior radiotherapy, an intercostal flap stripped of all periosteum or an omentum pedicle is used. These flaps not only buttress the anastomoses, but more importantly, separate them from the hilar vessels, helping to prevent bronchovascular fistulas.

Release Procedures When extensive resections are required the standard methods of mobilization by dissection in the pretracheal plane and flexion of the neck often do not allow a tension-free anastomosis. In these instances, further mobilization with “release” procedures is required. In our experience, this has been necessary in 8.3% of patients undergoing resections for postintubation stenosis and 15% of patients undergoing resections for tumors. 18 Certain release maneuvers are more effective for achieving additional mobility of the cervical trachea, whereas others are more effective for freeing the intrathoracic trachea. In resection of the upper trachea, additional length may be gained by releasing the lar ynx with a Montgomery suprahyoid release.27 This consists of dividing the muscles that insert on the superior aspect of the central part of the hyoid bone. The hyoid itself is then divided just medial to its lesser cornua on either side, and the stylohyoid tendons are divided (Figure 17-13). This provides an additional approximately 1.5 cm of length. It is important to realize that laryngeal release maneuvers may predispose patients to postoperative aspiration, especially of liquids. In time, however, this problem has resolved in virtually all patients.

For intrathoracic tracheal or carinal resections, additional length is best achieved by hilar release. 2 8 Mobilization of the right hilum should be done first, along with division of the inferior pulmonary ligament. Then, a U-shaped incision is made in the pericardium below the inferior pulmonary vein. If required, the pericardium can be incised 360° around the hilus for maximal mobility. In this event, the vascular and lymphatic pedicle to the main stem bronchus is left preserved behind the pericardium. The left hilum may be similarly mobilized (Figure 17-14) in the unusual case where unilateral mobilization is insufficient. However, left-sided hilar release can only be accomplished easily through a median sternotomy by opening the pericardium anteriorly, bilateral thoracotomies, or an extended clamshell incision. As with most airway surgery, neck flexion is helpful. Laryngeal release has not been shown to produce meaningful mobility at the level of the carina.29

Tracheal Resection in an Irradiated Field In patients who have received radiation therapy prior to coming to surgical resection, the risk of anastomotic dehiscence is increased. The detrimental effects of irradiation on tissue and, more specifically, tracheal healing have been amply demonstrated in animals. The early Massachusetts General Hospital experience with tracheal resection in patients who had received high doses of radiation, particularly when this occurred remotely in time, confirmed these findings.30 In these patients there was a markedly increased incidence of anastomotic failure. When a patient has received either high-dose irradiation (more than 4,500 cGy) or who has undergone irra-

FIGURE 17-13. The dotted lines indicate the point where the hyoid bone is divided, separating its body from the greater horn on each side. Reprinted with permission from Montgomery ww.27

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FIGURE 17-14. The left-side intrapericardial hilar release technique shows the U-shaped pericardial incision allowing 1 to 2 cm of upward hilar mobility to facilitate the creation of a tension-free anastomosis. Reprinted with permission from Newton JR.28

diation more than 12 months before resection, we now wrap the anastomosis with a vascularized tissue flap. Key technical issues include assuring that the tissue is flush against the airway and that the tissue pedicle is neither kinked nor under tension, which might compromise its blood supply. We have found omentum to be the most reliable tissue wrap, delivered into the chest through the substernal space. Bringing the omentum into the neck frequently requires resection of one of the clavicular heads or a portion of the manubrium. Other options, if the omentum is unavailable, for example after gastric surgery, include pericardial fat pad, intercostal muscle, and pleura.

Repair of Tracheoinnominate and Tracheoesophageal Fistulas Tracheoinnominate fistulas are often discovered at bronchoscopy performed to evaluate a premonitory bleed. Most of these fistulas now result from a stoma placed too low, such that the tube itself erodes into the artery. In the event of massive hemorrhage with this type of fistula, control may be obtained by finger compression through the stoma, pushing forward against the sternum at the site of bleeding. A small endotracheal tube is slipped into the airway beyond the finger and the cuff firmly inflated to ventilate and protect the lungs from aspiration of blood. The patient is then rapidly transported to the operating room. Exposure is obtained through a collar incision at the level of the stoma with a vertical extension for sternotomy. With the finger continuing to maintain hemostasis, proximal dissection of the origin of the artery is performed and a clamp applied, followed by distal control at the point of bifurcation.

The damaged segment of artery is resected and the proximal and distal ends oversewn with double suture lines. These stumps are then buried under surrounding healthy tissue—usually either thymus or strap muscle. Neurologic sequelae are rare. A new tracheal stoma is created at a higher level and a tracheostomy tube long enough to pass beyond the previous stoma is employed. Strap muscle is sutured over the original stoma to hasten its healing. Tracheoinnominate fistulas caused by a high-pressure cuff erosion or the tip of a tracheostomy tube will usually cause bleeding too low to be tamponaded by a finger. In these cases, hemorrhage may be controlled by placing a well-inflated endotracheal tube cuff over the bleeder. The operation then proceeds as described above, except in these cases, a concomitant tracheal resection is likely to be required. The tracheostomy that will be needed at the end of these cases (since it was needed before the case) must be placed so that the cuff will be well away from the anastomosis. Acquired, nonmalignant tracheoesophageal fistulas usually lie at the level of the cuff and generally include not only the fistula itself but also circumferential tracheal injury (Figure 17-15).31 If the fistula is identified while the patient remains on ventilator support, repair is postponed—the esophagus is kept free of tubes, and cuff overinflation is assiduously avoided. The tube is positioned so that the occluding balloon rests below the fistula, preventing contamination of the tracheobronchial tree. The lowest inspiratory pressures that accomplish adequate ventilation are used to avoid extension of the fistula. Gastrostomy and jejunostomy tubes are placed for drainage and feeding, and the patient is weaned from the respirator.

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A collar incision is performed which circumscribes the stoma (Figure 17-16). Dissection identical to that described above for simple tracheal resection is performed up to the point of division of the trachea below the fistula. As the posterior wall of the trachea is

dissected from inferior to superior, the fistulous connection is isolated circumferentially. It is detached from the esophagus with a small rim of normal esophageal tissue and kept attached to the tracheal segment with which it will be removed (Figure 17-17). After removal of the specimen, the esophagus is closed longitudinally with two layers of 4-0 silk (Figure 17-18A and B). The sternohyoid or sternothyroid muscle is sutured into place to buttress the esophageal closure and interpose healthy tissue between the esophageal and tracheal suture lines (Figure 17-19). The end-to-end tracheal anastomosis is then performed as described previously. If the fistulous opening is long and the tracheal wall is not circumferentially damaged as far down as the fistula extends, the margin of the tracheal opening may be excised as a V and repaired with a vertical suture line prior to creating the end-to-end tracheal anastomosis. In the rare case where there is no significant damage to the trachea associated with the fistula, tracheal resection is unnecessary, and simple esophageal and tracheal repair with muscle buttress is performed.

Postoperative Issues

FIGURE 17-15. Endoscopic view of tracheoesophageal fistula.

The patient’s postoperative course is largely determined by intraoperative technique. The goals of both intraoperative and postoperative care are the maintenance of good pulmonary toilet and the promotion of anastomotic

FIGURE 17-16. Exposure for most tracheoesophageal fistulas is through a low collar incision. Occasionally, a partial upper sternotomy is required for more distal exposure of the trachea. Reprinted with permission from Mathisen DJ et al.31

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healing. Patients are instructed preoperatively in the techniques of chest physiotherapy. Postoperatively, patients are supplied with humidity by facemask to facilitate clearance of secretions. Most patients are able to clear their airway by coughing. If this fails, we perform a therapeutic flexible bronchoscopy at the bedside and perform suctioning under direct vision. Ideally, patients should be extubated in the operating room. The need for postoperative ventilation is a contraindication to tracheal resection in most circumstances. Patients that have marginal lung function need to be managed carefully during the operation. Intraoperative maneuvers that help to avoid postoperative ventilation include the avoidance of a paralyzing anesthetic and the prevention of secretions and blood from running distally into the lungs during the proce-

FIGURE 17-17. Circumferential dissection above and below fistula is very near trachea to avoid injury to the recurrent laryngeal nerve. Division of the damaged trachea gives excellent exposure of the esophageal defect. Reprinted with permission from Mathisen DJ et al.31

FIGURE 17-18. The esophageal defect is closed in layers. A, The first layer closes the esophagus. B, The esophageal muscle is closed over the first layer. Reprinted with permission from Mathisen DJ et al.31

FIGURE 17-19. A local strap muscle is used to buttress the esophageal closure and separate it from the suture line. Reprinted with permission from Mathisen DJet al.31

Techniques of Tracheal Resection and Reconstruction / 229

dure. Postoperatively, these include minimizing fluids, elevating the head of the bed and administering racemic epinephrine to help prevent laryngeal edema. Rarely, an especially high laryngotracheal resection will cause enough laryngeal edema to necessitate one or two doses of steriods to avoid impending re-intubation and/or tracheostomy. Heliox, with its low viscosity, is sometimes useful in these circumstances since it can occasionally gain enough time for the other maneuvers to take effect. The patient is cautioned against unnecessary speech during this period, as it can contribute to the laryngeal edema. Cervical flexion is maintained with the chin-to-chest suture for 5 to 7 days, after which time the patient is advised not to extend the neck for another week. Before removing the chin-to-chest suture, we routinely examine the anastomosis with a flexible bronchoscope or obtain tracheal tomograms to assure normal healing. Oral alimentation is begun cautiously, particularly in patients who have undergone a laryngeal release. Water is offered initially, since its aspiration is better tolerated and more easily dealt with than more substantial foods.

Results and Complications Results of tracheal resection have been impressive. For simple resections of postintubation stenoses, including our earliest experience and reoperations, of 503 patients there were only 12 deaths and 18 failures.32 Four-hundred and forty (87%) had good and 31(6%) satisfactory results. Of 80 patients undergoing laryngotracheal resections for all causes of subglottic stenosis, there was one postoperative death. Results were excellent in 18 (22%), good in 52 (65%), and satisfactory in 8 (10%). In only two patients was there failure to achieve a functional airway. For primary tumors of the trachea, for which resection and reconstruction was performed, including carinal resections, there were 6 deaths in 132 patients.11 Five of the six were following the more complex carinal procedures. Six patients developed significant postoperative restenosis, but all of these underwent successful re-resection. The oncologic outcomes of patients with bronchogenic carcinoma has recently been separated out for carinal resections and reported by Mitchell and colleagues.26 In this series of bronchogenic carcinomas, 57% presented with N0 disease, 25% had N1 disease, and 18% had N2 or N3 disease. The overall 5-year survival was 42%. Lymph node status strongly influenced survival. The 5-year survival of N0, N1, and N2 or N3 patients was 51%, 32% and 12%, respectively (see Figure 17-3). Microscopically positive margins did not affect survival. Isolated carinal resection resulted in a

more favorable prognosis than more extensive resections, with a 5-year survival of 51%. The long-term survival data for resected adenoid cystic carcinoma of the trachea and carina have not been as well defined, partly because of the proclivity for late recurrence. The published experience of all tracheal adenoid cystic carcinomas, which includes carinal, suggests a much more favorable prognosis than bronchogenic carcinomas. Lymph node and margin status do not appear to significantly affect survival.11,12,23 Postoperative radiation therapy is recommended in all cases of adenoid cystic or bronchogenic carcinoma, unless contraindicated by performance status or anastomotic complications. The role of chemotherapy has not been established. Secondary cancers arising in the thyroid and invading the trachea have also been resected with good results. Of 27 patients undergoing resection and reconstruction of the trachea for thyroid cancer invading the airway, including patients with both simple and complex laryngotracheal reconstructions, two died in the postoperative period, one had a short segment tracheal necrosis requiring re-resection, and all others were provided with an adequate airway by their initial operation. Only two patients experienced an airway recurrence.13 In patients who have received radiation therapy prior to coming to surgical resection, the risk of anastomotic dehiscence is increased. Nineteen patients have undergone tracheal resections with vascularized tissue coverage at Massachusetts General Hospital following radiation therapy.30 Fifteen had a pedicied omental flap, 1 a pericardial fat pad flap, 1 an intercostal muscle flap, and 2 a pleural flap. Only one of these patients suffered an anastomotic dehiscence, and this resulted in death. Another patient required a T-tube. Following development of a paratracheal abscess, he ultimately died of recurrent squamous cell carcinoma. Two patients developed wound infections that responded to treatment. Overall, 15 patients experienced an excellent result without dyspnea, and 2 experienced a good result with dyspnea with moderate exercise. Our experience with the repair of tracheoesophageal fistulas involves the performance of 41 operations on 38 patients.31 Simple division and closure of the fistula was done in nine patients. Tracheal resection and reconstruction was combined with esophageal repair in the remainder. The esophageal defect was closed in two layers and a viable strap muscle interposed between the airway and esophageal suture lines in all cases. There were four deaths (11%). Three patients developed recurrent fistulas and one patient suffered a delayed tracheal stenosis. All were successfully managed with re-operation. Of the 34 survivors, 33 can swallow normally, and 32 breathe without the need for a tracheal appliance.

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Complications Despite these encouraging outcomes, complications do occur. They have generally been few for upper tracheal resections. Major complications more often have followed carinal or laryngotracheal resections. Inability to clear secretions with consequent atalectasis is the most common, though relatively minor, complication and this can be handled as described above. This management has limited the number of patients who have suffered pneumonia or respiratory failure after simple tracheal resection. Laryngeal edema may occur after procedures involving the larynx, but this generally regresses in approximately one week when treated as described above. Unilateral recurrent laryngeal nerve injury rarely occurs as a result of extensive resection, usually in patients with tracheal tumors. The most common late complication has been the formation of granulomas at the suture line. This is usually manifest as wheezing or minor hemoptysis. It has occurred more commonly following resection for inflammatory lesions than for tumor, as residual inflammation may be present in such cases despite efforts to wait out the acute inflammatory phase. Granulations can be managed by bronchoscopic removal under light anesthesia. Often a suture is found to have migrated into the lumen at the base of the granulation, and in such cases removal of the suture leads to ultimate healing. In some cases, however, multiple bronchoscopies are necessary over a period of time. The current use of Vicryl rather than nonabsorbable sutures has almost eliminated this once common problem. Suture line separation, the most dreaded complication, is almost invariably related to tension on the anastomosis or compromise of its blood supply. These problems, which occur most commonly following resection of long segments of trachea and following radiation, are more frequently associated with resection for tumor than for postintubation stenosis. Steroid use which has not been discontinued preoperatively has also been associated with anastomotic failure. Early, minimal air leakage at the suture line may seal without sequelae and can be managed with closed suction drains. True separation, however, is usually heralded by respiratory distress. Anastomotic separation in the immediate postoperative period suggests a serious technical error, and reoperation under these conditions is appropriate. Early separation that does not appear remediable by resuturing or a local muscle flap can be temporized by placement of a tracheostomy or a Montgomery T-tube, with corrective surgery to be performed months later after regression of the acute inflammatory response. Sometimes, with such a tube serving as a stent, the partial restenosis that results

may leave a tolerable airway, and this may be improved with endoscopic dilations. Stenosis may occur at the anastomotic site after the initial postoperative period, without evidence of a frank separation. This can be managed temporarily by rigid bronchoscopic dilation. Ultimately, most of these patients will require re-resection. This should be done no sooner than 4 months after the initial procedure in order to allow time for regression of inflammation. Other rare complications that we have seen include fatal hemorrhage from the pulmonary artery, likely related to erosion from an adjacent tracheobronchial anastomosis, innominate artery hemorrhage, tracheoesophageal fistula, esophagocutaneous fistula, empyema, and quadriplegia, which may have been related to overflexion of the chin to the chest.

Tracheal Substitutes and Tracheal Transplantation The advancement of techniques in tracheal surgery have allowed up to 50% of the trachea to be resected in favorable patients. This has rendered the majority of tracheal lesions requiring surgical treatment correctable with a single-staged resection and reconstruction. On rare occasions, the extent of a lesion involves more of the trachea than can be safely reconstructed with a primary end-toend anastomosis. These situations have lead investigators to attempt to reconstruct the trachea with prosthetic material. Early designs focused on solid tubes anastomosed endto-end with the trachea. Neville and colleagues were one of the first to report a small series on human subjects.33 Results were dismal. The nonporous silicone tubes failed to become incorporated with tissue and thus became infected and either extruded into the airway or eroded into the surrounding vascular structures. To avoid this fate, subsequent designs employed porous cylinders, usually fabricated from metal wire of all different elements and alloys. These prosthetic conduits were usually wrapped with an omental or muscle flap and then placed as an interposition graft in the trachea. The tissue flap was expected to provide an airtight seal and serve as a source of vascularized tissue in which the prosthesis would become incorporated and protected from the surrounding great vessels. Most of the investigations were in animals, and while the prostheses became successfully incorporated, they ultimately failed as the animals became obstructed from granulation tissue. 34–37 The lack of an epithelial surface essentially created an open festering wound encouraging granulation tissue to proliferate unchecked, resulting in airway stenosis. Small segments of trachea could be successfully replaced in this manner, since respi-

Techniques of Tracheal Resection and Reconstruction / 231

ratory epithelium would migrate for 1 to 2 cm from either anastomosis to cover the replaced portion of the airway. In larger segments, the respiratory epithelium would either not migrate such a distance or simply could not cover the distance fast enough to outpace and thus quell the exuberant granulation tissue. Recent investigators have supplied an epithelial lining by grafting either oral mucosa or splitthickness skin grafts on the inner surface of the porous prosthesis.38 These require a two-staged procedure where the pedicled tissue or prosthesis composite is created and allowed to mature before it is transposed as an interposition tracheal substitute. Early results are encouraging, but their complexity and inconsistent results make their clinical application unfeasible at this time. The lack of success with prosthetic tracheal replacements has encouraged many investigators to pursue an airway conduit made of all biological tissue, either viable allotransplantation or cryopreserved tracheas. Neither approach has achieved meaningful success. Tracheal transplantation suffers from several major limitations. First, the trachea lacks a single, sizable venous and arterial system. Instead, its vascular supply consists of multiple small vessels too fine to anastomose. To overcome this limitation, investigators have used the omentum to wrap tracheal transplants to allow for vascular ingrowth.39,40 However, results have been mixed, especially with longer segments. Second, unlike most other solid organ transplants, the trachea by virtue of its anatomical location is exposed to a heavy concentration of antigens and microorganisms. The result is an ischemic tracheal transplant, heavily contaminated with oropharyngeal microorganisms, in an immunodebilitated patient. Finally, many of the conditions which involve the entire trachea are benign processes that are safely managed with Silastic T-tubes and thus do not justify the detrimental effects of immunosuppressive therapy. In those cases where a malignant tracheal tumor requires resection of the entire trachea, immunosuppressive therapy should be avoided as well. In a move to avoid immunosuppressant therapy, investigators have begun to test methods of rendering allogenic tracheal grafts less or nonantigenic. The most important transplant antigens involved in graft rejection are expressed by the major histocompatibility complex (MHC). In the trachea, the mucosa and the submucosal glands express MHC-I and MHC-II.41 Cartilage does not express MHC antigens and is an immunologically privileged tissue that has been successfully used in allotransplantation for years without the use of immunosuppressive therapy. It is believed that the thick, avascular proteoglycan-collagen matrix that encapsulates the chondrocytes, shields them from recognition by the immune system. Moreover, since cartilage has no capil-

lary blood supply and survives from diffusion it can survive off the diffusion to and from an omental wrap. Investigators have designed methods to process fresh tracheas to remove the tracheal mucosa and submucosal glands while preserving the viability of the cartilage.42,43 In pilot dog studies, these grafts epithelialize and maintain viable cartilage without significant stenosis for up to one year. Control animals, which had the same procedure using a fresh unprocessed trachea instead, developed necrosis and stenosis over a few weeks. Others have used cryopreservation techniques to achieve similar results since cartilage tends to survive the process and the mucosa and glands do not.44,45 The results of these studies are encouraging because they demonstrate that a viable tracheal conduit can be transplanted, integrated, and accepted by the host and re-epithelialized. However, these studies were done for small segments of tracheal replacement, where the epithelium can be expected to migrate from the anastomotic ends and resurface the graft. Since this form of therapy will be used to treat near total or total tracheal replacement, these methods will need to be tested on longer segments.

Summary In conclusion, techniques of tracheal resection and reconstruction have advanced to a point where these procedures can be done with the anticipation of good results and an acceptable level of morbidity and mortality. Nonsurgical methods such as dilation, ablation, or stenting do not currently offer cure of tracheal stenoses, although these may each play a role in palliation or temporization prior to surgery. The current standard of care dictates that symptomatic benign tracheal stenoses that can be resected should be resected. For primary malignant tumors, squamous cell carcinomas should be resected when complete resection for cure is anticipated, while patients with the more indolent adenoid cystic carcinoma may benefit from even palliative resection with microscopically positive margins. Tracheal resection for low-grade thyroid carcinomas invading the airway should also be performed for cure or palliation, sometimes even in the presence of distant metastasis. The development of successful techniques of complete tracheal replacement in humans is an area of ongoing research but currently has no clinical applicability.

References 1. Grillo HC, Bendixon HH, Gephart T. Resection of carina and lower trachea. Ann Surg 1963;158:889–93. 2. Michelson E, Solomon R, Miura T. Experiments in tracheal reconstruction. J Thorac Cardiovasc Surg 1961;41:748–59.

232 / Advanced Therapy in Thoracic Surgery 3. Mulliken J, Grillo HC. The limits of tracheal resection with primary anastomosis: further anatomical studies in man. J Thorac Cardiovasc Surg 1964;48:741–50.

21. Grillo HC. Primary reconstruction of the airway after resection of subglottic and upper tracheal stenosis. Ann Thorac Surg 1982;33:39–58.

4. Grillo HC, Dignam EF, Miura T. Extensive resection and reconstruction of the mediastinal trachea without prosthesis or graft: an anatomical study in man. J Thorac Cardiovasc Surg 1964;48:741–50.

22. Grillo HC, Mathisen DJ, Wain JC. Laryngotracheal resection and reconstruction for subglottic stenosis. Ann Thorac Surg 1992;53:54–63.

5. Salassa JR, Pearson BW, Payne WS. Gross and microscopical blood supply of the trachea. Ann Thorac Surg 1977;24:100–7. 6. Grillo HC, Dignam EF, Miura T. Extensive resection and reconstruction of the mediastinal trachea without prosthesis or graft: an anatomical study in man. J Thorac Cardiovasc Surg 1964;48:741–50. 7. Cooper JD, Grillo HC. The evolution of tracheal injury due to ventilatory assistance through cuffed tubes: a pathologic study. Ann Surg 1969;169:334–48. 8. Cooper JD, Grillo HC. Experimental production and prevention of injury due to cuffed tracheal tubes. Surg Gynecol Obstet 1969;129:1235–41. 9. Whited R-E. A prospective study of laryngotracheal sequelae in long-term intubation. Laryngoscope 1984;94:367–77. 10. Gaissert HA, Lofgren RH, Grillo HC. Upper airway compromise after inhalation injury. Complex strictures of larynx and trachea and their management. Ann Surg 1993;218:672–8. 11. Grillo HC, Mathisen DJ. Primary tracheal tumors: treatment and results. Ann Thorac Surg 1990;49:69–77. 12. Regnard JF, Fourquier P, Levasseur P, et al. Results and prognostic factors in resections of primary tracheal tumors: a multicenter retrospective study. J Thorac Cardiovasc Surg 1996;111:808–14. 13. Grillo HC, Suen HC, Mathisen DJ, Wain JC. Resectional management of thyroid carcinoma invading the airway. Ann Thorac Surg 1992;54:3–9. 14. Grillo HC, Mark EJ, Mathisen DJ, Wain JC. Idiopathic laryngotracheal stenosis and its management. Ann Thorac Surg 1993;56:80–7. 15. Ashiku SK, Kuzucu A, Grillo HC, et al. Idiopathic laryngotracheal stenosis: effective definitive treatment by laryngotracheal resection. J Thorac Cardiovasc Surg 2004;127:99–107. 16. Weber AL, ed. Symposium on the larynx and trachea. Radiol Clin N Am 1978;16:227–309. 17. Felson B, Wiott JF, editors. The trachea. Semin Roentgenol 1983;18:1–64. 18. Mathisen DJ. Surgery of the trachea. Curr Probl Surg 1998;35:45–-542.

23. Grillo HC. Carinal neoplasia. In: Grillo HC, Austen WG, Wilkins EW, et al, editors. Current therapy in cardiothoracic surgery. Hamilton (ON): BC Decker Inc; 1989. p. 134. 24. Mathisen DJ, Grillo HC. Carinal resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1991;102:16–22. 25. Mitchell JD, Mathisen DJ, Wright CW, et al. Clinical experience with carinal resection. J Thorac Cardiovasc Surg 1999;117:39–53. 26. Mitchell JD, Mathisen DJ, Wright CW, et al. Resection of bronchogenic carcinoma involving the carina: long-term results and the effect of nodal status on outcome. J Thorac Cardiovasc Surg 2001;121:465–71. 27. Montgomery WW. Suprahyoid release for tracheal anastomosis. Arch Otolaryngol 1974;99:255–60. 28. Newton JR, Grillo HC, Mathisen DJ. Main bronchial sleeve resection with pulmonary conservation. Ann Thorac Surg 1991;52:1272–80. 29. Grillo HC. Carinal Neoplasia. In: Grillo HC, Austen WG, Wilkins EW, et al. editors. Current therapy in cardiothoracic surgery. Hamilton (ON): B.C. Decker Inc.; 1989. p. 134. 30. Muehrcke DD, Grillo HH, Mathisen DJ. Reconstructive airway operation after irradiation. Ann Thorac Surg 1995;59:14–8. 31. Mathisen DJ, Grillo HC, Wain JC, Hilgenberg AD. Management of acquired nonmalignant tracheoesophageal fistula. Ann Thorac Surg 1991;52:759–65 . 32. Grillo HC, Donahue DM, Mathisen DJ. Postintubation tracheal stenosis: treatment and results. J Thorac Cardiovasc Surg 1995;109:486–93. 33. Neville We, Bolanowski JP, Kotia GG. Clinical experience with the silicone tracheal prosthesis. J Thorac Cardiovasc Surg 1990;99:604–12. 34. Teramanchi M, Nakamura T, Yamamoto Y. Porous-type tracheal prosthesis sealed with collagen sponge. Ann Thorac Surg 1997;64:965–9. 35. Satoh S, Elstrodt J, Hinrichs WL, Feinjen J. Prevention of infection in porous tracheal prosthesis by omental wrapping. ASAIO Trans 1990;36:M438–40.

19. Mathisen DJ, Grillo HC. Endoscopic relief of malignant airway obstruction. Ann Thorac Surg 1989;48:469–75.

36. Schauwecker HH, Gerlach J, Planck H. Isoelastic polyurethane prosthesis for segmental tracheal replacement in beagle dogs. Artif Organs 1989;13:216–8.

20. Wilson RS. Tracheal resection. In: Marshall BE, Longnecker DE, Fairley HB, editors. Anesthesia for thoracic procedures. Boston (MA): Blackwell Scientific; 1988. p. 415–32.

37. Teramachi M, Kiyontani T, Takimoto Y. A new porous tracheal prosthesis sealed with collagen sponge. ASAIO Trans 1995;41:M306–10.

Techniques of Tracheal Resection and Reconstruction / 233 38. Suh SW, Kim J, Baek CH. Development of new tracheal prosthesis: atogenous mucosa-lined prosthesis made from polypropylene mesh. Int J Artif Organs 2000;23:261–7.

tracheal grafts can be reduced by removing the epithelium and mixed glands from the graft by detergent treatment. J Thorac Cardiovasc Surg 2000;120:108–14.

39. Li J, Xu P, Chen H. Successful tracheal autotransplantation with two-staged approach using greater omentum. Ann Thorac Surg 1997;64:199–202.

43. Yokomise H, Inui K, Wada H. High-dose irradiation prevents rejection of canine tracheal allografts. J Thorac Cardiovasc Surg 1994;107:1391–7.

40. Park YS, Lee DY, Paik HC. The role of omentopexy in tracheal transplantation in dogs. Yonsei Med J 1996;37:118–24.

44. Mukaida T, Shimizu N, Aoe M. Origin of regenerated epithelium in cryopreserved tracheal allotransplantation. Ann Thorac Surg 1998;66:205–8.

41. Bujia J, Wilmes E, Hammer C. Tracheal transplantation: demonstration of HLA class II subregion gene products on human trachea. Acta Otolaryngol 1990;110:149–54.

45. Mukaida T, Shimizu N, Aoe M. Experimental study of tracheal allotransplantation with cryopreserved grafts. J Thorac Cardiovasc Surg 1998;116:262–6.

42. Liu Y, Nakamura T, Yamamoto Y. Immunosuppressant-free allotransplanation of the trachea: the antigenicity of

CHAPTER 18

MANAGEMENT OF PULMONARY ARTERIOVENOUS MALFORMATIONS AND SEQUESTRATIONS FRANCIS C. NICHOLS, MD MARK S. ALLEN, MD

Pulmonary Arteriovenous Malformation

hemorrhagic telangiectasia (HHT), also known as the Rendu-Osler-Weber syndrome. In fact, up to 87% of PAVMs are found in patients with HHT, and approximately 20% of patients with HHT develop PAVMs. 7 Although the overwhelming majority of PAVM is congenital in origin, secondary or acquired PAVM can occur. The causes of acquired PAVM include trauma, actinomycosis, schistosomiasis, cirrhosis, systemic amyloidosis, mitral stenosis, and metastatic carcinoma.1 Although some patients with PAVM are asymptomatic, most patients are symptomatic. Clinical features in a recent Mayo Clinic series are shown in Table 18-1. The most common pulmonary symptom is dyspnea, and this correlates with the degree of shunting. Dyspnea can increase with a change in position from supine to upright and with exercise because of increased blood flow to the

Pulmonary arteriovenous malformations (PAVMs) are vascular lesions of the lung in which there is an abnormal connection between the pulmonary arterial and venous systems without an intervening capillary bed. PAVM has been described under a variety of pseudonyms including benign cavernous hemangioma, pulmonary arteriovenous angiomatosis, hamartomatous angioma of the lung, arteriovenous aneurysm, and arteriovenous fistula.1 The malformation leads to shunting of unoxygenated blood into the systemic circulation and may permit embolic material to pass unfiltered through the lungs. PAVMs are classified into simple or complex. A simple PAVM has a single feeding vessel, and a complex PAVM has multiple feeding vessels. PAVM was first described in 1897 by Churton in a 12year-old child.2 The first surgical intervention was reported by Shenstone who performed a pneumonectomy for a large central lesion.3 Several publications from our institution have focused on the surgical management of PAVM and most recently on the angiographic management.1,4–7 PAVM occurs more commonly than previously thought. It occurs with an incidence of 1 in 2,351 to 1 in 39,000 individuals. 8 The male-to-female incidence is equal; they are bilateral in 8 to 20% and multiple in 30 to 50% of patients.9 While PAVM can present as isolated pulmonary findings, it is often associated with hereditary

TABLE 18-1. Clinical Features in 93 Patients with Pulmonary Arteriovenous Malformation Clinical Feature Dyspnea Cyanosis Clubbing Cerebrovascular event Asymptomatic Hemoptysis Transient ischemic attack Cerebral abscess Seizure Adapted from Swanson KL et al (1999).7

234

Number (%) 53 (57) 27 (29) 18 (19) 17 (18) 15 (16) 14 (15) 11 (12) 5 (5) 5 (5)

Management of Pulmonary Arteriovenous Malformations and Sequestrations / 235

lower portion of the lungs where PAVMs are usually located. Depending on the degree of right-to-left shunting, the hypoxemia may be refractory to supplemental oxygen. Other clinical features include cyanosis, clubbing, and hemoptysis. The classic triad of dyspnea, cyanosis, and clubbing is found in 30% of adults. 1 Neurologic events are common with PAVM and include embolic disorders such as transient ischemic attacks and strokes. Dines and colleagues found a stroke to have occurred in 10% of all untreated patients followed for 4 to 10 years.5 Cerebrovascular events can also occur due to sludging secondary to polycythemia and complications from concomitant cerebral lesions. Seizures and cerebral abscesses also occur. In addition to the possible physical findings of cutaneous telangiectasia, cyanosis, and clubbing, a pulmonary bruit is present in 34% of patients.7 The characteristic finding on a plain chest radiograph is a circumscribed, lobulated density. Most PAVMs are located in the lower lobes and often are peripheral. Occasionally a feeding vessel can be seen on the chest radiograph (Figure 18-1). Currently, spiral computed tomography (CT) offers the least invasive and least expensive way to establish the presence of PAVM (Figure 18-2). If thin sections are utilized, intravenous contrast is not necessary to establish the diagnosis of

FIGURE 18-1. Chest radiograph in a 34-year-old female patient demonstrating a large feeding vessel supplying a pulmonary arteriovenous malformation in the lower lung field (black arrow). The vessel can be seen just medial to the left heart border, coursing to the lower lung fields (white arrow).

PAVM; however, contrast is required in order to prove patency. CT can elicit the number and size of the fistulas, and afferent and efferent vessels can be identified. However, unless the feeding artery or draining vein are identified, a PAVM cannot be distinguished from a pulmonary nodule.1 Magnetic resonance imaging (MRI) may be helpful but is less sensitive. Oxygen saturation should be measured to see if there is significant shunting. Two-dimensional contrast echocardiography with indocyanine dye or the injection of agitated saline can be useful in establishing the diagnosis and is less invasive than angiography.10,11 Furthermore, contrast echocardiography is useful in pregnant women, in whom ionizing radiation may be dangerous. The technique of contrast echocardiography involves the injection of agitated saline into a peripheral vein. The appearance of a cloud of bubbles in the left atrium confirms right-to-left shunting. Air bubbles will not survive a normal capillary bed, and if a patent foramen ovale has been excluded in the appropriate clinical setting, PAVM can be suspected.1 Angiography is the definitive test and can clearly outline the anatomy of PAVM (Figure 18-3). Pulmonary angiography identifies the location, size, and number of PAVMs. Additionally, it defines their blood supply and differentiates simple from complex PAVMs.7 Almost all patients with PAVM should be treated. Untreated PAVMs are associated with an 11% mortality and 26% morbidity rate.5 Asymptomatic patients with a single small (< 1 cm) PAVM occasionally will be observed; however, the risk of embolic stroke is increased in these patients. There are a few patients with severe pulmonary artery hypertension who would develop right

FIGURE 18-2. Computerized tomography of the chest with intravenous contrast. In the lung window settings, multiple pulmonary arteriovenous malformations are seen (arrows). With permission from Swanson KL et al.7

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heart failure if their large PAVM were suddenly occluded. Patients who are symptomatic should be treated, as should asymptomatic patients with HHT because of the

FIGURE 18-3. A, Pulmonary angiogram of the right pulmonary artery demonstrating a large pulmonary arteriovenous malformation (PAVM) in the right lower lobe. B, Pulmonary angiogram (magnified) of the left lower lobe pulmonary artery demonstrating a large PAVM in the left lower lobe. The feeding artery (white arrow) and draining vein (black arrow) are shown. With permission from Swanson KL et al.7

high likelihood of developing symptoms in the future. In fact, families of patients with HHT should be screened for PAVM to decrease the risk of a cerebrovascular event. Spontaneous thrombosis of a PAVM is rare; therefore, some sort of intervention is required to obliterate the malformation. The main therapeutic objective is to eliminate or reduce the right-to-left shunt and to prevent and treat complications. Surgical excision of PAVMs has been highly successful and is associated with a low morbidity and mortality rates and less than 2% recurrence rate.1,5,6,12 However, over the past decade, the standard of therapy for the majority of PAVM has been angiographic embolization. In fact, a recent review of our surgical experience with PAVM revealed that only one patient was operated on during the past 10 years.1 Angiographic embolization has the benefits of being less invasive and easily repeated. Currently, surgical excision is restricted to large central PAVM with a short neck, intrapleural PAVM that has ruptured and from which patients are actively bleeding, PAVM for which angiographic embolization has failed, and PAVM for which embolization is contraindicated.1 When surgical resection is necessary, wedge excision or segmentectomy is the procedure of choice. Angiographic embolization can be accomplished with either occlusion balloons, first described by Porstmann in 1977, or metallic coils, first done by Gianturco in 1975.13,14 White and colleagues described 76 patients who underwent obliteration of PAVM with angiographic balloon placement.15 These 76 patients had a total of 276 PAVMs; 266 could be occluded with balloons alone, and 10 patients required the addition of intravascular coils to occlude the fistula. Eighty percent of these PAVMs were simple, and 20% were complex. Complications were infrequent and included air embolus causing transient angina pectoris in 4%, postprocedure pleurisy in 10%, and paradoxical emboli in 0.7%. All PAVMs were successfully occluded; however, follow-up data were not given. Haijema and colleagues in 1995 reported on 32 patients with a total of 92 PAVMs who underwent embolization with intravascular coils. 16 Complications occurred in 18% and included arrhythmia, hyperventilation, pleurisy, and, in two patients, dislocation of the coil. Other series, including those of Pollak in 1994, Jackson in 1990, and Dutton in 1995, have shown similar success and complication rates.17–19 The use of metallic coils or angiographic balloons seems to be an effective method of obliterating PAVM. We prefer to use embolic coils (Figure 18-4). 1 It is critically important to select the correct coil size and to place them accurately. In some patients with numerous PAVMs, multiple lesions require embolization (Figure 18-5). Although metallic coils are less expensive and do not prematurely deflate, many

Management of Pulmonary Arteriovenous Malformations and Sequestrations / 237

more coils than balloons must often be placed to achieve satisfactory occlusion.1 In our recent series of patients treated with angiographic embolization, 91% responded favorably as shown by an improvement in their symptoms or arterial blood gas analysis. The mean PaO2 rose from a preembolization level of 56 mm Hg to 77 mm Hg postembolization.7 Long-term follow-up is recommended in all patients with PAVM. Even after successful treatment, there can be growth of smaller lesions and recanalization of success-

FIGURE 18-4. Pulmonary angiogram after coil embolization (arrow). Stoppage of blood flow through the fistula is seen. With permission from Swanson KL et al.7

FIGURE 18-5. Chest radiograph after multiple coil embolizations. Each group of coils represents a separate pulmonary arteriovenous malformation (PAVM). A large PAVM was embolized in the right upper lobe. With permission from Swanson KL et al.7

fully embolized lesions. Recurrences can be successfully reembolized. Our recommendations for follow-up include an annual physical exam, chest radiograph, arterial blood gas analysis, and assessment of the right-to-left shunt if symptoms are present.7

Pulmonary Sequestration Pulmonary sequestration covers a spectrum of related developmental pulmonary anomalies. It was first described simultaneously by Rokitansky and Rektorzik in 1861.20,21 The term “sequestration” was first used by Pryce and is derived from the Latin verb sequestrare, to separate.22 The lung is, in effect, sequestered from the remainder of the lung. It is defined as a segment of lung that has no bronchial communication with the rest of the lung.23,24 The arterial supply comes from systemic circulation, including from the thoracic aorta, abdominal aorta, or intercostal arteries. The venous return is either to the pulmonary system or to the systemic circulation. Sequestrations are different from accessory pulmonary lobes, which are separated from the normal lung by pleural investments but maintain a normal communication with the tracheobronchial tree. Surgical interest in these lesions first arose when Harris and Lewis reported on an operative death resulting from injury to an anomalous artery supplying the lower lobe of the lung in a 5-year-old child.25 Pulmonary sequestrations are thought to arise as accessory lung buds that then migrate along with the developing esophagus. This may account for their variable blood supply and occasional foregut communication. Other authors believe that these anomalies are acquired and are the result of chronic infections. The latter view does not explain the fact that the lesion is often diagnosed antenatally without evidence of infection. 26 They are divided into two types: the more common intralobar sequestration and extralobar sequestration. In intralobar sequestration, the sequestered portion of lung is situated within normal lung parenchyma sharing a common visceral pleural envelope. In extralobar sequestration, the sequestered portion has its own visceral pleural lining separating it from the remaining lung tissue. Reporting on 233 patients with both intralobar and extralobar sequestrations, Carter found a 2:1 ratio favoring the left side, and for extralobar sequestrations, a 3:1 male-to-female ratio. 27 More recently, Savic and colleagues found no gender-specific distribution in either intralobar or extralobar sequestrations. 2 8 Table 18-2 summarizes common features of sequestrations. Extralobar sequestrations are typically pyramidshaped and usually sit next to the aorta in the inferior portion of the chest. Forty percent of these patients have

238 / Advanced Therapy in Thoracic Surgery

an associated congenital anomaly, most commonly a diaphragmatic hernia.26 Approximately 15% of extralobar sequestrations will occur below the diaphragm, and about one-fifth will have multiple systemic arteries present.29 Bizarre communications have been reported; for example, Silverman and colleagues described a patient who had a feeding vessel from a branch of the left circumflex artery.30 Although extralobar sequestrations are often asymptomatic, they may present in neonates and early childhood with respiratory distress, cyanosis, and feeding disorders. Intralobar sequestrations are usually located in the lower lobe, and approximately 95% have a venous return to the pulmonary system (Figure 18-6). 31 Symptoms usually result from an infection or abscess in the sequestered segment that developed from communications via the pores of Kohn. A typical presentation is a patient with repeated pulmonary infections. Unless one has a high index of suspicion, the diagnosis will not be made in a timely fashion. In fact on average, a patient with an intralobar sequestration has three admissions for pulmonary infections and a lapse of 17 months between presentation and diagnosis.32,33 Another form of presentation is hemoptysis, either from chronic infection or from erosion of an atherosclerotic vessel into the airway, which can cause massive hemoptysis.34 Because a sequestration is a form of a systemicpulmonary shunt, some patients will present with congestive heart failure. On examination, a murmur may be heard along the left heart border or in the posterior-inferior lung fields. Patients can also present with bleeding into the pleural space, the esophagus, or the sequestration itself. Bronchoscopy will usually be unremarkable. Diagnosis is usually confirmed by CT with contrast, which will identify the systemic vessel supplying the sequestration (Figure 18-7). If there is doubt, an angiogram can be performed. Duplex Doppler ultrasonography has demonstrated the anomalous systemic feeding without the morbidity of aortography.35,36 MRI can also be used to identify the lesion, although it usually is not necessary.37 Antenatal diagnosis is also possible. Adzik and others have described the antenatal ultrasonographic findings of a sequestration. The examination demonstrates a cystic fluid collection in either the pleural space or just below

the diaphragm.38 However, Dolkart and colleagues found that a definitive diagnosis of pulmonary sequestration based on ultrasonographic findings is possible in only 35% of cases.39 Additional antenatal findings may include polyhydramnios, fetal pleural effusions, and pulmonary hypoplasia. Interestingly, with the ability to diagnose the lesions before birth, several lesions have been seen to regress while in utero. Becmeur and colleagues found an absolute or relative regression in size in 50% of patients diagnosed between the 20th and 33rd weeks of gestation.40 Treatment of sequestration is aimed at resection of the infected area. The sequestered segments should always be resected at the time of diagnosis to alleviate symptoms or, if the patient is asymptomatic, to prevent future compli-

FIGURE 18-6. Computerized tomography of the chest of a 28-year-old patient demonstrating an intralobar sequestration in the medial portion of the right lower lobe.

TABLE 18-2. Common Features of Pulmonary Sequestration Feature

Extralobar

Intralobar

Frequency Sex incidence (male:female) Laterality Venous drainage Neonatal diagnosis Associated congenital defects

Less common 3:1 90% left Often systemic Common Common

More common 1:1 60% left Often pulmonary Uncommon Uncommon

FIGURE 18-7. Computerized tomography of the chest with intravenous contrast of a 49-year-old patient demonstrating an intralobar sequestration with its systemic blood supply (arrows) arising from the descending thoracic aorta.

Management of Pulmonary Arteriovenous Malformations and Sequestrations / 239

cations. For extralobar sequestration, this usually means removing just the extralobar segment, securely ligating the arterial and venous supply. For an intralobar sequestration a segmentectomy can be performed, but chronic infection often makes this technically impossible, and a lobectomy is thus required. Extra care should be taken when identifying and ligating the arterial supply since it has been reported that this vessel can retract underneath the diaphragm and lead to an exsanguinating hemorrhage. 2 5 It is possible to remove carefully selected pulmonary sequestrations videothoracoscopically. Retroperitoneal or intra-abdominal sequestrations may require a laparotomy or a thoracoabdominal approach. The treatment of patients when an antenatal diagnosis is made depends on the size of the lesion and the secondary pathophysiologic effects. In Becmeur and colleagues’ analysis of 10 antenatally diagnosed cases, 2 fetal interventions were necessary: paracentesis of ascites and amniotic fluid in one fetus and placement of a pleuroamniotic shunt for hydrothorax in another. All 10 patients underwent surgery after birth with no mortality and minimal morbidity.40 Fortunately, sequestrations occur only on a sporadic basis; therefore, parents of an infant with sequestration should be counseled that it is not hereditary.

References 1. Pick A, Deschamps C, Stanson AW. Pulmonary arteriovenous fistula: presentation, diagnosis, and treatment. World J Surg 1999;23:1118. 2. Churton T. Multiple aneurysms of the pulmonary artery. BMJ 1897;1:1223.

11. Bradshaw DA, Murray KM, Mull NH. Massive hemoptysis in pregnancy due to a solitary pulmonary arteriovenous malformation. West J Med 1994:161:600. 12. Puskas JD, Allen MS, Moncure AC, et al. Pulmonary arteriovenous malformations: therapeutic options. Ann Thorac Surg 1993;56:253. 13. Porstmann W. Therapeutic embolization of arteriovenous fistula by catheter technique. In: Kelop O, editor. Current concepts in pediatric radiology. Berlin: Springer; 1977. p. 23–31. 14. Gianturco C, Anderson JH, Wallace S. Mechanical devices for arterial occlusion. Am J Radiol 1975;124:428. 15. White RI Jr, Lynch-Nyhan A, Terry P, et al. Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy. Radiology 1988;169:663. 16. Haijema TJ, Overtoom TTC, Westermann CJJ, Lammers JWJ. Embolization of pulmonary arteriovenous malformations: results and follow-up in 32 patients. Thorax 1995;50:719. 17. Pollak JS, Egglin TK, Rosenblatt MM, et al. Clinical results of transvenous systemic embolotherapy with a neuroradiologic detachable balloon. Radiology 1994;191:477. 18. Jackson JE, Whyte MKB, Allison DJ, Hughes JMB. Coil embolization of pulmonary arteriovenous malformations. Cor Vasa 1990;32:191. 19. Dutton JAE, Jackson JE, Hughes JMB, et al. Pulmonary arteriovenous malformations: results of treatment with coil embolization in 53 patients. Am J Roentgenol 1995;165:1119. 20. Rokitansky C. Lehrbuch der Pathologischen Anatomie. 3rd ed. Vienna; 1861. p. 44. 21. Rektorzik E. Ueber Accessorischen Lungenlappen. Wochenbl Z Aerzte Wien 1861;17:4.

3. Shenstone NS. Experiences with total pneumonectomy. J Thorac Surg 1942;11:405.

22. Buntain WL, Woolley MM, Mahour GH, et al. Pulmonary sequestration in children: a twenty-five year experience. Surgery 1977;81:413–20.

4. Gomes MR, Bernatz PE, Dines DE. Pulmonary arteriovenous fistulas. Ann Thorac Surg 1969;7:582.

23. Pryce DM. Lower accessory artery with intralobar sequestration of the lung. J Pathol Bacteriol 1946;58:457–67.

5. Dines DE, Arms RA, Bernatz PA. Pulmonary arteriovenous fistulas. Mayo Clin Proc 1974;49:460.

24. Pryce DM, Sellors TH, Blair LG. Intralobar sequestration of the lung associated with an abnormal pulmonary artery. Br J Surg 1947;35:18–29.

6. Dines DE, Seward JB, Bernatz PA. Pulmonary arteriovenous fistulas. Mayo Clin Proc 1983;58:176. 7. Swanson KL, Prakash UB, Stanson AW. Pulmonary arteriovenous fistulas: Mayo Clinic experience, 1982–1997. Mayo Clin Proc 1999;74:671. 8. Marchuk DA. The molecular genetics of hereditary hemorrhagic telangiectasia. Chest 1997;111(Suppl):79S. 9. Mitchell RO, Austin EH III. Pulmonary arteriovenous malformation in the neonate. J Pediatr Surg 1993;28:1536. 10. Shub C, Tajik AJ, Seward JB, Dines DE. Detecting intrapulmonary right-to left shunt with contrast echocardiography: observation in a patient with diffuse pulmonary arteriovenous fistulas. Mayo Clin Proc 1976:51:81.

25. Harris HA, Lewis I. Anomalies of lungs with special reference to danger of abnormal vessels in lobectomy. J Thorac Cardiovasc Surg 1940;9:666. 26. Holder PD, Langston C. Intralobar pulmonary sequestration (a nonentity?). Pediatr Pulmonol 1986;2:147–53. 27. Carter R. Collective review: pulmonary sequestrations. Ann Thorac Surg 1969;7:68–8. 28. Savic B, Birtel FJ, Tholen W, et al. Lung sequestration: report of seven cases and review of 540 published cases. Thorax 1979;34:96–101. 29. Nutchtern JG, Harberg FJ. Congenital lung cysts. Semin Pediatr Surg 1994;3:233–43.

240 / Advanced Therapy in Thoracic Surgery 30. Silverman ME, White CS, Ziskind AA. Pulmonary sequestration: retrieving arterial supply from the left circumflex coronary artery. Chest 1994;106:948–9.

36. Kim HJ, Kim JH, Chung SK, et al. Coexistent intralobar and extralobar pulmonary sequestration: imaging findings. Am J Roentgenol 1993;160:1199.

31. Buntain WL, Woolley MM, Manhour GH, et al. Pulmonary sequestration in children: a twenty-five year experience. Surgery 1977;81:413.

37. Oliphat L, McFadden RG, Carr TJ, Mackenzie DA. Magnetic resonance imaging to diagnose intralobar pulmonary sequestration. Chest 1987;91:500.

32. John PR, Beesley SW, Mayne V. Pulmonary sequestration and related congenital disorders. A clinicoradiological review of 41 cases. Pediatr Radiol 1989;20:4.

38. Adzik NS. Fetal thoracic lesions. Semin Pediatr Surg 1993;2:103–8.

33. Collin P-P, Desjardins JG, Khan AH. Pulmonary sequestration. J Pediatr Surg 1987;22:750.

39. Dolkart LA, Reimers FT, Helmuth WV, et al. Antenatal diagnosis of pulmonary sequestration: a review. Obstet Gynecol Surv 1992;47:515.

34. Rubin EM, Garcia H, Horowitz MD, Guerra JJ Jr. Fatal massive hemoptysis secondary to intralobar sequestration. Chest 1994;106:954.

40. Becmeur F, Horta-Geraud P, Donato L, Sauvage P. Pulmonary sequestrations: prenatal ultrasound diagnosis, treatment, and outcome. J Pediatr Surg 1998;33:492.

35. Eisenberg P, Cohen HL, Coren C. Color doppler in pulmonary sequestration diagnosis. J Ultrasound Med 1992;11:175.

CHAPTER 19

MANAGEMENT OF HYDATID CYSTS ILGAZ DOGUSOY, MD

Hydatid disease, which is caused by the tapeworm Echinococcus granulosus or Echinococcus multilocularis, is known as echinococcosis or hydatidosis. Hydatid disease is a severe helminthic zoonosis with major medical, social, and economic impacts in countries in which it is seen. Echinococcosis is endemic in Australia, New Zealand, South Africa, South America, the Middle East, Alaska, and Canada, where it is widespread among aboriginal tribes.1,2 Hydatidosis or echinococcosis is certainly one of the oldest human diseases. Hippocrates referred to hydatid disease in the aphorism, “When the liver is filled with water and bursts into epiploon, the belly is filled with water and the patient dies.” Galen, in the first century also made reference to this disease. Thebesius described hydatid disease in the seventeenth century. Finally Rudolphi (1808) published a large treatise on the parasite, first using the term “hydatid cyst” to describe echinococcosis in humans.3,4 The first report of hydatid cyst in humans in the medical literature is attributed to Bremser in 1821.5 Hydatidosis is characterized by the development of cysts as a consequence of the parasitization of humans by the larva of Taenia echinococcus. Although there are four well-known species (E. granulosus, E. multilocularis, Echinococcus oligarthus, Echinococcus vogelii), only E. multilocularis and E. granulosus are human pathogens. The latter is the causative organism in most cases of human infection. E. vogelii and E. oligarthus may cause polycystic echinococcosis very rarely.6

losus is a little parasite, 2 to 7 mm in length, 0.6 mm in width, and is composed of a scolex (head), neck, and 2 to 3 proglottids. The head has four suckers and 30 to 40 hooklets that serve to fix the parasite in the intestinal wall of its definitive host, the dog or any other related canine. The first proglottid is not a well-defined segment; the second one contains the required equipment for sexual reproduction of this true hermaphrodite; and the third, also called the pregnant proglottid, contains the eggs, varying in number from 400 to 800. Average lifetime of the mature parasite in the dog’s intestines is 5 months. During this time period, after being eliminated with the feces, the eggs keep contaminating fields, irrigated land, and wells. After this segment is discharged, the anterior becomes pregnant for reproduction later on. The detached eggs are 40 microns in size and highly resistant to physical and chemical agents and survive in adverse conditions for several weeks or months (1 week in water, 4 months in ice, and 10 months in soil).7 These eggs are introduced into intermediate hosts either by direct contact with dogs or ingestion of contaminated grass, water, vegetables, and such. In the duodenum or in the upper part of the jejunum of the intermediate host, however, the chitinous embryophore that covers the eggs is ruptured by the action of digestive enzymes. The larval stage, which cannot occur in the main host, begins in the intermediate host and leads to the development of hydatid disease within the viscera of these animals. The cycle is completed with the ingestion of the infected viscera by carnivores (primary host), and thus the cycle continues. Following the rupture of the egg, the hexacanth embryo, with aid of its hooklets, attaches to and penetrates the mucosa of the duodenum and jejunum, enters

Parasite The Echinococcus belongs to the phylum Platyhelminthes and the family Taeniidae. In its adult stage, the parasite lives in the intestinal tract of carnivores. Mature E. granu241

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the mesenteric venules, and proceeds to the portal vein. Reaching the tributary veins of the liver, this embryo can be retained by the sinusoidal capillaries of the liver, or if they escape they may become lodged in the lung, where they would also be transformed into hydatids. Rarely embryos can bypass the pulmonary barriers through precapillary anastomoses. They are responsible for the sporadic cases of extrapulmonary and extrahepatic hydatidosis. The incidence of hepatic involvement in echinococcosis is 50 to 80%.7,8 The lungs are the second most common site of lodgment of the parasite, with an incidence varying between 10 to 30%.3,7,8 If the hexacanth embryo manages to get past the pulmonary filter, it reaches the left heart and, by way of the aorta, the remainder of the organism, mainly the kidney, spleen, and bones in the remaining 10%. It has been shown that the embryos can reach the lung via the lymphatic vessels, bypassing the liver. The embryo may enter the lymphatics of the small intestine, proceeds to the thoracic duct, to the internal jugular vein, to the right side of the heart, then to the lungs. Although some researchers have supported the possibility of direct pulmonary exposure through the inhalation of air contaminated with Echinococcus, it is doubtful whether the bronchial secretions can lyse the embryophore of the hexacanth to liberate the embryo. 9 After capillary embolization, many embryos are destroyed by phagocytosis, but some reach the larval stage of the echinococcus—the hydatid cyst. Although pulmonary cysts may establish in every lobe of the lungs, they are more frequent in lower lobes and mainly in the right hemithorax.1,8,10–12 In children, the presence of hydatid disease in the lungs has been reported to be up to 67%,13–15 whereas in adults cysts are more prominent in the liver.

adventitia (pericyst), is formed by thick connective tissue and in part by parenchymal tissue collapsed by compression. 2.

The parasite a. Chitinous or laminated membrane: The acellular outer layer is called the chitinous membrane. It is 1 to 3 mm thick and is surrounded by the pericystic layer. The laminated membrane is composed of a plexus of fine fibers with a dispersed, thick, reticular substance, which is permeable to calcium, potassium, chlorides, water, and urea.17,18 It is hyaline and elastic and is easily discernible from the pericystic layer. Nutritional and other substances useful to the parasite traverse the membrane by selective diffusion, but active transport may also play a role. b. Endocyst (germinative membrane): The cellular mass is formed in this layer. It is a thin transparent membrane that is lined with small papillae, which are brood capsules at different stages of development. The germinative membrane is the living part of the parasite and produces the laminated membrane and reproduces the parasite (Figure 19-2).

The daughter cysts are produced from the germinal membrane. These cysts contain 10 to 60 heads of baby scolices, which are called protoscolex. These cysts often detach from the vesicle’s inner wall and float in the fluid together with the protoscolices from the ruptured or dead daughter cysts, which constitute the so-called hydatid sand.

Pathology Hexacanth embryo loses its scolex at the organ in which it lodges, transforms into a cyst, and starts growing. Following the inflammatory reaction in the first few days, hydatic vesicula forms by the end of the first week. At the end of the 10th day, germinative membrane starts to mature and starts to be covered by cuticula. By day 90 a cyst of 4 to 5 mm with all layers complete is formed. Doubling time of the cyst is approximately 16 to 20 weeks, but the factors effecting this doubling time are unknown. Their diameter can increase, from a few millimeters up to approximately 5 cm in 1 year.16 The hydatid cyst is formed by two components: (1) the adventitia and (2) the parasite itself (Figure 19-1). 1.

Adventitia (host reactional layer; pericyst): With the host attempting to isolate the parasite from the rest of the adjacent structures, this membrane, the

FIGURE 19-1. The hydatid cyst and its components.

Management of Hydatid Cysts / 243

FIGURE 19-2. Hydatid cyst after excision (the germinative membrane).

The hydatid vesicle is filled with hydatid fluid, which is colorless and odorless and resembles crystal-clear water. The specific gravity of the fluid is 1.008 to 1.015; the pH is 6.7 to 7.2; and the concentration of sodium, potassium, chloride, and carbon dioxide is approximately that of the host’s blood serum. The function of the hydatid fluid is similar to that of amniotic fluid because it suspends the daughter cysts. Protoscolices and the freeswimming daughter cysts form the hydatid sand that can be seen at the bottom of the hydatid cyst. As the usual entrance of the hydatid embryo into the lung occurs by hematologic dissemination, the implantation sites are almost invariably peripheral; they usually cause bulging of the visceral pleura. However, during its growth, the cyst tends to assume a more central position. Usually, the rate of growth of the echinococcus in the lungs is progressive and constant, although at times it may appear to remain static. The growth is more rapid in organs like lung and peritoneum and slower in others of greater consistency. During the growth period of the pulmonary hydatid cyst, it can compress bronchial structures and produce pulmonary atelectasis accompanied by pneumonia. Rupture, infection, and calcification can affect its course. Rupture of a pulmonary cyst may occur spontaneously or during coughing, sneezing, or any other cause of increased intra-abdominal pressure or after injury during diagnostic paracentesis, surgery, or infection. Dissemination of the fluid produces general symptoms that vary widely from one patient to another. The rupture may occur within the boundaries of the pericystic layer, into the pleural space, or into a neighboring

organ, bronchus, or blood vessel. If it ruptures into the adjacent bronchus, the patient eliminates it in the form of cough and vomit, which may or may not be accompanied by hydatid membranes. The elimination of the cyst in this way may lead to cure or secondary infection. Rupture of a cyst toward a blood vessel can result in death from anaphylactic shock or from embolization with secondary infection by protoscolices. Rupture of a cyst into the pleural space may cause pneumothorax, pyopneumothorax, pneumohydatid thorax, or hydatid pleural implants.19 Infection of the cyst usually produces its suppuration. Cyst suppuration leads to the death of the metacestode, although some daughter vesicles may survive. The clinical signs include chills, fever, tachycardia, local pain, leukocytosis, and expectoration.20 Calcification is caused by the deposition of calcium salts in necrotic foci in the adventitial layer but does not always indicate that the hydatid is dead. Although calcification is common in hydatid cysts of the liver, it is rare in pulmonary cysts, perhaps because of their more rapid growth.

Clinical Features In 30 to 50% of cases E. granulosus does not produce characteristic symptoms. The typical clinical picture for the diagnosis of pulmonary hydatidosis is represented by a patient in his third or fourth decade who comes from an endemic region and presents with cough, chest pain, hemoptysis, and radiologic findings of cystic lesions in one or both lungs. Clinical manifestations depend on the site and size of the cyst. Thirty percent of our patients were symptom-free at the time of diagnosis. They were diagnosed during routine examinations or while having chest radiograph for other reasons. The growth of the cyst is slow, and it is symptomatic only when the cyst is large enough to cause compression. Common presenting symptoms are cough, purulent sputum, and chest pain in symptomatic patients. A nonproductive, irritant cough is the first complaint in 50 to 80% of patients (Table 19-1).11,21 If the hydatid cyst ruptures into an adjacent bronchus, vigorous coughing and vomit-like expectoration of salty or peppery water consisting of mucus, hydatid fluid, and, occasionally, fragments of laminated membrane (generally described as egg white membranous particles) together with bloody sputum occur. The rupture of a cyst sometimes occurs gradually, through a fissure, releasing only small amounts of hydatic fluid. In sensitized patients, this can produce pruritis, erythema, or generalized urticaria. Rupture of a fertile hydatid cyst into the mediastinum, pericardium, or pleural cavity can lead to secondary

244 / Advanced Therapy in Thoracic Surgery TABLE 19-1. Clinical Symptoms of Pulmonary Hydatid Cyst Symptoms Direct effects of the cyst Rupture of the cyst

Infection of the cyst

Cough, chest pain, hemoptysis, dyspnea Cough, vomit-like expectoration of germinative membrane or scolices (hydatoptysis), hemoptysis, chest pain Fever, hemoptysis, expectoration, weight loss Allergic Reactions

Lung Skin Cardiovascular Abdominal Other

Bronchospasm, dyspnea, pulmonary congestion, eosinophilic infiltration Pruritis, erythema, generalized urticaria, angioneuropathic edema Anaphylactic shock, tachycardia, sudden death Distention, cramps, diarrhea Autoimmune myopathy

implantations. When the hydatid cyst ruptures into the pleura it causes a hydatid hydropneumothorax. When a bronchoadventitial–pleural fistula is also present, secondary infection of the cavity will produce a hydatid pyopneumothorax, and this may be manifested by severe chest pain, dyspnea, dry cough, generalized malaise, and fever. In some patients, intense chest pain, persistent cough, and severe dyspnea and even cyanosis, shock, and suffocation may be observed. Allergic reactions to all degrees and even death can occur. Suppuration of the cyst can occur after rupture and secondary infection. Bacterial contamination from bronchial involvement can simulate a chronic lung abscess, with or without the chitinous membrane included in the purulent fluid. General symptoms of a chronic infection, fever, generalized malaise, and hemoptysis can occur in these patients. The diagnostic possibility of a ruptured hydatid cyst with a retained membrane should always be considered

FIGURE 19-3. Computed tomography scan of liver showing a large hepatic cyst in the right lobe with multiple vesiculation—a common finding in hepatic hydatid disease.

when the surgeon is confronted with a chronic abscess that is unresponsive to usual therapy. The coexistence of hepatic and pulmonary lesions should always be suspected. In 18 to 40% of pulmonary hydatidosis there can be simultaneous involvement of the liver and lung. 21,22 Hydatid cyst of the liver is mostly asymptomatic. In 60 to 85% of cases the cyst is localized in the right lobe of the liver (Figure 19-3). Pain in the right upper quadrant of the abdomen, hepatomegaly, nausea, and vomiting are the clinical manifestations of liver involvement. When the cyst in the liver becomes larger then 10 cm or ruptures, severe abdominal complications like obstructive jaundice, cholangitis, and pancreatitis may occur. If the hepatic cyst perforates the diaphragm, hydatic contents of the cyst reach the pleural space, producing a hepatic thoracic transdiaphragmatic pleural hydatidosis. This is often a dramatic clinical event with sudden and acute thoracic pain, cardiovascular collapse sometimes leading to shock, and hydatid allergy (urticaria, bronchospasm, and fever). Hepatic thoracic transdiaphragmatic hydatidosis may present in an acute fashion, with epigastric pain, cough, fever, shortness of breath, biliphtisis, and anaphylactic reactions.

Diagnosis In clinical practice, plain radiographs of the chest have been shown to be most reliable in diagnosing pulmonary hydatid disease. Radiographically an intact cyst appears as a round or oval shape, solitary or multiple, with homogeneous density and perfectly defined margins (Figures 19-4 and 9-5). Alteration from a spherical to an oval shape may be observed during deep inhalation (the Escudero-

FIGURE 19-4. Chest radiograph showing two peripheral hydatid cysts in the left lung.

Management of Hydatid Cysts / 245

Nenerow sign).23 Apically localized hydatid cysts may imitate Pancoast tumors. If the cyst is large it can even be the cause of vena cava superior syndrome. Their convexity is toward the lung. If a cyst is localized on the diaphragm its convexity is upwards, and this is referred to as the sunset sign (Figure 19-6). Centrally located cysts may compress the bronchovascular structures, presenting radiographically as an indentation at the site of pressure (the notch sign). If air enters the perivesicular space, becoming trapped between the adventitia and the unruptured vesicle, it is referred to as moon sign or crescent sign24 (pneomocyst,25 perivesicular pneuma,26 perivesicular meniscus,27 and pulmonary meniscus 7 signs). It is the first radiographic sign of impending rupture of the cyst. The diag-

FIGURE 19-5. Frontal chest radiograph showing an intact hydatid cyst in the right lung.

FIGURE 19-6. A cyst localized on the right diaphragm with upward convexity (sunset sign). Calcification, although a rare finding in the pulmonary hydatid disease, can be seen around the cyst.

nostic possibility of a ruptured hydatid cyst with a retained membrane should always be considered when the surgeon is confronted with a chronic abscess that is unresponsive to usual therapy, especially if an irregular fluid level is seen in the cavity (water lily sign28 or camelot sign26) (Figure 19-7). It is produced by the floating germinative membrane of the cyst. An incarcerated membrane folded back in the form of a barricade can appear as a fluid-filled abscess. Areas of pneumonitis, lung atelectasis, or bronchiectasis can accompany the chronic suppuration of the cyst. In these cases, the differential diagnosis with certain lesions such as bronchial carcinomas, benign tumors of the lung, pulmonary arteriovenous fistulas, metastatic tumors, sarcomas, and tuberculoma is difficult to challenge. If the germinal membrane has been expectorated completely, an aeric cyst may be misdiagnosed as bullae or pneumatocele of the lung. In the acute stage of rupture of the cyst into the pleural cavity, chest radiographs may show a blurred hemidiaphragm or a loculated pleural effusion. Often the patient will have a tension hydropneumothorax with mediastinal shift. A wanderer cyst changing its location with different radiologic positions can be demonstrated with plain chest radiographs, ultrasound, and computed tomography (CT) scanning (Figure 19-8). Although plain radiographs of the chest have a diagnostic accuracy of nearly 99%,9 CT has added to the diagnosis of hydatid disease of the lung, particularly to the early discovery of coexistent small cysts in the lung and existing ruptured cysts, and for establishing definitive diagnosis (Figures 19-9 and 19-10). It is also very valuable in the follow-up of patients who have had surgery for hydatid disease of the lung.

FIGURE 19-7. Frontal chest radiograph of a ruptured hydatid cyst in the right lower lobe. Air–fluid level can be seen clearly (water lily sign).

246 / Advanced Therapy in Thoracic Surgery

FIGURE 19-8. Computed tomography scan of a patient presenting with a pyothorax on the left side reveals a cyst floating in the pleural effusion (wanderer cyst).

Magnetic resonance imaging is not being used routinely in the diagnosis of hydatid disease of the lung. It may show detached membranes, daughter cysts, local host reactions, or communications between the cyst and the bronchial tree in ruptured cysts (Figure 19-11). Abdominal ultrasound or CT of the upper abdomen has to be performed routinely to determine whether liver cysts are present. Bronchoscopy was used in the diagnosis of pulmonary hydatidosis prior to imaging techniques such as CT and magnetic resonance imaging; its use has been limited by the risk of rupture of the cyst and the subsequent development of severe complications. It still may be useful in cases of ruptured hydatid cyst of the lung because it enables the visualization and removal of cystic membranes from the bronchial tree. When the initial chest radiograph leads to a suspicion of hydatid disease, several clinical laboratory tests can be carried out, including the peripheral blood eosinophil count, Casoni’s intradermal test, the Weinberg reaction test, and the erythrocyte sedimentation rate. Indirect hemagglutination test, latex agglutination, immunoelectrophoresis, double-diffusion immunoelectrophoresis, total immunoglobulin E (IgE) or specific IgE, indirect immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) are the serologic tests that are still being used.29–31 Peripheral blood eosinophilia is neither specific nor constant because not all patients with hydatidosis present eosinophilia and, on the other hand, eosinophilia can exist in patients with other parasites or allergic processes.

FIGURE 19-9. Computed tomography scan of a small, ruptured hydatid cyst in the right upper lobe showing a collapsed echinococcal membrane (water lily sign).

FIGURE 19-10. Computed tomography scan showing a giant hydatid cyst in the right hemithorax filling the entire thoracic cavity.

FIGURE 19-11. Magnetic resonance imaging scan showing multiple hydatid cysts in the left upper lobe with extrathoracic extension.

Management of Hydatid Cysts / 247

As eosinophilia occurs in 20 to 34% of the patients with echinococcosis,32 this test has little diagnostic value. The Casoni skin test consists of the intradermal injection of 0.2 to 0.3 mL of hydatid fluid from sheep cysts, filtered and undiluted, into the anterior aspect of the patient’s forearm, similar to the procedure used for the tuberculin test. The reaction is positive in 50 to 95% of cases, but a negative result does not rule out the presence of hydatid disease. On the other hand, false-positive reactions can occur in patients with other parasitic and nonparasitic diseases. As it lacks specificity, it is no longer recommended. The Weinberg reaction test, also referred to as complement fixation test is based on the existence, in the plasma of hydatid cyst carriers, of circulating reagins. It is not a specific test, and its sensitivity rate is reported to vary from 36 to 93%.33 The indirect hemagglutination test was introduced in 1957 by Garabedian.34 Its sensitivity ranges from 66 to 100%, and false-positive results are 1 to 2%. It has been the clinical test of choice for the last four decades. Six serologic tests were compared by Zarzosa and colleagues in 1999.35 IgG ELISA was found to have the highest sensitivity (84%), followed by IgM ELISA (62%), indirect hemagglutination test (61%), latex agglutination (58%), immunoelectrophoresis (51%), and specific IgE ELISA (44%). The specificity of all tests was found to be 98 to 100%. False-positive results were seen in patients who had parasitic diseases like Taenia saginata and Taenia solium or nonparasitic disease like lymphoma and leukemia. IgG ELISA, with its very high sensitivity and specificity rates, seems to be the serologic test of choice for use in the clinic. Pulmonar y hydatid disease may mimic several pulmonary diseases. Some of the pulmonary diseases that the surgeon must consider in the differential diagnosis of pulmonary hydatid disease are lung abscess, pulmonary tuberculosis, bronchiectasis, lung cancer, metastatic tumors, pneumonia, pleural effusions and empyema, mesothelioma, pneumothorax, bronchial cysts, pericardial cysts, benign neoplasms of the lung, fungal infections, and diaphragmatic hernias.

Treatment Rarely hydatid cysts of the lung heal by spontaneous rupture and evacuation into the bronchus, though complications such as infection, abscess formation, bronchogenic spread, and anaphylactic shock may occur. Medical Treatment The results of treatment of hydatid disease with benzimidazole compounds during the last two decades have been

described. Gil-Grande reported partial or complete clinical responses in 36 to 94% of the patients treated with mebendazole.36 Horton reported that albendazole therapy in E. granulosus infection can result in apparent cure in up to 30% of cases, with a further 40 to 50% showing objective evidence of response when followed in the short term.37 The effectiveness of these drugs is apparently dependent on the thickness of the cyst wall; the drug has to pass through it to reach the germinal layer of the cyst. Young patients and those with small cysts that have thin walls appear to benefit most from this medical therapy. 38 According to recent World Health Organization guidelines, chemotherapy is the preferred treatment when surgery is not available, when complete removal of the cyst is impossible, when cyst contents threaten to disseminate due to cyst rupture, or when cysts are too numerous.21,39 Despite the benefits afforded by chemotherapy in the management of pulmonary hydatidosis, to date surgery is still the treatment of choice based on results achieved and the low morbidity and mortality rates. 8,40–46 The different surgical techniques available for pulmonary hydatid cystic disease can be divided into two types: those involving conservation and those involving removal of lung parenchyma. Surgical Treatment Historically, the surgical management of hydatid disease has passed through different stages. In 1899 Posadas advised only suturing of the bronchial openings. As this method did not prevent air leaks, fixation of the edges of the sutured pericystic zone to the thoracotomy incision was later added. Incising the lung parenchyma and removing the cyst (simple enucleation) was reported by Ugon and colleagues in 1946.47 Barret in 1947 described removal of parasite and obliteration of the remaining cavity with a series of purse-string sutures (enucleation and capitonnage).48 Allende and Langer in 1947 supplemented capitonnage with suturing of the individual bronchial openings within the cavity.49 Pérez-Fontana in 1951 described a new method known as pericystectomy (capsule resection).50 All these techniques are conservative methods. The technical difficulty with Pérez-Fontana’s method (pericystectomy) is the creation of an appropriate plane through the pulmonary tissue, near and around the parasitic cyst, with the resulting bleeding and air leak. After resection of the pericyst the remaining cavity may be difficult to obliterate. The choice of surgical technique depends on the conditions encountered during surgery. Regardless the surgical methods adopted, removal of the entire parasite, prevention of its dissemination, maximal preservation of pulmonary function, and the immediate obliteration of the remaining cavity are the basis for effective therapy.

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Removing unilateral multiple cysts is not difficult. Bilateral lung cysts can be operated in one- or two-staged thoracotomies depending upon the condition of the patient. In a patient with bilateral hydatid disease the side with the larger cyst should be operated first. If the patient has bilateral disease with complicated cyst in one lung, the noncomplicated cyst should be removed first to prevent its future rupture. The lesions in the other lung can be operated on in the same session or 2 to 4 weeks after the first operation (Figure 19-12). Several surgeons have used a median sternotomy for bilateral lesions.42 It carries less morbidity than the bilateral standard posterolateral thoracotomy, but the sternotomy approach can pose a technical challenge, especially when the cysts are localized in the dorsal pulmonary segments and if a major resection of the lung tissue is indicated.

the most superficial part of the cyst in the visceral pleura. Excision of the intact hydatid cyst is accomplished by careful separation of the laminated membrane from the pericystic zone. The cyst is pushed out of its chamber with the aid of high-pressure ventilation provided by manual inflation of the corresponding arm of the double lumen tube. The laminated membrane should never be grasped with an instrument, before or during the delivery of the cyst. Delivery of the cyst can be carefully assisted with fingers only, to avoid cyst rupture (Figure 19-13A and B). Although the best method is the enucleation and obliteration of the residual cavity, as most of the cysts either are very large or very tense or localized deep in the lung parenchyma it is nearly impossible to enucleate the cyst. In such cases we prefer to aspirate the cyst contents with a needle and open the cavity with the cautery. As it is nearly impossible to protect the lung from spilled

Surgical Technique A posterolateral thoracotomy in the fifth or sixth intercostal space is accomplished with the patient under conventional general anesthesia and in the lateral decubitus position. All patients are intubated with a doublelumen endotracheal tube to prevent contralateral aspiration of blood and other secretions. If accidental rupture of the cyst occurs during anesthesia or surgery, contralateral aspiration of the cyst fluid and bronchial dissemination can be seen. After the cyst is identified, the surgical wound and adjacent lung tissue are covered with normal saline or 1% (vol/vol) povidone–iodine-impregnated gauzes to prevent seeding of possible daughter cysts. The cystic mass is usually seen as a soft, elastic, yellowish-white swelling on the surface of the pulmonary parenchyma. The pericystic membrane is opened by a short incision that surrounds

FIGURE 19-12. Multiple echinococcal cysts removed from the lung and pleura of the patient in Figure 19-8.

FIGURE 19-13. A, Dissection of the hydatid cyst. The pericystic membrane is opened and the parasite can be seen. B, Enucleation nearly completed. Note the Allis clamps hold the pericystic membrane only.

Management of Hydatid Cysts / 249

cystic contents during a needle aspiration, 41,45 every precaution should be taken; the operative field should be protected with normal saline or 1% (vol/vol) povidone–iodine-impregnated gauzes. The cyst cavity is punctured at the site of greatest projection, and cystic fluid is aspirated as completely as possible. After opening the most prominent part of the cyst by cautery, the germinative membrane is taken out by forceps. Gentle manipulation of the cyst and the lung parenchyma and irrigation of the cavity with a scolicidal agent to help prevent spillage and recurrence must be carried out in all cases. To prevent the hydatid fluid from escaping into the pericystic space, constant positive pressure must be maintained throughout the entire period of evacuation of the parasitic contents of the cyst. After removal of the cyst, the residual cavity must be cleaned and reexamined for spillage from daughter vesicles. In all patients the pericystic cavity must be irrigated with 1% povidone–iodine solution or hypertonic saline solution. Bronchial openings are found while maintaining constant positive pressure and filling the residual cavity with normal saline solution. Formation of bubbles through any bronchial openings can be visualized with this method. Bronchial openings are closed with polyglactin 910. In complicated cysts with a calcified, infected, or thickened pericystic layer, bronchial openings must be managed more carefully, with closer and deeper sutures. After the closure of bronchial openings, the cavity is obliterated with purse-string sutures from the base of the pericystic cavity upward, using polyglactin 910, every suture 1 cm from the lower one. Saidi7 and Turna and colleagues51 claimed that the approximation and suturing of the edges of the residual cavity are not necessary because the pulmonary parenchyma automatically obliterates the space. We have been using the capitonnage method in all cases, except for peripherally located small to moderate-sized noncomplicated cysts. In the acute stages of the rupture of the hydatid cyst, management is directed toward the prevention of major complications resulting from the evacuation of the cystic contents into the tracheobronchial tree or the pleural space. Bronchoscopy to clear the airway of secretions or cystic tissue and treatment of hydropneumothorax and anaphylactic reaction can be needed in the acute stages. After the acute period the most conservative treatment should be used to save as much lung tissue as possible. As a rule the lung parenchyma should be preserved as far as possible in patients with pulmonary disease, and radical procedures should be avoided. The principal indications for lobectomy are cysts involving at least twothirds of the lobe, cysts with severe pulmonar y suppuration unresponsive to preoperative treatment, multiple unilobar cysts, and sequela of hydatid disease

such as pulmonary fibrosis, bronchiectasis, and severe hemorrhage. Pneumonectomy should be used only when the whole lung is involved in the disease process and no salvageable pulmonary parenchyma remains.3

Conclusion Conservative surgery should be the primary treatment for most patients with pulmonary hydatidosis. Capitonnage is the best way to deal with a residual cavity. The cavity should be obliterated whenever possible. Resection of the lung tissue should be performed only when the surgeon is sure that the lung tissue is useless or open to complications. Surgery remains the best treatment of choice.

References 1. Burgos R, Varela A, Castedo E, et al. Pulmonary hydatidosis: surgical treatment and followup of 240 cases. Eur J Cardiothorac Surg 2001;19:918–23. 2. Wilson JF, Rausch RL, Wilson FR. Alveolar hydatid disease: review of the surgical experience in 42 cases of active disease among Alaskan Eskimos. Ann Surg 1995;221:315. 3. Aletras H, Symbas PN. Hydatid disease of the lung. In: Shields TW, LoCicero J, Ponn RB, editors. General thoracic surgery. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2000. p. 1113–22. 4. Dew H. Hydatid disease—its pathology, diagnosis and treatment. Sydney: Australasian Medical Publishing; 1928. 5. Romero-Torres R, Campbell JR. An interpretative review of the surgical treatment of hydatid disease. Surg Gynecol Obstet 1965;104:851. 6. Lymbery AJ, Thompson RCA. Species of echinococcus— pattern and process. Parasitol Today 1996;12:486–91. 7. Saidi F. Surgery of hydatid disease. Philadelphia (PA): W.B. Saunders; 1976. 8. Dogan R, Yuksel M, Cetin G, et al. Surgical treatment of hydatid cysts of the lung: report on 1055 patients. Thorax 1989;44:192–9. 9. Crysopathis P. Echinococcus cysts of the lung. Dis Chest 1966;49:278. 10. Mutaf O, Arikan A, Yazici M, et al. Pulmonary hydatidosis in children. Eur J Pediatr Surg 1994;4:70–3. 11. Karaoglanoglu N, Kurkcuoglu IC, Gorguner M, et al. Giant hydatid lung cysts. Eur J Cardiothorac Surg 2001;19:914–7. 12. Solak H, Ozgen G, Yuksek T, et al. Surgery in hydatid cyst of the lung – a report of 460 cases. Scand J Thorac Cardiovasc Surg 1998;14:134–40. 13. Tsakayiannis E, Pappis C, Mousatos G. Late results of conservative surgical procedures in hydatid disease of the lung in children. Surgery 1970;68:379–82. 14. Slim MS, Akel SR. Hydatidosis in children. Prog Pediatr Surg 1982;15:119–29.

250 / Advanced Therapy in Thoracic Surgery 15. Balci AE, Eren N, Eren S, Ulku R. Ruptured hydatid cysts of the lung in children: clinical review and results of surgery. Ann Thorac Surg 2002;74:889–92. 16. Sarsam A. Surgery of pulmonary hydatid cysts: review of 55 cases. J Thorac Cardiovasc Surg 1971;62:663.

35. Zarzosa MP, Orduna DA, Gutierrez P, et al. Evaluation of six serological tests in diagnosis and postoperative control of pulmonary hydatid disease patients. Diagn Microbiol Infect Dis 1999;35:255–62.

17. Morseth DJ. Fine structure of the hydatid cyst and protoscolex of echinococcus granulosus. J Parasitol 1967;53:312.

36. Gil-Grande LA. Treatment of liver hydatid disease with mebendazole: a prospective study of thirteen cases. Am J Gastroenterol 1983;78:584.

18. Schwabe CW. Host-parasite relationship in echinococcosis: observations on the permeability of the hydatid cyst wall. Am J Trop Med Hyg 1959;8:20.

37. Horton RJ. Albendazole in treatment of human cystic echinococcosis; 12 years of experience. Acta Trop 1997;64:79–93.

19. Vivo JN, Brandolino M. Rare infections of the pleural space. In: Pearson GF, Cooper JD, Deslauriers J, et al, editors. Thoracic surgery. 2nd ed. New York: Churchill & Livingstone; 2002. p. 1215–28.

38. Aletras H, Symbas P. Hydatid disease of the lung. In: Shields TW, editor. General thoracic surgery. 3rd ed. Philadelphia (PA): Lea & Febiger; 1989. p. 831–41.

20. Varela A, Burgos R, Castedo E. Parasitic diseases of the lung and pleura. In: Pearson GF, Cooper JD, Deslauriers J, et al, editors. Thoracic surgery. 2nd ed. New York: Churchill Livingstone; 2002. p. 613–23. 21. Isitmangil T, Sebit S, Tunc H, et al. Clinical experience of surgical therapy in 207 patients with thoracic hydatidosis over a 12-year period. Swiss Med Wkly 2002;132:548–52. 22. Aribas OK, Kanat F, Turk E, Kalayci MU. Comparison between pulmonary and hepatopulmonary hydatidosis. Eur J Cardiothorac Surg 2002;21:489–96.

39. WHO Informal Working Group on echinococcosis. Guidelines for treatment of cystic and alveolar echinococcosis in humans. Bull World Health Organ 1996;74:231–42. 40. Aytac A, Yurdakul Y, Ikizler C, et al. Pulmonary hydatid disease. Report of 100 patients. Ann Thorac Surg 1977;23:145–51. 41. Solak H, Yeniterzi M, Yuksek T, et al. The hydatid cyst of the lung in children and results of surgical treatment. Thorac Cardiovasc Surg 1990;38:45–7.

23. Sharma SK, Eggleston FC. Management of hydatid disease. Arch Surg 1969;99:59.

42. Cetin G, Dogan R, Yuksel M, et al. Surgical treatment of bilateral hydatid disease of the lung via median sternotomy: experience in 60 consecutive patients. Thorac Cardiovasc Surg 1988;36:114–7.

24. Barret NR, Thomas D. Pulmonary hydatid disease. Br J Surg 1952;40:222.

43. Safioleas M, Misiakos EP, Dosios T, et al. Surgical treatment for lung hydatid disease. World J Surg 1999;23:1181–5.

25. Deve F. Sur la sterilization du sable hydatique par les solutions formoles et les solutions iodées. CR Soc Biol 1935;119:352.

44. Xanthakis D, Efthimiadis M, Papadakis C, et al. Hydatid disease of the chest. Report of 91 patients treated. Thorax 1972;27:517–28.

26. Arce J. Hydatid cyst of the lung. Arch Surg 1941;43:789. 27. Peschiera CA. Hydatid cyst of the lung. In: Shields TW, editor. General thoracic surgery. Philadelphia (PA): Lea & Febiger; 1972. 28. Lagos Carcia C, Segers A. Consideraciones sobre un caso de quiste hidatico pulmonary abierto in bronquios. Semin Med Bs As 1924;31:271. 29. King C. Echinococcosis. In: Principles and practice of infectious disease. 4th ed. New York: Churchill & Livingstone; 1995. p. 2550–1. 30. World Health Organization. Echinococcosis, parasites and health. Bull World Health Organ 1999. 31. Ozdemir IA, Kalaycioglu E. Surgical treatment and complications of thoracic hydatid disease. Report of 61 cases. Eur J Respir Dis 1983;64:217–21. 32. Aletras HA. Hydatid cyst of the lung. Scand J Thorac Cardiovasc Surg 1968;2:218. 33. Kagan IG. A review of serological tests for the diagnosis of hydatid disease. Bull World Health Organ 1968;39:25. 34. Garabedian GA, Matossian RM, Djanian AY. An indirect hemagglutination test for hydatid disease. J Immunol 1957;78:269.

45. Yalcinkaya I, Er M, Ozbay B, Ugras S. Surgical treatment of hydatid cyst of the lung: review of 30 cases. Eur Respir J 1999;13:441–4. 46. Ayusa LA, Peralta GT, Lazaro RB, et al. Surgical treatment of pulmonary hydatidosis. J Thorac Cardiovasc Surg 1981;82:569–75. 47. Ugon AV, Victoria A, Suarez H, et al. La lobectomia en el tratamiento de las secuelas del quiste hidatice de pulmon. Bol Soc Cir Urug 1946;17:465. 48. Barret NR. Surgical treatment of hydatid cysts of the lung. Thorax 1947;2:21–57. 49. Allende JM, Langer L. Tratamiento de los quistes hidatidicos del pulmon. Bol Tr Soc Argent Cir 1947;31:539. 50. Pérez-Fontana V. Traitement chirurgical du kyste hydatique dus poumon. La méthode uruguayenne ou extirpation du perikyste. Arch Int Hydatid 1951;12:469. 51. Turna A, Yilmaz MA, Haciibrahimoglu G, et al. Surgical treatment of pulmonary hydatid cysts: is capitonnage necessary? Ann Thorac Surg 2002;74:191–5.

CHAPTER 20

SURGERY FOR FUNGAL AND MYCOBACTERIAL DISEASES MARK DE GROOT, MD, FRCSC

case is dimorphic in that it exists in nature as mycelium (mold) that bears infectious spores, which enter a host; they enter a yeast-like phase that is the tissue pathogen. The most common primary fungal diseases are histoplasmosis, coccidioidomycosis, and blastomycosis. Each is peculiar to certain endemic areas in the world. Serious morbidity is rare, and the most common indication for surgery is to differentiate from more serious disorders such as carcinoma or TB. Occasionally reaction to the infection results in calcification of the lung foci or resultant adenopathy. The calcification may serve to indicate the benign nature of the disease. Occasionally the calcification and distortion, particularly in the lymph nodes, may be prolific and lead to airway compromise. Erosion into the airways may result in cough, hemoptysis, and the extrusion of broncholiths (Figure 20-1).1,2 Surgery may be required in symptomatic cases and may involve lung resection or broncholithectomy.3

This topic comprises a vast range of pathogens, disease processes, and surgical applications. This chapter focuses on more common scenarios and situations where surgery may play a key role.

Fungal Infections of the Lung Fungi are defined as mushrooms, molds, and yeasts. The distinction between certain bacteria and fungi is vague, and some pathogenic organisms such as Nocardia and Actinomyces, often thought of as fungi, are generally considered to be bacteria. Although innumerable species of fungi are known and many species are in daily contact with mankind, few are pathogenic to healthy humans. Of the potentially pathogenic species most are saprophytic organisms. Following the sustained use of antibiotics, the normal bacteriological ecology may become disordered, allowing normally nonpathological fungi to multiply and become invasive. The use of steroids and cytotoxic and immune suppressive drugs may depress both cellular and humoral immunity. Similarly, debilitating diseases such as tuberculosis (TB), diabetes, and acquired immunodeficiency syndrome (AIDS) may also depress the immune system and provide an ideal milieu for proliferation. The term “opportunistic” frequently applies to the development of pulmonary fungal infections. Clinical approach will be modified by the circumstances leading to the infection.

Secondary Infections: Preexisting Lung Damage Healthy lungs are naturally resistant to fungal colonization. Parenchymal damage from other disease processes may lead to impairment of host defenses to clear inhaled spores. The spores may colonize and germinate in a variety of lung cavities. Typical cavities include those caused by TB, sarcoidosis, bronchiectasis, lung abscess, cavitated neoplasms, and other forms of fungal disease. The accumulation of layers of saprophytic fungus, cellular debris fibrin, and inflammatory cells forms a ball of necrotic material: a mycetoma or “fungus ball.” The ball may be attached to the wall of the cavity but is usually not. This leads to the “ball-in-a-hole” appearance with movement as seen on decubitus radiographs (Figure 20-2). Occasionally the mycetoma fills the cavity, limiting this move-

Primary Infections A “primary infection” presumes a de novo infection in an otherwise healthy human with normal lung parenchyma. In most cases this is usually self-limited, except in the case of overwhelming infection. The fungal agent in each 251

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FIGURE 20-2. Mycetoma. Young male presented with episodic hemoptysis. He had a history of being treated for tuberculosis as a child. Chest radiograph showed a classic “ball-in-a-hole” appearance of a mycetoma. FIGURE 20-1. Broncholithiasis. This male in his mid-20s presented with a history of minor hemoptysis and the coughing of “stones.” He had grown up along the St. Lawrence River in Canada. Chest radiograph and computed tomography show multiple calcified mediastinal lymph nodes. Bronchoscopy shows erosion into the left main stem bronchus just below the carina. The area was debrided for a quantity of calcified debris through the rigid bronchoscope with resolution of symptoms. Presumed cause was histoplasmosis.

ment but still often leaving a rim—the “air-crescent” sign. Usually fungal balls appear in the apices of lungs that reflect the origins of the preexisting lung disease. Tomography and computed tomography (CT) scans demonstrate the findings even better. The CT scan shows the fungal balls as sponge-like masses containing irregular air spaces. The radiological appearance is not absolutely pathognomonic, however, as a clot or necrotic lung tissue can lead to a similar appearance. Aspergillus fumigatus is the most frequent cause of mycetoma (an “aspergilloma”). Positive serum precipitins will be present in over 90% of patients but is not specific for aspergilloma and may be positive in other forms of pulmonary aspergillosis.4 Under normal circumstances it is nonpathogenic. Coccidioidomycosis can rarely cause fungus balls5 as may sporotrichosis (Figure 20-3). With mucormycosis, fungus balls may occasionally occur in the lung after aspiration but may occasionally heal spontaneously. Unlike aspergillus, the fungus often invades

hilar vessels and structures frequently leading to venous thrombosis and pulmonary infarction. The presence of the fungus sets up an intense local inflammatory reaction often with resultant proliferation of bronchial blood supply. Hemoptysis is seen in over 50% of patients and is occasionally massive. The mechanism of bleeding is unknown and has been attributed to friction, liberated endotoxins, or a type III inflammatory reaction in the cavity wall.6 Often it appears to result from superinfection and is often self-limited and simply treated with antibiotics. Rarely the fungus invades beyond the cavity, invading local structures or eroding into the pleural space. Local invasion is more common with impaired host defenses and may complicate malnutrition, diabetes, or steroid treatment. Occasionally the presence of a fungal ball may confuse the diagnosis of other coexistent disorders, such as carcinoma. Secondary Infection: Immune Suppression non–hiv-associated immune suppression Loss of immunity to infection can occur in a number of disease processes. The type of immune suppression determines to a large extent the risk and type of resultant fungal infection. Steroids and chemotherapeutic agents for malignancy cause depletion in most host responses. Granulocyte impairment is common with acute and chronic leukemia,

Surgery for Fungal and Mycobacterial Diseases / 253

ciency virus (HIV)-associated immune suppression is Candida albicans. Outside of diagnostic biopsy, surgical intervention is seldom indicated. Unfortunately, most patients present in terminal stages of disease with diffuse infection. The next most common fungal infection is mucormycosis, which tends to be more common in the more severely immune-suppressed patients, such as leukemia or bone marrow transplant patients. In neutropenic patients, pulmonary mucormycosis is similar to invasive aspergillosis with fever, pleuritic chest pain, and hemoptysis.8 Hemoptysis can be massive and fatal and is the result of angioinvasion causing pulmonary infarction.9 Infection with mucormycosis also occasionally complicates diabetes mellitus with ketoacidosis often being a precipitating factor (Figure 20-5). The most striking pathological feature is vascular invasion resulting in pulmonary infarction. Cavitation is common and in most cases represents sloughed lung. Once established, the infection may impair the insulin requirement and the ability to bring the blood sugar under control. Diabetes may also lead to progressive forms of normally selflimited disease processes, such as coccidioidomycosis, that may require early surgical intervention.10 FIGURE 20-3. Sporotrichosis. A 56-year-old male with a history of treated tuberculosis. He presented with frequent pulmonary infections and occasional minor hemoptysis. Radiograph shows appearance suggestive of aspergilloma. Sputum, however, grew sporotrichosis.

hiv and aids The world HIV pandemic is rewriting the book on mycoses and TB. The virus responsible for AIDS is a retrovirus that attaches to the CD4 surface glycoprotein

and irradiation. T-lymphocyte impairment is common in lymphoma, solid organ transplantation, and renal insufficiency. B-lymphocyte deficit is common in myeloma, lymphomas, and leukemia. Similarly, thymic aplasia, or splenectomy can result in a reduction of humoral immunity. A nonspecific reduction in host resistance occurs in advanced age, alcoholism, diabetes, malnutrition, or debilitation from advanced disease or malignancy. Fungal infections are not uncommon as a terminal complication in malignant lymphoma and myeloid leukemia. Aspergillus is a relatively uncommon infectious agent in AIDS; however, it is a major pathogen in patients with lymphoma or leukemia.7 In addition it is a major problem for patients being considered for bone marrow transplantation. The radiological appearance may be confused with infarct but may also cause occlusion by invasion of local vessels. The development of early pulmonary changes suggestive of aspergillus infection in these patients may create a treatment dilemma where resection may be required for diagnosis as well as for treatment of disease and prevention of progression during treatment (Figure 20-4). The second most common fungal infection in non–human immunodefi-

FIGURE 20-4. Invasive aspergillus. Young male patient undergoing chemotherapy for acute myelogenous leukemia developed fever. Radiograph shows infiltration of his left lower lobe. Sputum revealed aspergillus. Succumbed to disseminated aspergillus despite antifungal therapy.

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FIGURE 20-5. Mucormycosis. A and B, Middle-aged diabetic patient presented with ketoacidosis and sepsis. Radiograph shows deterioration despite broad-spectrum antibiotic coverage. A totally necrotic middle lobe was resected under antifungal drug coverage with eventual resolution of the infection.

of helper T-lymphocytes, monocytes, macrophages, and other antigen-producing cells. The virus replicates within helper T-lymphocytes, eventually destroying infected cells leading to the characteristic CD4 lymphocyte depletion. Cell-mediated immunity becomes increasingly depressed as the CD4 lymphocyte count falls. A normal person has more than 450 CD4 lymphocytes/mm3. As the count falls, patients become increasing prone to infections. When the count falls below 100 the patient typically becomes prone to TB, atypical mycobacterial infection, and fungal infections. Often during the course of AIDS treatment fungi tend to cause frequent minor infections, because total eradication requires an active cell-mediated response. Virtually all forms of fungal infections have been documented in AIDS patients.11,12 Antiretrovirals have prolonged the survival of AIDS patients with low CD4 counts and may contribute to the development of opportunistic infections. The use of broad-spectrum antibiotics and steroids all contribute to the development of fungal infections. The clinical symptoms are nonspecific, and major risk factors include neutropenia, which is often a side effect of various therapies for AIDS, and steroid administration. Pulmonary cryptococcosis is a frequent manifestation of the disease in patients with AIDS, appearing in about 2% of patients.13 The incidence of aspergillus infections in HIV-positive patients is less than 1%. This is in contrast to up to 41% in acute leukemia.14 This is due to the difference in the cell-mediated immune deficiency in the former and granulocyte-mediated deficit in the latter. Although the incidence is low, there is a tendency for the development of invasive and disseminated forms of aspergillus in AIDS patients.15 Most cases appear to occur in advanced stages of AIDS and have a dismal prognosis. Neutropenia appears to play a large role. Patients tend to have a very low CD4 count and frequently have comorbid illness such as pneumocystis pneumonia or cytomegalovirus and are often under treatment with antiviral drugs or chemotherapy for lymphoma or other AIDSrelated malignancies.16 Unlike other risk groups that tend to contract only one form of pulmonary aspergillosis, AIDS patients can develop the whole spectrum of aspergillosis-related pulmonary disorders, including chronic cavitary, invasive, and bronchial forms of aspergillosis.16,17 Patients with the chronic cavitary form of disease have an unusually high mortality due to fatal hemoptysis.17 Currently, little firm data exist to establish the role of surgery for thoracic fungal infections in patients with HIV infection and AIDS. Moreover, the risk factors for such interventions are not yet known. Most patients with fungal infections are in advanced stages of disease. As in other forms of surgical intervention in AIDS patients, the

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CD4 count may be helpful in determining the advisability and timing of surgery. Indications for Thoracic Surgical Intervention establishing a diagnosis Numerous fungal disease processes can mimic solitary pulmonary nodules, limited areas of consolidation, cavitating lesions, or other radiological presentations suggestive of pulmonary malignancy leading to diagnostic confusion (Figures 20-6 and 20-7). In cases where the patient is asymptomatic, young (less than age 40 years), and a nonsmoker or where old radiographs show no change in size, frequently observation can be justified. In other instances, such as in older patients, particularly smokers, the decision-making process can be difficult. Demonstration of calcification within nodules can be comforting and suggest a benign process; however, this is not 100% accurate. New modalities such as positron emission tomography scan can be equivocal in acute inflammatory processes.18 Alternately, the demonstration of fungal elements in the sputum is not specific for the diagnosis of infection over malignancy. In a series by Duperval and colleagues 25% of patients with radiological abnormalities and Cryptococcus neoformans in the sputum had a final diagnosis of malignancy. 19 Fungal infections can also mimic more diffuse presentation of malignancy and may provide considerable confusion in interpretation of diagnostic tests.20–22 I have been personally involved in two cases where invasive fungal infection and malignancy coexisted. At time of surgery the gross presentation can be confusing. In immune-suppressed individuals, common symptoms of cough, fever, and chest pain are nonspecific. In addition, most radiological signs are inconclusive. Concurrent bacterial infections are common and may occur in a high percentage of patients, and investigations are often not taken beyond this stage initially. Many serological tests are dependent on immune response and may be falsely negative. In a review by Tedder and colleagues, only 44% of mucormycosis patients were diagnosed antemortem and often ineffective treatment was applied.23 A diagnostic dilemma may arise where symptomatic infections are unresponsive to common antibiotic regimens and there is reluctance to subject a patient to prolonged and toxic antifungal treatment without proof. Furthermore, the commencement of induction chemotherapy with patients harboring a fungal infection can be a fatal event. Diagnosis can often be obtained by transbronchial biopsy or lavage, but in high-risk cases, open biopsy may be prudent. In cases where a diagnostic dilemma exists, a course of empiric treatment may be indicated. If no improvement occurs in 48 to 72 hours, surgical treatment should be considered. In these cases total extirpa-

FIGURE 20-6. Solitary pulmonary nodule: coccidioidomycosis. Middleaged smoking male presented with a well-circumscribed mass in the left upper lobe. Excision showed this to be secondary to coccidioidomycosis.

FIGURE 20-7. Mucormycosis. Middle-aged nonsmoking patient presented with cough. Chest radiograph shows a midzone right-sided lung mass. Bronchoscopy and fine needle biopsy nondiagnostic. Resected and shown to be due to mucormycosis. Underlying cause not apparent.

tion may provide both diagnosis and assistance in treatment.23,24 In all instances proper handling of specimens is essential for accurate diagnosis.

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In a review of 36 non–HIV-associated immunesuppressed patients eventually having thoracotomy for fungal infections by Temeck and colleagues, most were done on an urgent basis in symptomatic patients without a diagnosis.25 Therapeutic changes were instituted on 23 (64%) of these patients as a result of the intervention. Of note, survival was statistically related to the demonstration of angioinvasion in the pathology specimen. Other factors were low granulocyte count and the use of chemotherapy and steroids. Though 25% of patients had complications from the procedures, patients who succumbed tended to do so from the underlying disease or other infective factors. treatment of disease Aggressive operative treatment of fungal infections of the lungs combined with antifungal chemotherapy before transplant may offer the best hope of extended survival in patients with localized disease.26,27 In a series by Salerno and colleagues, surgical resection of invasive pulmonary aspergillosis (IPA) cleared the aspergillus infection in 69% of the patients in the perioperative period around bone marrow transplantation. 28 In immune-compromised patients with hematologic diseases or liver transplantation with IPA, early pulmonary resection should be strongly considered when the characteristic clinical and radiographic pictures appear and the disease is localized.29 Surgery may play an important role in IPA complicating treatment in leukemia patients. Baron and colleagues in a review of 18 patients observed improved survival in patients diagnosed with IPA.30 Furthermore, the point was made that hemoptysis was common in IPA patients despite antifungal treatment. It was also hypothesized that resection would likely reduce the relapse rate. Resection may also speed the reintroduction of essential chemotherapy in infected patients. Of note, of 36 patients with documented aspergillus infection compiled by Miller and colleagues, the only patient ultimately cured had resection for hemoptysis.17 It would be difficult to determine in a study whether “debulking” or removal of the only known site of fungal lung disease would have a positive impact on cure in cases of general immune suppression. A literature review by Wright and colleagues revealed that of 21 diabetic patients in whom mucormycosis occurred without underlying malignancy, only 7 survived.31 Of note, these 7 underwent operation. In a review by Tedder and colleagues of 92 patients in whom the diagnosis was made of mucormycosis, patients treated surgically had a significantly lower mortality (9.4% vs 50%, p = .01) than those treated medically.23 Prompt diagnosis of mucormycosis (usually requiring biopsy) is often essential to reduce the mortality rate to allow prompt treatment with amphotericin B and surgical excision of necrotic lung.32 Cryptococcal infections can occur in a

variety of circumstances. In certain instances the disease is focal and can be encompassed by resection (Figure 20-8). Major Hemoptysis Major hemoptysis may occur from the erosion into a pulmonary vessel by an acute fungal infection. It is frequently a terminal event. More frequently, recurrent hemoptysis occurs as a complication of a long-standing aspergilloma. In these cases the presence of the fungus creates an intense local reaction and the area becomes neovascularized over time. Hemoptysis occurs in approximately 50% of patients, and in 10% the hemoptysis is severe and recurrent. Superimposed bacterial infection usually accompanies the episodes of hemoptysis, and medical therapy with bed rest, antibiotics, and postural drainage was successful in controlling the hemorrhage in the majority of cases.33 The prognosis of aspergilloma is related primarily to the nature and severity of the underlying disease.34 For intermittent episodes of non–lifethreatening hemoptysis it may be argued that routine surgical excision of aspergilloma is not indicated. Where episodes are recurrent or life-threatening, resection of the mycetoma is indicated where possible. This will involve careful planning to resect the underlying damaged lung with maximal preservation of overall respiratory function. The surgery can be very difficult because of the intense inflammation often surrounding the fungus and obliterating normal tissue planes. For nonsurgical cases,

FIGURE 20-8. Cryptococcal infection. Sixty-eight-year-old female patient with history of central nervous system cryptococcal infection. Radiograph shows well-circumscribed cryptococcoma in the right lower lobe of the lung. Treated by prolonged course of antifungal chemotherapy.

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treatment by intracavitary amphotericin B may alleviate hemoptysis with no loss of lung function.35,36 Massive hemoptysis in the course of mucormycosis is a particularly lethal event, and most successful cases involve a combination of surgery and antifungal chemotherapy.37 Chest Wall Invasion or Infection Chest wall infection may occur with actinomyces and sporotrichosis in non–immune-compromised patients. In most cases the disease process is an extension of lung pathology. Other infection such as aspergillosis can involve the chest wall in the immune compromised host.38 Under ordinary circumstances antifungal therapy should suffice with surgical debridement reserved for severe cases. Trachea and Airway Involvement Tracheal involvement by mucormycosis, particularly in diabetics or severe immune compromise, can lead to extensive destruction of the trachea and death.39,40 While treatment with amphotericin B is the mainstay of therapy for pulmonary mucormycosis in diabetics, early aggressive surgical resection of the involved lung tissue may be indicated.41 Pseudomembranous and obstructing casts with aspergillus can lead to varying degrees of airway obstruction with aspergillus in AIDS. This manifestation of aspergillus infection appears to be AIDS-specific.17,42

viduals. Because of HIV and other factors, it is making a resurgence in many first-world countries. The development of drug-resistant strains in certain areas of the Western world appears to be directly linked to treatment of patients with coexistent AIDS and TB. The impairment of cellmediated response may make the tuberculin test falsely negative on 50 to 70% of patients with advanced AIDS, leading to diagnostic confusion (Figure 20–9). TABLE 20-1. Indications for Surgery for Tuberculosis Treatment of the disease itself Persistent positive sputum-drug sensitive Persistent positive sputum drug resistant Poorly compliant patient Patient with drug intolerance or allergy Multiple relapses despite good drug response Initial episode but residual cavitation despite good response Totally destroyed lobe/lung Cold Abscess of chest wall Treatment of complications of active tuberculosis Pleural extension Acute hemoptysis Obstructive lymphadenopathy Treatment of sequelae of old tuberculosis Bronchial stenosis Bronchiectasis Cysts and bullae Aspergilloma

Mycobacterial Infection TB Resection of affected lung parenchyma for TB became increasingly common in the 1940s; however, thoracoplasty (collapse treatment) remained the most popular treatment of choice until the introduction of effective antituberculous agents. With the development of rifampicin in 1966, surgery was seldom needed except for the occasional massive hemoptysis, bronchial stenosis, or bronchopleural fistula or to rule out cancer. In most developed countries TB steadily declined until 1985; thereafter there has been a steady increase worldwide with a 50% increase in reported cases in the last decade (World Health Organization statistics). With the rise of drugresistant TB, surgical procedures are again being needed in the primary treatment of mycobacterial disease. The general indications for surgery are listed in Table 20-1. The risk of TB infection depends on the concentration of the bacilli in the environment, which in turn is linked to poverty and overcrowding. For these and other economic and political reasons, pulmonary TB remains endemic in many parts of the lesser-developed world. In Africa, Myobacterium tuberculosis is the most common pathogen in HIV-infected patients. The increase in the general disease pool in turn increases the disease amongst non-HIV indi-

FIGURE 20-9. Tuberculosis in a patient positive for human immunodeficiency virus (HIV). Young male patient with known HIV presented with massive hemoptysis. Sputum was heavily positive for acid-fast bacilli. Chest radiograph shows patch consolidation predominantly in the right lower lobe. Hemoptysis settled with sedation and antituberculous drug therapy.

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Indications for Surgery treatment of tb The major indications for surgery of active TB are where patients remain sputum-positive despite adequate sensitivity-directed drug therapy (Figure 20-10) or harbor drug-resistant organisms (Figure 20-11). The objective of surgery will be to ablate areas of gross cavitation and destruction that act as sheltered reservoirs. Adequate chemotherapy should cover the patient in the peri- and postoperative period. Multidrug-resistant patients may require prolonged courses of treatment to maximize the potential for permanent cure. In a series of 62 patients undergoing pulmonary resection for drug-resistant strains of M. tuberculosis, 75% who were persistently sputum-positive at the time of operation immediately converted to a negative sputum smear and culture.43 For all patients who were sputumnegative after operation, 80% remain relapse-free by actuarial analysis. Other series have reported similar good results.44 For drug-resistant TB, sputum conversion can be achieved in over 75% of patients who had failed with drug therapy alone with a combination of surgery and antituberculous therapy.43 treatment of complications: active pulmonary tb Extension of pulmonary foci through the pleural surface of the lung may lead to tuberculosis effusion, pneumothorax, or combinations thereof. Infection of effusions via the bronchi or inappropriate chest drainage may lead to superinfection and the development of a tuberculous empyema. In most patients the diagnosis of the effusion is straightforward. In a smaller percentage of patients the cause of the effusion may be difficult to identify even with multiple aspirations and pleural biopsy. In these patients, the use of diagnostic thoracoscopy may provide the diagnosis in cases refractory to other methods. For simple tuberculous effusions, treatment with appropriate antituberculous therapy suffices in most instances. Where the volume of effusion is troublesome, then sterile aspiration may provide interim relief. One should avoid the use of intercostal drains unless absolutely necessary, for fear of introducing infection. For tuberculous-related pneumothorax, intercostal drainage in conjunction with chemotherapy is successful in most cases. When the underlying lung is severely damaged, this may lead to poor expansion; however, there is little indication for surgery at this stage. The provision of long-term drainage and TB treatment often will suffice (Figure 20-12). The occurrence of life-threatening hemoptysis is a rare but potentially lethal complication of acute pul-

FIGURE 20-10. Progression of tuberculosis (TB) despite drug therapy. Patient with persistent drug-sensitive TB despite 12-month antituberculous treatment. A, Chest radiograph shows persistent opacity in left upper lobe lung. Lung resection offered but refused. B, Progressive lung destruction over 24 months despite continuation of treatment.

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monary TB. It may occur as a complication of active TB, with cavitation extending to involve pulmonary arterial supply. Lung damage from disease may lead to

FIGURE 20-11. Young male patient with multidrug-resistant tuberculosis. Chest radiograph shows opacity predominantly in right upper lobe. Treated successfully with pneumonectomy plus a regimen of appropriate antituberculous drugs.

FIGURE 20-12. Tuberculous pyopneumothorax. Male patient under treatment for tuberculous developed sudden shortness of breath. A. Chest radiograph shows a large right hydro-pneumothorax. B and C, Treated with intercostal drainage for 2 months. Radiographs show progressive expansion of lung.

bronchiectasis (Figure 20-13) with neovascularization of areas, presumably a result of chronic inflammation. The bronchial arterial supply can be prolific in many instances (Figure 20-14). Cavitation may lead to mycetoma formation (see Figure 20-2). Our opinion is that such patients require hospital admission, preferably under the auspices of a service that can provide full treatment of all eventualities. Initial treatment consists of antituberculous treatment, sedation, and cough suppression and the treatment of common superinfection with broad-spectrum antibiotics. The site of hemorrhage is often evident on the plain chest x-ray film but on occasion is obscured by widespread TB or blood aspiration.

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The majority of patients respond to this regimen, but some may persist to the extent that surgery is indicated.

FIGURE 20-13. Posttuberculous bronchiectasis. Young female patient with a history of tuberculosis in childhood. Presented with chronic cough and copious daily sputum production. Chest radiograph shows a bronchiectatic right upper lobe. Treated with a right upper lobectomy.

Tuberculous adenopathy causing airway obstruction is most commonly seen in the pediatric population. The pathology is peribronchial nodal compression of the airway by surrounding lymph node groups (Figure 2015). Most cases respond to careful observation with antituberculosis treatment. A few will require steroid treatment and even fewer surgical intervention. The surgery consists of the emptying of the nodes of their caseating contents as the actual removal of the inflamed node attached to the bronchus may be met with serious airway damage.45 treatment of tb complications Bronchial stenosis may result from endobronchial TB. The damage may lead to secretion retention with resultant chronic infection leading to bronchiectasis or abscess formation. Partial obstruction may lead to lobar collapse or the development of bullae and hyperinflation (Figure 20-16). As often the distal lung is damaged beyond salvage, resection is often indicated. Bronchiectasis (Figure 20-17) may occur as a direct complication of tuberculosis infection or as a result of superimposed, often multiple, bacterial infections. The pathology of bronchial dilation, chronic pooling of secre-

FIGURE 20-14. Posttuberculous bronchiectasis with massive hemoptysis. Young male presented with multiple recurrent episodes of massive hemoptysis. He had a history of old tuberculosis and secondary bronchiectasis. His lung function precluded resection. A, Angiography revealed large bronchial arteries extending from the subclavian artery. B, These were embolized with coils with good result.

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tions leads to chronic fetid sputum and recurrent local and distant sepsis formation with the risk of serious complications such as hemoptysis or metastatic abscess formation.

The treatment is generally medical for minimally symptomatic disease or for instances where it is diffuse or multifocal. Where complications are evident and the disease localized, resection may be the treatment of choice. Chest Wall TB “Cold abscesses” of chest wall are rare and often act as an extension of intrathoracic disease. Often the lesions are solitary, the most frequent location being the rib shaft.46 In many instances, disease affecting the chest wall is a direct extension of pulmonary or pleural involvement (Figure 20-18). Primary sternal TB is rare but troublesome when encountered. Treatment may require debridement, muscle flap coverage, and long-term chemotherapy.47

FIGURE 20-15. Airway obstruction due to tuberculous adenopathy. Six-month-old infant presented with increasing stridor. Noted to have open tuberculosis case in immediate family. Gastric washing reveal acid-fast bacilli. Chest radiograph shows trachea compressed by adenopathy. Treated successfully with a combination of tuberculosis treatment and steroids.

Atypical Mycobacterial Infections Rarely, mycobacteria other than M. tuberculosis are identified as causes of pulmonary infection. These include Mycobacterium kansasii, Mycobacterium avium-intracellulare, Mycobacterium fortuitum and other species. They are ubiquitous organisms and often appear as contaminants when screening for TB and may occasionally be mistaken as multidrug-resistant tuberculosis species from culture. Radiologically, cavitation is frequent and may be indistinguishable from reactivation TB

FIGURE 20-16. Bulla secondary to tuberculosis. Middle-aged patient with known past history of treated tuberculosis presented with increasing shortness of breath. Chest radiograph shows a large bullae in the left hemithorax. Bronchoscopy showed a stenosis of the left upper lobe bronchial orifice. Treated with a left upper lobectomy.

FIGURE 20-17. Total lung bronchiectasis secondary to tuberculosis. Young male patient presented with recurrent lung infections. Treated for tuberculosis on two prior occasions. Chest radiograph shows a completely destroyed left lung. Treated with a left pneumonectomy.

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FIGURE 20-19. Nontuberculous mycobacterium infection. Young female patient originally treated for presumed drug-resistant tuberculosis. Radiograph shows total destruction of the right lung. Culture returned as Mycobacterium avium-intracellulare. Treated by pneumonectomy plus antituberculous chemotherapy. FIGURE 20-18. Rib destruction secondary to tuberculosis. Young female patient presented with cough, fever, and left-sided chest pain. Chest radiograph shows a pulmonary infiltrate and a lucency in the left seventh rib. Sputum was positive for acid-fast bacilli. Patient was treated with antituberculous treatment with resolution.

(Figure 20-19). On occasion, invasive characteristics may be displayed that are unresponsive to chemotherapy. In these scenarios treatment is according to similar criteria as for patients with drug-resistant TB.

Inflammatory Lung Disease Generally few Western centers have a large experience in surgery for inflammatory disease of the lung. Conversely, the experience with fungal diseases associated with transplantation and malignancy is higher. A contentious issue is the role of surgery in patients with HIV or AIDS. In populations with high incidences of HIV, there will be a subset of patients who are merely infected and not severely immune-depressed. In these cases the presence of the virus should not strongly influence the decisionmaking process. For AIDS patients, few data are available specifically for thoracic surgical operations, but other surgical procedures have supported a pragmatic approach, taking into consideration long- and shortterm prognostic indicators. Our own policy is to evaluate each case on its own merits.

The results for surgery for fungal diseases vary widely on the circumstances and indication for operation. Intuitively, operations in situations of healthy patients for the objective of diagnosis will vary tremendously from those conducted for salvage of patients in extremis where no other recourse is possible. Technical Approach Resections are often limited by preexisting lung damage.48 Procedures are often a challenge for the surgeon not acquainted with the nuances of resection for inflammatory lung disease. The general physical status of the patient and pulmonary function must be considered in selecting the patient for surgery. Detailed pulmonary function testing in conjunction with functional assessment of lung performance via quantitative perfusion scans may differentiate the necessity for a pneumonectomy from the need for a lobectomy. Preoperative preparation is foremost in importance, along with the timing of intervention. Where active infection and sputum production is heavy, antibiotics, postural drainage, and active physiotherapy are indicated. Abscess and empyema should be drained and treated prior to resection. Tight diabetic control should be instituted. Expert anesthetic control is pivotal to successful resection. With a standard thoracotomy position, risk of soiling the

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dependant lung is a danger. We routinely use a double lumen tube and only occasionally resort to bronchial blockers. Pre- and postoperative bronchoscopy is helpful with prolific secretions. Soiling during induction should result in the deferring of the procedure. In Conlan and colleagues49 one-third of deaths were because of spill, in Stevens and colleagues50 100% of deaths resulted from spill, and in Odell and Henderson 51 it was the most common cause of death. Pain control in the perioperative period is adequately managed by epidural analgesia, patient-controlled analgesia, or a combination of techniques. The aim at the end of a procedure should be the extubation of the patient in the operating room. We have never had occasion to electively use a sternotomy for inflammatory lung resection, though some authors advocate it.52 Conlan notes concerns of access to the posterior mediastinum, hilum, and diaphragm, particularly on the left, and risk of sternal and mediastinal sepsis.53 We have not found that resection of ribs as advocated by some authors improves exposure.54 In 1 of 25 of Massard and colleagues’ patients an additional incision was necessary to take down difficult diaphragmatic adhesions.55 We routinely start with a serratus sparing incision and only extend anteriorly if difficulties occur. In situations where double lumen control cannot be achieved (typicall in children), the use of the prone position may be advisable.49 In acute infective processes, pleural adhesions are often minimal and easily dissected.30 However, in chronic longstanding cases, intrapleural dissection is usually not achievable, but when possible it may minimize the blood loss.54 Reed and colleagues noted that extrapleural dissection was unhelpful because the inflammatory process extended into the endothoracic fascia.56 In many instances the mediastinum is fortunately spared from severe adhesions, presumably due to the motion of the contents.57,58 In addition Dugan and Samson note the general lack of adhesions to the aorta on the left as well.58 Despite the approach, blood loss can be high, with Regnard and colleagues reporting 71% of patients requiring blood transfusions.48 Use of electrocautery as a dissection tool may lead to excessive tissue thermal damage. Paramount to successful resection is control of the hilar vessels. Anatomical distortion can occur, as can obliteration of normal planes of dissection. Reed noted that most of her surgeons encountered distortion of the hilar vessels.52 Using a stepwise approach, the author has seldom had to resort to intrapericardial dissection. Massard and colleagues noted difficult hilar dissection in 9 of 25 patients and resorted to intrapericardial dissection in 6.55 We routinely staple pneumonectomy stumps and sew lesser resections. We bury our left stumps and close the right with a pleural flap. Reed stapled all stumps and did

not cover any.52 Pomerantz and colleagues advocate the routine use of muscle flaps when the sputum is positive for mycobacterium, polymicrobial contamination, and preoperative bronchopleural fistula.59 I agree with Conlan and colleagues, who note that the peribronchial neovascularization will likely enhance the healing potential.49 In his series of 124 patients, 72 were stapled (4 fistulas) and 52 hand-sewn (3 fistulas). I do not advocate the routine use of muscle flap as have other authors 60 but rather reserve them for the treatment of complications. Frequently, patients with aspergilloma have extensive lung damage and cannot be considered for resection. Regnard and colleagues found cavernostomy to be a satisfactor y alternate where resection cannot be tolerated.48 Muscle interposition into the cavity may be a logical extension. 6 1 Intracavitary administration of amphotericin through an indwelling catheter should be considered for any patient who has troublesome sputum production, hemoptysis, or systemic symptoms attributable to an aspergilloma.62

References 1. Faber LP, Jensik RJ, Chawla SK, Kittle CF. The surgical implication of broncholithiasis. J Thorac Cardiovasc Surg 1975;70:779–89. 2. Trastek VF, Pairolero PC, Ceithaml EL, et al. Surgical management of broncholithiasis. J Thorac Cardiovasc Surg 1985;90:842–8. 3. Potaris K, Miller DL, Trastek VF, et al. Role of surgical resection in broncholithiasis. Ann Thorac Surg 2000;70:248–51. 4. Freundlich IM, Israel HL. Pulmonary aspergillosis. Clin Radiol 1973;24:248–53. 5. Winn RE, Johnson R, Galgiani JN, et al. Cavitary coccidioidomycosis with fungus ball formation. Diagnosis by fiberoptic bronchoscopy with coexistence of hyphae and spherules. Chest 1994;105:412–6. 6. Johnson JS. Pulmonary aspergillosis. Semin Respir Med 1987;9:187–99. 7. Herbert PA, Bayer AS. Fungal pneumonia (Part 4): invasive pulmonary aspergillosis. Chest 1981;80:220–5. 8. Majid AA, Yii NW. Granulomatous pulmonary zygomycosis in a patient without underlying illness. Computed tomographic appearances and treatment by pneumonectomy. Chest 1991;100:560–1. 9. Loevner LA, Andrews JC, Francis IR. Multiple mycotic pulmonary artery aneurysms: a complication of invasive mucormycosis. AJR Am J Roentgenol 1992;158:761–2. 10. Baker EJ, Hawkins JA, Waskow EA. Surgery for coccidioidomycosis in 52 diabetic patients with special reference to related immunologic factors. J Thorac Cardiovasc Surg 1978;75:680–7.

264 / Advanced Therapy in Thoracic Surgery 11. Stansell JD. Pulmonary fungal infections in HIV-infected persons. Semin Respir Infect 1993;8:116–23. 12. Cendan I, Klapholz A, Talavera W. Pulmonary actinomycosis. A cause of endobronchial disease in a patient with AIDS. Chest 1993;103:1886–7. 13. Wasser L, Talavera W. Pulmonary cryptococcosis in AIDS. Chest 1987;92:692–5. 14. Meyer RD, Young LS, Armstong D. Aspergillosis complicating neoplastic disease. Am J Med 1973;54:6–15. 15. Klapholz A, Salomon N, Perlman DC, Talavera W. Aspergillosis in the acquired immunodeficiency syndrome. Chest 1991;100:1614–8. 16. Mylonakis E, Barlam TF, Flanigan T, Rich JD. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Chest 1998;114:251–62. 17. Miller WT Jr, Sais GJ, Frank I, et al. Pulmonary aspergillosis in patients with AIDS. Clinical and radiographic correlations. Chest 1994;105:37–44. 18. Orino K, Kawamura M, Hatazawa J, et al. [Efficacy of F-18 fluorodeoxyglucose positron emission tomography (FDGPET) scans in diagnosis of pulmonary nodules]. Jpn J Thorac Cardiovasc Surg 1998;46:1267–74. 19. Duperval R, Hermans PE, Brewer NS, Roberts GD. Cryptococcosis, with emphasis on the significance of isolation of Cryptococcus neoformans from the respiratory tract. Chest 1977;72:13–9. 20. Brombacher-Frey I, Wockel W, Kreusser T. [Thoracic actinomycosis versus bronchial cancer]. [German]. Pneumologie 1992;46:12–9. 21. Hsieh MJ, Liu HP, Chang JP, Chang CH. Thoracic actinomycosis. Chest 1993;104:366–70. 22. Kaestel M, Meyer W, Mittelmeier HO, Gebhardt C. Pulmonary aspergilloma—clinical findings and surgical treatment. Thorac Cardiovasc Surg 1999;47:340–5. 23. Tedder M, Spratt JA, Anstadt MP, et al. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994;57:1044–50. 24. Sarosi G, Armstrong D, Barabee RA, et al. Treatment of fungal diseases. Am Rev Respir Dis 1979;120:1393–7. 25. Temeck BK, Venzon DJ, Moskaluk CA, Pass HI. Thoracotomy for pulmonary mycoses in non–HIV-immunosuppressed patients. Ann Thorac Surg 1994;58:333–8. 26. Lupinetti FM, Behrendt DM, Giller RH, et al. Pulmonary resection for fungal infection in children undergoing bone marrow transplantation. J Thorac Cardiovasc Surg 1992;104:684–7. 27. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis 1990;12:1147–201. 28. Salerno CT, Ouyang DW, Pederson TS, et al. Surgical therapy for pulmonary aspergillosis in immunocompromised patients. Ann Thorac Surg 1998;65:1415–9.

29. Robinson LA, Reed EC, Galbraith TA, et al. Pulmonary resection for invasive Aspergillus infections in immunocompromised patients. J Thorac Cardiovasc Surg 1995;109:1182–96. 30. Baron O, Guillaume B, Moreau P, et al. Aggressive surgical management in localized pulmonary mycotic and nonmycotic infections for neutropenic patients with acute leukemia: report of eighteen cases. J Thorac Cardiovasc Surg 1998;115:63–8. 31. Wright RN, Saxena A, Robin A, Thomas PA. Pulmonary mucormycosis (Phycomycetes) successfully treated by resection. Ann Thorac Surg 1980;29:166–9. 32. McAdams HP, Rosado-de-Christenson M, Strollo DC, Patz EF. Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Am J Roentgenol 1997;168:1541–8. 33. Faulkner SL, Vernon R, Brown PP, et al. Hemoptysis and pulmonary aspergilloma: operative versus nonoperative treatment. Ann Thorac Surg 1978;25:389–92. 34. Varkey B, Rose HD. Pulmonary aspergilloma. A rational approach to treatment. Am J Med 1976;61:626–31. 35. Shapiro MJ, Albelda SM, Mayock RL, McLean GK. Severe hemoptysis associated with pulmonary aspergilloma. Percutaneous intracavitar y treatment. Chest 1988;94:1225–31. 36. Hargis JL, Bone RC, Stewart J, et al. Intracavitary amphotereicin B in the treatment of symptomatic pulmonary aspergillomas. Am J Med 1980;68:389–94. 37. Zapatero J, Flandes J, Ruiz-Zafra J, et al. Bronchovascular mucormycosis: an urgent surgical problem. Eur J Cardiothorac Surg 1995;9:286–8. 38. Caligiuri P, MacMahon H, Courtney J, Weiss L. Opportunistic pulmonary aspergillosis with chest wall invasion. Plain film and computed tomographic findings. Arch Intern Med 1983;143:2323–4. 39. Andrews DR, Allan A, Larbalestier RI. Tracheal mucormycosis. Ann Thorac Surg 1997;63:230–2. 40. Schwartz JR, Nagle MG, Elkins RC, Mohr JA. Mucormycosis of the trachea: an unusual cause of acute upper airway obstruction. Chest 1982;81:653–4. 41. Bigby TD, Serota ML, Tierney LM Jr, Matthay MA. Clinical spectrum of pulmonar y mucormycosis. Chest 1986;89:435–9. 42. Lortholary O, Meyohas MC, Dupont B, et al. Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. French Cooperative Study Group on Aspergillosis in AIDS. Am J Med 1993;95:177–87. 43. van Leuven M, De Groot M, Shean KP, et al. Pulmonary resection as an adjunct in the treatment of multiple drugresistant tuberculosis. Ann Thorac Surg 1997;63:1368–72. 44. Pomerantz BJ, Cleveland J-CJ, Olson HK, Pomerantz M. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg 2001;121:448–53.

Surgery for Fungal and Mycobacterial Diseases / 265 45. Worthington MG, Brink JG, Odell JA, et al. Surgical relief of acute airway obstruction due to primary tuberculosis. Ann Thorac Surg 1993;56:1054–62. 46. Faure E, Souilamas R, Riquet M, et al. Cold abscess of the chest wall: a surgical entity? Ann Thorac Surg 1998;66:1174–8. 47. Sarlak AY, Gundes H, Gundes S, Alp M. Primary sternal tuberculosis: a rare unhealed case treated by resection and local rotational flap. Thorac Cardiovasc Surg 2001;49:58–9. 48. Regnard JF, Icard P, Nicolosi M, et al. Aspergilloma: a series of 89 surgical cases. Ann Thorac Surg 2000;69:898–903. 49. Conlan AA, Lukanich JM, Shutz J, Hurwitz SS. Elective pneumonectomy for benign lung disease: modern-day mortality and morbidity. J Thorac Cardiovasc Surg 1995;110(4 Pt 1):1118–24. 50. Stevens MS, de Villiers SJ, Stanton JJ, Steyn FJ. Pneumonectomy for severe inflammatory lung disease. Results in 64 consecutive cases. Eur J Cardiothorac Surg 1988;2:82–6. 51. Odell JA, Henderson BJ. Pneumonectomy through an empyema. J Thorac Cardiovasc Surg 1985;89:423–7. 52. Reed CE. Pneumonectomy for chronic infection: fraught with danger? Ann Thorac Surg 1995;59:408–11. 53. Laros CD, Westermann CJ. Dilatation, compensatory growth, or both after pneumonectomy during childhood and adolescence. A thirty-year follow-up study. J Thorac Cardiovasc Surg 1987;93:570–6.

54. Deslauriers J. Indications for completion pneumonectomy. Ann Thorac Surg 1988;46:133. 55. Massard G, Dabbagh A, Wihlm JM, et al. Pneumonectomy for chronic infection is a high-risk procedure. Ann Thorac Surg 1996;62:1033–8. 56. Reed CE, Parker EF, Crawford FA Jr. Surgical resection for complications of pulmonary tuberculosis. Ann Thorac Surg 1989;48:165–7. 57. Sarot IA. Extrapleural pneumonectomy and pleurectomy in pulmonary tuberculosis. Thorax 1949;4:173–99. 58. Dugan DJ, Samson PC. Surgical significance of the endothoracic fascia: the anatomic basis for empyemectomy and other extrapleural technics. Am J Surg 1975;130:151–8. 59. Pomerantz M, Madsen L, Goble M, Iseman M. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 1991;52:1108–11. 60. Treasure RL, Seaworth BJ. Current role of surgery in Mycobacterium tuberculosis. Ann Thorac Surg 1995;59:1405–7. 61. Ono N, Sato K, Yokomise H, Tamura K. Surgical management of pulmonary aspergilloma. Role of single-stage cavernostomy with muscle transposition. Jpn J Thorac Cardiovasc Surg 2000;48:56–9. 62. Jackson M, Flower CD, Shneerson JM. Treatment of symptomatic pulmonary aspergillomas with intracavitary instillation of amphotericin B through an indwelling catheter. Thorax 1993;48:928–30.

CHAPTER 21

SURGICAL TREATMENT OF BRONCHIECTASIS AND BRONCHOLITHIASIS JEAN DESLAURIERS, MD, FRCSC

Bronchiectasis

ment, and prognosis differ considerably (Table 21-1).3 Localized bronchiectasis is usually the result of childhood pneumonia and often has a benign course characterized by recurrent pulmonary infections always in the same anatomic territory (Figure 21-1). By contrast, diffuse bronchiectasis is often related to immune deficiencies, is bilateral, and may lead to death from respiratory failure. This chapter specifically addresses some of the important issues in the pathogenesis, pathology, investigation, and management of true bronchiectasis.

Bronchiectasis is defined as permanent dilatations of the bronchi with destruction of the bronchial wall. This definition differentiates true bronchiectasis from functional bronchiectasis or pseudobronchiectasis, which is expected to return to normal once control of infection has been achieved. From the time of Laennec’s description of the disease in 18191 to the discovery of antibiotics, bronchiectasis was considered a morbid disease with a high mortality rate from respiratory failure and cor pulmonale. With the advent of specific antibiotics and prompt recognition and effective treatment of pulmonary infection in childhood, the incidence and surgical significance of bronchiectasis has decreased significantly over the last century. In developing countries, however, bronchiectasis still constitutes a significant problem.2 In the context of clinical practice, there are two types of bronchiectasis, in which the pathogenesis, manage-

History In 1819, Laennec, in his Traité de l’auscultation médiate ou traité du diagnostic des maladies des poumons et du cœur, was the first to describe bronchial dilatations.1 He attributed this condition to accumulation and stagnation of bronchial secretions and emphasized that bronchial dilatations were more likely to occur in the dependent portions of the lung. He further proposed to classify

TABLE 21-1. Localized and Diffuse Bronchiectasis Anatomy Clinical signs

Imaging

Bronchoscopy Spirometry Management Prognosis

Localized Bronchiectasis

Diffuse Bronchiectasis

Confined to one site distal to segmental,lobar, or main bronchus Repeated infections characterized by fever, cough, purulent sputum, and sometimes chest pain and hemoptysis Localized pneumonic infiltrate Loss of volume Localized dilatation on computed tomography Must be done to rule out foreign body or tumor Often normal Surgery for repeated infections, hemoptysis Good

Multisegmental, multilobar, and often bilateral

266

Repeated infections, daily purulent bronchorrhea, sinusitis Rhonchi always present Clubbing common in advanced disease Diffuse disease predominantly in lung bases

Must be done for culture and sensitivity of secretions Mixed obstruction and restriction with decreased Pa02 Surgery seldom indicated Poor with eventual hypoxemia, pulmonary hypertension, and cor pulmonale

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them as cylindrical, saccular, and ampullary. Other significant highlights in the history of bronchiectasis have been eloquently outlined by Ochsner, 4 who mentioned the contributions of Hasse,5 who gave the name bronchiectasis to this condition in 1846, and of Heller,6 who believed that bronchial dilatations were due to external traction secondary to peribronchial scarring. In 1933, Kartagener described the uncommon triad of bronchiectasis, sinusitis, and situs inversus (Figure 21-2).7 Although a successful partial lobectomy was performed for bronchiectasis in 1901 by Heidenhain,8 surgical therapy was not addressed until the anatomy of the disease could be delineated by insufflated bismuth subcarbonate powder9 or iodized oil (Lipiodol)10 into the bronchi. Following these reports, surgery was enthusiastically accepted as the treatment of choice for bronchiectasis. In recent years, however, the number of publications on the surgical treatment of bronchiectasis has decreased considerably, at least in developed countries. This decline is due to the overall improvement of health care and availability of more potent and more specific antibiotics.

FIGURE 21-1. A, Standard PA chest radiograph. B, Bronchogram. C, Computed tomography scan. All three studies show left lower lobe localized varicose bronchiectasis in a 39-year-old symptomatic woman.

Pathology and Anatomic Classification Bronchiectasis is pathologically defined as a condition in which there are abnormal and permanent dilatations of proximal bronchi with predominance at the level of the second to the sixth bronchial division. In general, bronchiectasis affects the most dependent portions of the lung, which include the posterior basal portions of the lower lobes, the middle lobe, and the lingula. Bronchiectasis associated with congenital or familial disorders are often bilateral and diffuse and may involve multiple segments of both lower and upper lobes. Isolated upper lobe bronchiectasis generally relates to prior tuberculosis, bronchopulmonary aspergillosis, or bronchial obstruction. Overall, one-third of cases of bronchiectasis are unilateral and affect a single lobe, onethird are unilateral but affect more than one lobe, and one-third are bilateral. The “middle lobe syndrome” consists of a small atelectatic lobe, often owing to extrinsic bronchial compression secondary to enlarged peribronchial nodes. Factors that are important in the pathogenesis of middle lobe syndrome include the length and small caliber of the middle lobe bronchus, the acute angle of its take-off,11 and the lack of collateral ventilation owing to the relative completeness of the adjacent fissures.12 In addition, lymph nodes located in the vicinity of the middle lobe bronchus receive drainage from the entire right lung. In the context of middle lobe syndrome, several authors have recently indicated that many of these patients may have a neoplasm as the cause of atelectasis.12,13

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Although several anatomic classifications for bronchiectasis have been proposed, the method suggested by Reid in 1950 is certainly the most widely used and easier to correlate with radiologic findings.14 In this morphologic classification, bronchiectasis is divided into (1) a cylindrical variety, in which the dilated bronchi maintain a regular outline until they reach the junction

with smaller airways, where there is obstruction by secretions, (2) a varicose pattern, in which dilated bronchi have irregular contours similar to varicose veins (Figure 21-3), and (3) a more severe form of cystic (Figure 21-4) or saccular bronchiectasis, in which there are cystic dilatations in a patent bronchus or air fluid levels are noted. Reid has also shown that distal destruction was more severe in the saccular than in the cylindrical variety of bronchiectasis and that the dilated airways are commonly filled with pools of thick and purulent material. They can also be occluded by secretions, scar tissue, or distortion. In a classic and elegant study of the pathology and pathogenesis of bronchiectasis published in 1952,

FIGURE 21-2. A, Standard PA chest radiograph, and B, right bronchogram showing the classic image of Kartagener’s syndrome characterized by dextrocardia and bronchiectasis (cylindrical) in the anatomic left lower lobe (patient’s right side).

FIGURE 21-3. A, Standard PA chest radiograph, and B, Computed tomography scan showing varicose bronchiectasis in a 45-year-old asthmatic patient. In this case, the bronchiectasis was thought to be secondary to bronchopulmonary aspergillosis.

Surgical Treatment of Bronchiectasis and Broncholithiasis / 269

signs of atelectasis, chronic pneumonitis, fibrosis, and loss of function.

FIGURE 21-4. Cystic bronchiectasis of the left upper lobe seen in a 24-year-old male.

Whitwell tried to correlate the pathology of bronchiectasis to the patient’s age, symptoms, duration of disease, and the nature of causative illnesses.15 He suggested that bronchiectasis should be divided into (1) follicular bronchiectasis, characterized by excessive formation of lymphoid tissue both in the walls of dilated bronchi and in enlarged lymph nodes and thought to be sequelae of whooping cough, measles, or bronchopneumonia, (2) saccular bronchiectasis, characterized by loss of bronchial structures in the sacculi and of alveoli around them, and (3) atelectatic bronchiectasis, in which lung collapse leads to bronchiectasis. More recently, Ashour proposed a functional classification, which not only reflects the degree of severity of the disease but also predicts whether the involved lung has function with regard to gas exchange.16,17 In his review of 17 patients with bilateral bronchiectasis, he was able to correlate perfused bronchiectasis with intact pulmonary artery flow and cylindrical changes and nonperfused bronchiectasis with absent pulmonary artery flow, retrograde filling of the pulmonary artery through the systemic circulation, and cystic bronchiectatic changes. Gross examination of bronchiectatic lungs shows dilatations of the bronchi that are filled with suppurative yellow-green secretions. The bronchial mucosa is often edematous, ulcerated, or frankly necrotic. It is interesting to note that within a lobe, the disease is often limited to one or two segments while the others appear entirely normal. Microscopically, the disease is characterized by the loss of ciliated epithelium, mucoelastic tissue, and occasionally cartilage. Ultimately, the scarring of the bronchial wall will result in contraction of peribronchial tissues, creating further bronchial dilatations. There is often bronchial artery hyperplasia with abnormal communications between systemic and pulmonary arterial circulation. In general, the distal lung demonstrates

Pathophysiology and Pathogenesis The development of bronchiectasis is associated with a wide spectrum of causative factors (Table 21-2), which often interact together and lead to retention of secretions, infection, and secondary damage to the bronchi and lung. In general terms, pathogenicity can be divided into factors related to the host, which are often congenital or familial, and factors related to an acquired disease process. Bronchiectasis resulting from congenital causes is more likely to be diffuse, whereas if caused by infection, it is more likely to be localized. Most cases of bronchiectasis are acquired and result from prior bacterial or viral bronchopneumonia. In a review of 123 patients with documented bronchiectasis analyzed by Brooke Nicotra and colleagues, 86 patients (70%) gave a history of a significant pulmonary event preceding the onset of the respiratory symptoms, most of whom were able to specify when they felt the event had occurred. 1 8 A single severe pneumonia or repeated moderate infection can lead to destruction of the bronchial cilium, retention of secretions, or irreversible damage to the bronchial wall. Any type of poorly treated or prolonged viral or bacterial pneumonia—such as those caused by pertussis, measles, or influenza—can predispose to the development of bronchiectasis. In such cases, the specific nature of the infection is not as important as the bronchial obstruction, prolonged infection, and delayed resolution. Although uncommon in developed countries, pulmonary tuberculosis is still prevalent in underdeveloped countries, and it can produce bronchiectasis by bronchial obstruction secondary to enlarged nodes or by distortion of segmental bronchi adjacent to a healing cavity. Bronchial obstruction from either endobronchial pathology or external compression can also be an acquired factor predisposing to the development of TABLE 21-2. Pathogenesis of Bronchiectasis Acquired factors

Host factors (15%)

Unknown factors (10%)

Infection (60%) Bacterial or viral Tuberculosis Obstruction (15%) Intrinsic: foreign bodies, aspiration Extrinsic: enlarged nodes Congenital ciliary defects, Kartagener’s syndrome Cystic fibrosis Immunoglobulin deficiencies Alpha-1-antitrypsin deficiencies Others

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bronchiectasis. Aspirated foreign bodies or gastric contents, slow-growing neoplasms, and mucous impaction can all cause local retention of secretions, secondary infection, and bronchiectasis. Inhalation of peanuts is specifically dangerous in children, in whom bronchiectasis can develop within a matter of a few days. Functional bronchial obstruction can also be a factor in the pathogenesis of diffuse bronchiectasis in cases of chronic bronchitis or allergic bronchopulmonary aspergillosis. Perhaps the most common extrinsic factor related to the development of bronchiectasis is the bronchial aspiration of infected mucus from the nasal accessory sinuses. Host factors per se are uncommon causes of bronchiectasis, although it is likely that in many cases, immunodeficiency cannot be adequately documented by laboratory testing. To date, the strongest association is that with primary ciliary dyskinesia (PCD) (Figure 21-5) and cystic fibrosis (CF). In congenital ciliary defects, including the Kartagener syndrome, the defect, which is an autosomal recessive disorder, is a structure abnormality of the dyneic arm of the cilia causing impaired ciliary function and poor clearance of secretions.19–21 Due to this impaired mucociliary transport, bronchopulmonary infections occur and these may be important causes of bronchiectasis. Patients with Kartagener syndrome present with sinusitis, situs inversus, bronchiectasis, decreased serum levels of immunoglobulin (Ig) A (IgA), and abnormal ciliary motility due to dyneic arm abnormalities, which result in failure of the cilia to beat.22,23 It is worth noting that most male patients with ciliary defects are also infertile because of dysfunction in spermatozoid movements (Table 21-3). In CF, the sol layer is affected by the disease. 1 9 According to Boucher, alveolar secretion of water appears deficient, and sodium and water reabsorption in the airways is increased.19 Thus, the sol layer is constricted, and the mucous layer impacts on the cilia, interferes with their beating, and slows clearance. Because of that, mucous plugging and lobar collapse are common occurrences in CF. Bronchiectasis associated with CF tends to involve primarily the upper lobes. Immunoglobulin deficiencies can also lead to bronchiectasis by predisposing to recurrent and severe

FIGURE 21-5. Bronchogram showing cylindrical bronchiectasis (arrow) in the left lower lobe in a 51-year-old man with congenital ciliary defects.

bronchopulmonary infection, and often these infections are caused by organisms of relatively low virulence, such as Pneumocystis carinii or cytomegalovirus. In patients with immunoglobulin deficiencies, the incidence of bronchiectasis is in the range of 10%, and most patients have a mixed deficiency of IgA and IgG. Bronchiectasis is also prevalent in patients with human immunodeficiency virus (HIV) infection and in the transplant population. Other rare congenital disorders that are associated with bronchiectasis include (1) Williams-Campbell syndrome,24 characterized by congenital absence of cartilage beyond segmental bronchi, (2) Young’s syndrome (see Table 21-3), characterized by sinopulmonary infections and epididymal disease causing infertility, and (3) Mounier-Kuhn syndrome,25 which consists of dilatation of the trachea and main bronchi secondary to abnormalities of the connective tissue of the airways. Alpha-1-

TABLE 21-3. Congenital Ciliary Defects and Bronchiectasis Syndrome

Bronchiectasis

Cilia

Epididymal Disease

Spermogram

Sweat Test

Ciliary defects

Yes

Abnormal

No

Normal

Cystic fibrosis Young’s syndrome

Yes Yes

Normal Normal

Yes Yes

Immobile spermatozoids Azoospermy Azoospermy

Abnormal Normal

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antitrypsin deficiencies usually lead to panacinar emphysema, but in some cases, it has been reported to be associated with bronchiectasis.26 There remains a group of patients in whom no acquired or host factors can be positively identified but yet who develop bronchiectasis. These patients often have diffuse bronchiectasis and sinusitis, and it is likely that most have some degree of immunologic deficiency, even though it may not be measurable. Diagnosis clinical presentation The clinical presentation of patients with bronchiectasis is variable and depends on the etiology of bronchiectasis and on whether the condition is localized or diffuse (see Table 21-1). However, the hallmark of this pathology consists of chronic cough, bronchial suppuration, and purulent bronchorrhea, which in some cases can amount to 500 mL daily. In the past, some bronchiectasis has been described as being nonproductive or “dry,” although in retrospect these were mostly cases of post-tuberculous bronchiectasis located in the upper lobes. Patients with bronchiectasis typically present with a history of recurrent febrile episodes, and indeed the diagnosis of bronchiectasis is often made at the time of an acute infectious exacerbation. Repeated infections can lead to the occurrence of hemoptysis of variable amounts but usually not massive or life threatening. In the series by Brooke Nicotra and colleagues, cough was the most important symptom affecting 90% of the cohort (Table 21-4).18 Hemoptysis occurred in 51% of patients, with the episodes tending to recur. A history of recurrent episodes of fever frequently accompanied by pleuritic chest pain was also present in most patients, as was dyspnea. Physical examination is often nonspecific, with clubbing being present in less than 5% of cases. Occasionally, TABLE 21-4. Symptoms and Signs of Bronchiectasis Symptoms Cough Daily sputum Hemoptysis Recurrent fever Recurrent pleurisy Dyspnea Signs Crackles Wheezing Squeaks (rhonchi) Clubbing

No. (%) of Patients with Finding 111 (90.2) 93 (75.6) 63 (51.2) 86 (69.9) 57 (46.3) 88 (71.5) No. (%) of Patients with Finding 86 (69.9) 42 (34.1) 64 (43.9) 4 (3.2)

From Brooke Nicotra M, et al. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest 1995; 108:955–61.

nasal polyps associated with chronic sinusitis will be seen. Crepitation, wheezing, and coarse expiratory rhonchi may be heard over the lung bases, whereas clinical signs of cor pulmonale and denutrition are uncommon and indicate advanced disease. Routine clinical assessment should include a careful recording of personal and familial history, which may indicate an inherited disorder. Complaints of sinus problems, repeated infections at other sites, infertility, or a family history of similar problems may all be important in selecting the proper management strategy. imaging Standard chest radiographs are usually the first examinations done, and although the changes noted are nonspecific, they may indicate the need for further investigation. Recognizable signs include linear markings due to peribronchial fibrosis and retained secretions, patchy or confluent pulmonary shadows, or evidence of lobe collapse. Occasionally, a dilated bronchus will be seen as an image of bronchocele. Computed tomography (CT) scanning is currently the best technique to establish the presence, severity, and distribution of bronchiectasis,27–29 replacing Lipiodol bronchography, which is considered more invasive and more unpleasant to the patient as well as being occasionally associated with complications such as alveolitis or allergy to the local anesthetic agent or contrast medium. In addition, there can be considerable disagreement between experienced radiologists and clinicians in the interpretation of bronchograms. For accurate assessment of bronchiectasis, both bronchography and CT scanning should be done at least 6 to 8 weeks after the end of an acute infectious episode. The CT scan has a sensitivity of 66% and specificity of 92% with 10 mm thick sections30 but a sensitivity of 84% and specificity of 92% with thin sections of 1.5 mm.31 False-negative images are essentially found in territories adjacent to cardiac cavities but this limitation has decreased with the use of high-resolution and spiral CT. Another advantage of CT scanning over bronchography is the better imaging of peribronchial inflammation and parenchymal disease. The nature of CT scan images depends on the number, size, type, and contents of bronchial dilatations as well as on the axis of the pathologic bronchi versus the axis of the CT scan cut. Perfusion isotopic scans are considered important in the preoperative evaluation of patients with bronchiectasis because they may demonstrate abnormal territories considered normal on CT scans but representing potential areas of bronchial dilatations. This is explained by bronchial artery hyperplasia creating flow reversal through systemic to pulmonary artery shunting, thus causing areas of defective perfusion on the isotopic scan.

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Such amputations may not only indicate more extensive disease than assessed by CT scan, but their presence may also influence the choice of therapy. By contrast, normal perfusion indicates that there is no significant bronchiectasis, for which surgery is not indicated,16,17 and is also seen with complete segmental or lobar atelectasis and replacement of the anatomic territory by adjacent normal lung (false-negative). other investigations Other tests that should be done in cases of bronchiectasis include bronchoscopy to rule out a foreign body or tumor, bacteriological examination of bronchial secretions for culture and sensitivity, a sweat test for CF, radiographs or CT scanning of the sinuses, and a simple immunologic work-up consisting of measurements of serum levels of immunoglobulin (B lymphocytes), lymphocyte count and cutaneous tests (T lymphocytes), white blood cell count and differential (phagocytes), and assays of individual components of complement (CH50, C3, C4).32 Pulmonary function studies are usually normal in patients with localized bronchiectasis. In patients with diffuse bronchiectasis, several authors have found evidence of airway obstruction similar to that observed in chronic bronchitis.33 In patients with severe bronchiectasis, a mixed obstructive and restrictive pattern with hypoxemia has been observed. Other examinations that may be done if necessary include bronchial arteriography to document the origin of hemoptysis, esophageal studies if gastroesophageal reflux is suspected, and ultrastructural examination of cilia from biopsy of the nasal respiratory epithelium if ciliary dyskinesia is suspected. Medical Management The initial treatment strategy for nearly all patients with bronchiectasis should be conservative (Table 21-5). This includes infection control, bronchodilation, and active physical therapy. In general, antibiotics tend to reduce the daily amount of sputum, its purulence, and the number of hospital days. Long-term administration of antibiotics may also be helpful in some individuals. Bronchodilators, usually administered by nebulizer, tend to reduce mucosal edema and associated bronchospasm. Physical TABLE 21-5. Objectives of Conservative Treatment Elimination of underlying cause (if reversible) Treatment of associated and contributing conditions (eg, sinusitis or gastroesophageal reflux) Control of infection (antibiotics) Improved clearance of secretions (physical therapy and postural drainage) Reversal of air-flow limitation (bronchodilators)

therapy is most important in patients with multisegmental disease, and it includes postural drainage34 with clapping done several times daily, breathing exercises, and the teaching of principles of respiratory hygiene. Other measures that are part of the medical management of bronchiectasis include the use of humidity to increase mucous fluidity, mucolytic and expectorant drugs, and the reduction of exposure to irritants such as tobacco smoke and industrial products. Perhaps the most important aspect of medical management is the aggressive treatment of associated conditions such as sinusitis, gastroesophageal reflux, or immunoglobulin deficiencies, and the elimination of reversible underlying causes (eg, endobronchial tumors or foreign bodies). Immunizations against pertussis or measles and influenza vaccine given yearly are also helpful. Surgical Treatment and Results According to Hodder and colleagues, patients who are candidates for surgical resection must fulfill the following criteria35: (1) have localized bronchiectasis adequately documented preoperatively by bronchography or CT scanning, (2) have adequate cardiopulmonary reserve to tolerate the proposed resection, (3) have an irreversible process and not an early radically treatable condition, (4) have significant symptoms with a continued chronic productive cough, repeated or significant hemoptysis, or recurring major episodes of pneumonia, and (5) have failed an adequate trial of medical management. If these conditions are fulfilled, complete resection of all dilated segments is usually possible, and the results of surgery are excellent. In all patients undergoing pulmonary resection, it is imperative to clearly determine preoperatively the extent of resection to be done because at surgery it may be difficult to judge with great accuracy the segments that are involved. Indirect signs that may be helpful during operation are the poor expansion of involved segments or lobes, the actual palpation of ectatic bronchi, and the lack of anthracotic pigment over the abnormal lung, indicating lack of function. All patients undergoing surgery must also be adequately prepared by specific antibiotics given for at least 48 hours prior to operation and by active physical therapy with clapping and postural drainage. Every type of resection is possible for bronchiectasis, the purpose of surgery being to remove all involved segments while preserving maximum function. Technically, the surgery of bronchiectasis can be either very easy or extremely difficult, and a double-lumen tube should always be used to avoid possible intraoperative contamination of contralateral lobes. Technical difficulties may arise with dense adhesions, hyperplastic lymph nodes around the pulmonary artery and its branches,

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and incomplete fissures. Bronchial artery hyperplasia around the bronchus may be finally the source of intraor postoperative bleeding if these vessels are not carefully identified and ligated. It is worth noting that because of bronchial artery hyperplasia and good vascular supply to the bronchus, patients with bronchiectasis undergoing lobectomy are expected to have a lower incidence of postoperative bronchopleural fistula than similar patients undergoing lobectomy for lung cancer. Although the results of surgery are excellent in patients with limited and localized disease, these results are less predictable in patients with diffuse and multisegmental disease, and operation should generally be avoided in these individuals. In this group, patients who may benefit from surgery have the following indications: (1) disease that is symptomatic, unresponsive to medical treatment, and can be completely resected; (2) hemoptysis that cannot be controlled or recurs after bronchial artery embolization, and (3) the need for palliative surgery in which the most involved lobe or segments are resected to improve symptoms. In select individuals, limited resections of targeted segments may achieve lasting symptomatic improvement. In one series from France, total disappearance or regression of preoperative symptoms occurred in 75% of such patients.36 Surgical resection of bronchiectasis in patients with CF or in patients with PCD is more controversial and very few patients with these conditions will benefit from operation. In one small series from the Netherlands, 11 of 13 patients who underwent surgical resection of bronchiectasis associated with PCD felt better after the operation.21 Patients with CF are even less likely to benefit from surgery because their condition is compounded by nutritional deficiencies, colonization of sinuses and airways with resistant organisms, and systemic comorbidities including hepatic and pancreatic dysfunctions.37 Although many authors have presented the results of surgery for bronchiectasis, the past and current literature is difficult to interpret because of the nonhomogeneity of inclusion criteria, methods of diagnosis, and treatment strategies. For the purpose of clarity, I have chosen to review only three series,2,3,38 all of which present similar results, although there is a 35-year interval between these three publications (Table 21-6). In the series by Sealy and colleagues, 140 patients underwent resection of bronchiectasis between 1954 and

1963, and of these, 70 had localized disease and 70 had diffuse multisegmental bronchiectasis considered to be part of a panrespiratory tract involvement.3 Of the 70 patients with localized disease, 42 could relate the onset to an episode of pneumonia (n = 37) or aspiration of a foreign body (n = 5), whereas only 19 of the 70 patients with multisegmental bronchiectasis could trace the onset to a previous episode of pneumonia. One hundred and five patients complained of a persistent productive cough, and “the more extensive the disease, the greater the sputum volume.” Hemoptysis occurred in 75 patients and varied from blood streaking to brisk hemorrhage. In that series, postoperative complications were uncommon, and the operative mortality was 2 of 157 operations (1.3%). For 95% of patients, the operation was considered beneficial, and a greater number of good results was obtained in those patients with localized disease. Fifteen patients had bilateral resections and 13 of 15 were considered to have a good result or were improved, while in 13 of 22 patients with bilateral disease, a second operation was never required because of good outcome after resection of the more involved side. In the series by Agasthian and colleagues from the Mayo Clinic, 134 patients underwent pulmonary resection for bronchiectasis between 1976 and 1993.38 The mean duration of symptoms was 6 years and included a productive cough (n = 104), recurrent infections (n = 81), and hemoptysis (n = 56). In that series, the operative mortality was 2.2% and the morbidity rate was 24%. Overall, 61 patients (59.2%) became asymptomatic during follow-up, and symptoms were improved in an additional 30 patients (29.1%). In a more recent series from Turkey, 166 patients underwent surgery for bronchiectasis, mostly because of chronic infection and daily significant bronchorrhea.2 At follow-up (mean of 4.2 years), 75% of patients were asymptomatic and an additional 20% had improved symptoms and quality of life. Although several prognostic factors for good results after surgery have been described, 3 9 Fujimoto and colleagues were able to extract only three significant prognostic factors by logistic regression,40 and these were cylindrical type of bronchiectasis, absence of sinusitis, and complete resection of the diseased parenchyma. From personal experience41 and a review of the literature, it is clear that surgery for bronchiectasis can be

TABLE 21-6. Results of Surgery for Bronchiectasis Author Sealy et al (1966)3 Agasthian et al (1996)38 Kutlay et al (2002)2

Year 1954–1963 1976–1993 1990–2000

Number of Patients

Operative Mortality

140 134 166

1% 2% 2%

Morbidity — 25% 11%

Asymptomatic 58% 59% 75%

Asymptomatic and Improved 95% 88% 96%

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done with minimal complications and that it improves symptoms and quality of life, mostly in younger patients with localized disease.

Broncholithiasis Broncholithiasis is a condition in which a calcified mass is found within, or has eroded into, the lumen of a bronchus. According to Faber and colleagues, the first description of lithoptysis or the “spitting of stones” is that of Aristotle in the year 300 BC.42 In the year 1600, Shenk and Groftenberg reported 17 patients with lithoptysis,43 and in 1744, Boerhaave described the expectoration of 400 broncholiths by the botanist Vallentius.43 A number of clinical reports have documented that the usual causes of broncholithiasis are tuberculosis and histoplasmosis. Pathogenesis and Bacteriology The source of broncholithiasis is usually a lymph node that has undergone calcification through precipitation of calcium salts following an acute infectious lymphadenitis. Because of the constant respiratory movements of the bronchi, this now calcified node eventually causes a bronchial stricture with distal infection and bronchiectasis or a complete bronchial obstruction with distal atelectasis. These nodes can also erode into adjacent vascular structures, usually the pulmonary artery, or into the esophagus, creating a bronchoesophageal fistula. In many cases of nodal histoplasmosis, this process of erosion is helped by the morphology of bronchioliths, which have a sharp and narrow ossified rim.44 Most cases of broncholithiasis occur on the right side because of the greater number and particular anatomy of nodes on that side. Although the original infective organisms may be difficult to isolate from resected specimens, most cases of broncholithiasis are believed to be caused by either tuberculosis or nodal infection by Histoplasma capsulatum. Other organisms possibly involved include Coccidioides immitis, Cryptococcus neoformans, and Blastomyces dermatitidis. In the report of Cole and colleagues, the offending organism was isolated in only 15 of 42 cases (36%),43 while in the series by Faber and colleagues, the organism was found in only 2 of 43 patients (5%).42 Rare causes of broncholithiasis include renal stone erosion, silicosis,43 and sarcoidosis. Diagnosis Most patients with broncholithiasis are symptomatic, and only a handful will actually spit stones. The most common symptom is that of protracted and severe cough, often present for years and unresponsive to the usual treatment.45 This cough, which is due to mechanical irritation of the bronchial mucosa, may be accompanied by

purulent bronchorrhea if there is associated lung infection. Hemoptysis may result from direct vascular erosion or from granulation tissue that has formed over the site of bronchial erosion. Of the 43 patients with broncholithiasis presented by Faber and colleagues, hemoptysis was a major complaint in 16 patients, and in 11 of the 16, it was recurrent.42 It is important to remember that unlike what is seen with bronchiectasis, hemoptysis associated with broncholithiasis can be life threatening. Other symptoms include wheezing, if the broncholithiasis is obstructive of a bronchus, and chronic suppuration. The diagnosis of broncholithiasis can be suspected from standard radiographs showing extensive hilar or multiple areas of calcification with distal atelectasis or parenchymal consolidation.42 One interesting radiologic feature is the migration of calcified foci identified on previous radiographs. The definitive diagnosis of broncholithiasis is usually made by a combination of CT scanning46 and bronchoscopy, which may show the actual broncholith or other nonspecific abnormalities, such as granulation tissue, edema, or extrinsic compression with stenotic bronchi. Management Options Three treatment modalities are available for the management of patients with broncholithiasis,47,48 and these are surgical intervention, endoscopic removal, and observation. Indications for surgery include recurrent hemoptysis, intractable cough, bronchiectasis and suppurative lung disease, bronchial stenosis, and, less often, bronchoesophageal or bronchovascular fistulas. In 2000, Potaris and colleagues from the Mayo Clinic reported on 47 patients with broncholithiasis who underwent operation.48 Indications for surgery were hemoptysis in 20 patients, recurrent pneumonia in 11, and other reasons in 16 patients. As a rule, resection should aim at preserving as much normal lung as possible, but at the same time, it should be extensive enough to remove both the broncholith and distal bronchiectatic lung.42 Whenever possible, sleeve lobectomies or sleeve bronchial resections should be done instead of pneumonectomies. During surgery, dissection of individual blood vessels may be dangerous, and it is recommended that proximal control of the pulmonary artery be attained before dissection is begun more distally.42 In the surgical group of 47 patients reported by Potaris and colleagues, both pulmonary resection and broncholithectomy were performed in 30 patients while broncholithectomy without pulmonary resection was done in 9 patients.48 In that series, intraoperative complications occurred in six patients, but none were fatal. These included lacerations

Surgical Treatment of Bronchiectasis and Broncholithiasis / 275

of the pulmonary artery in four patients, esophagus in one, and main stem bronchus in one other patient. There were no operative deaths, and most patients were asymptomatic at follow-up. The role of therapeutic bronchoscopy remains controversial. In the series by Cole and colleagues, of 42 patients with broncholithiasis, bronchoscopy was performed in 40, with successful stone removal achieved in 8 (20%).43 Cole and colleagues recommended that, while removing bronchial stones, excess force or traction should be avoided and that the use of bronchial irrigation may help to separate the stone from the bronchial wall. They also concluded that an attempt at endoscopic stone removal should be undertaken before complications develop. In the absence of significant symptoms or complications, observation alone may be the best management strategy.

References 1. Laennec RT. A treatise on diseases of the chest and mediate ausculation. 4th ed. Translated by J Forbes. New York: S. Woodsons; 1835. p. 100. 2. Kutlay H, Cangir AK, Enön S, et al. Surgical treatment in bronchiectasis: analysis of 166 cases. Eur J Cardiothorac Surg 2002;21:634–7. 3. Sealy WC, Bradham RR, Young WG. The surgical treatment of multisegmental and localized bronchiectasis. Surg Gynec Obst 1966;123:80–90. 4. Oschner A. Bronchiectasis. Disappearing pulmonary lesion. N Y State J Med 1975;75:1683–9. 5. Perry KMS, Sellers TH (eds). Chest diseases. London: Butterworth; 1963. 6. Heller G. Beitrage zur lehre van den fremdkorpern in den luftwegen. Göttingen: WF Kaestner; 1890. 7. Kartagener M. Zur pathogenese der bronchiectasien. Bronchiectasien bei situs inversus viscerum. Beitr Klin Tuberk 1933;8:489–501. 8. Heidenhain L. Ausgedehnte lungenresektion wegen zahlmeicher eiternder bronchiectasien in einem unterlapen, verlandl.deutsch. gesselsch. Chir 1901;30:636. 9. Jackson C. The bronchial tree: its study by the insufflation of opaque substances in the lung. Am J Roentgenol 1918;5:454. 10. Sicard JA, Forestier J. Iodized oil as contrast medium radioscopy. Bull Mem Med Hôp de Paris 1922;46:463. 11. Brock RC. Post-tuberculous bronchostenosis and bronchiectasis of the right middle lobe. Thorax 1950;5:5. 12. Wager KB, Johnston MR. Middle lobe syndrome. Ann Thorac Surg 1983;35:679–86. 13. Saha SP, Mayo P, Lang GA, McElvein RB. Middle lobe syndrome: diagnosis and management. Ann Thorac Surg 1982;33:28–31.

14. Reid LM. Reduction in bronchial subdivision in bronchiectasis. Thorax 1950;5:233–47. 15. Whitwell F. A study of the pathology and pathogenesis of bronchiectasis. Thorax 1952;7:213–9. 16. Ashour M. Hemodynamic alterations in bronchiectasis: a base for new subclassification of the disease. J Thorac Cardiovasc Surg 1996;112:328–34. 17. Ashour M, Al-Kattan K, Rafay MA, et al. Current surgical therapy for bronchiectasis. World J Surg 1999;23:1096–104. 18. Nicotra MB, Rivera M, Dale AM, et al. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest 1995;108:955–61. 19. Davis AL, Pierce AK, Naidich D, et al. Bronchiectasis. Am Rev Respir Dis 1986;134:824–5. 20. Eliasson R, Mossberg B, Canner P, Afzelius BA. The immobile-celia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infection and male sterility. N Engl J Med 1977;297:1–6. 21. Smit HLM, Schreurs JM, Van den Bosch JMM, Westermann CJJ. Is resection of bronchiectasis beneficial in patients with primary ciliary dyskinesia. Chest 1996;109:1541–4. 22. Tkebuchrava T, Neiderhauser U, Weder W, et al. Kartagener’s syndrome. Clinical presentation and cardiosurgical aspects. Ann Thorac Surg 1996;62:1474–9. 23. Vevaina JR, Teichberg S, Buschman D, Kirkpatrick CH. Correlation of absent inner dyneic arms and mucociliary clearance in a patient with Kartagener’s syndrome. Chest 1987;91:91–5. 24. Wayne KS, Taussig LM. Probable familial congenital bronchiectasis due to cartilage deficiency (WilliamsCampbell syndrome). Am Rev Respir Dis 1976;114:15–22. 25. Mounier-Kuhn P. Dilatation de la trachée: constatations radiographiques et bronchoscopiques. Lyons Med 1932;150:106–9. 26. James DK, Godden D, Cavanagh P. Alpha-1-antitrypsin deficiency presenting as bronchiectasis. Br J Dis Chest 1985;79:301–4. 27. Grenier P, Maurice F, Mussel D, et al. Bronchiectasis: assessment by thin-section CT. Radiology 1986;161:95–9. 28. Muller NL, Begin CJ, Ostrow DN, Nichols DM. Role of computed tomography in the recognition of bronchiectasis. Am J Radiol 1984;143:971–6. 29. Kang EY, Miller RR, Müller N. Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens. Radiology 1995;195:649–54. 30. Cooke JC, Currie DC, Morgan AD, et al. Role of computed tomography in the diagnosis of bronchiectasis. Thorax 1987;42:272–7. 31. Munro NC, Cooke JC, Currie DC, et al. Comparison of thin-section computed tomography with bronchography for identifying bronchiectatic segments in patients with chronic sputum production. Thorax 1990;45:135–9.

276 / Advanced Therapy in Thoracic Surgery 32. Chipps BE, Talamo RC, Winkelstein JA. IgA deficiency, recurrent pneumonias, and bronchiectasis. Chest 1978;73:519–26.

41. Deslauriers J, Dion L. Le traitment des bronchiectasies primitives. Indications chirurgicales et resultats. Semin Hôp Paris 1985;18:1199–201.

33. Ellis DA, Thornley PE, Wrightman AJ, et al. Present outlook in bronchiectasis: clinical and social study and review of factors influencing prognosis. Thorax 1981;36:659–64.

42. Faber LP, Jensik RJ, Chawla SK, Kittle CF. The surgical implication of broncholithiasis. J Thorac Cardiovasc Surg 1975;70:779–89.

34. Jaffe HJ, Katz S. Current ideas about bronchiectasis. Am Fam Physician 1973;7:69–76.

43. Cole FH, Cole FH Jr, Kandedar A, Watson DC. Management of broncholithiasis: is thoracotomy necessary? Ann Thorac Surg 1986;42:255–7.

35. Hodder RV, Cameron R, Todd TRJ. Bacterial infections. In: Pearson FG, et al, eds. Thoracic surgery. New York: Churchill Livingstone: 1995. p. 433–70. 36. Mazières J, Murris M, Didier A, et al. Limited operation for severe multisegmental bilateral bronchiectasis. Ann Thorac Surg 2003;75:382–7. 37. Barlow CW, Robbins RC, Moon MR, et al. Heart-lung versus double-lung transplantation for suppurative lung disease. J Thorac Cardiovasc Surg 2000;119:466–76. 38. Agasthian T, Deschamps C, Trastek VF, et al. Surgical management of bronchiectasis. Ann Thorac Surg 1996;62:976–80.

44. Schwartz J, Schaen MD, Picardi JL. Complications of the arrested primar y histoplasmic complex. JAMA 1976;236:1157–61. 45. Dixon GF, Donnenberg RL, Schonfeld SA, Whitcomb ME. Clinical commentary. Advances in the diagnosis and treatment of broncholithiasis. Am Rev Respir Dis 1984;129:1028–30. 46. Kowal LE, Goodman LR, Zarro VJ, et al. CT diagnosis of broncholithiasis. J Comput Assist Tomogr 1983;7:21–3.

39. Ripe E. Bronchiectasis. Scand J Respir Dis 1971;52:96–112.

47. Trastek VF, Pairolero PC, Ceithame EL, et al. Surgical management of broncholithiasis. J Thorac Cardiovasc Surg 1985;90:842–8.

40. Fujimoto T, Hillejan L, Stamatis G. Current strategy for surgical management of bronchiectasis. Ann Thorac Surg 2001;72:1711–5.

48. Potaris K, Miller DL, Trastek VF, et al. Role of surgical resection in broncholithiasis. Ann Thorac Surg 2000;70:248–52.

CHAPTER 22

BLOOD SUBSTITUTES ROBERT M. WINSLOW, MD

Blood substitutes are solutions that are intended to be used instead of blood. In fact, there are many “blood substitutes” in clinical use now, including colloids and crystalloids, which are given to perform one function of transfused blood: plasma volume expansion. However, the term “blood substitutes” is usually reserved for solutions that also carry and deliver oxygen. Various workers in the field of blood substitutes research have used other terms to more accurately describe these new solutions, including “oxygen carriers,” “oxygen-carrying plasma expanders,” or, in reference to those solutions based on hemoglobin, “hemoglobin-based oxygen carriers.” Although perfluorocarbon-based oxygen carriers also have been tested extensively, as a class they have limitations that have slowed development. In this chapter, main emphasis is placed on hemoglobin-based products, since they hold the most promise for successful clinical application. The search for alternatives to blood transfusion is almost as old as the practice of medicine itself.1 Prior to the discovery of blood types, around 1900, and the introduction of blood banks, just prior to the outbreak of World War II, there was no effective replacement for blood lost in hemorrhage. Great efforts have been invested in alternatives to products based on hemoglobin, such as the perfluorocarbons. Perfluorocarbons are synthetic materials that have greatly increased solubility for O2 and that can be produced cheaply and in large volume. They suffer from two significant problems, however: they are completely immiscible with aqueous solutions and so must be emulsified prior to infusion, and under normal circumstances they cannot transport sufficient O2 to effectively oxygenate tissue. Clinical trials have not been convincing,2 and no product is currently approved for use in patients.

Other more exotic solutions to the blood substitute problem have been devised, including artificial red cells (liposomes) 3 and a variety of approaches based on recombinant hemoglobins.4 However, the products that have been most successful in clinical development to date have been chemical modifications of either human or animal (cow) hemoglobin.5

Historical Background In 1949 Amberson published a landmark paper that described a case report of a 22-year-old female with severe postpartum hemorrhage as a result of retained placenta (Figure 22-1).6 Her hemoglobin was 5 g/dL, and all compatible blood in the hospital had been exhausted. She remained in shock, and her blood pressure was not responsive to conventional plasma expanders or crystalloids. She was finally given an experimental hemoglobinsaline solution that Amberson had been developing in the laboratory. Upon administration of this solution, the blood pressure rose dramatically and the heart rate fell. Over two liters of hemoglobin solution were administered to this patient, and for a time she seemed to improve. Eventually however her urine output diminished as renal failure progressed and she finally died. In his discussion of this case, Amberson expressed his belief that the hemoglobin solution had been effective treatment for shock. However, he cautioned that the blood pressure responses and the abrupt fall in heart rate were peculiar properties of hemoglobin solutions, and he felt that these effects were most likely owing to impurities. Amberson concluded, “It must be emphasized that every investigator in this field has used a different method for the preparation of his hemoglobin-saline 277

278 / Advanced Therapy in Thoracic Surgery

been approved by the US Food and Drug Administration, and only fragmentary information is available regarding the progress of the trials.5



-Hemoglobin: A Research Model

FIGURE 22-1. Administration of a purified, unmodified hemoglobin solution to a patient in shock. Initially, plasma, glucose, and blood were given but failed to increase blood pressure. The hemoglobin solution promptly increased blood pressure but decreased the heart rate and produced significant fever. In spite of the apparently improved hemodynamics, the patient eventually died with renal failure.6

solutions. Conflicting results and claims have therefore inevitably arisen. A standard hemoglobin solution is needed, prepared in such a way that stability is insured. The field is a difficult one beset with many hazards.” In the period following Amberson’s report, considerable strides were made in the purification of hemoglobin.7,8 Furthermore the exact molecular structure of hemoglobin was discovered in the 1950s, showing that this protein consisted of four subunits (2
and 2 ) arranged in a tetramer. Outside of the red blood cell, these subunits break down into dimers (
), which are rapidly cleared by the kidney. In addition to research on the purification of hemoglobin, strategies were devised to chemically crosslink the subunits to prevent their dissociation when outside of the red blood cell, reducing the tendency to be quickly eliminated by the kidney.9 In the decades leading up to 1980 most work was focused on polymerization of hemoglobin using bifunctional reagents such as glutaraldehyde10 or o-raffinose.11 Glutaraldehyde links molecules together to form polymers of various sizes. The chemistry was difficult to control since at its endpoint the protein solution forms a gel. Thus, many efforts were aimed at control of this reaction and the elimination of both high and low molecular weight polymers. Three varieties of polymerized hemoglobin were chosen for commercialization and eventually reached clinical trials. At present, none has

The recognition that human immunodeficiency virus (HIV) could be transmitted by blood transfusions in the early 1980s was a landmark for blood substitutes research. Although many strides had been taken by this time, still Amberson’s plea for purified and standardized hemoglobin solution had not been heeded. In 1985 the U.S. Army recognized the threat to the blood supply on the battlefield and placed renewed emphasis on the research program at the Letterman Army Institute of Research (LAIR). A contract was awarded to Baxter Healthcare to produce a “standard” hemoglobin for research. This product was called

-hemoglobin (

Hb), since the chemistry was based on a very specific chemical crosslink placed between
chains of human hemoglobin when the reaction was done in the deoxygenated condition.12 The product was well characterized and widely distributed for experimental use. Alpha-alpha hemoglobin, later to be known as diaspirin cross-linked hemoglobin (DCLHb) or HemeAssist (Baxter), had a molecular weight of 64 kD, the same as native unmodified human hemoglobin. The viscosity at approximately 8 to 10 g/dL was 1.0 cP, about the same as water. The colloid osmotic pressure (oncotic pressure) was about 20 mm Hg, the same or slightly less than human plasma. A particularly important feature of this compound was that its P50 (the PO 2 at halfsaturation) was approximately 30 mm Hg, the same as human red blood cells. Numerous animal studies carried out by the Army as well as by Baxter showed that the half-life of

-Hb was longer than that of unmodified hemoglobin in many animal models (about 12 hours) and that hemoglobinuria was minimal, suggesting that renal failure may not be a problem.13 In many animal experiments,

-Hb produced significant elevations in blood pressure. Preparing for Operation Desert Storm in 1990, the US Army devised a protocol to simulate anticipated battlefield injury. 14 Immature pigs were first deprived of water to achieve dehydration by about 8% of total body weight. After instrumentation they were then subjected to an experimental hemorrhage of 50% of estimated blood volume in the awake state. After 30 minutes, animals were resuscitated with albumin, purified hemoglobin, Ringer’s lactate, or

-Hb.15 The results of this study are shown in Figure 22-2. The blood pressure recovery with either albumin or Ringer’s lactate resuscitation was to prebaseline levels.

Blood Substitutes / 279

However the blood pressure responses after resuscitation with either purified hemoglobin (Ao) or

-Hb was a marked overshoot compared with baseline, and both hemoglobin solutions caused a modest reduction of heart rate relative to baseline, consistent with Amberson’s earlier observations (see Figure 22-1). Although volume restitution was the same with all the solutions, the cardiac output failed to return even to baseline with either hemoglobin solution. In contrast, cardiac output rose to levels even higher than baseline after resuscitation with either albumin or Ringer’s lactate. The result of these physiological changes was a marked increase in systemic vascular resistance (Resistance = Pressure/Flow) after resuscitation with any hemoglobin solution. Finally, this increased resistance completely offset any added O 2 -carrying capacity afforded by infusion of hemoglobin solution.

In summary, the US Army had succeeded in producing a suitable model hemoglobin that had the aimed-for characteristics: • is sterile • is free of red cell membranes • is endotoxin-free • does not dissociate into
 subunits • does not cause significant renal toxicity Nevertheless,

-Hb still caused significant hypertension in pigs. Of even more concern, however, was the fact that cardiac output was depressed, presumably because of intense vasoconstriction, as evidenced by severely increased vascular resistance. The overall conclusion was that there was no advantage of resuscitation with

-Hb compared with Ringer’s lactate. The mechanism of this vasoactivity was not clear, and the Army concluded that more basic research was needed in the field in order to Heart Rate

MAP 200

160

190 140

Albumin Ao RL aaHb

120

Albumin Ao RL aaHb

180

H

170

/min

100

160 150

80 140 60 130 40

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1

2

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4

5

-1

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Hours

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3

4

5

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8

3500 Albumin Ao RL aaHb

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dyne secc cm-5

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FIGURE 22-2. Simulation of a battlefield injury by the US Army. Dehydrated pigs were subjected to hemorrhage (arrow at 0 hours) and then resuscitated with test solution (arrow at 1 hour). The pattern of increased pressure, decreased cardiac output, and markedly elevated vascular resistance is the hallmark reaction to first-generation hemoglobin-based blood substitutes.15

280 / Advanced Therapy in Thoracic Surgery

produce a safe and efficacious blood substitute. The Army not only abandoned

-Hb as an experimental product but discontinued further research in the field as well.16 Baxter continued to develop

-Hb until phase III clinical trials in stroke17 and trauma18 showed increased mortality in treated patients. Vasoconstriction and Its Physiological Basis The focus of research efforts in the post-Army era became understanding of the mechanism of hemoglobininduced vasoconstriction. Experiments carried on the hamster skinfold model of the microcirculation led to new insight into the cause of hypertension. Figure 22-3 shows a study of functional capillary density, defined as the number of capillaries in a given microscopic field in which cells can be observed to be moving. Functional capillary density decreases when precapillary arterioles constrict. Thus, if blood volume does not change, arteriolar vasoconstriction produces hypertension and decreased functional capillary density.19 In the experiment in Figure 22-3, animals were progressively hemodiluted with dextran or hemoglobin solutions. When the hematocrit fell below 20% and plasma hemoglobin concentration increased, functional capillary density fell rapidly. In contrast to this normal response, when animals were progressively hemodiluted with

-Hb, the drop in functional capillary density occurred at a much higher hematocrit, directly demonstrating the marked vasoactivity of this product. A polymerized human hemoglobin demonstrated this effect to a lesser degree, and a hemoglobin modified by surface decoration with polyethylene glycol (PEG) was even less vasoactive. These experiments suggested that not all hemoglobin solutions are equally vasoactive.

In rats, hypertension produced by these three types of modified hemoglobins was directly correlated with the fall in functional capillary density observed in hamsters (Figure 22-4). That is, PEG-modified hemoglobin had no significant effect on rat blood pressure, polymerized hemoglobin had a small effect, and cross-linked hemoglobin was markedly hypertensive. Thus, in the early 1990s products from all classes of modified hemoglobins were entering advanced clinical trials in humans, but there was still no good explanation for the hemodynamic pattern observed more than 40 years previously. One potential explanation seemed obvious when NO was identified as an endothelial-derived relaxing factor.20 Hemoglobin was well known to bind NO with high affinity,21 and experiments with isolated vascular rings seemed to support this explanation.22 One problem with this as a complete explanation, however, was that hemoglobin within red blood cells also binds NO, but without a hypertensive effect. A second problem was that different modified hemoglobins demonstrated hypertension to differing degrees, depending on the type of chemical modification (see, for example, Figure 22-4).

A New Model for Blood Substitute Design A problem with this interpretation, however, is that the reactivity with NO does not correlate with the degree of vasoactivity. Rohlfs and colleagues prepared solutions of modified hemoglobins with differences in molecular size and other significant properties (Table 22-1).24 The crosslinked hemoglobin was the Army’s

-Hb, with a molec160

100

mm HG

90

FCD (%)

Polymerized Crosslinked PEG

140

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70

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80 0

50 60

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40

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20

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40

50

60

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FIGURE 22-3. Functional capillary density (FCD) as a function of hematocrit in the hamster skinfold model with progressive hemodilution with the indicated solutions. Data for dextran and

-Hb are from Tsai A et al (1995).19 Data for PEG-Hb and polymerized hemoglobin are unpublished (personal communication, A Tsai and M Intaglietta,).

FIGURE 22-4. Blood pressure in the rat in response to infusion of test “blood substitutes.” Table 22-1 gives the properties of the test solutions. Infusion is via a femoral vein, starting at 30 minutes as shown by the arrow. Note that the degree of blood pressure elevation is inversely proportional to functional capillary density, as shown in Figure 22-3 (unpublished data).

Blood Substitutes / 281

ular weight close to that of unmodified hemoglobin. The polymerized hemoglobin was human hemoglobin modified with o-raffinose,11 with a molecular weight more than twice that of the cross-linked hemoglobin. The PEG-Hb was bovine hemoglobin modified with about 10 to 12 strands of PEG, each with a molecular weightof 5 kD. The molecular weight of the PEG-Hb is somewhat greater than the cross-linked, but less than the polymerized Hb. Note that the PEG-Hb has about twice the radius of the polymerized Hb, but its molecular weight is much less. This is because PEG is very hydrophilic and creates a “shell” of water around the protein molecule. The oxygen affinities of the 3 molecules are also very different:

-Hb has a P50 close to that of native human red blood cells, while the polymerized Hb is much higher and the PEG-Hb much lower. The viscosities and oncotic pressures of the three preparations are different as well, in the order PEG-Hb > polymerized Hb > cross-linked Hb. Finally, Table 22-1 shows that the NO-hemoglobin “on” rate constant for these three molecules is essentially the same. Although there were some differences in the “off ” reactions, it would be expected that essentially no NO dissociates from these molecules as they circulate. In summary, the experiments demonstrate that the different degrees of vasoactivity for these three modified hemoglobins cannot be explained on the basis of their reactivity with NO. Instead, the results turn our attention to the possibility that vasoactivity could be regulated by molecular size, oxygen affinity, viscosity, or oncotic pressure. These findings, and a review of the basic mechanisms of control of microvascular blood flow, led to a new hypothesis to explain the vasoactivity of hemoglobin solutions. Lindbom and coworkers had shown that arterioles in the microcirculation of the rabbit tenuissimus muscle constrict when the oxygen supply increases and dilate when the supply decreases.25 Furthermore, studies on “facilitated” diffusion by oxymyoglobin and oxyhemoglobin26 suggested that even small amounts of plasma hemoglobin could dramatically increase the availability of oxygen supply to the vascular wall. Finally, Johnson27 and

Intaglietta28 and their coworkers had proposed that the microcirculation is controlled at PO2 levels much higher than those found in working muscle. These elements led to the hypothesis that the two critical elements in control of arteriolar vascular tone are molecular size of the modified hemoglobin and its oxygen affinity.29,30 According to the new theory, vasoconstriction is a normal mechanism that operates at the precapillary arteriolar level. The purpose of the mechanism is to regulate oxygen availability in the microcirculation. When hemoglobin molecules are free in the plasma, they are able to diffuse and markedly increase the total oxygen concentration in the plasma. This situation arises from the exceedingly low solubility of oxygen in plasma normally. The theory predicts that the vessel wall senses this increased “facilitated” oxygen availability and undergoes reflexive vasoconstriction. This hypothesis makes certain predictions about the design of an effective blood substitute based on hemoglobin. The diffusion of oxyhemoglobin (D HbO2 ) is governed by the Stokes-Einstein equation: k T= ??  where k is Boltzmann’s constant, T the absolute temperature,  the viscosity, and r the molecular radius. Thus the diffusion constant for hemoglobin can be limited by increasing either the radius or viscosity of the molecule. Furthermore, hemoglobin diffusion will be maximal when the hemoglobin saturation is greatest between the center and edge of the vessel. Thus, decreasing P50 should also reduce the delivery of O2 to vessel walls when the PO2 is in the range 20 to 40 mm Hg. These concepts have been incorporated into the newest generation of surface-modified hemoglobin molecules (see Table 22-1) and were tested in an artificial capillary system. 3 1 The findings supported the theor y and suggested that a modified hemoglobin could be designed that delivers oxygen to the vessel wall in exactly the same manner as red blood cell, thereby preventing engagement of O2-sensitive vasoconstriction.

TABLE 22-1. Modification

Cross-linked Hemoglobin

Molecular weight (kD) Radius (nm) P50 (mm Hg) Viscositiy (cP) Colloid osmotic pressure (mm Hg) Kon (µm-1s-1)§ *From Vandegriff K et al (1997).23 Calculated according to Vandegriff K et all (1997).23 ‡ From McCarthy MR et al (2001).31 § All values from Rohlfs RJ et al (1998).24 †

69* 3.1* 34 1.0‡ 23* 31  2

Polymerized Hemoglobin 60* 4.9* 52 1.4‡ 16* 29  2

PEG-Modified Hemoglobin 117 14† 10 3.2 118 30  3

282 / Advanced Therapy in Thoracic Surgery Hemorrhage 1.0

Fraction alive

0.8 0.6 Hb,, g/dl

0.4 0.2

Controls 13.8 Crosslinked 10.2 Polymerized 11.0 Pentastarch 6.8 PEG-Hb 7.6

0.0 0

20

40

60

80

100

120

140

Minutes after start of hemorrhage

FIGURE 22-5. Survival of rats after 50% exchange transfusion with “blood substitutes” followed by hemorrhage of 60% of blood volume. For properties of the hemoglobin solutions, see Table 22-1. Pentastarch was used as an additional control because its viscosity and oncotic pressure are similar to those of PEG-Hb. The hemorrhage starts at 0 minutes and takes place over 60 minutes. The controls represent a group of animals that were not exchange-transfused. The hemoglobin concentrations are the values measured at the start of the hemorrhage.32

The test of any design has to be in animals and then humans. In anticipation of clinical trials, rats were exchange-transfused 50% of their blood volume and then subjected to a 60% hemorrhage over 1 hour.32 The result of this study was that animals exchanged with a new experimental PEG-modified human hemoglobin survived the hemorrhage, while 50% of the control subjects (no exchange) and animals exchanged with either cross-linked or polymerized hemoglobins did not (Figure 22-5). A striking feature of this experiment was the difference in hemoglobin concentrations in the various groups of animals. The controls had a hemoglobin of 13.8 g/dL, while the PEG-Hb animals began the hemorrhage with a hemoglobin of only 7.6 g/dL. According to conventional clinical practice, these animals were at or near the transfusion trigger at the beginning of hemorrhage. These findings point to one of the most important aspects of blood substitutes research and eventual clinical use: “blood substitutes” are not simply blood replacements but rather represent an entirely new category of oxygen delivery therapy based on a new understanding of oxygen transport physiology.

Alternative Explanations for Vasoconstriction The theoretical basis for the success of PEG-modified hemoglobin is not yet completely proven and remains controversial. Many workers in the field believe that NO

binding does account for hemoglobin-induced vasoconstriction. Recombinant hemoglobins with mutations that reduce NO binding have been shown to cause less hypertension than native hemoglobin.33 Others believe that extravasation of hemoglobin is responsible, on the theory that hemoglobin in the interstitial space more effectively scavenges NO than hemoglobin in the vascular space.34,35 Some workers in the field have shown that vasoactivity is related to plasma viscosity36 and that shear stress is transduced by endothelial cells to alter the release of vasoactive molecules such as NO and prostacyclins.37 Still others believe that vasoactivity or, more generally, toxicity, results from O2 free radical generation as hemoglobin cycles through redox reactions.38 It is possible, of course, that the final explanation may lie with a combination of these causative factors.

The Future of Blood Substitutes Whatever the ultimate explanation for vasoactivity produced by cell-free hemoglobin, it is very unlikely that any product that is approved for clinical use will bear much resemblance to blood beyond its color. It is very unlikely that a hemoglobin-based red cell substitute can be produced that has the same hemoglobin concentration as normal red blood cells and the same oxygen affinity as red blood cells, with the same viscosity and oncotic pressure as human blood. Nevertheless, as shown in Figure 22-5, solutions with properties very different from those of human blood can effectively reduce the need for transfusion of allogeneic blood. The problem for clinical implementation of such solutions, also demonstrated in Figure 22-5, is that the hemoglobin concentration per se will no longer be a useful guide, or trigger, for giving a transfusion. Rather, clinicians in the future must broadly evaluate each patient’s need for supplemented tissueoxygenating capacity and be prepared to administer the therapy that best meets that need. In this evaluation process, physiological and clinical data will need to be obtained and rapidly integrated into a reliable transfusion trigger. As safer, more effective solutions are developed for clinical testing, revision of the transfusion trigger and definition of optimal clinical applications represent a major challenge for the developing field of “blood substitutes.” As research and development with these products continues, it is likely that the unique physiology of oxygen transport will be better understood, and it should be possible to more effectively oxygenate tissue while reducing or avoiding allogeneic blood transfusion.

Blood Substitutes / 283

References 1. Winslow R. Hemoglobin-based red cell substitutes. Baltimore (MD): Johns Hopkins University Press; 1992. 2. Gould S, Rosen A, Sehgal L, et al. Fluosol-DA as a red-cell substitute in acute anemia. N Engl J Med 1986;314:1653–6. 3. Rudolph A. Encapsulation of hemoglobin in liposomes. In: Winslow R, Vandegriff K, Intaglietta M, editors. Blood substitutes. Physiological basis of efficacy. New York: Birkhaüser; 1995. 4. Looker D, Abbott-Brown D, Cozart P, et al. A human recombinant haemoglobin designed for use as a blood substitute. Nature 1992;356:258–60. 5. Stowell CP, Levin J, Spiess BD, Winslow RM. Progress in the development of RBC substitutes. Transfusion 2001;41:287–99. 6. Amberson W, Jennings J, Rhodes C. Clinical experience with hemoglobin-saline solutions. J Appl Physiol 1949;1:469–89. 7. Christensen S, Medina F, Winslow R, et al. Preparation of human hemoglobin Ao for possible use as a blood substitute. J Biochem Biophys Methods 1988;17:143–54. 8. Rabiner S, Helbert J, Lopas H, Friedman L. Evaluation of stroma-free haemoglobin for use as a plasma expander. J Exp Med 11967;26:1127–42. 9. Bunn H, Jandl J. Renal handling of hemoglobin. II. Catabolism. J Exp Med 1967;129:925–34. 10. Payne J. Polymerization of proteins with glutaraldehyde. Soluble molecular-weight markers. Biochem J 1973;135:867–73. 11. Hsia J, Song D, Er S, et al. Pharmacokinetic studies in the rat on a o-raffinose polymerized human hemoglobin. Artif Cells Blood Substit Immobil Biotechnol 1992;20:587–95. 12. Chatterjee R, Welty E, Walder R, et al. Isolation and characterization of a new hemoglobin derivative crosslinked between
chains (Lysine 99
1-Lysine 99
2). J Biol Chem 1986;261:9929–37. 13. Keipert PE, Gomez CL, Gonzales A, et al. Diaspirin crosslinked hemoglobin: tissue distribution and long-term excretion after exchange transfusion. J Lab Clin Med 1994;123:701–11. 14. Hess J, Macdonald V, Winslow R. Dehydration and shock: an animal model of hemorrhage and resuscitation of battlefield injury. Artif Cells Blood Substit Immobil Biotechnol 1991;19:518.

18. Sloan EP, Koenigsberg M, Gens D, et al. Diaspirin crosslinked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock. A randomized controlled efficacy trial. JAMA 1999;282:1857–64. 19. Tsai A, Kerger H, Intaglietta M. Microcirculatory consequences of blood substitution. In: Winslow R, Vandegriff K, Intaglietta M, editors. Blood substitutes. Physiological basis of efficacy. New York: Birkhäuser; 1995. p. 143–54. 20. Ignarro L, Buga G, Wood K, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987;84:9265–9. 21. Gibson QH, Roughton FJW. The kinetics and equilibria of the reactions of nitric oxide with sheep hemoglobin. J Appl Physiol 1956;136:123–34. 22. Palmer R, Ferrige A, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–6. 23. Vandegriff K, McCarthy M, Rohlfs R, Winslow R. Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated. Biophys Chem 1997;69:232–30. 24. Rohlfs RJ, Bruner E, Chiu A, et al. Arterial blood pressure responses to cell-free hemoglobin solutions and the reaction with nitric oxide. J Biol Chem 1998;273:12128–34. 25. Wittenberg J. Myoglobin-facilitated oxygen diffusion: role of myoglobin in oxygen entry into muscle. Physiological Reviews 1970;50:559–636. 26. Lindbom L, Tuma R, Arfors K. Influence of oxygen on perfusion capillary density and capillary red cell velocity in rabbit skeletal muscle. Microvasc Res 1980;19:197–208. 27. Intaglietta M, Johnson P, Winslow R. Microvascular and tissue oxygen distribution. Cardiovasc Res 1996;32:632–43. 28. Vandegriff K, Winslow R. A theoretical analysis of oxygen transport: a new strategy for the design of hemoglobinbased red cell substitutes. In: Winslow R, Vandegriff K, Intaglietta M, editors. Blood substitutes. Physiological basis of efficacy. New York: Birkhäuser; 1995. 29. Winslow RM, Vandegriff KD. Hemoglobin oxygen affinity and the design of red cell substitutes. In: Winslow RM, Vandegriff KD, Intaglietta M, editors. Advances in blood substitutes. Industrial opportunities and medical challenges. Boston (MA): Birkhäuser; 1997. p. 167–88.

15. Hess J, Macdonald V, Brinkley W. Systemic and pulmonary hypertension after resuscitation with cell-free hemoglobin. J Appl Physiol 1993;74:1769–78.

30. McCarthy MR, Vandegriff KD, Winslow RM. The role of facilitated diffusion in oxygen transport by cell-free hemoglobin: implications for the design of hemoglobin-based oxygen carriers. Biophys Chem 2001;92:103–17.

16. Hess J, Riess R. Resuscitation and the limited utility of the present generation of blood substitutes. Transf Med Rev 1996;10:276–85.

31. Winslow RM, Gonzales A, Gonzales M, et al. Vascular resistance and the efficacy of red cell substitutes. J Appl Physiol 1998;85:993–1003.

17. Saxena R, Wijnhoud AD, Carton H, et al. Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke. Stroke 1999;30:993–6.

32. Richmond KN, Shonat RD, Lynch RM, Johnson PC. Critical PO(2) of skeletal muscle in vivo. Am J Physiol 1999;277(5 Pt 2):H1831–40.

284 / Advanced Therapy in Thoracic Surgery 33. Doherty DH, Doyle MP, Curry SR, et al. Rate of reaction with nitric oxide determines the hypertensive effect of cellfree hemoglobin. Nature Biotechnology 1998;16:672–6. 34. Baldwin AL. Modified hemoglobins produce venular interendothelial gaps and albumin leakage in the rat mesentery. Am J Physiol 1999;277(2 Pt 2):H650–9. 35. Bucci E. Hemoglobin based oxygen carriers at a cross road: the old paradigms must be abandoned and much more basic science investigation is necessary [editorial]. Artif Cells Blood Substit Immobil Biotechnol 2001;29:vii–x.

36. Tsai AG, Friesenecker B, McCarthy M, et al. Plasma viscosity regulates capillary perfusion during extreme hemodilution in hamster skinfold model. Am J Physiol (Heart Circ Physiol 44) 1998;275:H2170–H2180. 37. Frangos JA, Eskin SG, McIntire LV, Ives CL. Flow effects on prostacyclin production in cultured human endothelial cells. Science 1985;227:1477–9. 38. D’Agnillo F, Alayash AI. Redox cycling of diaspirin crosslinked hemoglobin induces G2/M arrest and apoptosis in cultured endothelial cells. Blood 2001;98:3315–23.

CHAPTER 23

UPDATE IN THE MANAGEMENT OF PULMONARY HYPERTENSION AUSTIN B. THOMPSON, MD, FACCP

Classification of Pulmonary Hypertension

The WHO symposium of 1998 also provided a functional classification that is a modification of the New York Heart Association functional classification (Table 23-2).

The first classification of pulmonary hypertension was proposed at a World Health Organization (WHO) symposium in 1973. Pulmonary hypertension was classified based upon etiologies with primary pulmonary hypertension (PPH) classified as a separate class, that of pulmonary hypertension of unknown etiology and lacking associated clinical conditions. PPH was further subdivided into three groups based on pathology: plexogenic, recurrent thromboembolism, and veno-occlusive disease. Later it became apparent from epidemiological data and the pathology of pulmonary hypertension that no distinct pathological findings were pathopneumonic for PPH, including lesions consistent with plexogenic arteriopathy. Epidemiological studies have demonstrated a growing list of diagnoses that are associated with a clinical condition and are indistinguishable from PPH. In 1998, the WHO convened a second symposium to update the classification system of pulmonary hypertension and collate state-of-the-art understanding of pulmonary hypertension. In the new classification system (Table 23-1), PPH is one of a group of entities that share common clinical and pathological presentations included under the broader heading of pulmonary arterial hypertension (PAH). 1 Four other classifications of pulmonary hypertension include pulmonary venous hypertension, pulmonary hypertension associated with disorders of the respiratory system or hypoxemia, pulmonary hypertension due to chronic thrombotic or embolic disease, and pulmonary hypertension due to disorders directly affecting the pulmonary vasculature.

Physiology and Pathobiology Normally the pulmonary circulation is a low-pressure, high-flow vascular bed that has a remarkable capacity to permit increased cardiac output, such as exercise, without increasing pulmonary arterial pressure. The ability of the pulmonary vasculature to respond to increases in cardiac output is felt to be the result of the recruitment of underperfused vessels and engorgement of highly capacitant vessels in response to increases in blood flow. The physiology and histology of the pulmonary vasculature reflect the normal state of affairs as the native smooth muscle tone of pulmonary arterioles is lower and the smooth muscle layer is thinner than that of the systemic circulation. Pulmonary arterial pressure is a function of the pulmonary venous pressure, cardiac output, and pulmonary vascular resistance (Table 23-3). The National Institutes of Health (NIH) Registry defined a normal mean pulmonary artery pressure at rest of 25 mm Hg, rising to 30 mm Hg with exercise.2 A recent report of a series of estimates of pulmonary arterial systolic pressure measured by Doppler transthoracic echocardiography found that normal pulmonary artery pressures may be higher than previously appreciated. 3 In this study of 3,790 echocardiographically normal subjects, pulmonary arterial systolic pressure increased with age, body mass index, and sex. Twenty-eight percent had pulmonary artery systolic pressure > 30 mm Hg; it was suggested that the upper limit of normal may reach 40 mm Hg in older patients or obese patients. 285

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The onset of pulmonary hypertension, depending upon etiology, is often insidious and is characterized by delayed diagnosis.2,4–6 Patients may present with dyspnea on exertion with normal resting physiological parameters but are found to have elevations of the pulmonary arterial pressures with exertion. Associated with dyspnea, the finding of elevated pulmonary artery pressures with exercise is highly suggestive of early pulmonary arterial hypertension. However, the normal spectrum of the exercise response of the pulmonary arterial pressures has not

TABLE 23-1. Classification of Pulmonary Hypertension Pulmonary Arterial Hypertension Primary pulmonary hypertension Sporadic Familial PH with associated medical conditions Collagen vascular disease Portal hypertension HIV infection Ingestion of drugs or toxins Fenfluramine, dexfenfluramine, aminorex, toxic rapeseed oil, amphetamine, L-tryptophan, cocaine, chemotherapeutic agents Persistent PH of the newborn Other Pulmonary Venous Hypertension Left atrial or ventricular disease Left-sided valvular heart disease Extrinsic compression of central pulmonary veins Pulmonary veno-occlusive disease Other

been well characterized. The finding of elevated pulmonary arterial pressures with an absence of clinical symptoms may represent a normal physiological variant. The formula in Table 23-3 illustrates that the pulmonary vascular resistance is dependent not only on the pulmonary arterial pressure, but rather the gradient across the vascular bed. Reflective of the remarkable capacitance of the pulmonary circulation to respond to increased cardiac output without significant increase in pulmonary artery pressures, acute changes in pulmonary arterial flow and pulmonary venous pressures are not associated with significant pulmonary hypertension. In contrast, persistence of increased flow through the pulmonary vasculature or venous pressures will lead to vasoconstriction, vascular remodeling, and affect a loss of the cross section of the resistant vessels. Investigations of the mechanisms that maintain normal vascular tone have led to insights, some of which have had important therapeutic implications. Several mechanisms have been described for the maintenance of TABLE 23-2. Functional Assessment of Pulmonary Hypertension Class I

Class II

Class III

Associated with Hypoxemia or Lung Disease COPD Interstitial lung disease Sleep disordered breathing Alveolar hypoventilation Chronic high altitude exposure Neonatal lung disease Alveolocapillary dysplasia Other Chronic Thrombotic or Emboloic Disease Thromboembolic obstruction of the proximal arteries Obstruction of distal pulmonary arteries Pulmonary embolism Thrombus, tumor, parasitic, foreign material In situ thrombosis Sickle cell anemia Disorders Directly Affecting the Pulmonary Vasculature Inflammatory Schistosomiasis Sarcoidosis Other Pulmonary capillary hemangiomatosis Adapted from Wolf M et al.24 COPD = chronic obstructive pulmonary disease; HIV = human immunodeficiency virus; PH = pulmonary hypertension.

Class IV

No limitation of physical activity. Activities of daily living do not cause undue dyspnea, fatigue, chest pain, or near syncope. Slight limitation of physical activity, but comfortable at rest. Activities of daily living cause undue dyspnea, fatigue, chest pain, or near syncope. Marked limitation of physical activity, but comfortable at rest. Less than the normal activities of daily living cause undue dyspnea, fatigue, chest pain, or near syncope. Marked limitation of physical activity, possibly dyspneic or fatigued at rest, any increase in physical activity increases discomfort. Possible signs of right heart failure.

Adapted from Wolf M et al.24

TABLE 23-3. Hemodynamics and Approximate Normal Pulmonary Values for Adults PVR (mm Hg min L
1) = (MPAP
MLAP)/CO Pulmonary arterial pressure Systolic Diastolic Mean Left ventricular end-diastolic pressure (left atrial mean) Right ventricular end-diastolic pressure (right atrial mean) Cardiac index Pulmonary vascular volume Capillary blood volume Pulmonary vascular resistance

22–30 mm Hg 6–12 mm Hg 10–12 mm Hg 6–12 mm Hg 0–6 mm Hg 2.7–3.5 L/min per m2 290 mL/m2 80–120 mL 150–200 dynes/cm2

CO = cardiac output; MLAP = mean left atrial pressure; MPAP = mean pulmonary artery pressure; PVR = pulmonary vascular resistance.

Update in the Management of Pulmonary Hypertension / 287

pulmonary vascular tone.7 Platelets, endothelial cells, smooth muscle cells, and the extracellular matrix all are important for the maintenance of normal vascular tone. Perturbations of the normal function of all these elements have been postulated to contribute to the pathological changes of PAH. Table 23-4 lists examples of cell products and functions that contribute to normal vascular tone and alterations associated with PPH. Hypoxic vasoconstriction is the most important physiological mechanism of pulmonary vasoconstriction. The mechanisms that lead to hypoxic vasoconstriction are incompletely described. Hypoxia at the level of the alveoli causes local vasoconstriction, which is acutely reversible by administration of oxygen. If this phenomenon occurs globally, then pulmonary hypertension results. Chronic states of hypoxia lead to vascular remodeling and result in fixed increases in pulmonary vascular resistance. Hypoxia may further stimulate pulmonary hypertension through the release of cytokines from the endothelial cell. Inflammatory cells may contribute as well through a production of cytokines and growth factors. Several of the vasoactive compounds are also mitogens and may to contribute to vascular remodeling. Endothelial cells are capable of producing a number of vasoactive substances including vasodilators and vasoconstrictors. Abnormality in the metabolism of these substances, favoring vasoconstriction, has been noted in patients with PPH and in experimental animal models of pulmonary hypertension. Growth factors released from the endothelial cell may stimulate to vascular remodeling and alteration of the extracellular matrix. In the smooth muscle cells, much attention has been placed upon the role of calcium and potassium channel regulation. K+ channels regulate calcium influx into the cell through a number of mechanisms. Influx of calcium into the smooth muscle cell leads to activation of the contractile apparatus and vasoconstriction and possibly initiates mitogenic effects as well. Acute hypoxia triggers

pulmonary vasoconstriction at least in part by inhibiting one of the K + channels found in pulmonary artery smooth muscle cells. Vascular remodeling is a central feature of pulmonary hypertension from all causes and has been used to both classify and grade the severity of pulmonary hypertension. Vascular remodeling includes changes in the intima (fibrosis, media, hypertrophy, and muscularization) and adventitia (increased deposition of extracellular matrix). Endothelial injury early in the course of PAH has been hypothesized to permit exudation of factors that stimulate smooth muscle cells to release mitogens such as basic fibroblast growth factor directly and adenosine indirectly. Membrane-bound metalloproteins and serine elastases have been postulated to be central in this process. The recent identification of mutations in the gene for bone morphogenetic protein receptor II in patients with familial PPH promises to provide insight into the pathogenesis of PPH.8,9 Bone morphogenetic protein receptor II is a member of the transforming growth factor  (TGF-) receptor family. TGF- family of growth factors have pleiotropic effects on endothelial cells, smooth muscle cells, and fibroblasts. The activities of the TGF- family are dependent upon the cellular milieu; they are modified by complex cytokine networks in ways that may be as divergent as promoting or inhibiting endothelial cell proliferation. Thus, describing the common pathway that leads to PPH continues to present significant investigational challenges.

Primary Pulmonary Hypertension Primary pulmonary hypertension is a rare condition with an estimated annual incidence of one to two per million people per year in Europe and the United States. 6,10 However, this may be an underestimate, as autopsy studies have shown a prevalence of 1,300 per million population. The incidence of PPH rises drastically among users of appetite suppressants to 25–50 per

TABLE 23-4. Examples of Pathogenetic Factors in Pulmonary Arterial Hypertension Source

Factor

Normal Function

Association with PAH

Platelets Thrombomodulin Thromboxane A2 Endothelial cells

Serotonin Inhibits platelet aggregation Vasoconstrictor; stimulates platelet aggregation Prostacyclin NO Thromboxane A2 Endothelin K+ channels Serine elastases Matrix-bound: SMC mitogens MMP

Vasoconstrictor; EC mitogen Elevated Elevated Vasodilator Vasodilator Vasoconstrictor; stimulates platelet aggregation Vasoconstrictor Ca+-mediated SMC relaxation Liberate SMC mitogens from ECM

Elevated

Diminished Diminished Elevated Elevated Down-regulated Elevated

Stimulate SMC proliferation Degrades ECM

Elevated Elevated

Smooth muscle cells Extracellular matrix

EC = endothelial cell; ECM = extracellular matrix; MMP = matrix metalloproteinase; NO = nitric oxide; SMC = smooth muscle cell.

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million people per year.11 The U.S. NIH Registry demonstrated that PPH can occur at any age and has a peak incidence at 36 years. The disease is more common in females than males with a ratio of about 2:1. Familial cases of PPH were noted in the registry. This observation led to further understanding of the genetic basis of PPH (see below). Familial PPH occurs in approximately 10% of cases. There is no association between race and PPH. There is a spectrum of clinical signs and symptoms that occur at presentation in PPH (Table 23-5). The most common presentation, however, is the insidious onset and progression of dyspnea on exertion. The nonspecific nature of the presentation led to a delay in diagnosis on an average of 2 years in the NIH Registry. Physical findings may suggest the diagnosis. Most commonly noted are an accentuated second heart sound and a right ventricular S4. As the condition worsens, the right ventricle becomes hypertrophied, which leads to a right ventricular heave and tricuspid regurgitation. Dilatation of the annulus of the pulmonary valve or right ventricle outflow track leads to a murmur of pulmonic regurgitation. A right ventricular S3 gallop occurs with right ventricular failure and is an ominous sign, associated with decreased cardiac output and increased right atrial pressures. The diagnosis of PPH is a diagnosis of exclusion. Following the recommendations and experience gained from the NIH Registry open lung biopsy is no longer recommended for the diagnosis of PPH. Quite often, patients will have had a series of tests to evaluate their dyspnea prior to the diagnosis of pulmonary hypertension. Typically, these tests include pulmonary function tests, which may be normal or demonstrate early restrictive disease (which may become prominent in severe PPH) and mild to moderate impairment of the diffusing capacity. The chest radiograph commonly shows large pulmonary arteries (Figure 23-1).12 The right pulmonary interlobar artery is considered enlarged when it is 16 mm or greater in men and 15 mm or greater in women. With enlargement, the left main pulmonary artery causes a convexity under the aortic arch. Pulmonary function tests

and chest radiograph are of assistance also in ruling out significant pulmonary airway or parenchymal diseases as the cause of the dyspnea. The initial evaluation of the pulmonary hemodynamics is best made by echocardiography. Transthoracic echocardiography can characterize the shape and size of the chambers and identify hypertrophy of the right

A

B

TABLE 23-5. Prevalence of Symptoms of Primary Pulmonary Hypertension

Dyspnea Fatigue Chest pain Near syncope Syncope Leg edema Palpitations Adapted from 61.

As Presenting Symptoms (%)

At Time of Disease (%)

60 19 7 5 8 3 5

98 73 47 41 36 37 33

FIGURE 23-1. Young woman with primary pulmonary hypertension associated with anorexigen use. A, Chest radiograph demonstrates mild cardiomegaly, enlargement of the interlobar artery (small arrow), and convexity resulting from enlargement of the left main pulmonary artery (large arrow). B, Chest computed tomography scan demonstrates normal pulmonary parenchyma and confirms that cardiomegaly is due to right ventricular enlargement.

Update in the Management of Pulmonary Hypertension / 289

ventricle. Decreased filling of the left ventricle may be noted, as may paradoxical movement of the intraventricular septum towards the left ventricle. Doppler echocardiography can be used to estimate the pulmonary arterial systolic pressure. This is done by measuring systolic flow velocity across pulmonic valve or, more accurately, by regurgitant flow across the tricuspid valve.3 The echocardiogram is also useful in ruling out intracardiac shunts, which cause high flow states and secondary pulmonary hypertension. Small shunts are best demonstrated by transesophageal echocardiography. Once the diagnosis of pulmonary hypertension is confirmed, associated medical conditions need to be excluded. Blood tests are obtained to screen for liver disease, connective tissue diseases, and serology for human immunodeficiency virus (HIV)-1 infection. Sufficient screening tests for connective tissue disorders in patients who are otherwise asymptomatic include antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and an erythrocyte sedimentation rate. A major category of disease that needs to be excluded is thromboembolic disease. Ventilation perfusion scan or computed tomography (CT) angiography can be used to exclude chronic thromboembolic disease. If chronic thromboembolic disease is suggested, then pulmonary angiography should be performed to further characterize the degree and distribution of the thromboembolic deficits.13 Polysomnography is indicated if there are clinical findings suggestive of sleep apnea.14 If testing rules out secondary causes of pulmonary hypertension, the diagnosis of PPH can be made. However, further physiological evaluation is appropriate. In particular, cardiac catheterization is needed to fully assess right ventricular and left ventricular hemodynamics to confirm echocardiogram estimates of right ventricular and pulmonary artery pressures and to further rule out left-to-right shunts. If risk factors for coronary artery disease are present, the inclusion of coronary artery angiography is useful as patients with PPH often present with, or develop, atypical chest pain. Cardiac catheterization should include acute vasodilator testing. Results from the NIH Registry show that a positive response to acute vasodilator test is predictive of clinical response to oral vasodilatory agents. A positive acute vasodilator test is one in which there is a fall in the pulmonary artery pressures of 20% or 10 mm Hg with either no change or an increase in cardiac output.15 A 6-minute walk test provides important information about the potential need for supplemental oxygen therapy. It is less time-consuming and expensive than a formal cardiopulmonary stress test and is more easily repeated for monitoring of response to therapy. Following the diagnosis of PPH and initiation of ther-

apy, transthoracic echocardiography can be used for sequential estimates of pulmonary artery systolic pressure to monitor response to therapy. Follow-up with 6minute walk tests is useful for ongoing titration of supplemental oxygen. The medical therapy of PPH has three aims. The first is vasodilation, the second is modulation of pulmonary vascular remodeling, and the third is the prevention of in situ thrombosis. Vasodilator therapy is directed by the results of the acute vasodilatory test performed in the cardiac catheterization lab and the severity of pulmonary hypertension upon presentation. Historically, observations on the use of multiple vasodilators identified that only a minority of patients would respond to these agents. The responsive patients are identified by the acute vasodilator test in the cardiac catheterization lab, and oral therapy with a calcium channel blocker is indicated. The dosage should be titrated to the maximal recommended dose if tolerated, avoiding systemic hypotension.16 Intravenous infusion of epoprostenol (prostacyclin, or PGI2) has been shown to be efficacious even in patients who do not have a positive acute vasodilator test.17 In the majority of these patients, epoprostenol has been shown to improve hemodynamics, increase exercise tolerance, and prolong survival. Epoprostenol has the disadvantage of a very short half-life of 3 to 5 minutes, requiring continuous intravenous infusions. Administration requires an indwelling vascular catheter. Meticulous care of the catheter is essential, as line sepsis can quickly become life threatening in patients with fixed flow through their pulmonary vasculature. Epoprostenol has less worrisome side effects as well, including jaw pain (a claudication-like pain relieved by chewing), headache, rash, diarrhea, and musculoskeletal pains, particularly in the ankles and feet. The dose of the drug is titrated to provide for maximum exercise tolerance and is limited by discomfort from the minor side effects. There is apparent tachyphylaxis to epoprostenol and dosing needs to be continuously advanced to maintain efficacy. A newer alternative to epoprostenol is bosentan, an inhibitor of both the endothelin 1 and endothelin 2 receptors.18 This drug has been demonstrated to improve hemodynamics and exercise tolerance in patients treated following the initial diagnosis of their PPH. Long-term studies documenting survival advantage are not yet available. Bosentan clearly has the advantage of not requiring a continuous infusion, but liver toxicity and dosedependent fall in hemoglobin require frequent monitoring. The possibility of switching patients from epoprostenol to bosentan has not yet been formally investigated. Data to guide the selection of either epoprostenol or bosentan upon initial presentation do not yet exist. Thus, one sug-

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gestion is that patients with class IV dyspnea on exertion receive epoprostenol, reserving a trial of bosentan for patients with class III dyspnea on exertion. Other oral and subcutaneous preparations are undergoing evaluation in the United States or are available in Europe. As these become available, and until improvement in mortality is documented, beginning patients with class IV dyspnea on exertion on epoprostenol would remain a valid recommendation. Care must be taken with the administration of any of the vasodilators for PPH. The sudden cessation of vasodilator therapy may lead to rapid rebound in pulmonary artery pressures, which can be life threatening. There is investigational evidence that both epoprostenol and bosentan have antimitogenic activities. There has also been some suggestion in the investigational literature that calcium channel blockers may have similar, if not as potent, activities. Thus, therapies with these vasodilatory drugs also address the issue of vascular remodeling. Occasionally, patients do not show improvement in their pulmonary artery pressures following treatment with epoprostenol for up to 12 months. This delay in response supports the contention that the drug is effecting vascular remodeling and is not acting merely as a vasodilator. In situ thrombosis is an important complicating feature of primary pulmonary hypertension. Nonrandomized trials in which anticoagulation was initiated with patients with abnormal ventilation–perfusion scans but not in those with normal scans demonstrated a survival advantage for patients receiving warfarin.16 On the basis of these trials, the standard of care includes anticoagulation with warfarin to maintain the international normalized ratio (INR) between 2 and 3. The use of digoxin in patients with cor pulmonale is controversial. Some authorities recommend its use because of its inotropic activity and reversal of the neurohumoral activation that occurs with right heart failure. Diuretics should be used judiciously in patients with cor pulmonale. They are indicated for peripheral edema associated with cor pulmonale or secondary to high-dose calcium channel blockers. Ascites can be a very difficult complication of cor pulmonale to manage and may respond to the addition of spironolactone to loop diuretics. Patients on diuretics must be closely monitored for electrolyte abnormalities and to ensure that intravascular volume is not depleted. Surgical approaches to PPH include atrial septostomy. This has been suggested for patients with severe rightsided heart failure that is refractory to diuretics and in patients with syncope resulting from poor filling of the left ventricle. The resulting right-to-left shunt leads to decompression of the right ventricle and improved filling

of the left ventricle, but it is also associated with significant desaturation, which may not respond to oxygen supplementation. If medical therapy fails, then lung transplantation may be a lifesaving intervention. Single or double lung transplants may be offered to patients with PPH. Heart–lung transplantation is generally reserved for patients with abnormal left ventricular function or congenital anomalies. Outcomes for lung transplantation for pulmonary hypertension are slightly worse than for other diagnoses. Primarily this is because of higher morbidity and mortality in the immediate postoperative period, which results from the stress placed upon the transplanted vascular bed by the hypertrophied right ventricle. One and fiveyear survival rates are respectively 64 and 42%. PPH tends to be a disease of young women. Thus, pregnancy is a frequent issue in the care of these patients. Since patients with PPH have a cardiac output fixed by their abnormal pulmonary vasculature, the hemodynamic changes associated with pregnancy and the immediate postpartum period may be life threatening. Successful pregnancies with safe deliveries have been reported, but contraception should be recommended as a rule. Oral contraceptives are contraindicated as they may increase the risk of deep venous thrombosis and pulmonary embolism. Prognosis for untreated PPH is poor with a mean survival time of 212 years in the NIH Registry.19 Patients who respond to oral vasodilation have a 95% 5-year survival rate. 1 6 The nonresponders treated with epoprostenol have significant improvement in their survival rate as reflected by the fact that, in one study, 91% of the patients with pulmonary hypertension avoided listing for lung transplantation after initiation of therapy.20 As listed in Table 23-1, ingestions and a number of clinical conditions have been identified as probable etiologies for PAH. Some such as HIV, portal hypertension, and collagen vascular diseases are long-term conditions that have the potential to modify the pulmonary vasculature on an ongoing basis. Others, particularly the toxic ingestions and use of weight-reduction aids, suggest that PAH can be triggered by limited injury or exposure. It has been suggested that these short-term exposures, either by increasing shear forces or by direct stimulation, alter endothelial cell biology, which sets off a vicious, self-sustaining cycle of changes that eventuate in pulmonary arterial hypertension.

Update in the Management of Pulmonary Hypertension / 291

Chronic Thromboembolic Pulmonary Hypertension Chronic thromboembolic pulmonary hypertension (CTPH) results as a rare sequela of pulmonary embolism. It accounts for a small fraction of patients who survive acute pulmonary emboli, estimated at 0.1 to 0.5%. Since pulmonary emboli can be an asymptomatic event, the true incidence of patients with CTPH is not known. However, estimates place the total number in the United States between 500 and 2,500 patients. Patients with CTPH can present with the insidious onset of dyspnea on exertion in a manner identical to the presentation of PAH. Since there is an effective surgical intervention available, it is important to distinguish CTPH from other causes of pulmonary hypertension.10 Acute pulmonary embolism rarely causes pulmonary hypertension. The exception occurs with massive acute pulmonary embolism in which the embolus occludes 50% or more of the pulmonary vasculature in patients with normal cardiopulmonary physiology or 30% for patients with pulmonary or cardiac disease. In patients with massive pulmonary embolism, the risk of death is greatest in the first few hours following the acute event. The vast majority of the patients who survive the first few hours go on to have their embolus resolved within 3 weeks, with normalization of the pulmonary artery pressures. However, as noted above, in a minority of patients resolution is incomplete. Residual obstruction of 40% of the pulmonary vasculature is associated with pulmonary hypertension on the basis of the obstruction of large (ie, main, lobar, or proximal segmental) arteries.21 Progression of pulmonary hypertension occurs with recurrent embolization or in situ thrombosis in the pulmonary arteries. Alternatively, progression of pulmonary hypertension can occur as a result of vascular remodeling, with pathological changes indistinguishable from those found in pulmonary arterial hypertension. In these cases, pulmonary hypertension is out of proportion to the degree of embolic obstruction of the pulmonary arteries, hemodynamic worsening occurs without evidence of recurrent thromboembolic events even in patients who are fully anticoagulated, and, in cases where open biopsies were performed, the pathological changes of PAH in the small distal arterioles were noted. Only those patients whose hemodynamic abnormalities are proportionate to the degree of proximal arterial obstruction are candidates for thromboembolectomy.10,22 As mentioned above, the presentation of patients with CTPH is the same as with other forms of pulmonary hypertension. Dyspnea on exertion with insidious onset and relentless worsening is the hallmark. The other symptoms, noted in Table 23-5, occur as the pulmonary

hypertension progresses. On the whole, CTPH presents with physical findings identical to PAH. One distinguishing characteristic on physical exam is the finding of bruits that are presumed to originate from turbulent flow through partially occluded pulmonary arteries in 30% of patients.23 The evaluation of patients with suspected CTPH is similar to the evaluation of patients with PPH. However, effort should be undertaken to assure that ongoing silent pulmonary embolism is not a continuing problem. Duplex scanning of the legs is noninvasive and indicated in the clinic evaluation. A large fraction of duplex scans in patients with CTPH reveal evidence of prior venous thrombosis (35–45%) and are useful to rule out acute active thrombosis. Patients should also be evaluated for coagulopathies that put them at risk for recurrent emboli and failure of standard anticoagulation. Up to 10% of patients have been found to have anticardiolipin antibody. 24,25 Ventilation–perfusion scanning is often the study that provides the initial suspicion for CTPH. In patients with CTPH, mismatched perfusion defects are seen usually at the segmental or larger levels. However, ventilation–perfusion scans cannot be used to judge the extent of obstruction in thromboembolic disease. 26 Angiography, angioscopy, or surgery often shows more extensive disease than that revealed by ventilation– perfusion scanning. The role of CT angiography in the evaluations of patients with CTPH is undefined. Obstruction or partial obstruction of main, lobar, or segmental arteries is common but is not yet felt to be a substitute for angiography for defining the extent of disease. Right heart catheterization is indicated, as for PPH, for accurate hemodynamic characterization. Pulmonary angiography can be safely performed in patients with pulmonary hypertension but requires modifications of standard practices and careful monitoring and thus should be performed in centers with experience. 13,27 Angiography provides the best characterization of the extent of chronic thromboembolic disease and the determination if the disease is present in surgically approachable vessels. The angiographic appearance of chronic thromboemboli differs from acute pulmonary embolus. Rather than the well-delineated intraluminal filling defects seen in acute pulmonary emboli, patients with CTPH have defects that are irregular and partially recanalized and which may appear as bands or webs. Angioscopy employing a fiberoptic device has also been used to characterize CTPH patients. However, this is not widely available. Angioscopy has been used at its originating center to help characterize the extent of thromboembolism in patients with milder pulmonary hypertension and ques-

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tionable angiographic findings and to determine operability in patients with severe pulmonary hypertension with inadequate findings on angiography to justify surgery.28 Pulmonar y thromboendarterectomy remains a complicated procedure that is best carried out at centers with expertise. In the most experienced hands, the mortality is 7%, with reports of mortality ranging as high as 24%.10 Reperfusion injury following the procedure remains the major cause of morbidity and mortality. The surgery is contraindicated in patients with severe underlying lung disease. Advanced age, severe right heart failure, and significant collateral disease are relative contraindications. Coronary artery angiography is performed for all patients with risk factors for coronary artery disease with the possibility of coronary artery bypass grafting concurrent with thromboendarterectomy, if warranted. Placement of an inferior venacaval filter is recommended prior to surgery to assure that pulmonary embolism does not recur. Following the thromboendarterectomy, a reduction in the pulmonary vascular resistance of approximately 65% is expected. This is associated with improvements in gas exchange and exercise tolerance with patients improving from New York Heart Association class III or IV to class I or II after surgery. Lifelong anticoagulation is recommended. A subgroup of patients who have had acute pulmonary embolism with apparent resolution or who have chronic thromboembolic disease in the pulmonary artery but of an extent too small to explain the progression and severity of pulmonary hypertension present with a syndrome very similar to PPH. Once these patients are ruled out as candidates for surgical therapy, the medical therapies recommended for PPH are appropriate. An inferior venacaval filter should be considered if there is any question of failure of anticoagulation therapy.

Pulmonary Veno-Occlusive Disease Pulmonary veno-occlusive disease (PVOD) was initially recognized as a subcategory of PPH. The presentation of PVOD is clinically similar to PAH.29 However, a pathological hallmark is the diffuse occlusion of pulmonary veins by fibrous tissues. Pathological findings suggest evolution of the fibrotic lesions from loose, edematous fibrosis to dense, sclerotic fibrosis. Typically, intimal involvement is seen in venules and smaller veins, but involvement of larger veins can be seen as well. Medial thickening tends to be eccentric and heterogenous as seen in the small arterioles in PAH. In time the thickened intima may become arterialized and completely occluded vessels may become revascularized.30 It is felt that the cause of elevated pulmonary vascular resistance lies in the venous changes. As might be ex-

pected in response to the raised pulmonary artery pressures, the pulmonary arterioles may demonstrate medial hypertrophy, but other findings of pulmonary arterial hypertension such as plexiform lesions are absent. PVOD, historically, accounted for 5 to 25% of PAH. As for PAH, the age of onset spans life expectancy. 2 9 However, unlike for PAH, the ratio of men to women is approximately 1:1. Infections with various agents have been suggested as leading to PVOD. Some of these agents are Toxoplasma gondii, measles, Epstein-Barr virus, cytomegalovirus, and HIV. A genetic risk has been suggested by case reports in siblings, but unlike PPH, no gene has, as yet, been linked to the condition. A case report suggested an association with sniffing cleaning powder.31 A better-characterized association has been found with chemotherapy including bleomycin, mitomycin, and carmustine and with both allogeneic and autologous bone marrow transplantation.32,33 An autoimmune association has been suggested by the presentation of patients with associated myopathy, alopecia, rheumatoid arthritis, systemic lupus erythematosus, CREST syndrome, and positive antinuclear antibodies. However, these associations are missing in most individuals. A distinguishing radiographic feature of PVOD is the presence of radiographic changes in the pulmonary parenchyma.34 Since the vascular obstruction is postcapillary, the pulmonary capillaries are exposed to higher pressures and, thus, radiographic changes associated with interstitial edema may be observed, such as Kerley’s B lines and pleural effusions. Patchy pulmonary infiltrates may be observed as well and, when present, may be associated with crackles on physical exam. On highresolution CT scan, ground glass opacities, thickened septal lines, and multiple small nodules have been observed. Physiologically, there is little to distinguish PVOD from PAH. Cardiac catheterization will show elevated pulmonary artery pressures and, if the pulmonary artery catheter is successfully wedged, normal pulmonary artery wedge pressures. Failure to obtain a pulmonary artery wedge pressure tracing is common in PVOD.34 In the pulmonary function lab, the diffusion capacity of the lung for carbon monoxide is usually reduced. Spirometry and lung volumes may be normal or demonstrate a restrictive impairment. The finding of PAH, evidence of pulmonary edema on the chest radiograph, and normal ventricular function has been suggested to be diagnostic of PVOD. However, patients with PVOD may not demonstrate radiological findings. Open lung biopsy is a possible approach for the definitive diagnosis of PVOD. Confirming the diagnosis has been felt to be appropriate as treatment with vasodilators may be hazardous. An alternative approach

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is to cautiously test the hemodynamic response of patients with suspected PVOD with short-acting vasodilators during cardiac catheterization prior to initiation of therapy. Patients with PVOD are at increased risk for the administration of pulmonary vasodilators.35,36 The dilation of pulmonary arterioles, in the presence of fixed venous occlusion, can lead to sudden increase in pulmonar y capillar y pressure with formation of pulmonary edema and even death. However, as PVOD is a relentlessly progressive and fatal disease, cautious administration of vasodilators may be warranted. The response of PVOD to vasodilators is not well established. However, some studies have suggested alleviation of elevated pulmonary vascular resistance in response to vasodilators. 37 Similarly, anticoagulation is suggested based on the experience with PPH. Oxygen should be administered to hypoxic patients. If therapeutic modalities fail, then PVOD becomes an indication for consideration for lung transplantation. Pulmonary hypertension may also result from the occlusion of large pulmonary veins. Inflammatory diseases or neoplastic diseases of the mediastinum can impinge upon and obstruct the pulmonary veins. Fibrosing mediastinitis is a rare cause of pulmonary vein occlusion. It is characterized by exuberant fibrotic response to inflammation in mediastinal lymph nodes, which often spills over into other mediastinal structures. Some cases have been associated with histoplasmosis infections by the finding of organisms on culture of surgical specimens, while other cases have no clear documented etiology. Successful surgical bypass of the affected veins has been reported. Case reports suggest efficacy for treatment with tamoxifen.

Lung Disease Associated with Pulmonary Hypertension Secondary causes of pulmonary hypertension are by far more common than PAH, and the most common cause of secondary pulmonary hypertension is lung diseases. The initial presentation of pulmonary hypertension associated with lung diseases is that of the underlying lung disease. Lung diseases commonly associated with pulmonary hypertension include COPD, restrictive lung disease including the interstitial lung diseases, and syndromes associated with hypoventilation. A central characteristic of these diseases is alveolar hypoxia. Alveolar hypoxia causes vasoconstriction. Teleologically, this mechanism helps to recruit pulmonary vascular circulation distant from an area of injury (eg, an underventilated portion of the lung involved with pneumonia). When the alveolar hypoxia

becomes global, the vasoconstriction results in pulmonary hypertension. Persistent alveolar hypoxia leads to vascular smooth muscle hypertrophy and vascular remodeling eventually leading to fixed pulmonary hypertension.38 Other mechanisms unique to the underlying pulmonary pathology are associated with pulmonary hypertension caused by pulmonary diseases. In COPD, emphysematous changes lead to loss of alveolar septa and the associated pulmonary capillary bed. Progressive air trapping leads to raised intra-alveolar pressure, which has the effect of collapsing alveolar vessels, further contributing to the raised pulmonary artery pressure. In COPD, factors that exacerbate hypoxia such as desaturation with exercise or desaturation associated with sleep-disorder breathing can worsen the pulmonary hypertension.39 The therapeutic approach to pulmonary hypertension in COPD is to maximize bronchodilation, relieving areas of poor ventilation and air trapping, and supplemental oxygen, especially during periods of increased physiological stress such as with exercise and sleep.40 Pulmonary hypertension associated with COPD tends to occur in more severe lung disease and is predictive of mortality.41 However, the correlation between pulmonary function tests and pulmonary hypertension in COPD is somewhat variable. Patients who have a predominantly chronic bronchitic picture, with severe ventilation– perfusion mismatch and sleep-disorder breathing, can have pulmonary hypertension fairly early in the course of their disease. On the other hand, patients with a primarily emphysematous picture do not tend to develop pulmonary hypertension until the forced expiratory volume in 1 second drops well below 1 L. The best determinants for suspicion of pulmonary hypertension in patients with COPD are the clinical findings of cor pulmonale.42, 43 Restrictive lung diseases can be associated with pulmonary hypertension as well. Restrictive lung diseases are defined by impairment of the total lung capacity. These can be divided into a group of diseases that cause parenchymal lung disease and those that cause abnormalities of the muscles of respiration and the thoracic cage. The former group includes idiopathic interstitial lung diseases (eg. idiopathic pulmonary fibrosis, eosinophil granuloma, and sarcoidosis) and the pneumoconioses (eg, asbestosis and hypersensitivity pneumonitis). The latter group includes diseases causing gross distortions of the thoracic cage such as severe kyphoscoliosis and neuromuscular disorders, which affect the diaphragm. The fibrosing interstitial lung diseases cause pulmonary hypertension in part through the mechanisms associated with alveolar hypoxia. Additionally, progres-

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sive fibrosis causes destruction of normal parenchymal structures leading to distortion and destruction of the pulmonary vasculature.44 Pulmonary hypertension can occur with exercise in patients with fairly well-preserved lung volumes (total lung capacity in the range of 50 to 80% of predicted). Pulmonary hypertension at rest tends to occur when total lung capacity falls below 50%. The treatment of interstitial lung diseases, once fibrosis has occurred, is universally disappointing. Specific therapies for some conditions such as prednisone for sarcoidosis and prednisone and removal from exposure to the inciting agent in hypersensitivity pneumonitis can be quite effective early in the course of the disease at a stage in the disease preceding the usual appearance of pulmonary hypertension. Recently, an association has been described between pulmonary hypertension and sarcoidosis. In a subset of patients with sarcoidosis, pulmonary artery pressures have been known to be elevated and progressive in a manner similar to that in PAH. These patients are now classified as a subgroup of patients with conditions that directly affect the pulmonary vessels. Patients with sarcoidosis and pulmonary hypertension should be evaluated and treated medically as described above for patients with PAH.45 Disorders of the muscles of respiration and the thoracic cage cause pulmonary hypertension through a variety of mechanisms.46 The most obvious is hypoxia due to hypoventilation. However, the distribution of ventilation is not homogenous, leading to areas of atelectasis and of exaggerated ventilation–perfusion mismatch, which contribute to alveolar hypoxia, vasoconstriction, and eventual fixed vascular changes of pulmonary hypertension. The treatment of pulmonary hypertension for patients with disorders of ventilation is primarily mechanical in nature. Supplemental oxygen can minimize the severity and progression of pulmonary hypertension. However, the atelectasis and uneven distribution of ventilation can only be addressed by mechanical support. Nocturnally administered continuous positive airway pressure or bilevel positive airway pressure (BiPAP) can be efficacious. However, if the condition results from a progressive disease, such as multiple sclerosis, then full mechanical support via tracheostomy may be indicated. Treatment of pulmonary hypertension associated with pulmonary diseases by the use of vasodilators has not been shown to be effective. Anecdotal reports have suggested efficacious response in individuals, but control trials have not supported vasodilator therapy. Theoretically, vasodilation of diseased lungs would be expected to cause a variable response across the vascular bed possibly leading to worsening of ventilation– perfusion mismatch and, in turn, more severe alveolar hypoxia.

Cardiac Disease Associated with Pulmonary Hypertension The frequency of pulmonary hypertension due to cardiac disease is second only to that due to pulmonary disease. Pulmonary arterial hypertension due to cardiac diseases can be attributed to different mechanisms. In patients with left ventricular failure or mitral valve stenosis, pulmonary hypertension is a result of passive increase in the pulmonary venous pressure. Acutely, this causes recruitment of pulmonary vascular bed followed by elevated pulmonary capillary pressure resulting in transudation of fluid, which causes pulmonary edema if pulmonary venous pressure is not relieved. A reversal of acute elevation of pulmonary venous pressure and pulmonary vascular congestion leads to reversal of pulmonary pressures. However, interstitial edema is associated with areas of alveolar hypoxia, which can be exacerbated by desaturation during exercise and sleep, which over time, can lead to fixed arterial changes characteristic of chronic hypoxia.47 Mitral stenosis causes PAH in analogous fashion. However, if not surgically corrected, stenosis progresses, as do the pulmonary venous pressures; vascular remodeling occurs on the arterial side in response to chronic increase in a passively increased pulmonary artery pressure. PAH can also be a manifestation of high flow states.48 Congenital abnormalities of the heart, such as ventricular septal defect, atrial septal defect, and patent ductus arteriosus, are associated with left-to-right shunts. Chronic exposure of the pulmonary arterial bed to high flow leads to initially reversible changes of medical hypertrophy and intimal hyperplasia but eventually will be characterized by occlusion of vascular lumens by intimal hyperplasia and the formation of plexiform lesions. Repair of the congenital anomaly while the lesions are still reversible can potentially lead to normalization of the pulmonary artery pressure. Echocardiography with infusion of saline bubbles is effective for demonstrating shunts. Transesophageal echocardiography is especially useful for the investigation of the intra-atrial septa. Sampling of the oxygen content of the blood at the time of right heart catheterization can also document a left-to-right shunt. Finally, measurement of the pulmonary artery wedge pressure will confirm the diagnosis of left ventricular dysfunction.

Surgical Implications of Pulmonary Hypertension Pulmonary hypertension puts patients at increased risk for anesthesia and surgical procedures.49 The sudden shifts in intravascular volume are poorly tolerated by patients with pulmonary hypertension because of their relatively fixed cardiac output. Optimization of medical therapy should

Update in the Management of Pulmonary Hypertension / 295

occur, if possible, prior to surgery. Vasodilator therapy should be optimized and clinical conditions contributing to secondary pulmonary hypertension, such as hypoxia, should be corrected when possible.50 In cases of acute PAH due to pulmonary embolism, acute interventions with more selective pulmonary vasodilators, such as inhaled nitric oxide or epoprostenol infused into the central venous system, may assist in control of hemodynamic status. Pulmonary hypertension is an indication for intraoperative monitoring with a pulmonary artery catheter to provide for more precise control of volume status. Patients with PAH anticoagulated with warfarin should not have their anticoagulation discontinued, if possible, until the time of surgery. Either the anticoagulation can be reversed and the patient placed on heparin, or the warfarin may be discontinued and bridged to operation using daily injections of low molecular weight heparin.

References 1. Rich S. Primary pulmonary hypertension. The World Symposium—Primary Pulmonary Hypertension 1998. Available at: www.who.int/ncd/cvd/pph.html. 2. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216–23. 3. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation 2001;104:2797–802. 4. Rubin LJC. Primary Pulmonary Hypertension; ACCP Consensus Statement. Chest 1993;104:236–50. 5. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111–7. 6. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352:719–25. 7. Archer S, Rich S. Primary pulmonary hypertension. A vascular biology and translational research “work in progress”. Circulation 2000;102:2781–91. 8. Newman JH, Wheeler L, Lane KB, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345:319–24. 9. Loscalzo J. Genetic clues to the cause of primar y pulmonary hypertension. N Engl J Med 2001;345:367–70. 10. Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonar y hypertension. N Engl J Med 2001;345:1465–72. 11. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;335:609–16.

12. Rich S, Pietra GG, Kieras K, et al. Primary pulmonary hypertension: radiographic and scintigraphic patterns of histologic subtypes. Ann Intern Med 1986;105:499–502. 13. Nicod P, Peterson K, Levine M, et al. Pulmonary angiography in severe chronic pulmonary hypertension. Ann Intern Med 1987;107:565–8. 14. Kessler R, Chaouat A, Weitzenblum E, et al. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J 1996;9:787–94. 15. Rich S, Kaufmann E. High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing. J Am Coll Cardiol 1991;18:1323–7. 16. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primar y pulmonary hypertension. N Engl J Med 1992;327:76–81. 17. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338:273–7. 18. Rubin LJ, Badesch DB, Barst R, et al. Bosentan therapy for pulmonar y arterial hypertension. N Engl J Med 2002;346:896–903. 19. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registr y. Ann Intern Med 1991;115:343–9. 20. Conte JV, Gaine SP, Orens JB, et al. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant 1998;17:679–85. 21. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685–92. 22. Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg 2000;37:165–252. 23. Auger WR, Moser KM. Pulmonary flow murmurs: a distinctive physical sign found in chronic pulmonary thromboembolic disease. Clin Res 1989;37:145A. 24. Wolf M, Boyer-Neumann C, Parent F, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J 2000;15:395–9. 25. Auger WR, Permpikul P, Moser KM. Lupus anticoagulant, heparin use, and thrombocytopenia in patients with chronic thromboembolic pulmonary hypertension: a preliminary report. Am J Med 1995;99:392–6. 26. Fishman AJ, Moser KM, Fedullo PE. Perfusion lung scans vs pulmonary angiography in evaluation of suspected primary pulmonary hypertension. Chest 1983;84:679–83. 27. Pitton MB, Duber C, Mayer E, Thelen M. Hemodynamic effects of nonionic contrast bolus injection and oxygen inhalation during pulmonary angiography in patients with chronic major-vessel thromboembolic pulmonary hypertension. Circulation 1996;94:2485–91.

296 / Advanced Therapy in Thoracic Surgery 28. Sompradeekul S, Fedullo PF, Kerr KM, et al. The role of pulmonary angioscopy in the preoperative assessment of patients with thromboembolic pulmonary hypertension (CTEPH). Am J Respir Crit Care Med 1999;159:A456. 29. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2000;162:1964–73. 30. Pietra GG, Edwards WD, Rich S, et al. Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonar y Hypertension Registr y. Circulation 1989;80:1198–206. 31. Liu L, Sackler JP. A case of pulmonary veno-occlusive disease: etiological and therapeutic appraisal. Angiology 1973;23:299–304. 32. Doll DC, Yarbro JW. Vascular toxicity associated with chemotherapy and hormonotherapy. Curr Opin Oncol 1994;6:345–50. 33. Salzman D, Adkins DR, Craig F, et al. Malignancyassociated pulmonary veno-occlusive disease: report of a case following autologous bone marrow transplantation and review. Bone Marrow Transplant 1996;18:755–60. 34. Brown CH, Harrison CV. Pulmonary veno-occlusive disease. Lancet 1966;2:61–5. 35. Dufour B, Maitre S, Humbert M, et al. High-resolution CT of the chest in four patients with pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease. Am J Roentgenol 1998;171:1321–4. 36. Palmer SM, Robinson LJ, Wang A, et al. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonar y veno-occlusive disease. Chest 1998;113:237–40. 37. Davis LL, deBoisblanc BP, Glynn CE, et al. Effect of prostacyclin on microvascular pressures in a patient with pulmonary veno-occlusive disease. Chest 1995;108:1754–6. 38. Cutaia M, Rounds S. Hypoxic pulmonary vasoconstriction: physiologic significance, mechanism, and clinical relevance. Chest 1990;97:706–18.

39. Douglas NJ, Flenley DC. Breathing during sleep in patients with obstructive lung disease. Am Rev Respir Dis 1990;141(4 Pt 1):1055–70. 40. Salvaterra CG, Rubin LJ. Investigation and management of pulmonary hypertension in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148:1414–7. 41. Bishop JM, Cross KW. Physiological variables and mortality in patients with various categories of chronic respiratory disease. Bull Eur Physiopathol Respir 1984;20:495–500. 42. Oswald-Mammosser M, Apprill M, Bachez P, et al. Pulmonar y hemodynamics in chronic obstructive pulmonary disease of the emphysematous type. Respiration 1991;58:304–10. 43. Traver GA, Cline MG, Burrows B. Predictors of mortality in chronic obstructive pulmonary disease: a 15-year follow-up study. Am Rev Respir Dis 1979;119:895–902. 44. Enson Y, Thomas HM, Bosken CH. Pulmonary hypertension in interstitial lung disease: relation of vascular resistance to abnormal lung structure. Trans Assoc Am Physicians 1975;88:248–55. 45. Preston IR, Klinger JR, Landzberg MJ, et al. Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension. Chest 2001;120:866–72. 46. Bergofsky EH. Respiratory failure in disorders of the thoracic cage. Am Rev Respir Dis 1979;119:643–69. 47. Dexter L. Pulmonary vascular disease in acquired heart disease. In: Moser KM, editor. Pulmonary vascular disease. New York: Marcel Dekker; 1979. p. 427–88. 48. Rabinovitch M. Mechanisms of pulmonary hypertension in chronic high flow states. In: Weir EK, Reeves JT, editors. Pulmonary vascular physiology and pathophysiology. New York: Marcel Dekker; 1989. p. 469–512. 49. Hohn L, Schweizer A, Morel DR, et al. Circulatory failure after anesthesia induction in a patient with severe primary pulmonary hypertension. Anesthesiology 1999;91:1943–5. 50. Kaplan J, Reich D, Konstadt S, Stammers A. Cardiac anesthesia. 1999.

CHAPTER 24

MODERN MANAGEMENT OF CHRONIC PULMONARY THROMBOEMBOLISM INCLUDING PULMONARY THROMBOENDARTERECTOMY MICHAEL M. MADANI, MD STUART W. JAMIESON, MB, FRCS

Pulmonar y hypertension as a result of chronic pulmonary thromboembolic disease is a common yet underdiagnosed condition. Patients with this syndrome may present with a wide variety of debilitating pulmonary or cardiac symptoms. Once properly diagnosed, the only curative treatment is surgical removal of the disease, by means of pulmonary thromboendarterectomy (PTE). Medical management is only palliative, and surgery by means of transplantation is an inappropriate use of resources with less than satisfactory results. PTE is a technically demanding yet highly successful operation for chronic pulmonary thromboembolic disease. The procedure is widely misunderstood, and though many have attempted it, it is performed with success at only a few centers. Proper patient selection, meticulous surgical technique, and careful postoperative management at selected centers have now clearly shown that it is an effective therapy. The operation seems difficult to perform well; a true endarterectomy (not an embolectomy) of all affected parts of the lung remains the key to success. This chapter considers the place of the operation in the spectrum of patients with pulmonary hypertension and describes the preoperative work-up, the technical details of the operation, and the current results at the University of California, San Diego (UCSD).

Pulmonary hypertension is a manifestation of many cardiac and pulmonary diseases. Cardiac causes include the result of congenital and acquired heart disease. The pulmonary causes can be divided in three general categories: primary, parenchymal, and vascular. In primary pulmonary hypertension, the microvasculature is affected by an uncertain process, which is generally considered progressive and irreversible. Parenchymal pulmonary disease includes a group of patients with an underlying pulmonary disease, such as emphysema or pulmonary fibrosis, which could progress in pulmonary hypertension. Pulmonary vascular causes refer to patients with acute and chronic pulmonary thromboembolic disease, as well as pulmonary veno-occlusive disease. The prognosis for patients with pulmonary hypertension is poor, and it is worse for those who do not have intracardiac shunts. Thus, patients with primar y pulmonary hypertension and those with pulmonary hypertension due to pulmonary emboli fall into a higher risk category than those with Eisenmenger’s syndrome and encounter a higher mortality rate. In fact, once the mean pulmonary pressure in patients with thromboembolic disease reaches 50 mm Hg or more, the 3-year mortality approaches 90%.1 297

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Patients with pulmonary hypertension present one of the more difficult therapeutic challenges. Medical treatment is generally unsatisfactory and palliative at best. Surgical options are dependent on both the primary disease process and the reversibility of the pulmonary hypertension. With the exception of thromboembolic pulmonary hypertension, lung transplantation is the only effective therapy for patients with pulmonary hypertension, when the disease reaches end-stage. Pulmonary transplantation is also still used in some centers as the treatment of choice for those with thromboembolic disease. However, a true assessment of the effectiveness of any therapy should take into account the total mortality once the patient has been accepted and put on the waiting list. Thus, the mortality for transplantation (and especially double-lung transplantation) as a therapeutic strategy is much higher than is generally appreciated because of the significant loss of patients awaiting donors. In addition, the long-term use of anti-rejection medications with their associated side effects, the higher operative morbidity and mortality, and the long waiting time clearly make transplantation an inferior option to PTE, and we consider it to be inappropriate. PTE should be applied as a treatment for thromboembolic disease whenever possible, provided acceptable results can be achieved. It reduces the mortality rate of patients on the waiting list and avoids immunosuppression. Further, it appears to be permanently curative.

Embolic Pulmonary Hypertension Laennec originally described pulmonary embolism in 1819, and related the condition to deep venous thrombosis.2 Virchow recognized that the three factors predisposing to venous thrombosis were stasis, hypercoagulability, and vessel wall injury.3 Despite our progressive understanding of the etiology and pathology of this condition, deep venous thrombosis with subsequent pulmonary thromboembolism remains a significant cause of morbidity and mortality. Acute pulmonary embolism, after cancer and heart disease, remains the third most common cause of death in the United States. Acute pulmonary thromboembolism is thus a much more common condition than is generally appreciated, and in many cases, it is asymptomatic. Dalen and Alpert in 1975, calculated that pulmonary embolism resulted in 630,000 symptomatic episodes in the United States yearly, making it, at the time, about one-half as common as acute myocardial infarction and three times as common as cerebral vascular accidents.1 However, this may be a low estimate, since autopsy studies have shown that the diagnosis of acute pulmonary embolism was unsuspected in 70 to 80% of those patients in whom it

was the principal cause of death. 4,5 Another autopsy analysis of 13,216 patients showed pulmonary thromboembolism in 5.5%, and up to 31.3% in the elderly.6 It is almost axiomatic that heightened interest in a given disease leads to an increased incidence of discovery. Therefore current opinions regarding the rarity of extensive pulmonary thromboembolism may well be revised in the future, and available estimates of its incidence should be viewed in this light.7

In addition to patients suffering from acute pulmonary embolism from deep vein thrombosis, there are other special circumstances. For example chronic indwelling central venous catheters and pacemaker leads can be associated with pulmonary emboli. Patients with intracardiac shunts who develop pulmonary hypertension may have other factors involved, such as direct chemical irritation of the pulmonary vascular bed. Other rare causes include tumor emboli; tumor fragments from kidneys, breasts, and stomach have been demonstrated to cause chronic pulmonary arterial occlusion. Tumor emboli could also originate from right atrial myxomas. However, not every case is the result of embolic material. In situ thrombosis, either as a result of coagulopathy, endothelial damage, or a secondary phenomenon after an initial embolism has well been described. What happens to the embolic material, once wedged in the pulmonary artery, depends on a few different factors. In the majority of patients, spontaneous resolution of acute pulmonary emboli is the rule. However, a small but uncertain percentage develop chronic thromboembolic pulmonary hypertension. Again, the mechanisms responsible for the failure of the body to dissolve the material remain unclear. The volume of the embolic material may simply be too overwhelming for the lytic mechanisms. The emboli may be made of a substance that cannot be resolved—materials such as already wellorganized fibrous thrombus, fat, or tumor. Further, repetitive emboli may not be able to be resolved. On the other hand, there may be an abnormal lytic mechanism, or some patients may have a propensity for thrombus or a hypercoagulable state. Interestingly, the majority of those presenting with chronic pulmonary thromboembolic disease are unaware of a past thromboembolic event and give no history of deep venous thrombosis, despite the fact that the origin of most cases is from acute embolic episodes. The clinical picture is generally nonspecific until right heart failure becomes evident. Thus, although the exact percentage of those who suffer acute pulmonary embolism and later develop pulmonary hypertension is uncertain, significant pulmonary hypertension due to chronic pulmonary embolism is not a rare disease. Presti and colleagues found chronic massive thrombosis of major pulmonary

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arteries in nearly 1% of 7,753 autopsies.8 This remains a low estimate for the incidence of operable pulmonary hypertension, since many patients who have had relief of their pulmonary hypertension following PTE have had disease confined to their minor pulmonary arteries, and chronic thrombus in these smaller pulmonary vessels is probably often overlooked in autopsy series. The vast majority of cases of pulmonary hypertension due to pulmonary artery occlusion are the result of “spontaneous” thromboembolism. In a small percentage (5 to 11%), however, coagulation abnormalities can be detected, such as lupus anticoagulant, protein C deficiency, or antithrombin III deficiency.9 A few patients have a paradoxical response to heparin, with apparent heparin-induced platelet antibodies. In such cases, special precautions must be taken during cardiopulmonary bypass and the perioperative period, and great care must be taken to eliminate heparin from all intravenous lines. Studies of the pulmonary vascular endothelium in affected patients have failed to demonstrate any consistent abnormality; however, an elevation in factor VIII-related antigen has been shown to occur in association with extensive intimal damage.10,11 After a pulmonary embolus, the unresolved residual pulmonary artery clot organizes and obstructs the pulmonary arteries to a variable extent, at the main pulmonary artery, lobar, segmental, or subsegmental level.8 The resultant pulmonary vascular hypertension may be a very complex process, and factors other than the simple hemodynamic consequences of redirected blood flow with higher pressures and flow are most likely involved. In general, more than 50% of the pulmonary vasculature must be occluded for patients to become pulmonary hypertensive. However, very frequently we encounter patients with significant pulmonary hypertension with less than 50% of the vascular bed occluded by thromboembolic material. There may be a sympathetic neural, hormonal, or combined neurohormonal signal that initiates pulmonary hypertensive changes on the initially unaffected pulmonary vascular bed—a process that can occur in either lung, regardless of the original site of occlusion. In these cases, the operation will open the vessels occluded by the thromboembolic material or intimal hyperplasia but cannot resolve the small-vessel disease of reactive pulmonary hypertension (Figures 241–24-3). Irrespective of the exact etiology, the resultant pulmonary hypertension and the secondary vasculopathy is a serious debilitating condition, potentially inoperable. With our increasing experience with patients with thromboembolic pulmonary hypertension, we have become much more inclined toward early operation to avoid these deleterious consequences.

FIGURE 24-1. A, Pulmonary artery (PA) chest film of a 72-year-old physician with severe pulmonary hypertension (PA pressure above systemic levels, pulmonary vascular resistance 1,250 dynes/sec/cm
5). Note the right heart enlargement, prominent pulmonary artery shadow, and hypoperfusion of areas of right and left lungs. B, Lateral view of chest. Note right heart enlargement and anterior proximity to sternum.

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Diagnosis Chronic pulmonary hypertension is most common in patients who are older than 40 years; however, the disease has been described in patients who range in age from 15 months to 90 years. There is no sex difference, and in the initial stages of the disease, the diagnosis may be quite difficult because of the insidious nature of the clinical symptoms. History Although in at least 90% of patients, the origin of the thromboembolic material is from a deep venous thrombosis, as mentioned above, less than one-half the patients with chronic thromboembolic pulmonary hypertension can give a histor y of deep venous thrombosis or pulmonary embolism. The clinical history may, therefore, not be helpful; but predisposing causes for deep venous

FIGURE 24-2. A, Right pulmonary arteriogram of the patient shown in Figure 24-1. Note loss of distal flow to much of the upper, middle, and lower lobes. B, Left pulmonary arteriogram of the patient shown in Figure 24-1. There is less definition on this side with maintained filling of the major vessels.

FIGURE 24-3. The surgical specimen obtained from the patient shown in Figures 24-1 and 24-2. Note the extensive specimen obtained from the right side. There was no embolic obstruction on the left side. All changes were the result of small vessel (type IVa) disease. Scale is in centimeters. Preoperatively the lung scan showed most of the flow to the left side; post-operatively the patient had normal pulmonary artery pressures and pulmonary vascular resistance. All flow by lung scan was now to the right side.

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thrombosis should be sought, as should a history of leg swelling, chest pain, cough, hemoptysis, or anything to indicate episodes of pulmonary embolism. The initial symptoms, being vague, are often attributed to other causes, such as coronary or myocardial disease, interstitial lung disease, asthma, or age. Many cases remain undiagnosed, especially since the patients may be asymptomatic and have normal pulmonary artery pressures at rest. Other symptoms that may occur, usually in the later stages of the disease, include exertional chest pain, cough, and hemoptysis. Physical Examination Clinical examination is usually nonproductive and unrewarding if right heart failure has not developed, even if the patient has a history of severe dyspnea. Cyanosis is usually absent, unless it is peripheral and related to severely depressed cardiac output or central as the result of rightto-left shunting in the setting of patent foramen ovale or an atrial septal defect. Clubbing of the fingers is not usually present. Flow murmurs may be heard, especially over the back, owing either to flow through narrowed pulmonary arteries or to aggressive bronchial flow. Diagnostic Tests Chest roentgenogram, electrocardiogram, and pulmonary function tests are of little value in differentiating thromboembolic pulmonary hypertension from other forms of pulmonary hypertension. However, these investigations often give the initial clues that pulmonary hypertension exists when the physical findings are less conclusive. The radiographic signs of pulmonary hypertension on chest film may be difficult to determine. Enlargement of the pulmonary artery and paucity of flow to the pulmonary vascular bed may indicate occlusion of major vessels (see Figure 24-1A). The lateral chest film will often show right ventricular hypertrophy (see Figure 24-1B). Echocardiography demonstrates enlarged right-sided heart chambers and varying degrees of tricuspid regurgitation. Standard two-dimensional echocardiography is also helpful in defining the presence and severity of pulmonary hypertension and excluding certain other causes such as Eisenmenger’s syndrome. Continuouswave Doppler echocardiography of the tricuspid regurgitant jet will estimate the pulmonary artery systolic pressure. Occasionally, proximal, chronic, organized thrombus in the main pulmonary artery or main right and left pulmonary arteries can be seen with transthoracic echocardiography; however, this technique lacks sensitivity and is inadequate for visualization of the lobar vessels, where the embolic material is often localized. Transesophageal echocardiography has proved to be more promising, especially with multiplane probes that allow

angulation of the imaging plane so that the origin of most of the lobar vessels can be identified. Early attempts are being carried out at visualizing the pulmonary arteries with transbronchial echocardiography. A perfusion scan is almost always performed. The major differential diagnosis is primary pulmonary hypertension, in which the scan is usually normal or has a patchy and mottled appearance, in contrast to the multiple punched-out lobar or segmented defects of chronic thromboembolic disease. The perfusion scan tends to underestimate the degree of occlusion of the pulmonary vessels. A computed tomography (CT) scan may be useful, 12 and recent work has been performed using computer-enhanced images of CT scanning, both in the acute and chronic forms of this condition. These images are capable of confirming occlusion in at least the main and lobar pulmonary arteries. Further, a mosaic pattern of lung attenuation on CT is a sign of variable regional perfusion and may suggest chronic pulmonary thromboembolism as a cause for pulmonary hypertension.13 Once pulmonary hypertension as a result of chronic thromboembolic disease is suspected, the evaluation of the patient prior to planning surgical intervention depends on right heart catheterization and pulmonary angiography. These are essential to evaluate the severity of pulmonary hypertension, to define the presence of thromboembolic disease, to assess the operative risk and surgical accessibility, and to exclude other diagnoses. In some patients with only moderate pulmonary hypertension at rest, a striking increase in pulmonary artery pressure will be seen with only minimal exercise. Though concern is regularly expressed that angiography places the pulmonary hypertensive patient at great risk, we have not found this to be the case,14 and pulmonary arteriography is performed on pulmonary hypertensive patients on almost a daily basis at our center. Selective power injections of the right and left pulmonary trunks, using nonionic contrast agents to prevent the cough response, are well tolerated. The typical findings of chronic thromboembolic disease on pulmonary angiogram include an irregular lumen, indicating thrombus attached to the vessel wall, and the appearance of bands or webs across the lumen of vessels, sometimes with poststenotic dilatation. Other findings may include occlusion of branches with lack of filling out to the periphery, often with an abrupt termination of pulmonary vessels with a pouch-like appearance (Figures 24-2 and 24-4). In addition to pulmonary angiography, patients over 35 years of age undergo coronary arteriography and other cardiac investigation as necessary. If significant disease is found, additional cardiac surgery is performed at the time of PTE.

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In approximately 20% of cases, the differential diagnosis between primary pulmonary hypertension and distal and small vessel pulmonary thromboembolic disease remains unclear and hard to establish. In these patients, pulmonary angioscopy is often helpful.15 The pulmonary angioscope is a fiberoptic telescope that is placed through a central line into the pulmonary artery. The tip contains a balloon that is then filled with saline and pushed against the vessel wall. A bloodless field can thus be obtained to view the pulmonary artery wall. The classic appearance of chronic pulmonary thromboembolic disease by angioscopy consists of intimal thickening, with intimal irregularity and scarring, and webs across small vessels. These webs are thought to be the residue of resolved occluding thrombi of small vessels, but are important diagnostic findings. The presence of embolic disease, occlusion of vessels, or the presence of thrombotic material is diagnostic.

Treatment The prognosis for patients with untreated pulmonary hypertension is poor. The 5-year survival rate is only

30% for patients with mean pulmonary artery pressures higher than 30 mm Hg and only 10% for those with pressures over 50 mm Hg.16 Medical therapy for embolic pulmonary hypertension (using anticoagulants, vasodilators, or thrombolytic agents) is seldom even transiently effective.17,18 Although the surgical operation for acute pulmonary embolism remains controversial, operation for chronic pulmonar y embolism is ver y well established. As Trendelenburg first described in 1908, the bronchial circulation protects the lung parenchyma from ischemia when a thrombus occludes a pulmonary vessel.19 The lungs can thus sustain an embolic event without parenchymal necrosis, in contrast to the heart or brain, both of which lack this supplemental blood supply. Resolution or removal of embolic occlusion even years afterward will therefore result in resumption of functional oxygenation in the affected portion of the lung. Since there is no restriction in the timing of the operation as with awaiting a donor in transplantation for primar y pulmonar y hypertension, pulmonar y endarterectomy may be performed electively and allows the patient’s condition to be optimized preoperatively.

FIGURE 24-4. A, Right pulmonary angiogram of a 37-year-old man with severe pulmonary hypertension. B, Left pulmonary angiogram of the same patient.

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Most patients referred for PTE surger y have a pulmonary vascular resistance of more than 1,000 dynes/sec/cm
5 , and many have suprasystemic pulmonary artery pressures. We have operated on patients ranging in age from 14 to 83 years. The documented history of pulmonary vascular occlusion has been as brief as a few months to as long as 24 years. Prior to PTE surgery, an inferior vena cava filter is always placed. Patients are thereafter treated with anticoagulants indefinitely.

Operation There are some guiding principles that are essential to a successful outcome in this challenging operation. First, the operation must be performed on both lungs, since patients with significant chronic embolic pulmonary hypertension invariably have bilateral disease. Second, cardiopulmonary bypass (CPB), with periods of circulatory arrest, is essential to achieve adequate exposure in the face of the copious bronchial blood flow. Third, a true endarterectomy in the plane of the media must be accomplished. It is essential to appreciate that the removal of visible thrombus is largely incidental to this operation. Indeed, in the majority of patients, no free thrombus is present, and on initial direct examination the pulmonary vascular bed may appear normal. The operation is thus performed through a median sternotomy and on cardiopulmonary bypass. 20 This allows a bilateral approach and also the use of circulatory arrest under profound hypothermia. The circulatory arrest periods are limited to 20 minutes, with restoration of flow between each interruption. With our increased experience, the endarterectomy usually can be performed with a single period of circulatory arrest on each side. Although retrograde cerebral perfusion has been advocated for total circulatory arrest in other procedures, it is not helpful in this operation since it does not allow a completely bloodless field, and with the short arrest times that can be achieved with experience, it is not necessary. During circulatory arrest, progressive circumferential dissection is carried into all the involved lobar, segmental, and subsegmental vessels. With proper exposure, all the residua of thromboembolic occlusion can be removed, no matter how distal, and it is possible to remove occluding material as far distally as the diaphragmatic level. The patient is prepared as for any open-heart procedure, with arterial and pulmonary artery catheters and electroencephalogram monitoring. A femoral artery line is also placed because the profound vasoconstriction that tends to occur after hypothermic circulatory arrest makes

readings from the radial artery catheter unreliable during the immediate postoperative period. A median sternotomy incision is made and the sternum divided. The right heart is invariably enlarged, with variable degrees of tricuspid regurgitation. Bypass is instituted with high ascending aortic cannulation and two caval cannulae. Standard flow for cardiopulmonary perfusion is used and the patient cooled, maintaining a 10°C gradient between arterial blood and bladder or rectal temperature.21 A temporary pulmonary artery vent is inserted. Once ventricular fibrillation occurs, a second vent is placed in the left atrium through the right upper pulmonary vein. This prevents distention from the large amount of bronchial arterial blood flow that is common with these patients. The patient’s head is surrounded by ice and the cooling blanket turned on. During perfusion the venous saturations increase; saturations of 80% at 25°C and 90% at 20°C are typical. Hemodilution is carried out to decrease the blood viscosity during hypothermia and to optimize capillary blood flow. The hematocrit is maintained in the range of 18 to 25 during profound hypothermia. Phenytoin is administered intravenously during cooling at 15 mg/kg, to a maximum dose of 1 g. During the cooling period some preliminary dissection can be carried out, with full mobilization of the ascending aorta from the pulmonary artery. The superior vena cava is mobilized all the way to the innominate vein and dissected free of the right pulmonary artery. The azygos vein is exposed but not divided. The reflection of the right pulmonary artery to the left atrium is separated. Most of this dissection is performed with electrocautery, because with advanced right heart failure and hepatic congestion, coagulation is usually abnormal. However, care must be taken to preserve the integrity of the right phrenic nerve lying lateral to the superior vena cava. All dissection of the pulmonary arteries occurs intrapericardially, and it is not necessary to enter either pleural cavity. The right pulmonary artery is now exposed so that the take-off of upper and middle lobes can be seen. The upper pulmonary vein is usually not visualized but reflected upward from the plane of the pulmonary artery wall. An incision is made in the right pulmonary artery from beneath the ascending aorta out under the superior vena cava and entering the lower lobe branch of the pulmonary artery just after the take-off of the middle lobe. It is important that the incision stay in the center of the vessel. Only one incision is needed, and it is easier to endarterectomize the right upper lobe from a central incision than through a separate incision in the upper lobe artery. The distal limit of the incision is usually approximately 1 cm distal to the take-off of the upper

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lobe artery and is dictated by the accessibility required in order to repair this subsequently. Any loose thrombus is now removed, and if the bronchial circulation is not excessive, the endarterectomy plane can be found. However, although a small amount of dissection can be carried out prior to the initiation of circulatory arrest, it is unwise to proceed unless perfect visibility is obtained, since the development of a correct plane is essential. As mentioned above, the surgical therapy for chronic thromboembolic pulmonary hypertension involves not only an embolectomy of chronic laminated thrombus, where this is present, but also a true endarterectomy of the pulmonary arterial bed. It is most important to recognize that, first, an embolectomy without endarterectomy is quite ineffective and, second, in 90% of patients with chronic thromboembolic hypertension direct examination of the pulmonary vascular bed at operation shows no obvious embolic material. Thus, to the inexperienced or cursory glance, the pulmonary vascular bed may appear normal. There are four broad types of pulmonary occlusive disease related to thrombus that can be appreciated, and we use the following classification: 1.

2.

3.

4.

Type I disease (approximately 10% of cases of thromboembolic pulmonary hypertension). Major vessel clot is present. As mentioned above, all central thrombotic material has to be completely removed prior to the endarterectomy. Type II disease (approximately 70% of cases). No major vessel thrombus can be appreciated, and the endarterectomy plane is raised in the main, lobar, or segmental vessels. Type III disease (approximately 20% of cases). In this, the most challenging surgical situation, the disease is very distal and confined to the segmental and subsegmental branches. The endarterectomy plane has to be carefully and painstakingly raised in each segmental and subsegmental branch. Type III disease is most often associated with presumed repetitive thrombi from indwelling catheters, such as pacemaker wires, or ventriculatory shunts. Type IV disease. This does not represent primary thromboembolic pulmonary hypertension and is inoperable. In this entity, there is intrinsic smallvessel disease, though secondary thrombus may occur as a result of stasis. The small-vessel disease either occurs as a result of a high-flow state similar to Eisenmenger’s syndrome (Type IVa) or with primary pulmonary hypertension (Type IVb).

When the patient’s temperature reaches 20°C, the aorta is cross-clamped and a single dose of cold cardioplegic solution (1 L) administered. Additional myocardial

protection is obtained by the use of a cooling jacket. The entire procedure is carried out with a single aortic crossclamp period with no further administration of cardioplegic solution. After cross-clamping of the aorta, thiopental is administered (500 mg to 1 g) until the EEG becomes isoelectric. When circulatory arrest is initiated, all monitoring lines to the patient are turned off to prevent aspiration of air, and the patient is exsanguinated. The endarterectomy plane is then developed, and the endarterectomy specimen is progressively followed all the way to the subsegmental vessels. Each lobe is endarterectomized, and then each segmental and subsegmental artery pursued distally. Although many of these vessels cannot be seen initially, progressive dissection and traction allow a complete endarterectomy of the entire pulmonary vascular bed (Figures 24-3 and 24-5). A special instrument has been developed for this purpose—a dissector with a rounded tip, the body of which is attached to suction (see Figure 24-5). It is important that each subsegmental branch be followed and freed individually until it ends in a “tail,” beyond which there is no further obstruction. Circulatory arrest periods are limited to 20 minutes, followed by, if necessar y, a reperfusion period. Reperfusion is carried out at 18°C for a minimum of 10 minutes. After this time, the venous oxygen saturations return to above 90%. With experience, the entire endarterectomy on one side can be performed within a 20-minute circulatory arrest period, and the reperfusion period can be used to repair the arteriotomy on the right side before proceeding to the left. On the left side, an incision is made from the main pulmonary artery down, again intrapericardially, past the

FIGURE 24-5. The specimens removed from the patient whose angiograms are shown in Figure 24-4. The dissection instrument (Jamieson dissector; Fehling Corporation) is shown.

Modern Management of Chronic Pulmonary Thromboembolism Including Pulmonary Thromboendarterectomy / 305

take-off of the left upper lobe. Any loose thrombus is removed, and an endarterectomy, under profound hypothermia with circulatory arrest, again is carried out. The most difficult part of this operation on the left side is that of the left lower lobe, which proceeds posterior to the left bronchus, thus making visibility more difficult. Progressive traction and freeing of each segmental branch makes this possible. Care must be taken not to tear the distal end of the pulmonary arteriotomy during traction on the endarterectomy specimen. After the completion of the endarterectomy, cardiopulmonary bypass is reinstituted and warming commenced. Methylprednisolone (500 mg intravenously) and mannitol (12.5 g, intravenously) are administered, and during warming, a 10°C temperature gradient is maintained between the perfusate and body temperature. If the systemic vascular resistance is high, nitroprusside is administered to promote vasodilatation and warming. The warming period generally takes about 90 minutes but varies according to the body mass of the patient. During this time, the left pulmonary arteriotomy is repaired. The right atrium is examined to remove any incidental thrombus and to close an atrial septal defect or persistent foramen ovale, if this is present. This is important since right-to-left shunting may contribute to postoperative hypoxemia if pulmonary pressures do not immediately return to normal. Although tricuspid valve regurgitation is invariable in these patients and is often severe, tricuspid valve repair is not performed. Right ventricular remodeling occurs within a few days with return of tricuspid competence. If other cardiac procedures are required, such as coronary artery or mitral or aortic valve surgery, these are conveniently performed during the systemic warming period. Upon coming off bypass, the systemic vascular resistance is generally low, and -adrenergic drugs (eg, NeoSynephrine) may be necessary to keep the systemic blood pressure within a low normal range. The cardiac output is generally high. A vigorous diuresis is usual for the following few hours, also a result of the previous systemic hypothermia. Wound closure is routine, though both atrial and ventricular pacing wires are left in situ.

Postoperative Care Meticulous postoperative management is essential to the success of this operation. All patients are mechanically ventilated for at least 24 hours, and all are subjected to a maintained diuresis with the goal of reaching the preoperative weight within 24 hours. Although the pulmonary artery pressures in most patients come down immediately to normal levels, some may have a residual low

capacitance of the pulmonary vascular bed (usually patients with longstanding chronic thromboembolic disease), which resolves after about 24 hours. The pulmonary artery systolic pressure may thus remain transiently high; however, if a good endarterectomy has been performed, the diastolic pressure is low, indicating rapid run-off in residually stiff vessels. With time, the pulmonary artery regains its capacitance, and the systolic pressure falls. Most patients can be extubated on the first postoperative day and leave the hospital within 7 to 10 days. A specific complication that occurs in a small percentage of these patients is reperfusion edema, or the “reperfusion response.” In this condition, a capillary leak occurs in the endarterectomized areas of the lung. The cause of this leak is multifactorial. It certainly occurs when the endarterectomy plane is too deep, but it may also be encountered in a seemingly technically perfect operation in a response similar to reactive hyperemia. The endarterectomized areas are then preferentially perfused, with diversion of blood away from the normal areas of the lung. Since the perfused areas are the focus of the capillar y leak, severe hypoxia results, and this is compounded by secondary hypoxic pulmonary vasoconstriction of the normal vessels. Treatment is supportive, since reperfusion pulmonary edema will eventually resolve if oxygenation can be maintained. Careful management of ventilation and fluid balance is required; the hematocrit is kept high, aggressive diuresis is effected, even if this requires ultrafiltration, and the FiO2 is kept as low as is compatible with an oxygen saturation of 90%. On occasion, we have used extracorporeal perfusion support (extracorporeal membrane oxygenation or extracorporeal CO2 removal) until ventilation can be resumed satisfactorily, usually after 7 to 10 days.

Results of Operation Early Results More than 1,400 pulmonary thromboendarterectomy operations have been performed at UCSD Medical Center since 1970. Most of these operations (over 1,200) have been completed since 1990, when the surgical procedure was modified, as described earlier. The better exposure, together with a more expeditious operation, has resulted in improved mortality and morbidity; the mortality rate has been about 6% in the last 1,000 patients, and 4.5% in the 387 patients operated upon in the last 36 months. The majority of deaths have been related to persistent pulmonary hypertension and right heart failure as a result of failure to remove distal obstruction (50%) or

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the development of severe reperfusion edema and hypoxemia, progressing to a nonreversible respiratory distress syndrome (25%). In those cases in which the pulmonary pressures failed to fall, the underlying diagnosis was, in retrospect, more probably related to small-vessel rather than thromboembolic disease (type IV disease). The differentiation between these groups of patients remains difficult in some cases, particularly since distal thrombosis occurs in the late stages of primary pulmonary hypertension. It is our belief that when the etiology of pulmonary hypertension is entirely thromboembolic, a surgical resolution is always possible. Thus, the risk of operation is considerably less in the group of patients (50%) who have a clear history of thromboembolism than in the patients who do not. Perioperative confusion and stroke are no more frequent than with conventional open-heart surgery. Despite the prolonged operation, wound infections are infrequent.

awareness of both the prevalence of this condition and the possibility of a surgical cure should avail more patients of the opportunity for relief from this debilitating and ultimately fatal disease.

Late Results The hemodynamic and functional improvement achieved in survivors has been excellent. Right heart catheterization routinely shows a marked and sustained reduction in pulmonary artery pressure and pulmonary vascular resistance as well as a substantial improvement in cardiac output. Significant recovery of right ventricular function and resolution of tricuspid regurgitation is apparent on cardiac echocardiography. This improvement in hemodynamics seems to be maintained indefinitely (all patients have an occlusive inferior vena caval umbrella placed prior to surgery and are kept on Coumadin for life). Whereas preoperatively more than 95% of the patients are in the New York Heart Association (NYHA) functional class III or IV, at 1-year postoperatively, 95% of patients remain in NYHA functional class I or II.22

6. Panasiuk A, Dzieciol J, Nowack HF, et al. Pulmonary thromboembolism — random analysis of autopsy material. Pneumonol Alergol Pol 1993;61:171–6.

Summary Thromboembolic pulmonary hypertension carries a poor prognosis. The only therapeutic alternative to PTE is lung transplantation. The advantages of thromboendarterectomy include a lower operative mortality and excellent long-term results without the risks associated with chronic immunosuppression and chronic allograft rejection. The mortality for thromboendarterectomy at UCSD is now in the range of 5%, with sustained benefit. These results obviously compare favorably with those for transplantation and are much better in the long term. Although PTE is technically demanding for the surgeon and requires careful dissection of the pulmonary artery planes and the use of circulatory arrest, excellent short- and long-term results can be achieved. Increased

References 1. Dalen JE, Alpert JS. Natural histor y of pulmonar y embolism. Prog Cardiovasc Dis 1975;17:259–70. 2. Laennec RTH. Traite de l’auscultation mediate et des maladies des poumons et du coeur. Paris; 1819. 3. Virchow R. Uber die Verstopfung der Lungenarteria. Reue Notizen auf Geb d Natur u Heilk 1846;37:26. 4. Goldhaber SZ, Hennekens CH, Evans DA, et al. Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med 1982;73:822–6. 5. Rubinstein I, Murray D, Hoffstein V. Fatal pulmonary emboli in hospitalized patients: an autopsy study. Arch Intern Med 1988;148:1425–6.

7. Houk VN, Hufnagel CA, McClenathan JE, Moser KM. Chronic thrombotic obstruction of major pulmonary arteries: report of a case successfully treated by thromboendarterectomy and review of the literature. Am J Med 1953;35:269–82. 8. Presti B, Berthrong M, Sherwin RM. Chronic thrombosis of major pulmonary arteries. Hum Pathol 1990;21:601–6. 9. Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg 2000;37:165–252. 10. Hughes RL, Mann S, Smith LJ, et al. Recurring pulmonary emboli: clinical conference in pulmonary disease from Northwestern University Medical School, Chicago. Chest 1982;81:230–6. 11. Rossi EC, Green D, Rosen JS, et al. Sequential changes in Factor VIII and platelets preceding deep vein thrombosis in patients with spinal cord injur y. Br J Haematol 1980;2:285–6. 12. Schwickert HC, Schweden F, Schild HH, et al. Pulmonary arteries and lung parenchyma in chronic pulmonary embolism: preoperative and postoperative CT findings. Radiology 1994;191:351–7. 13. King MA, Bergin CJ, Yeung DW, et al. Chronic pulmonary thromboembolism: detection of regional hypoperfusion with CT. Radiology 1994;191:359–63. 14. Nicod P, Peterson K, Levine M, et al. Pulmonary angiography in severe chronic pulmonary hypertension. Ann Intern Med 1987;107:565–8. 15. Shure D, Gregoratos G, Moster KM. Fiberoptic angioscopy: role in the diagnosis of chronic pulmonary arterial obstruction. Ann Intern Med 1985;103:844–50.

Modern Management of Chronic Pulmonary Thromboembolism Including Pulmonary Thromboendarterectomy / 307 16. Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary embolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151–8. 17. Dantzker DR, Bower JS. Partial reversibility of chronic pulmonary hypertension caused by pulmonary thromboembolic disease. Am Rev Respir Dis 1981;124:129–31. 18. Dash H, Ballentine N, Zelis R. Vasodilators ineffective in secondar y pulmonar y hypertension. N Engl J Med 1980;303:1062–3. 19. Trendelenburg F. Uber die operative behandlung der embolie derlungarterie. Arch Klin Chir 1908;86:686–700.

20. Jamieson SW, Auger WR, Fedullo PF, et al. Experience and results of 150 pulmonary thromboendarterectomy operations over a 29-month period. J Thorac Cardiovasc Surg 1993;106:116–27. 21. Winkler MH, Rohrer CH, Ratty SC, et al. Perfusion techniques of profound hypothermia and circulatory arrest for pulmonary thromboendarterectomy. J Extra Corpor Technol 1990;22:57–60. 22. Moser KM, Auger WR, Fedullo PF, Jamieson SW. Chronic thromboembolic pulmonary hypertension: clinical picture and surgical treatment. Eur Respir J 1992;5:334–42.

CHAPTER 25

EXTRACORPOREAL MEMBRANE OXYGENATION AND EXTRACORPOREAL AND ARTERIOVENOUS CARBON DIOXIDE REMOVAL SCOTT K. ALPARD, BS DAVID B. LORAN, MD JOSEPH B. ZWISCHENBERGER, MD

Life Support Organization (ELSO) has maintained the voluntary Neonatal, Pediatric, and Adult ECMO Registry since 1989 and provided improved outcomes data for all ECMO populations since that time.

Extracorporeal gas exchange, including extracorporeal membrane oxygenation (ECMO), extracorporeal carbon dioxide removal (ECCO2R), and arteriovenous carbon dioxide removal (AVCO2R), has undergone a revolution over the last 30 years, allowing such techniques to leave the animal laboratory and significantly impact clinical outcomes in critically ill patients. These techniques, developed from engineering principles of cardiopulmonary bypass (CPB) for heart surgery, provide temporary replacement or augmentation of ventilation, oxygenation, and cardiac function. ECMO circuits use a modified heart–lung bypass machine, usually with a distensible venous blood drainage reservoir, a servoregulated roller pump, a membrane for gas exchange, and a countercurrent heat exchanger for thermoregulation (Figure 25-1). Continuous heparin anticoagulation prevents circuit thrombosis and thromboembolus formation. Although most initial work has been done in neonatal and pediatric populations, recent advances in adult extracorporeal gas exchange have extended the application of these techniques to populations traditionally thought to have worse outcomes. The Extracorporeal

FIGURE 25-1. Extracorporeal membrane oxygenation circuit. 308

Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 309

ECMO in the Pediatric Population Extracorporeal circulation for respiratory failure was first attempted in newborns in the 1960s. 1 Bartlett and colleagues began clinical trials in 1972 and reported the first successful use of ECMO in newborn respiratory failure in 1976.2 During the initial experience in neonates, ECMO had an overall survival rate of 75 to 95%.3–5 These results helped to establish the therapeutic effectiveness of ECMO in infants having met criteria predicting greater than 80% mortality. In 1986, Bartlett and colleagues published their first 100 cases of ECMO for neonatal respiratory failure with an overall survival rate of 72%.6 The collaborative UK ECMO trial concluded that ECMO support reduces the risk of death without a concomitant rise in severe disability.7 ECMO has become the standard treatment for unresponsive severe respiratory failure in neonates based on successful phase I studies, 2 two prospective randomized studies,8,9 and worldwide application in over 27,219 patients with an overall 76% survival rate.10 Pediatric patients also may benefit from extracorporeal support required for severe parenchymal lung damage and impaired gas exchange. Most pediatric ECMO patients have received progressive mechanical ventilation with high FiO2, peak and mean inspiratory pressures, and positive end expiratory pressure (PEEP) for several days and have imposed ventilator-induced lung injury. These factors, along with secondary organ damage that may also be present, contribute to the longer duration of ECMO required for pediatric patients. On average, pediatric patients with unresponsive severe respiratory failure spend about 2 weeks on ECMO, with some survivors receiving ECMO for periods of up to 4 to 6 weeks before lung recovery.11 Bartlett and colleagues have reported an ECMO survival rate of 30% in children and infants beyond the neonatal period with acute respiratory failure (ARF) whose predicted survival rate with conventional therapy was thought to be < 10%.4 Green and colleagues reported the results from the Pediatric Critical Care Study Group multicenter analysis of ECMO for pediatric respiratory failure.12 ECMO was associated with a significant reduction in mortality versus conventional or high-frequency ventilation (74% survival with ECMO vs 53% survival in control subjects). As of July 2003, ECMO had been used in over 2,548 children with respiratory failure achieving an overall survival rate of 64%.10 ECMO has also been used for children needing cardiac support with a survival rate of 56%.10 Patients who would have been excluded from ECMO in the past because of such conditions as immunosuppression following treatment for malignancy, burns, meningococcemia, and other diseases are now reported in the litera-

ture as ECMO survivors.13–16 If ECMO is to be used to full advantage as a therapeutic option for cardiorespiratory failure, more detailed information is needed on longterm outcome, morbidity, health care costs, and costbenefit analyses.

Adult Respiratory Distress Syndrome and Extracorporeal Gas Exchange Traditional ventilatory management of adult respiratory distress syndrome (ARDS) is associated with barotrauma from high inspiratory pressures, volutrauma from overdistention of alveoli, and toxicity due to high oxygen concentrations. These lung injuries lead to progressive deterioration in lung compliance, functional residual capacity, and gas exchange, with impairment of cardiac function by the associated high positive pressures. 17 Recent advances in pulmonary management suggest that lower airway pressures will lessen barotrauma and volutrauma.18 In particular, the ARDS Network Trial demonstrated improved survival with lower tidal volumes (6 mL/kg).19 However, low tidal volume ventilation can cause alveolar hypoventilation and hypercapnic acidosis and may require higher levels of PEEP and FiO2 to maintain adequate oxygenation. These factors may contribute to oxidant-induced lung injury. Utilization of ECMO can remove excess carbon dioxide and improve oxygenation, despite the inability of the lung to maintain adequate gas exchange, while avoiding the volutrauma and barotrauma associated with normal mechanical ventilation. Despite numerous advances in critical care, ARDS still has a mortality of approximately 40 to 50%, stimulating an interest in expanding extracorporeal gas exchange to adult populations. Hill and colleagues reported the first successful use of adult ECMO in 1972.20 After a number of small, somewhat successful studies, a national study of adult ECMO sponsored by the National Heart, Lung, and Blood Institute was performed in the late 1970s.21 Although 300 patients were to be entered, the study was discontinued after 90 patients, with an approximately 90% mortality in both the control and treatment groups. Following these results, interest in adult ECMO all but ceased. However, in 1986 Gattinoni and colleagues reported a 49% survival in patients with severe respiratory failure treated with a form of ECMO,22 and several investigators regained enthusiasm. Since expected survival with ECMO is approximately 50%, ECMO is appropriate when survival is predicted to be less than 20%.23 Indications for ECMO therefore include acute reversible respiratory or cardiac failure unresponsive to optimal ventilator and pharmacologic management with a predicted mortality rate of ≥ 80% but from which recovery can be expected within a reasonable period (several days to 3 weeks) of extracorporeal support.

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The specific inclusion criteria for adult ECMO are controversial and remain somewhat dependent on the experience and capabilities of the specific ECMO center. The etiological origin of acute respiratory failure must be taken into account, although primary and secondary ARDS can be supported. A PaO2 to FiO2 (P:F) ratio of less than 100 or transpulmonary shunts ratio of greater than 30% are often used as indications for ECMO. Reversible processes, such as bronchospasm from severe reactive airway disease or severe hypothermia, can also be supported or corrected by ECMO. Patients with factors once thought to be contraindications to ECMO, such as sepsis, bacteremia, or even trauma, can receive extracorporeal support. Other processes that may resolve and are amenable to ECMO include fat emboli syndrome, neardrowning, and thoracic trauma. Irreversible processes, such as pulmonary fibrosis, should exclude patients from consideration for extracorporeal support. Until larger ECMO trials are complete, specific indications and criteria remain institution-dependent. There are several different extracorporeal gas exchange techniques including ECMO, CPB, ECCO 2R, AVCO2R, and the nascent artificial lung (Table 25-1). The exact method of extracorporeal gas exchange is dependent on the pathophysiology of the disease process and the experience of the ECMO center. Patients requiring

cardiac support need venoarterial (VA) ECMO, whereas those requiring only respiratory support can use venovenous (VV) ECMO (Table 25-2) or one of the carbon dioxide removal circuits (ECCO 2 R or AVCO 2 R). VA ECMO is generally reserved for patients with cardiovascular instability or for those who fail to maintain adequate cardiac outputs during the course of respiratory failure. Once ECMO has been initiated, ventilatory settings are rapidly decreased, with low-rate sustained inflations above alveolar opening pressures applied to prevent total lung collapse. Disadvantages of VA ECMO include the need for major arterial access, reduced pulmonary blood flow, arterial discharge of emboli, further impairment of left ventricular function by volume overload, and circulatory dependence on an extracorporeal circuit. Advantages include lack of dependence on cardiac function to maintain oxygenation. If cardiac function improves, the patient may be converted from VA to VV bypass. Adult patients with unresponsive severe respiratory failure require VV ECMO or ECCO2R. VV ECMO emphasizes oxygenation, in addition to CO 2 removal, achieved through the use of higher flow rates (about 5 L) and a parallel configuration of two oxygenators to increase surface area. Patients with more advanced respiratory failure and high transpulmonary shunt fractions

TABLE 25-1. Comparison of Extracorporeal Membrane Oxygenation (ECMO), Cardiopulmonary Bypass (CPB), Low-Flow Positive-Pressure Ventilation with Extracorporeal Carbon Dioxide Removal (LFPPV ECCO2R), Arteriovenous Carbon Dioxide Removal (AVCO2R), and Artificial Lung ECMO

CPB

ECCO2R

AVCO2R

Artificial Lung

Setting

Respiratory or cardiac failure

Cardiac surgery

Respiratory failure

Location Type of support Cannulation

Extrathoracic Intrathoracic VA (cardiac); VV (respiratory) VA (total bypass) VA: neck; VV: neck and groin; Direct cardiac; 2 2 cannulas (surgical or cannulas (surgical) percutaneous); 1 cannula (VVDL)

Respiratory failure (investigational) Extrathoracic AV (respiratory) (CO2) Groin; 2 cannulas (percutaneous)

Respiratory failure (experimental) Extrathoracic PA-PA or PA-LA Transthoracic to major vessels

Blood flow High (70–80% CO) Ventilatory support Pressure-controlled ± high PEEP; 10–12 breaths/min Blood reservoir Small (50 cc) Arterial filter No Blood pump Roller or centrifugal Heparinization ACT 200–260 Average length of Days to weeks extracorporeal support Complications Bleeding; organ failure Causes of death Support terminated: PAP > 75% systemic; irreversible lung disease; cardiac dysrhythmias

Yes (> 1 liter) Yes Roller or centrifugal ACT > 400 Hours

Extrathoracic VV (respiratory) (CO2) Neck and groin; 2 cannulas (surgical or percutaneous); 1 cannula (VVDL) Med (30% CO) High PEEP; 2–4 breaths/min; high FiO2 Small (50 cc) No Roller or centrifugal ACT 200–260 Days to weeks

Intraoperative Intraoperative; air embolism

Bleeding Multiorgan failure; septic shock; hemorrhagic

Total (100% CO) None (anesthesia)

Low (10–15% CO) Total (100%) Pressure- or volumeNone necessary controlled (algorithm-driven) No No No No None None ACT 200–260 ACT 200–260 Days to weeks Days

Bleeding Respiratory failure

Bleeding Right heart failure

Adapted from Alpard SK, Zwischenberger JA. Extracorporeal membrane oxygenation for severe respiratory failure. Chest Surg Clin N Am 2002;12:355–78. ACT = activated clotting time; AV = arteriovenous; LA = left atrium; PA = pulmonary artery; PAP = positive airway pressure; PEEP = positive end expiratory pressure; VA = venoarterial; VV = venovenous; VVDL = venovenous double lumen.

Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 311 TABLE 25-2. Comparison of Venoarterial and Venovenous Extracorporeal Membrane Oxygenation (ECMO) Cannulation sites

Organ support Systemic perfusion Pulse contour CVP PA pressure Effect of right-to-left shunt Effect of left-to-right shunt (PDA) Blood flow for full gas exchange Circuit SvO2 Circuit recirculation Arterial pO2 Arterial oxygen saturation Indicators of O2 insufficiency

Carbon dioxide removal Oxygenator Ventilator settings Decrease initial vent settings

Venoarterial ECMO

Venovenous ECMO

Internal jugular vein, right atrium, or femoral vein plus right common carotid, axillary, or femoral artery or aorta (directly) Gas exchange and cardiac output Circuit flow and cardiac output Reduced pulsatility Unreliable Unreliable Mixed venous into perfusate blood Pulmonary hyperperfusion may shunt 80–100 cc/kg/h Reliable None 60–150 torr ≥ 95% Mixed venous saturation or pO2; calculated oxygen consumption

Internal jugular vein alone (double-lumen or single-lumen tidal flow); jugular-femoral; femoro-femoral; sapheno-saphenous; right atrium (directly) Gas exchange only Cardiac output only Normal pulsatility Accurate guide to volume status Reliable None No effect on flow; require increased flow usual PDA physiology 100–120 cc/kg/h Unreliable 15–30% 45–80 torr 80–95% Cerebral venous saturation; Da-VO2 across the membrane; patient PaO2; premembrane saturation trend; combinations of all of the above Sweep gas flow and membrane lung-size dependent

Sweep gas flow and membrane lung-size dependent 0.4 or 0.6 Minimal Rapidly

0.6 or 0.8 Minimal–moderate (depending on patient size) Slowly

Adapted from Alpard SK, Zwischenberger JA. Extracorporeal membrane oxygenation for severe respiratory failure. Chest Surg Clin N Am 2002;12:355–78. CVP = central venous pressure; PDA = patent ductus arteriosus.

will require the additional oxygen transfer supplied by VV ECMO. In a recent retrospective review of 94 patients, Bartlett’s group concluded that percutaneous cannulation can be utilized for VV ECMO in adults.24 VV ECMO (Figure 25-2) has the advantage of maintaining normal pulmonary blood flow and avoiding arterial cannulation with its risk of systemic microemboli. Total support of gas exchange with VV perfusion, returning the perfusate blood into the venous circulation through the femoral vein or a modified jugular venous drainage catheter, also has the advantage of avoiding carotid artery ligation. 25 Bartlett’s group developed a polyurethane double-lumen catheter for single-site cannulation of the internal jugular vein.26,27 A tidal flow VV system with a single-lumen catheter has been developed to aid venous gas exchange.25 Efficient wire-wound cannulas, which are capable of sufficient flow for total gas exchange, can be inserted in large children (>15 kg) and adults by percutaneous insertion (Seldinger technique). Since the 14French VV double-lumen (DL) catheter became commercially available in 1989, over 2,248 neonates have been treated with an 87% overall survival.10 As of July 2003, VA versus VV DL survival is 76% versus 87% respectively,10 but the increased survival seen with VV is felt to be due to selection bias. A multicenter retrospective comparison of VA access to VV DL for newborns with respiratory failure undergoing ECMO was undertaken in a matched review with no advantage to VV ECMO.27

FIGURE 25-2. Venovenous bypass using the superior vena cava (SVC) as the venous outflow tract and the femoral vein as the arterial inflow tract. IVC = inferior vena cava. Reproduced with permission from Bartlett RH. Extracorporeal life support for cardiopulmonary failure. Curr Probl Surg 1990;27:635.

The current practice of waiting until the natural lungs become severely dysfunctional and then having to support cardiopulmonary function almost completely with VA ECMO may give way to the concept of early lung assistance. Single-site cannulation has already become the method of choice in neonates for ECMO. A single

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cannula tidal flow VV ECMO system has been developed that even allows percutaneous access.28,29 ECCO2R is a venovenous support mode that emphasizes carbon dioxide removal through low-flow (1–2 L/min) bypass, utilizing low-frequency positive pressure ventilation.22,30 In contrast to ECMO, ECCO2R is designed as a ventilation sparing modality by uncoupling oxygenation (which is maintained via the patient’s lungs using near-apneic oxygenation) and CO2 removal (which is accomplished through an extracorporeal membrane lung). Total CO2 removal is possible, allowing support of the lungs with continuous positive airway pressure and apneic oxygenation for the prevention of ventilatorinduced lung injury (VILI). The lower blood flows limit the amount of oxygen transfer, which may be insufficient for patients with very severe oxygenation failure. With this method, oxygen uptake and CO2 removal are dissociated: oxygenation is accomplished primarily through the lungs, whereas CO2 is cleared through the extracorporeal circuit. Even the most severely injured lungs are capable of oxygen transfer if they are not required to provide any ventilatory function (apneic oxygenation).22,31 The lungs are inflated to moderate pressures (15–20 cm H2O) to maintain functional residual capacity and oxygen concentration is reduced, while CO2 is removed by low flow partial VV bypass. Low-frequency positive-pressure ventilation (LFPPV) ECCO2R is performed at an extracorporeal blood flow of 20 to 30% cardiac output. Vascular access is achieved via combinations of jugularfemoral, femoral-femoral, or saphenous-saphenous veins. Gattinoni and coworkers using his modified ECMO technique (LFPPV ECCO2R) achieved 49% survival in adult ARDS.22 The improvement in survival is also in part attributed to better patient selection, VV perfusion, better regulation of anticoagulation, and ventilator management directed toward “lung rest.” Bartlett’s experience, initially reported by Anderson and colleagues in 1993, demonstrated 47% survival in adults with severe respiratory failure.32 In a retrospective review of 100 adult patients treated by Bartlett’s group, Kolla and colleagues reported a 54% overall survival.33 Pre-ECMO variables found to be significant independent predictors of outcome included number of days of mechanical ventilation, P:F ratio, and patient age. Patients with respiratory failure alone had the best prognosis, with a mortality rate of 40%. Mortality increased substantially with increases in the number of organ failures. Each organ system failure was approximately equally contributory to mortality rate. Rich and colleagues also retrospectively evaluated Bartlett’s “standardized management protocol” for acute respiratory failure utilizing “lung protective” mechanical ventilation and ECMO in 141 patients. 34 Forty-one

patients showed improvement with the initial protocol of ventilator management (83% survival), while 100 patients required ECMO support because of persistent respiratory failure (54% survival). Overall, lung recovery occurred in 67% of the patients with a 62% survival. As of July 2003, 891 adults treated with ECMO have been entered in the ELSO Registry with an overall survival rate of 58%.10 A secondary benefit of ECMO is to enable the use of protective ventilatory strategies and other therapies that would not be possible without extracorporeal gas exchange. AVCO2R is a low-flow support mode for carbon dioxide removal analogous to ECCO2R but incorporating a simplified pumpless arteriovenous circuit connected to a gas exchange device. Near-total CO 2 removal can be achieved, enhancing the ability to support lung-rest strategies for reducing the risk of VILI. Like ECCO2R, however, no significant oxygen transfer occurs, and this mode does not offer support for oxygenation in the face of severe oxygenation failure. Its simplicity and ability to support lung rest strategies, however, make it attractive in the management of acute lung injury. AVCO2R utilizes a commercially available, low-resistance gas exchanger in a simple percutaneous arteriovenous shunt to achieve near-total extracorporeal removal of CO2 production with only 800 to 1,200 mL/min flow. AVCO2R involves cannulation of the femoral artery and vein with a membrane oxygenator interposed in the circuit. 3,32,35 Blood flows spontaneously through the oxygenator according to the pressure gradient between the artery and vein. The circuit is essentially identical to that used for continuous arteriovenous hemofiltration. The difference is the use of a gas exchange device (membrane oxygenator) in place of a hemofilter, and larger vascular cannulae (12 French arterial, 14–16 French venous) to accommodate flows about five times greater. There are many theoretical advantages to this approach over VV ECCO 2R. The first is the use of a small, highly efficient low-resistance fiber membrane oxygenator. This allows the use of a much smaller priming volume (< 300 mL). In addition, this system does not require any type of mechanical pump, greatly simplifying its application and providing a greater degree of safety. From our animal and initial patient safety trials, AVCO2R allows decreased respiratory rate, tidal volume, and peak airway pressures such that peak inspiratory pressure (PIP) is predictably less than 30 cm H2O and respiratory rate 4–5 breaths/minute with an increase in P:F and no significant decrease in white blood cell count, platelets, or increased complement while maintaining CO2 and pH homeostasis.36–46 The use of a simple arteriovenous shunt eliminates the roller pump and a substantial portion of tubing and ECMO-related components, reducing the

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foreign surface area, priming fluid and blood transfusion volume. During AVCO2R, CO2 removal and O2 transfer are uncoupled: CO2 is excreted across the membrane gas exchanger, whereas O2 diffuses across the native lungs at a much lower minute ventilation utilizing the principles of apneic oxygenation31 similar to low-flow VV ECMO. Arteriovenous shunt flows of 10 to 15% of the cardiac output can support total CO2 removal at levels of PaCO2 that are physiologically tolerable. A series of studies in large animals using a commercially available microporous hollow fiber membrane oxygenator has confirmed the predictions of a mathematical model and reaffirmed the efficacy and short-term safety of AVCO2R.47,48 Recent studies of AVCO2R in sheep with severe smoke inhalation injury have demonstrated significant reductions in minute ventilation and peak airway pressures while removing 96% of CO2 production.44 Clinical application of AVCO 2 R is continuing to evolve. Hypercapnic respiratory failure is a significant clinical problem associated with morbidity and mortality. A substantial part of the morbidity is due to complications of endotracheal intubation and mechanical ventilation, including pulmonary injury, pulmonary aspiration, laryngeal and tracheal injury, nosocomial pneumonia, and hypoxemia. Avoidance of mechanical ventilation or a reduction in the duration of mechanical ventilation may result in a reduction of these complications. Hypercapnia also commonly results from implementation of lung-rest strategies (low tidal volume, low respiratory rates) and can limit the degree to which ventilator settings can be reduced and the lungs rested. Initial feasibility studies in patients with severe, unresponsive ARDS and hypercapnia showed percutaneous, bedside femoral access for AVCO2R was possible and could achieve 70% CO2 removal without hemodynamic compromise while allowing decreased mechanical ventilatory support.48 A phase I clinical study of AVCO2R in patients with acute hypercapnic ventilatory failure followed. AVCO2R significantly decreased PaCO2 from 90.8 mm Hg to 51.8 mm Hg and normalized pH from 7.19 to 7.37 while allowing a decrease in minute ventilation from 6.92 L/min to 3.00 L/min. No significant change in hemodynamic parameters, white blood cell count, plasma free hemoglobin or complement occurred during AVCO2R.41 Because of its simplicity and ability to impact lung rest, AVCO2R may have a role in strategies designed to reduce the risk of VILI. A prospective, randomized, controlled, unblinded, multicenter outcomes studies is currently underway to compare the effect of percutaneous extracorporeal AVCO2R with low tidal volume (6 mL/kg) mechanical ventilation on allcause mortality and ventilator-free days in children with acute, severe respiratory failure secondary to burn injury

with or without severe smoke inhalation and in adults with ARDS (P:F < 200). Severe progressive ARDS with P:F < 100 and profound hypoxia exceed the capacity for AVCO 2R to reverse the pathophysiology despite CO 2 homeostasis. Initial large animal studies of chronic ambulatory AVCO2R to assist CO2 removal in chronic CO2 retention disorders have been completed.49

Techniques and Management Several formats of extracorporeal gas exchange have evolved including ECMO (VA and VV), traditional CPB, ECCO2R, AVCO2R, and the developing artificial lungs. Each presents advantages and disadvantages depending upon the physiology to be corrected and the expertise of the ECMO team. A comparison of the different extracorporeal treatment modalities is shown in Table 25-1.50,51 Cannulation In general, all age groups are cannulated with VA access if cardiac support is required for acute hemodynamic compromise (cardiac arrest) or for transport on ECMO. VV access is used in most cases without hemodynamic compromise and is the method of choice for neonates or patients with primary respiratory failure. For VV access in neonates, the right internal jugular vein is preferred for drainage and reinfusion using a double-lumen catheter. For children and adults, the right internal jugular vein for drainage and the right femoral vein for reinfusion is preferred. Other centers report improved flow rates and pulmonary artery mixed venous oxygen saturations with femoral-atrial flow schemes.52 Venovenous double lumen (VVDL) catheters are also available, allowing for single site access. Survival results with VVDL ECMO are thought to be equivalent to VA ECMO but selection bias precluded prospective, randomized, outcomes studies. As these patients often have a number of comorbid conditions, access is dependent on the exact clinical situation and experience of the ECMO center. VA ECMO may be performed by extrathoracic cannulation (carotid artery and jugular vein, or femoral artery and vein), or transthoracic cannulation through the median sternotomy incision (the aorta and the right atrium). Carotid-jugular cannulation may best be used in patients who are weaned from CPB in the operating room and develop myocardial dysfunction with cardiogenic shock after operation. Advantages of this approach are a separate incision site remote from the median sternotomy wound and a lower incidence of bleeding from the mediastinal wound. Both of these factors may contribute to a decreased risk of mediastinal infection.53 In patients with a cavopulmonary connection (Glenn or Fontan circulation), direct access from the jugular vein

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to the right atrium is not feasible; therefore a transthoracic approach is required. Femoral venoarterial cannulation can be used in certain older children, with placement of intravascular catheters into the inferior vena cava or right atrium through the femoral vein and into the common femoral or iliac artery for arterial return. The venous return with this type of cannulation may be restrictive unless a centrifugal type pump, which provides active venous drainage, is used. The advantage of this peripheral technique includes the noninvasive surgical approach and more secure cannula fixation. Transthoracic cannulation is preferable in patients who cannot be weaned from cardiopulmonary bypass in the operating room or in those circumstances where the chest was opened for the purpose of resuscitation in the postoperative period. The major disadvantage of the transthoracic approach includes the potential risks of mediastinal hemorrhage, infection, and cannula dislodgment during repositioning or transport. The prevention of cardiac distention and minimization of myocardial energy expenditure is vital to potential myocardial recovery. When left atrial pressures remain elevated despite optimal flow, it is critical to vent the left atrium to the venous drainage system either by direct left atrial cannulation in the operating room or transatrial septal cannulation in the cardiac catheterization laboratory. The preoperative use of ECMO in infants with congenital heart disease is controversial. In patients with cyanotic heart disease and cardiopulmonary collapse associated with hypercyanotic spells, pulmonary hypertension, or sepsis, indications for ECMO includes arterial oxygen saturation < 60% on maximal medical therapy with hypotension and metabolic acidosis.53 Airway Management Once ECMO is established and appropriate pH, PaO2, and PaCO2 values are obtained, ventilator settings are reduced to minimize barotrauma and oxygen toxicity (PIP, 15–20 cm H2O; rate, 10 breaths/min; FiO2, 0.3). The optimum PEEP level is uncertain, but many programs use high PEEP (12–15 cm H2O) with mean airway pressures of 13 to 16 cm H2O, based on experimental studies in a neonatal lamb model of meconium aspiration54 that showed decreased time of ECMO without increased barotrauma. A prospective, randomized study in neonates has also concluded that higher PEEP safely prevents deterioration of pulmonary function during ECMO and results in more rapid lung recovery.55 Because the patient is on extracorporeal support and does not have to breathe, airway management techniques unique to ECMO can be evaluated. For a large bronchopleural fistula, selective ventilation of the opposite lung for a period of time, selective occlusion of the

offending bronchus with a balloon catheter for one or two days, or cessation of ventilation altogether while the air leak seals are available management options. Once the air leak has been sealed for 48 hours, alveoli are recruited by hourly lung conditioning with application of continuous static airway pressure in the range of 20–30 cm H2O. If the primary problems include excessive exudate or occlusion of the airways, flexible bronchoscopy with lavage can often help to clear the airway. ECMO can also be used in patients with severe airway obstruction secondary to status asthmaticus or airway occlusion due to blood clots or other foreign material. 5 6 In these circumstances, oxygenation is usually more than adequate, and the major problem is CO2 retention, high intrathoracic pressures with cardiovascular compromise, or barotrauma with uncontrolled pneumothorax.

Complications and Management Complications during ECMO are the rule, not the exception,57,58 as the management of the patient on ECMO, including patient-related complications, spans the entire field of critical care. We will limit this section to complications unique to ECMO. Cannulas are inserted with great care to avoid vascular damage during insertion, since loss of control of the internal jugular vein can result in massive mediastinal bleeding, and dissection of the carotid artery intima can progress to a lethal aortic dissection. Minor surgical procedures may be required during ECMO; however, because of the risk of bleeding with systemic anticoagulation they should not be taken lightly. Tube thoracostomy may be required to drain hemothorax or pneumothorax. At the time of these minor invasive procedures, skin incisions can be made with the coagulation mode of an electrocautery. Muscles should be cauterized and not torn. Although bleeding may be a significant problem, liberal use of cautery, application of fibrin or biologic glue, and a low threshold for reexploration permit nearly any procedure to be performed. The major complication of postcardiotomy ECMO in pediatric patients is hemorrhage. Approximately 40 to 50% of children require reexploration for hemorrhage during ECMO. To minimize the magnitude of bleeding, the activated clotting time (ACT) is maintained at approximately 200 seconds and the platelet count is kept > 100,000/mm3. The primary determinant of significant hemorrhage is the duration of ECMO. 59 Keeping the chest open is sometimes necessary to facilitate drainage and to prevent periods of cardiac tamponade or hemothorax. The use of heparin-coated circuits and oxygenators presents promising possibilities with improved biocompatibility and less complement activation. 6 0

Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 315

Aminocaproic acid use has been recommended for ECMO patients at high risk for bleeding complications. The use of Amicar has been shown to reduce bleeding complications when patients undergo other surgical procedures while on ECMO, but has failed to reduce the incidence of intracranial hemorrhage in the pediatric population.61 Thrombocytopenia is expected during the use of ECMO as platelets are altered and as platelet aggregates in the extracorporeal circuit are preferentially sequestered in the lung, liver, and spleen.62–64 Thrombocytopenia must be avoided by using platelet transfusion as often as necessary to maintain adequate platelet counts during, as well as after, ECMO when thrombocytopenia may occur. The development of heparin-bonded, nonthrombogenic surfaces is attractive, but the initial experiences with heparin-bonded circuits have not shown significant advantages. Catastrophic hemodynamic deterioration is unusual while a patient is on VA ECMO. The factors that deserve immediate evaluation when this occurs include venous catheter displacement, inadequate systemic volume status, and the possibility of ECMO circuit failure. Pericardial tamponade and tension hemothorax or pneumothorax show a similar pathophysiology of increasing intrapericardial pressure and decreasing venous return. Perfusion is initially maintained by the nonpulsatile flow of the ECMO flow and progressive hemodynamic deterioration. With decreased venous return to the heart, pulmonary blood flow as well as the native cardiac output is decreased. Therefore, the relative contribution of the extracorporeal circuit to peripheral perfusion is increased, and peripheral perfusion is initially maintained by the nonpulsatile flow of the ECMO circuit (post-oxygenator pO2 > 300 torr). The triad of increased PaO2, decreased peripheral perfusion (as evidence by decreased pulse pressure and decreased SvO2) followed by decreased ECMO flow with progressive hemodynamic deterioration is consistently associated with tension pneumothorax.65–67 Tension hemothorax and pneumothorax is initially identified by chest radiograph. An echocardiogram will demonstrate a pericardial effusion or hemothorax with or without cardiac compression. For emergency drainage of tension hemothorax, pneumothorax, and pericardial tamponade, a percutaneous drainage catheter should be placed to remove the blood or fluid and reverse the pathophysiology. Sepsis is both an indication for and a complication of ECMO. However, according to the ELSO Registry, only 5% of all patients requiring ECMO demonstrate positive blood cultures. This is a remarkably low incidence given the duration of cannulation, the large surface area involved, and frequency of access to the circuit. Infection

rates vary by institution and are as high as 27%.68 Over one-half of all nosocomially acquired infections in patients on ECMO are bacterial with gram-positive organisms predominating, while 30% of infections are fungal. To decrease the incidence of infection, broadspectrum coverage with antibiotics based on institutionspecific bacterial patterns, aseptic technique, and attempts to minimize the time on ECMO are encouraged. When ECMO is initiated, a patent ductus arteriosus (PDA) is often present in the newborn. The pathophysiology of persistent fetal circulation is a right-to-left shunt through a PDA during severe respiratory failure in the newborn. When pulmonary hypertension resolves, flow through the ductus reverses (becomes left-to-right shunting). A persistent left-to-right shunt across the ductus arteriosus may lead to pulmonary edema. Decreased systemic oxygenation may result both from pulmonary edema and decreased systemic blood flow. Both of these conditions will require increasing ECMO flow to maintain adequate gas exchange and perfusion. A PDA on ECMO may present with various signs: (1) a decreased PaCO2; (2) decreased peripheral perfusion; (3) decreased urine output; (4) acidosis; and (5) rising ECMO flow and volume requirements. The clinical diagnosis may be confirmed as with other neonatal patients using Doppler echocardiography or angiography. Some centers have tried using intravenous indomethacin to treat PDA while on ECMO; however, this may increase the risks of bleeding in patients on ECMO because of its effects on platelet function. Once the diagnosis is established, most programs will “run the patient relatively dry” while maintaining supportive ECMO flow until the PDA closes. While this often means a few additional days on ECMO, surgical ligation is rarely necessary. Occasionally, a patient’s respiratory status does not improve despite 2 to 3 weeks of ECMO support. An echocardiogram is repeated to ensure an absence of PDA with predominant left-to-right shunt as well as congenital heart defect such as total anomalous venous return.

Weaning and Decannulation As native lung function improves, flow rates are decreased until the native lung is supporting the majority of gas exchange. The patient is then subjected to ventilator trials, with the circuit excluded. If gas exchange and hemodynamic parameters remain adequate, decannulation occurs. Patients requiring cardiac support undergo a similar trial but also have ECMO flow reduced to 10 to 20% of supportive flow. If filling pressures remain low and contractility remains adequate, with or without inotropes, the patient may be decannulated. If percuta-

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neous catheters were used, they are removed and local pressure is applied for at least an hour. If operative placement of the cannulas was required, operative removal and hemostatic control is necessary. Femoral vessels usually require repair. Repair of neck vessels is controversial, since immediate embolism or late stenosis can result. Many centers prefer ligation of the vessels, since the vessel was already obstructed by the cannula. If not already present, a tracheostomy may be placed for ventilator weaning and patient comfort in adults.

Specific Therapies Congenital Diaphragmatic Hernia In 1981, the first cases of infants with congenital diaphragmatic hernia (CDH) treated with ECMO were reported.69 CDH has the lowest survival rate of all categories of neonatal respiratory failure for which ECMO is used. 10 The impact on mortality, however, has been institution-specific, with survival rates ranging from 43 to 87%. Aggregate survival data in the ELSO registry is 62%.10 At first, infants were placed on ECMO only after they developed severe respiratory failure following immediate repair of the diaphragmatic defect. ECMO then was used preoperatively in attempts to stabilize the patient prior to definitive repair. Current strategies involve delay of surgical repair as long as possible while employing ventilator management techniques to optimize preductal arterial saturation, avoid high airway pressures in the hypoplastic lungs, and correct underlying pulmonary vascular resistance. Wung and colleagues have reported 85% overall survival with a strategy based on surgery delayed until pulmonary hypertension is minimized by respiratory care based on spontaneous respiration, permissive hypercapnea, and no chest tube.35 ECMO is required in only 14% of these patients pre- or postoperatively. Although the role of ECMO as a treatment option for patients with CDH has been widely accepted, the timing of the surgical repair and timing of ECMO initiation has drastically changed over the last 10 years. Previously, the overall mortality rate of CDH had remained approximately 50% with the increased utilization of ECMO support.70–74 Delayed repair until the patient’s hemodynamic and pulmonary parameters are stabilized is now generally accepted as the standard of care. Patients with low PIP and minimal shunting are repaired within the first 24 to 48 hours of life with good survival outcomes. High PIPs are managed with a variety of ventilator schemes including low tidal volume, permissive hypercapnea, and early employment of high frequency oscillator ventilation until they are controlled and maintained

< 25 cm H2O.35,75 Pulmonary hypertension can be diagnosed by the pre- or postductal saturation gradient or by echocardiogram. Although inhaled nitric oxide (iNO) has not been shown to improve overall survival in CDH,76 there is a subset of patients who will respond to iNO therapy. Maintaining a patent ductus arteriosis with prostaglandin if necessary in special circumstances can also allow for right ventricular decompression and prevent ventricular failure. ECMO is reserved for those patients who show rapid deterioration with preductal hypoxemia and severe right to left shunting secondary to high PVR and who have failed medical therapies mentioned above. Institutions that have implemented these strategies of delayed repair and judicious use of ECMO have shown improved survival from < 50 to > 75% while reducing the use of ECMO to < 15% of cases involving CDH.35,75,77–80 Operative repair of the defect while on ECMO has shown variable survival rates.81–85 Delaying repair until the infant is off ECMO is an option in which favorable results have been reported. 86,87 The cannulation technique is determined by operator experience and patient’s need. No difference has been shown in the rate of complications, time to recovery, or overall survival between VV ECMO and VA ECMO.88,89 A recent report from the Congenital Diaphragmatic Hernia Study Group showed neonates who do not require ECMO for support at any point during their hospitalization have the best survival rates (94%) followed by those repaired after stabilization by and weaning from ECMO (83%). Those patients repaired while on ECMO had a survival rate of only 49%. 9 0 Selection bias is clearly a factor with these results since the only repairs currently done on ECMO are patients who do not initially improve or wean from the ventilator. Cardiac Support ECMO applied to patients with severe cardiac failure was first reported in the 1950s but it was not commonly used until the 1980s.91 Since then, the use of ECMO has been extended to both infants and children after cardiac surgery. 9 2 – 9 4 There have been nearly 4,000 patients supported with ECMO for myocardial dysfunction, with overall survival of about 37%,10 ECMO provides greater flexibility in dealing with some forms of complex congenital heart disease in which pulmonary hypertension and hypoxia contribute significantly to the pathophysiology.95 The effect of ECMO on the heart includes a decrease in preload, a slight increase in afterload, and a concomitant elevation in left ventricular wall stress. Advantages include support of both right and left ventricles, improvement of systemic oxygenation, and ease of placement. VA cannulation provides the optimal cardiac support when ventricular dysfunction predominates the