Kidney Diseases and Hypertension, Part II, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine) (Pt. 2)

Prim Care Clin Office Pract 35 (2008) xi–xiii

Preface

Edgar V. Lerma, MD, FACP, FASN, FAHA Guest Editor

Chronic kidney disease (CKD) is a major public health problem. According to the National Health and Nutrition Examination Survey (NHANES) 1999–2004, approximately 20 million Americans are diagnosed with CKD; that is, 1 out of 9 adults in the US satisfy the criteria for the diagnosis of CKD. Another 20 million are estimated to be at risk. This projection points to the fact that patients with CKD will soon far outnumber trained nephrologists in the US. This dilemma can be solved only by a collaborative approach between primary care providers and nephrologists. We, as nephrologists, are well aware that the primary care providers occupy a unique and vital role in this team approach (Table 1). Primary care providers are at the forefront of this war against CKD. They are in a position to be the first to identify and screen patients at risk for CKD, eg, those with diabetes, hypertension, etc. They also are providers of long-term care and management of these patients. Nephrologists and nephrology teams contribute to this collaborative process by being involved in the earlier stages of CKD, perhaps at the time of diagnosis, and also by providing assessments of patientsÕ conditions and strategic guides to overall management [1]. An example of this is the administration of erythropoietin, a proven and effective treatment strategy that is not available in many primary care establishments [1]. To be effective, however, our ultimate goal, as primary care providers and nephrologists alike, is to be able to educate and empower patients so that they will be able to take charge of their disease. 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.005 primarycare.theclinics.com

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Table 1 Team approach to the role of primary care physician and nephrologist in chronic kidney disease What the primary care physician does

What the nephrologist does

Identifies and screens for risk factors of CKD, including:  Diabetes  Cardiovascular disease  Anemia Provides ongoing management of patients with CKD Provides role-specific patient education

Diagnoses and assesses patient

Assists in developing strategic guidance Recommends and implements patient care Provides role-specific patient education

Abbreviation: CKD, chronic kidney disease. Data from BeActive slide deck. Ortho Biotech, Bridgewater, NJ.

As guest editor of two issues on ‘‘Kidney Diseases and Hypertension,’’ I feel privileged with a unique opportunity to contribute to this goal. I have carefully chosen the different topics that I feel are of great interest to our colleagues involved in primary care practice. The first issue deals with the typical topics faced by primary care providers, such as common fluid and electrolyte disorders, as well as acid-base problems. These articles discuss the diseases with predominant involvement of renal pathophysiology, such as glomerular and tubulointerstitial diseases, and common systemic diseases, such as diabetic nephropathy, systemic lupus erythematosus, congestive heart failure, etc. The various treatment modalities and approaches are also rendered towards the end of each article. An article discussing the new classification of chronic kidney disease and the various complications that may arise secondary to it is also included. The last two articles deal with common upper and lower urinary tract problems, such as infections and stones. The second issue focuses on the various treatment strategies, namely renal replacement therapy or dialysis and renal transplantation. Hypertension, a common problem encountered in the outpatient setting and also the second most common cause of CKD, is discussed in greater detail. Over the past decades, with so many advances in technology, as shown by our new understanding of the various disease processes and pathophysiologies, there has been a very noticeable increase in representation of the geriatric population in those afflicted by renal disease processes, the so-called ‘‘gerontologizing of nephrology.’’ I believe that a discussion on this new trend is appropriate, and so it is presented in the last article. I would like to take this opportunity to thank my fellow authors who collaborated with me on this project. All of the authors were asked to give a specific discussion related to kidney diseases and hypertension, while taking into consideration that our target audience would be the primary care providers whom we collaborate with on a regular basis.

PREFACE

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I am hopeful that primary care providers will find the information provided in this text quite useful in their practice of daily medicine. As medicine is ever-changing and developing, future studies will be published that may either differ or provide updates to the recommendations presented herein. I encourage readers to stay updated with the medical literature and to use it in their practices as they deliver healthcare. Edgar V. Lerma, MD, FACP, FASN, FAHA Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine 820 S. Wood Street Chicago, IL 60612-4325 Associates in Nephrology, SC 210 South Desplaines Street Chicago, IL 60661 E-mail address: [email protected]

Reference [1] Schoolwerth A. The Scope of the cardio-CKD-anemia triad. Taking control of chronic kidney disease: beyond the kidney. Presented at the ANNA Meeting. Orlando, May 25, 2002.

Prim Care Clin Office Pract 35 (2008) 407–432

Treatment Options for End Stage Renal Disease Paul W. Crawford, MD, FACPa,b,*, Edgar V. Lerma, MD, FACP, FASN, FAHAc,d a

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA b Evergreen Park Dialysis Unit, 9730 S. Western Avenue, Suite 326, Evergreen Park, IL 60805, USA c Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine, 820 S. Wood Street, Chicago, IL 60612-4325, USA d Associates in Nephrology, SC, 210 South Desplaines Street, Chicago, IL 60661, USA

Currently, more than 480,000 United States citizens are receiving dialysis [1]. More than 314,000 are receiving hemodialysis, more than 25,000 are receiving peritoneal dialysis, and another 143,000 have had transplants [1]. Significantly, 16.8% of the population has chronic kidney disease (CKD) [2]. The latest National Health and Nutrition Study revealed an increasing incidence of kidney disease among aging baby boomers, as the incidence of diabetes mellitus and hypertension rises. Because of this trend, a greater proportion of a primary care physician’s practice will involve patients with CKD, and consequently, end stage renal disease (ESRD) or CKD patients receiving dialysis [3]. Unfortunately, far too many of these CKD patients are referred to a nephrologist very late. More often than not, the opportunity for secondary preventive intervention, with the goal of avoiding renal replacement therapy, is lost [4]. When should a patient with CKD be referred to a nephrologist? The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend a referral to a nephrologist when the glomerular filtration rate (GFR) is less than 30 mL per minute per 1.73 m2 [5]. A more aggressive approach is to encourage referral when the * Corresponding author. Evergreen Park Dialysis Unit, 9730 S. Western Ave., Suite 326, Evergreen Park, IL 60805. E-mail address: [email protected] (P.W. Crawford). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.05.003 primarycare.theclinics.com

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GFR is less than 60 mL per minute per 1.73 m2. As a cautionary note, a consultation when the GFR is greater than 60 is warranted in the presence of rapidly declining GFR with or without hematuria or proteinuria. Late referral to the nephrologist is considered by most clinicians to be ‘‘when management pf patients with chronic kidney disease could have been significantly improved by earlier contact with the nephrology team,’’ and surprisingly, it is extremely common in the United States. In most cases, it is when one is referred within 3 months or less before start of dialysis therapy [6]. With an early referral, the patient and family are given the advantage of participating in educational classes concerning CKD, as well as of receiving oneon-one counseling with a multidisciplinary kidney care team, including a nurse practitioner, physician, dietitian, and social worker. These team interventions (informed selection of dialysis modality, timely placement of appropriate dialysis access, as well as preemptive transplant) are paramount in helping the patient and family overcome many of the fears and myths associated with dialysis, as well as to arm them with skills needed to cope with the CKD, its complications, or ESRD diagnosis and treatment [7]. Similarly, other benefits associated with early referral include nonemergent initiation of dialysis, lower morbidity and improved rehabilitation, less frequent and shorter hospital stays, lower cost, and improved survival [8]. Moreover, many CKD patients are able to remain stable (within the same CKD stage), or improve CKD stage with aggressive intervention. The National Kidney Foundation classifies CKD stages into stages 1 through 5, as illustrated in Table 1. Unfortunately, many patients with ESRD have been threatened with dialysis by primary care providers or family members. Though well intentioned, the use of the threat of dialysis as a tool for motivating compliance with prescribed treatments and medications ultimately results in a patient who fears the treatment (dialysis) more than the disease (ESRD), with all the accompanying complications. All too often, this leads to patients with CKD Stage 5 refusing renal replacement therapy for a prolonged time (more than a year in some cases) or even never consenting to this life-saving treatment. Table 1 National Kidney Foundation stages of chronic kidney disease Stage

Description

GFR (mL/min/1.73 m2)

1 2 3 4 5

Kidney damage with normal or [ GFR Kidney damage with mild Y GFR Moderate Y GFR Severe Y GFR Kidney failure

R 90 60–89 30–59 15–29 !15 (or dialysis)

Chronic kidney disease is defined as either kidney damage or GFR less than 60 mL per minute per 1.73 m2 for greater than or equal to 3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. From National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S46; with permission.

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It is ironic that, given our current armamentarium, our success in managing comorbidities associated with CKD Stage 5, such as anemia, hypertension, metabolic acidosis, and secondary hyperparathyroidism with hyperphosphatemia leads our patients to question whether dialysis can improve their quality of life. With diligent management of these comorbidities, patients no longer need suffer from symptoms of fatigue, weakness, loss of mental alertness, lethargy, severe pruritus, recurrent chronic heart failure, shortness of breath, and inability to perform activities of daily living (ADLs). Instead, they are able to work, walk miles on a treadmill, golf, bowl, swim, dance and perform all ADLs without difficulty, despite having a GFR of less than 15 mL per minute. Indications for renal replacement therapy ESRD is always a diagnosis of exclusion; it is only after all exams have ruled out all reversible causes for renal failure that a diagnosis of ESRD should be made. No assumptions can be made in the work-up. A comprehensive, meticulous work-up includes an extensive history and physical, laboratory exams, renal ultrasound, chest X-Ray, and CT scan and MRI when indicated. Previous medical records must be reviewed. The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines define CKD as: 1. Kidney damage for greater than or equal to 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR and manifest by either: Pathologic abnormalities; or Markers of kidney damage, including abnormalities in the composition of blood or urine, or abnormalities in imaging tests 2. GFR less than 60 mL per minute per 1.73 m2 for greater than or equal to 3 months, with or without kidney damage (Table 2) [9].

Table 2 KDOQI criteria for initiation of renal replacement therapy Criteria for initiation of renal replacement therapy Prior approach Diabetics Nondiabetics Transplant Current approach All patients Patients with symptomatic severe left ventricular dysfunction, symptomatic uremia, uncontrollable hyperkalemia or metabolic acidosis Transplant

GFR !15 mL/min !10 mL/min Not candidate until on dialysis GFR !15 mL/min 15–20 mL/min

!20 mL/min

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According to KDOQI guidelines, hemodialysis is also indicated when the GFR has not yet decreased to or below 15 mL per minute per 1.73 m2, in the presence of [9]: Intractable extracellular fluid volume overload Hyperkalemia Hyperphosphatemia Hypercalcemia or hypocalcemia Metabolic acidosis Anemia Neurologic dysfunction (eg, neuropathy, encephalopathy) Pleuritis or pericarditis Otherwise unexplained decline in functioning or wellbeing Gastrointestinal dysfunction (eg, nausea, vomiting, gastroduodenitis) Weight loss or other evidence of malnutrition Hypertension

diarrhea,

After the diagnosis of ESRD is determined, a decision concerning the most appropriate mode of renal replacement for the patient must be made. The various modes of dialysis must be very carefully discussed with patients and families as a life saving treatment for those with ESRD who, without this opportunity to receive treatment, will die prematurely of uremic complications. If the primary care provider is unable to dedicate the time for this often very lengthy, emotional discussion, then it is best left to the nephrology team. Options for renal replacement therapy for ESRD Kidney Transplantation a. Deceased donor b. Living donor Peritoneal Dialysis a. Continuous ambulatory peritoneal dialysis (CAPD) b. Continuous cycler peritoneal dialysis (CCPD) c. Nocturnal intermittent peritoneal dialysis (NIPD) d. NIPD-wet day e. Tidal peritoneal dialysis Hemodialysis (HD) a. Conventional: 3 to 5 hours, 3 times per week i. In-center HD ii. Home HD iii. Nocturnal home HD iv. Nocturnal in-center HD (not widely available) b. Daily home HD (day or nocturnal) c. Day or nocturnal 8–10 hour HD

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Variations of the above referenced renal replacement therapies are being attempted in an effort to improve outcomes, such as reduction of morbidity, mortality, and hospitalization days, in accordance with current ongoing demonstration projects. Goals of renal replacement therapy include: Prolongation of life Reversal of symptoms of uremia Return the patient to their prior lifestyle/activities of daily living Maintenance of a positive nitrogen balance and an adequate energy intake Minimization of patient inconvenience Maximization of quality of life

Selection of renal replacement therapy mode The nephrologist has great influence over the patient’s selection of peritoneal versus hemodialysis. The nephrologist’s preferences are greatly dependent upon their training, orientation, and practice location. A significant percentage of Nephrology Fellows come into practice with no prior experience in peritoneal dialysis. Subsequently, these nephrologists are much less likely influence a patient to choose peritoneal dialysis because of a lack of confidence in their ability to successfully manage peritoneal dialysis patients and staff. Lack of experienced and adequately trained staff can be, and often is, a major deterrent to a nephrologist recommending CAPD, even when they believe this to be the best option for the patient. Fear of insecure, inexperienced staff can also make an already apprehensive and fearful new ESRD patient even more anxious and reluctant to take on the responsibility of self-care (Table 3).

Table 3 Considerations when determining mode of renal replacement therapy Consideration Access

Hemo

CAPD

Desired: arteriovenous Tenckhoff catheter; no (AV) fistula AV access Alternate: catheter Frequency/duration 3 times per week/4 hrs Four exchanges daily per session Patient manual Not a factor Partner is dexterity recommended Patient intellectual Not a factor Partner is capacity recommended Family support An advantage Necessary

CCPD Tenckhoff catheter; no AV access Cycler at night Partner is recommended Partner is recommended Necessary

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Hemodialysis History Georg Haas performed the first human hemodialysis in 1924 in Giessen, Germany. Using collodian tubes arranged in parallel cylinders, blood came in contact with exchange fluid. Since that time, there have been numerous breakthroughs with various membranes, including cellophane, cellulose acetate, and cupraphane, all in the search for more biocompatible dialysis membranes and ultimately, disposable kidneys. In 1946, Gordon Murray created a dialyzerda coil design on steel framed and used his invention on a patient in acute renal failure, performing the first successful dialysis in North America. Many patients start dialysis with the perception that their kidneys are going to recover and that dialysis is ‘‘only temporary.’’ This is despite counseling to the contrary by multiple care providers that their kidney disease is irreversible and that they will need renal replacement therapy for the rest of their life. Such denial is common in patients starting renal replacement therapy and is to be expected for the first 6 to 12 months of dialysis. This is true even for the patient who has received early, in depth education about the need for renal replacement therapy. Contraindications to hemodialysis Hemodialysis contraindications include hemodynamic instability, hypotension, unstable cardiac rhythm and patient refusal. Vascular access Vascular access has been called the Achilles heel of dialysis. Without adequate access to the circulation, it is impossible to achieve adequate dialysis results. Blood flow of between 200 mL to 500 mL per minute is required for adults, depending on their size. For patients needing chronic hemodialysis, creation of an arteriovenous (AV) fistula (connecting an artery to a vein using a surgical anastomosis of the native vessels) in an upper extremity is imperative. Early identification of patients requiring AV access Patients in CKD Stage 4 should have vein mapping with ultrasound. After mapping has identified that the patient has adequate size vessels for the creation of a native AV fistula, a surgical referral for creation of an AV fistula should be made. Only a native AV fistula should be placed. The decision to place any other form of access should be reviewed with the nephrology team, patient, and family. Some surgeons believe an AV graft using artificial veins (PTFE) are also fistulas. However, the nephrologists must not relegate the decision of appropriate AV access placement to the vascular surgeon.

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The selection and order of preference for placement of AV fistula are a wrist (radial-cephalic) primary AV fistula or and elbow (brachial-cephalic) primary AV fistula. If unable to establish AV access with the preceeding methods, then use an artificial vein graft of synthetic material or a transposed brachial-basilic vein fistula. Typical longevity of an AV fistula is 80% over a 3-year period as compared with 50% over 3 years for an AV-PTFE graft. Location of an AV graft should be determined by the anatomic size of vessels, as shown by vein mapping, the surgeon’s skills, and the anticipated duration of dialysis, as noted in the KDOQI guidelines. After an AV fistula is placed, a period of 4 to 16 weeks is required until adequate venous enlargement and thickening of vessel walls results in a fistula suitable for cannulation (Figs. 1 and 2). The implications, potential complications, and risks associated with catheter placement must be weighed carefully to avoid increased morbidity and mortality. Unfortunately, there are instances wherein the patient may require hemodialysis on a rather emergent manner, such as in cases of acute poinsonings or intoxications, acute renal failure with uremic signs and symptoms at presentation, or in situations where the patient has not been adequately prepared for hemodialysis, such that no AV access has been placed. In these situations, the use of double lumen, noncuffed, nontunneled, short (9 cm–13 cm) hemodialysis catheters have been the preferred method for vascular access. Such catheters can be inserted into the jugular, subclavian, or femoral veins, via a modified Seldinger guidewire technique. Because they are noncuffed, they are considered temporary and they can be inserted at the bedside under sterile conditions. Radiologic imaging guidance is not commonly required during their placements. The subclavian route is discouraged because of increased risk of subclavian stenosis and thrombosis. For femorally inserted catheters, a length of 18 cm or less is recommended to minimize recirculation.

Fig. 1. Primary radiocephalic arteriovenous fistula. A side-to-side anastomosis becomes a functional artery side-to-venous-end anastomosis by ligation of the distal venous limb close to the AV anastomosis (L1) or more distally (L2). Abbreviations: A, radial artery; V, cephalic antebrachial vein. (From Feehally J, Johnson R. Comprehensive Clinical Nephrology, 2nd Edition. New York: Mosby, an imprint of Elsevier; 2003. p. 930; with permission.)

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Fig. 2. Arteriovenous polytetrafluoroethylene graft in the forearm. (From Feehally J, Johnson R. Comprehensive Clinical Nephrology, 2nd Edition. New York: Mosby, an imprint of Elsevier; 2003. p. 931; with permission.)

Internal jugular catheters can be left in place for 2 to 3 weeks, while femoral catheters should be removed after one use in ambulatory patients, or 3 to 7 days in those who are bed-ridden. The most common complications that arise from such catheters are infections. At times, such temporary catheters have to be changed to the less thrombogenic, permanent, cuffed catheters that can be used for longer periods, such as up to 6 months. For these purposes, the double lumen silastic/silicone, cuffed catheters are used. Because of their larger size, fluoroscopy is usually required for placement. The majority of such catheters are loss to bacteremia. Thrombosis, stenosis, and infection of the catheters are also common complications. In comparing AV fistulas or grafts to catheters, the latter usually require an increase in hemodialysis duration of treatment by approximately 20% to achieve equivalent urea removal with the former [10]. In fact, using ultrasound dilution techniques, there is an estimated 20% to 30% decrease in blood flow (based on blood pump reading) when using a catheter as opposed to an AV access. Hemodialysis basics The basic unit of an artificial kidney is a semipermeable membrane made up of several thousand hollow fibers with a surface area of from 0.5 m2 to

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2.0 m2. Arranged in parallel, these fibers provide separation of the patient’s blood and dialysate fluid. Blood from the patient circulates through the dialyser and is returned to the patient with the assistance of a pump and tubing. Dialysate makes just a single pass through the dialyzer (Fig. 3A). There are several types of extracorporeal therapy: hemodialysis, hemofiltration, hemodiafiltration, and hemoperfusion. For the purpose of management of chronic renal failure in the outpatient setting, this discussion will be limited to that of hemodialysis. There are several variants of hemodialysis. These include: Conventional hemodialysis, which uses a conventional low flux (small pore size) membrane. The primary mechanism of solute removal is diffusion. High efficiency hemodialysis, which uses a low flux membrane with higher efficiency for removal of small solutes (eg, use a large surface area membrane). High flux hemodialysis, which uses a high flux (large pore size) membrane that is more efficient in removing large solutes. Hemodialysis machines have several key components (Fig. 3B), such as: Blood pumpddelivers blood to the artificial kidney at a constant rate of approximately 500 mL per minute. Monitorsdensures pressure inside blood circuit is not excessive. Detectordmonitors leakage of red blood cells from the blood circuitry component into the dialysate compartment. Air detector/shut off devicedprevents air from entering the patient. Dialysate pumpddelivers dialysate to the artificial kidney. A proportioning systemdassures proper dilution of the dialysate concentrate. Heaterdwarms the dialysate to approximately body temperature. Ultrafiltration controllerdprecisely regulates fluid removal. Conductivity monitordchecks dialysate ion concentrations (Fig. 4). With all the above devices, the artificial kidney can safely and reliably exchange water and solute in the physiologic ranges necessary to maintain chemical homeostasis as well as hemodynamic stability. Water transport and solute clearance Ultrafiltration coefficients are used to measure effectiveness of water transport across the dialysis membrane. Ultrafiltration coefficients are usually 2 mL to 5 mL per hour per mm Hg, with conventional membranes and 15 mL to 60 mL per hour per mm Hg with high flux membranes [11]. Stable patients may tolerate 5-L ultrafiltration or fluid removal over the 4-hour dialysis treatment, with close monitoring of vital signs.

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Mass transfer coefficient (Ko) and membrane surface area (A) determine solute transport of dialysis membranes, expressed as mass transfer-area coefficient Ko A as molecular size increases and diffusive clearance of solutes decreases. Therefore, small molecules, such as urea, are readily cleared at rates much higher than normal glomerulus of the kidney. However, 4 hours of dialysis 3 times per week cannot replace 24 hours, 7 days-a-week of clearance at the rate of 168 hours per week. Dialysate composition Dialysate sodium at or above plasma sodium prevents hemolysis from abrupt decrease in plasma sodium. Potassium often is kept low to decrease plasma potassium. Bicarbonate concentrate is usually high to correct acidosis. Today, acetate is seldom used in the United States because of problems with transient hypoxemia, metabolic acidosis, intradialytic hypotension, and cardiac arrhythmia. Calcium concentration in dialysate may vary depending on individual needs of the patient. Magnesium is usually low for ESRD patients who tend to be hypermagnesemic. For all patients, to avoid hypoglycemia, the glucose in the bicarbonate bath is usually kept at 200 mg/dL.

Complications of hemodialysis Hemodialysis today is a relatively safe procedure; however, complications do occur. Hypotension The most common complication of hemodialysis is hypotension. This can be either intradialytic or after dialysis. Etiology of hypotension Dialysis-related hypotension is attributed to changes in body volume. Both the amount of fluid removed and the rapidity of the removal from the intravascular space can affect the development of hypotension, as can

= Fig. 3A. Diagram of a hemodialysis circuit. Labels point to blood removed for cleansing, arterial pressure monitor, blood pump, heparin pump to prevent clotting, dialyzer, inflow pressure monitor, air detector clamp, venous pressure monitor, air trap and air detector, and clean blood returned to body. (From the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Treatment Methods for Kidney Failure Hemodialysis (KU-152). Available at http://kidney.niddk.nih.gov/kudiseases/pubs/choosingtreatment/index.htm.) Fig. 3B. Blood circuit for hemodialysis. (a) The blood circuit. (b) The pressure profile in the blood circuit with an arteriovenous fistula as the vascular access. (From Feehally J, Johnson R. Comprehensive Clinical Nephrology, 2nd Edition. New York: Mosby, an imprint of Elsevier; 2003. p. 955. with permission.)

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Fig. 4. Design of a modern hollow-fiber dialyzer. (From Feehally J, Johnson R. Comprehensive Clinical Nephrology, 2nd Edition. New York: Mosby, an imprint of Elsevier; 2003. p. 953; with permission.)

changes in serum osmolality and sympathetic tone. Patients taking oral antihypertensive medication before dialysis can experience intradialytic hypotension. In addition, patients eating while being dialyzed can experience hypotension secondary to splanchnic pooling. Management of intradialytic and post dialysis hypotension Treatment of hypotension may include: Normal saline infusion Recumbency Discontinuing ultrafiltration Increasing dry weight Decreasing the temperature of the dialysate

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Sodium modeling during hemodialysis Isolated ultrafiltration Withhold antihypertensive medications before dialysis Midodrine, an oral selective a1-agonist has been used in some cases with satisfactory results. The use of salt-poor albumin has been shown not to demonstrate any advantage over normal saline infusion, and may actually be more costly. Hypertension Hypertension during or immediately after dialysis is another common complication, and it is primarily volume-dependent in its etiology. There are patients, with so-called ‘‘dialysis-resistant hypertension,’’ whose blood pressures remain elevated despite adequate fluid removal. Such patients tend to have underlying long-standing hypertension and often have excessive interdialytic weight gains. They may have a hyperactive renin angiotensin system in response to fluid removal [12]. Use of erythropoietin has also been associated with a 20% to 30% incidence of new onset of hypertension, or exacerbation. Cardiac arrhythmia Cardiac arrhythmias can occur in any patient, but are most often seen in patients on multiple cardiac medications and when a low K bath is being used. The numbers of patients with cardiovascular disease and arrhythmia developing ESRD are continuing to rise and warrant close attention [13]. Arrhythmia prevention Preventive measures may entail use of bicarbonate dialysate with close monitoring of the potassium and calcium levels in the patient’s serum and the dialysate. The use of zero potassium dialysate is arrhymogenic in itself and should not be used, especially if the patient is on maintenance digoxin. Steal syndrome Steal syndrome is commonly seen in patients with radiocephalic arteriovenous fistulas or grafts, where blood flow to the involved hand is diverted and diminished. These patients should be evaluated for signs and symptoms of ischemia, such as subjective coldness and paresthesia, objective reduction in skin temperature, or intact sensory or motor functions. Neurologic changes and muscle wasting tend to occur in severe cases. Mild ischemia can be treated with analgesics or by wearing a glove. Those that do not respond to conservative measures may require surgical intervention with banding or access correction or even ligation.

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Muscle cramps Muscle cramps are common when a patient drops below their dry weight or when they undergo ultrafiltration that is too rapid. Peripheral arterial disease (PAD) is common in kidney patients with CKD and can produce muscle cramps [14]. As expected, they tend to occur toward the latter part of the dialysis session, tending to involve the lower extremities, most commonly. This is also the reason for a significant proportion of patients discontinuing dialysis treatment session prematurely. Muscle cramp management Large intradialytic weight gain can be avoided with fluid restrictions of 1,000 cc to 1,500 cc plus urine volume per 24 hours, a task that requires extreme self-discipline for some patients whose thirst center is overactive. In the past, quinine sulfate, given 2-hours before dialysis, was favored by many physicians. The United States Food and Drug Administration currently regards quinine sulfate as both unsafe and ineffective for prevention of muscle cramps. Oxazepam has been used by some physicians with varying rates of success. The value of sodium modeling in relieving muscle cramps has been shown in at least one study [15]. Evaluation for PAD with Ankle Brachial Index (ABI) may indicate presence of PAD that requires further treatment and evaluation. Restless leg syndrome Patients usually complain of crawling sensations on both lower extremities, which seem to occur during periods of inactivity (while the patient is sleeping or seated). Sometimes it is perceived as pain. Prompt relief is usually obtained by moving the legs, hence, the term ‘‘restless legs.’’ Many patients have difficulty sleeping and can have a poor quality of life. Use of certain antidepressants (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors, and lithium) can exacerbate the symptom. Restless leg syndrome has to be differentiated from peripheral neuropathy, which tends to be more constant and is not relieved by movement. Gabapentin has been shown to be effective and can also help with the insomnia. Recently, ropinirole, a dopamine agonist approved for use in Parkinson’s disease, has shown to be a promising agent [16]. Disequilibrium syndrome This syndrome may occur when too much fluid is removed over too short a time period. Disequilibrium syndrome may manifest as a range of symptoms, including headache, nausea, vomiting, altered mental status, seizure, coma, and death.

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Disequilibrium syndrome management Fortunately, disequilibrium syndrome is much less common in patients who are referred to a nephrologist for timely initiation of dialysis. Early referral coupled with improved technology has made this syndrome much rarer than in the past. Anaphylaxis Anaphylactic reactions may manifest with burning or heat over the access site or throughout the body, chest or abdominal pain, difficulty breathing, hypotension or hypertension, fever, chills, pruritis, emesis, urticaria, flushing, and even cardiopulmonary arrest. The typical onset of symptoms is usually within the first 5 minutes of initiating dialysis, although it may be delayed by up to 20 minutes. Fortunately, improved technology has decreased the incidence and frequency of anaphylactic reactions to the dialysis membrane. Modern membranes are much more biocompatible. Using bicarbonate dialysis rather than acetate dialysis has also decreased the occurrence of anaphylaxis. Thorough rinsing of the dialyzer before use, helping to remove any noxious materials or contaminants that became attached to the membrane during manufacturing, has also reduced the occurrence of anaphylaxis. Eliminating the reuse of dialyzers prevents patient exposure to contamination of membranes by chemicals used during sterilization and reprocessing and reduces the risk of anaphylaxis caused by sensitivity to these chemicals. Postdialysis syndrome An ill-defined, washed-out feeling or malaise during or after hemodialysis is seen in approximately one third of patients [17]. It has been attributed to several factors: decreased cardiac output, peripheral vascular disease, depression, deconditioning, electrolyte abnormalities, hypotension, and myopathy, among others. Infectious complications Patients with ESRD primarily die from cardiovascular events. However, infections are the second most common cause of death [18,19] Temporary dialysis catheters are the source for most infections. AV fistulas carry the least risk of infection. Staphylococcus aureus and Staphylococcus epidermidis are the bacterial culprits most frequently found. Frequent infection control in services and follow-up training to staff are required policy for all dialysis units, whether hemodialysis or peritoneal dialysis units. Hepatitis B was prevalent in the 1970s. Currently Hepatitis C is more prevalent and increasing risk for liver failure and cirrhosis in ESRD

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patients. Unfortunately, the mode of transmission is not yet established. Screening for Hepatitis B is mandatory and patients presenting or developing this condition require isolation. Vaccination for Hepatitis B, Flu, and pneumonia are offered to appropriate patients. Patients are considered candidates for the vaccines unless a specific contraindication, such as established antibody levels for Hepatitis B, is present (Table 4). Role of water treatment in hemodialysis complications Water treatment is the most critical component of hemodialysis. Fortunately, it is also the most monitored, regulated, and precisely accurate segment of dialysis. Purification of water from municipalities is critical because of inherent levels of contaminants, as well as hardness that varies from location and water source. Inadequate removal of calcium, aluminum, bacteria, chloramine, and other water components that may be either naturally occurring or as a result of contamination can lead to deadly consequences. There is no room for error in proportioning systems whose function is to maintain proper osmolality, electrolyte content, and pH balance. Improper

Table 4 Vaccination table for patients with ESRD Vaccine Anthrax DTaP/Tdap/Td Hib Hepatitis A Hepatitis B Influenza (TIV) Influenza (LAIV) Japanese Encephalitis MMR Meningococcal Pneumococcal Polio (IPV) Rabies Rotavirus Smallpox Typhoid Varicella Yellow Fever

Recommended

May use if otherwise indicated

Contraindicated

a

X Xa Xa Xa X X X Xa Xa Xa X Xa Xa Xb Xa Xa Xa Xa

a No specific Advisory Committee on Immunization Practices recommendation for this vaccine exists for renal dialysis patients and patients with chronic renal disease. b Children with primary immunodeficiency disorders and both children and adults who have received hematopoietic, hepatic, or renal transplants are at risk for severe or prolonged rotavirus gastroenteritis and can shed rotavirus for prolonged periods. (Data from Advisory Committee on Immunization Practices, unpublished data.)

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temperature range can lead to hemolysis. Air leak detectors ensure against air embolism that can arise from a defective blood circuit.

Peritoneal dialysis Peritoneal dialysis is the author’s first choice for renal replacement therapy for a patient with ESRD if a kidney transplant is not possible or available. Peritoneal dialysis was initially used only to treat patients who were in acute kidney failure. Typically used exclusively in intensive care units (ICU), a hard plastic catheter was placed into the peritoneal cavity, allowing the infusion of peritoneal dialysis fluid. The dialysis fluid was supplied in 2-liter glass bottles. The ICU nurse would perform exchanges every 1 to 2 hours, documenting hourly volume of intake and output, and calculating a positive or negative fluid balance. This was a very laborious task for nursing staff, often requiring a one-to-one patient-to-staff ratio (hardly available in today’s nursing shortage era). By the mid-1970s, continuous ambulatory peritoneal dialysis was introduced. Currently, more than 25,000 patients with ESRD are on peritoneal dialysis. Fundamentals of peritoneal dialysis Peritoneal dialysis involves an exchange of solutes and fluids across the peritoneal membrane, which serves as the dialysis surface, via diffusion and convective transport regulate solute movement. Urea, creatinine, and potassium move into the peritoneal cavity dialysate across the peritoneal membrane, while bicarbonate and calcium move in the opposite direction. The concentration gradient between dialysate and blood facilitates small molecule movement. Convection is also responsible for solute movement across the peritoneal membrane. Patients perform the exchanges at home on a daily basis and have follow-up at the dialysis center or home therapy center twice monthly. Peritoneal dialysis patients are typically seen by the nephrologist once a month and by the staff twice a month for social, dietary, and financial needs. Monthly laboratory work is required at a minimum; more frequent laboratory work may be required (Fig. 5). A high concentration of glucose in the peritoneal dialysis fluid is used as solute driving fluid removal, creating an osmotic gradient for ultrafiltration of fluid, and providing a dwell time that is not prolonged. Crucial to effective exchanges and fluid removal are peritoneal blood flow, dialysate volume, and the integrity of the peritoneal membrane (Table 5). The peritoneal dialysis catheter is inserted by a surgeon or nephrologist as an out-patient procedure. Most catheters are double-cuffed, curled tip Tenckhoff catheters. Other types of catheters are available, but they are infrequently used.

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Fig. 5. Diagram of a patient receiving peritoneal dialysis. Dialysis solution in a plastic bag drips through the catheter into the abdominal cavity. CAPD is the most common form of peritoneal dialysis. (From the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Kidney Failure: Choosing a Treatment That’s Right for You (KU-50). Available at: http:// kidney.niddk.nih.gov/kudiseases/pubs/choosingtreatment/index.htm.)

Table 5 Peritoneal dialysate fluid composition Peritoneal dialysate fluid composition Sodium Potassium Calcium Lactate Magnesium Glucose Osmolality pH

132 mEq/L 0 mEq/L 3.5 mEq/L 40 mEq/L 0.5 mEq/L 1.5 g/dL, 2.5 g/dL, or 4.25 g/dL 346, 396, 485 5.2

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Continuous ambulatory peritoneal dialysis CAPD uses 9 L to 10 L of peritoneal dialysis fluid per day, usually in 2-L to 3-L bags. Four to six exchanges are typically performed over a period of 24 hours. The peritoneal dialysis fluid is infused into the peritoneal cavity via catheter. The fluid remains in the cavity for 4 to 6 hours, is then drained out, removing water and solutes, including urea and creatinine. The number of exchanges and the volume of the peritoneal dialysis fluid bags are determined by patient size, peritoneal membrane permeability, and residual kidney function (Fig. 6). Automated continuous cycling peritoneal dialysis While the mechanism of dialysis is the same, patients on CCPD use a cycler. A cycler is a small bedside device that is programmed to set volumes of infusion, dwell times and drain times. After programming, the device automatically performs exchanges while the patient is either asleep or resting. Because the process is automated, the patient is able to rest without interruption, with the exception of an alarm that sounds as a result of a problem detected by the cycler (Fig. 7).

Fig. 6. Flush-before-fill strategy used with Y transfer sets. (A) A small volume of fresh dialysis solution is drained directly into the drainage container (either before or just after drainage of the abdomen). This washes away any bacteria that may have been introduced in the limb of the Y leading to the new bag at the time of connection. (B) Fresh solution is introduced through the rinsed connector. (From NIH Publication No. 01-4688, May 2001. Available at: http://www. intelihealth.com/IH/ihtIH/WSIHW000/23,847/25,944/273,441.html?d¼dmtContent#works.)

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Benefits of self care using CAPD or CCPD Self discipline Ownership of disease and self-management Responsibility Family involvement Overcomes denial Residual renal function preservation Better quality of life Lower morbidity and mortality Adequacy of peritoneal dialysis is measured through determination of KT/V where K equals urea clearance, T equals per unit time, and V equals total body water. The combination of creatinine clearance of peritoneum and residual renal function should reach a weekly KT/V of 2. Failure to achieve the guideline level of 2 may result in uremic symptoms, decreased protein intake, and increased mortality (Table 6). Complications of peritoneal dialysis Peritonitis is the most common complication of peritoneal dialysis. This complication is usually discovered when the patient reports a cloudy drainage bag. A diagnosis of peritonitis is confirmed through a positive gram stain, cell count, and sensitivity culture, as well as signs and symptoms of peritoneal inflammation. Empiric treatment is started to treat gram-positive or gram-negative organisms by instillation of intraperitoneal antibiotics.

Objective criteria for rationing dialysis? In the early days of dialysis in the United States, dialysis was only offered at university teaching centers. It was considered a high risk, experimental, but life saving procedure. Dialysis was only offered to those with ESRD who were accepted by the ‘‘God Committees’’ as eligible for dialysis. Criteria were very limiting; for example, patients had to be under the age of 55 and could not be diabetic. I will never forget having to inform a 55year-old father of two children that the committee voted he was not eligible for dialysis. Never again do I wish to see a committee decide who may be treated and who is essentially given a death sentence. Yet some 35 years later, this pendulum of death appears to be resurfacing in the medical

= Fig. 7. Example of a system used for cycler-assisted peritoneal dialysis. Solution is heated before use and weighed after use. The last bag of solution may have a different concentration to last throughout the day. (From NIH Publication No. 01-4688, May 2001. Available at: http:// www.intelihealth.com/IH/ihtIH/WSIHW000/23,847/25,944/273,441.html?d¼dmtContent# works.)

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Table 6 Common laboratory parameters measured in patients receiving dialysis Measure

Expected level

KT/V Hemoglobin Parathyroid hormone Phosphorus HbA1c Albumin Calcium Tsat Ferritin Blood pressure Low-density lipoprotein Standardized mortality rate

R1.2 (Hemodialysis) R 2 (Peritoneal dialysis) 11 g/dL –12 g/dL 150–300 4.5–5.5 %7.0 R4.0 8,5–10.0 O20% !500 130/80 !100 !18%

community, as use of medical resources based on costs is becoming more prevalent. The role of the medical field is to ‘‘do no harm.’’ To accomplish this health care providers must always weigh benefits against the risk for any procedure, including dialysis and transplant. For patients who cannot maintain adequate perfusion of vital organs secondary to hypotension resulting from hemodialysis, the risk of dialysis outweighs the benefits. In a patient for whom previous abdominal surgery has resulted in multiple adhesions obstructing inflow and drainage of peritoneal dialysis fluid, or for those who develop sclerosing peritonitis, the risk of peritoneal dialysis outweighs the benefits. Dialysis, even when benefits outweigh the risk, is contraindicated if the patient cannot understand the procedure and give informed consent, and do not have family or a guardian who can do so on their behalf. Other patients perceive, even when the benefit is evident to the physician, that the procedure is torturous and not beneficial to them. Those patients should not be coerced to undergo dialysis, despite the ultimately grave outcome. The author is not a proponent of socialized medicine systems that refuse dialysis to patients over a certain age, or that deny dialysis to patients with certain diseases, or that block access to dialysis based on ability to pay for treatment, or that refuse treatment based on race, gender or ethnic group. Ultimately, the decision of who should or should not receive dialysis must be made by an informed, educated patient and family, in conjunction with the medical care team that includes the nephrologist, primary care physician, nurses, social workers, and spiritual leader. Kidney transplantation Much literature has been published attesting to the survival benefits of patients who have undergone renal transplantation as compared with those

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on dialysis. Comparisons on rates of mortality have been made between those patients who are on the waiting list (for renal transplant) and those who are already transplant recipients. From these studies, the question arose of whether transplantation of these patients before initiation of dialysis (preemptive transplantation) would translate into significantly improved outcomes. Several studies published recently [20–23], show significantly improved patient and allograft survival in those with preemptive transplants as opposed to those who were on dialysis for a period of time before transplantation. There have been lower rates of delayed graft function or acute rejection episodes (biopsy-confirmed) associated with preemptive transplantation. Interestingly, preemptive transplant recipients have better socioeconomic and demographic features [24] that were also correlated with better outcomes. Examples of these include younger age, white race, higher degree

Box 1. Initial evaluation of the potential renal transplant recipient Complete history and physical examination (includes detailed surgical and psychosocial history) Blood type, complete blood count, blood urea nitrogen, creatinine, electrolytes, calcium, phosphorous, albumin, liver function tests, prothrombin time, and partial thromboplastin time Serologic testing for HIV, cytomegalovirus, varicella virus, herpes simplex virus, Epstein Barr virus, hepatitis virus A, B, and C, rapid plasma reagin, and fluorescent treponemal antibody Urinalysis and urine or bladder-wash culture Purified protein derivitive Chest X-ray and electrocardiogram In men: testicular examination and, in those over the age of 50, measurement of prostate specific antigen and a digital rectal examination. In women: breast examination and, in those over the age of 40, mammography. The age for mammography should be lowered to 35 if there is a history of breast cancer in the premenopausal years in a first-degree relative. HLA antigen typing and a panel reactive antibody assay to detect for previous sensitization Chest radiography Renal ultrasonography (post-void residual is optional) Two-dimensional echocardiography Thallium scintigraphy or dobutamine stress echocardiography

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of education, and employment. They also had fewer HLA antigen mismatches. It is therefore reasonable to recommend possibly avoiding dialysis with early preemptive transplantation in certain situations. This should be considered, especially in younger individuals with very minimal comorbidities, if at all. The role of hemodialysis versus peritoneal dialysis as before-transplant dialysis modality in predicting outcomes remains controversial. Studies have also shown that successful renal transplantation significantly improves quality of life and decreases the risk of mortality as compared with maintenance dialysis. However, because of the donor organ shortage, there is an ever increasing number of candidates waiting on the transplant list, and wait times are also increasing. Some groups are trying to find ways to alleviate this donor shortage, such as specialists in xenotransplantation, proponents of paired-exchange transplantation, as well as good Samaritan or altruistic transplantation. The Consensus Conference [25] (United Network for Organ Sharing) currently recommends that adult candidates for renal transplant should have progressive renal disease and a GFR less than 18 mL per minute for them to be placed on the cadaveric renal transplant waiting list. The evaluation of both potential renal transplant donor and recipient tends to be tedious and exhaustive (Box 1). Before a patient is accepted for renal transplantation, one has to take into consideration, certain contraindications (Box 2). Advanced age, history of

Box 2. Contraindications to renal transplantation Relative Active infection Coronary heart disease Active hepatitis Active peptic ulcer disease Cerebrovascular disease Proven habitual medical noncompliance HIV infection (Although most centers exclude patients who are HIV positive; in certain cases, those considered to have well-controlled HIV infection are still eligible for solid organ transplantation) Absolute Untreated current infection Active malignancy with short life expectancy Chronic illness with life expectancy of less than 1 year Poorly controlled psychosis Active substance abuse

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previous transplantation, as well as underlying kidney disease diagnosis, are not contraindications to renal transplantation. Certain renal diseases, such as focal segmental glomerulosclerosis and IgA nephropathy, have high recurrence rates in the transplanted organ, yet are not considered as contraindications. Unfortunately, there is still a large proportion of patients who are referred for actual renal transplantation who are eventually excluded. Reasons for exclusion are varied, and include medical contraindication, patient decision, obesity, death, and insurance or financial reasons [26]. The most common medical reasons were heart disease, malignancy, and noncompliance. References [1] U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD); 2007. [2] Saydah S, Eberhardt M, Rios-Burrows, et al. Prevalence of Chronic Kidney Disease and Associated Risk FactorsdUS 1999–2004. MWR 2007;56(8):161–5. [3] Wetterhall SF, Olson DR, DeStefano F, et al. Trends in diabetes and diabetic complications, 1980–1987. Diabetes Care 1992;15:960–7 [Abstract]. [4] Levin A. Consequences of later referral on patient outcomes. Nephrol Dial Transplant 2000; 15(Suppl 3):8–13. [5] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Part 4. Definition and Classification of Stages of Chronic Kidney Disease. Available at: http://www.kidney.org/Professionals/ Kdoqi/guidelines_ckd/p4_class_g2.htm. Accessed July 22, 2008. [6] Stevens LA, Levey AS. Chronic kidney disease: staging and principles of management. In: Greenberg A, editor. Primer on kidney diseases. 4th edition. Philadelphia: National Kidney Foundation; 2005. p. 461. [7] Crawford PW. Changing Trends in Referral Source of ESRD Patients in a Nephrology Practice Between 1995 and 2005 [Abstract]. Presented at the National Kidney Foundation 2006 Spring Clinical Meeting. Chicago, April 19–23, 2006. [8] Kausz AT, Pereira BJ. Late referral to nephrologists of patients with chronic kidney disease. In: Rose BD, editor. UpToDate. Wellesley (MA): UpToDate; 2008. [9] National Kidney Foundation. NKF K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations. 2006 Updates. Available at: http://www.kidney.org/ Professionals/kdoqi/guideline_upHD_PD_VA/hd_rec1.htm. Accessed July 22, 2008. [10] Schwab SJ. Acute hemodialysis vascular access. In: Rose BD, editor. UpToDate. Waltham (MA): UpToDate; 2008. [11] Cheung AK. Hemodialysis and hemofiltration. In: Greenberg A, editor. Primer on kidney diseases. 4th edition. Philadelphia: National Kidney Foundation; 2005. p. 467. [12] Rahman M, Dixit A, Donley V, et al. Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients. Am J Kidney Dis 1999;33:498–506. [13] Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004;164:659–63. [14] Jaar BG, Plantinga LC, Astor BC, et al. Novel and traditional cardiovascular risk factors for peripheral arterial disease in incident-dialysis patients. Adv Chronic Kidney Dis 2007;14:304–13. [15] Sandowski RH, Allred EN, Jabs K. Sodium modeling ameliorates intradialytic and interdialytic symptoms in young hemodialysis patients. J Am Soc Nephrol 1993;4:1192–8.

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[16] Pellecchia MT, Vitale C, Sabatini M, et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release. Clin Neuropharmacol 2004;27:178–81. [17] Parfrey PS, Vavasour HM, Henry S, et al. Clinical features and severity of nonspecific symptoms in dialysis patients. Nephron 1998;50:121–8. [18] Bloembergen WE, Stannard DC, Port FK, et al. Relationship of dose of hemodialysis and cause-specific mortality. Kidney Int 1996;50:557–65 [Medline]. [19] US Renal Data System: USRDS 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2000. [20] Kasiske BL, Snyder JJ, Matas AJ, et al. Preemptive kidney transplantation: the advantaged and the disadvantaged. J Am Soc Nephrol 2002;13:1358–64. [21] Meier-Kriesche HU, Port FK, Ojo AO, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000;58:1311–7. [22] Mange KC, Joffe MM, Feldman HI. Effect of use or non-use of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 2001;344:726–31. [23] Gill JS, Tonelli M, Johnson N, et al. Why do preemptive kidney transplant recipients have an allograft survival advantage? Transplantation 2004;78:873–9. [24] Butkus DE, Dottes AL, Meydrech EF, et al. Effect of poverty and other socioeconomic variables on renal allograft survival. Transplantation 2001;72:261–6. [25] Consensus conference on standardized listing criteria for renal transplant candidates. Transplantation 1998;66:962–7. [26] Holley JL, Monaghan J, Byer B, et al. An examination of the renal transplant evaluation process focusing on cost and the reasons for patient exclusion. Am J Kidney Dis 1998;32(4): 567–74.

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Management of the Kidney Transplant Recipient Aparna Padiyar, MDa,b, Fadi H. Akoum, MDa,b, Donald E. Hricik, MDa,b,* a

Division of Nephrology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA b University Hospitals Case Medical Center, 11100 Euclid Avenue, Room 8124 Lakeside Building, Cleveland, OH 44106, USA

Recent trends in kidney transplantation During the past two decades, remarkable strides have been made to increase the success of kidney transplantation and to prolong the lives of patients with end-stage renal disease. General advances in medical science, including improvements in surgical techniques and the development of effective antimicrobial agents, undoubtedly have played a role in this success story. However, the current success of kidney transplantation has been related more directly to an improved understanding of the immunobiology of allograft rejection and the development of immunosuppressive drugs capable of preventing and treating rejection. Today, the incidence of acute rejection experienced during the first posttransplantation year is less than 20%, and 1-year graft survival rate exceeds 90% at most centers. As a consequence of improved graft and patient outcomes, kidney transplantation has become the renal replacement therapy of choice for patients with endstage renal disease, offering a survival advantage over dialysis irrespective of age, ethnicity, or underlying kidney disease [1]. Long-term graft and patient survival rates also have improved in recent years, but as many as 30% of transplanted kidneys continue to fail within 5 years of transplantation. Currently, the most common causes of graft loss after the first posttransplant year are: 1) ‘‘chronic allograft

This work was supported, in part, by funding from the Leonard Rosenberg Research Foundation. * Corresponding author. University Hospitals Case Medical Center, 11100 Euclid Avenue, Room 8124 Lakeside Building, Cleveland, OH 44106. E-mail address: [email protected] (D.E. Hricik). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.03.003 primarycare.theclinics.com

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nephropathy,’’ a common but poorly understood entity that likely has both immune and non-immune causes (see below); and 2) death with a functioning graft. It is possible that death with a functioning graft is related directly to the toxicities of the very immunosuppressants that have yielded such impressive short-term outcomes. The available maintenance drugs variably contribute to the risks of cardiovascular disease, infection, and malignancy, which are the main causes of late mortality in transplant recipients [2,3]. In the field of kidney transplantation, the focus of patient management has shifted from short- to long-term management issues, including strategies to reduce long-term exposure to toxic immunosuppressants. This has become especially relevant with the advancing age of the kidney transplant recipient population. Although transplantation offers a survival advantage and improved quality of life for most patients with end-stage kidney disease, a continued disparity between the supply of allografts from deceased donors and the demand for these organs by a growing population of transplantation candidates has led to a continued increase in the size of the waiting list and in waiting times. Death of patients on the kidney waiting list is becoming more common [4]. The net shortage of deceased donor kidneys has forced the transplantation community to extend the criteria for acceptable donors, including use of donors after cardiac death [5]. The shortage of deceased donors has also fueled a recent increase in the use of living related and living unrelated donors as well as related efforts to expand the living donor pool via desensitization protocols, nondirected donations, and living donor exchange programs.

Role of the primary care physician As patients live longer with functioning allografts, the number of prevalent solid organ transplant recipients will continue to increase, making it likely that a vast majority of primary care physicians ultimately will be exposed to recipients of kidney and other solid organ allografts. The growing number of transplant recipients has resulted in a paradigm shift in attitudes regarding long-term patient management issues at many transplantation centers. In an earlier era, many centers were keen on providing both primary and tertiary care to their relatively small populations of successful transplant recipients. Growth in the volume of transplantation patients has not been paralleled by comparable growth in resources (professional personnel, space, administrative infrastructure) required to provide comprehensive care to all patients. Both posttransplantation care and the regular re-evaluation of patients on ever-growing waiting lists require more time and space than ever. In addition, regulatory agencies are increasingly demanding medical follow-up of living kidney donors, posing even further demands for resources at transplantation centers.

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In this setting, the transplantation community increasingly will look to primary care physicians to play a role in the long-term management of kidney transplant recipients and possibly in the long-term follow-up of living kidney donors. The primary care physician should be aware of common medical problems confronting kidney transplant recipients, have some rudimentary knowledge of immunosuppressive medications and their interactions with other drugs, and, most importantly, develop a good sense for when it is appropriate to refer a transplantation patient back to the transplantation center. Common complications of kidney transplantation Cardiovascular disease Patients with end-stage renal disease (ESRD) experience rates of cardiovascular morbidity and mortality 10 to 20 fold greater then that of the general population. Kidney transplantation clearly mollifies this risk. Transplant recipients have repeatedly been shown to enjoy a persistent survival advantage compared with waitlisted ESRD patients, evident by 3 months post transplantation. This survival advantage is in a large part due to a reduction in cardiovascular risk accompanying the improved renal function that an allograft provides. However, cardiovascular morbidity and mortality still remain prevalent in the posttransplantation population, accounting for 25% to 40% of patient deaths [6–8]. The various causes of long-term mortality in kidney transplant recipients are shown in Fig. 1. Data from the United States Renal Data System (USRDS) estimate the incidence of cardiovascular disease in kidney transplant recipients to be twice that of the general population [7]. Not surprisingly, a history of cardiovascular disease before transplantation is a major risk factor for posttransplantation cardiovascular morbidity. Hypertension, hyperlipidemia, and diabetes are widespread in this patient population and contribute to posttransplantation cardiac risk. Many transplant recipients have stage II to III chronic kidney disease (CKD) (based upon the National Kidney Other 22%

Cardiovascular 45%

Malignancy 19% Infection 14%

Fig. 1. Common causes of late mortality in kidney transplant recipients.

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Foundation [NKF] classification schema), and CKD is a well-established risk factor for cardiovascular disease. Moreover, corticosteroids, calcineurin inhibitors (CNIs), and target of rapamycin (TOR) inhibitors each have distinctive side effects that individually play a role in cardiovascular risk. Traditional risk factors (age, smoking, blood pressure, gender, total and high density cholesterol as accounted for in the Framingham risk score) do not fully account for the accelerated rates of cardiovascular disease seen in kidney transplant recipients [6,7]. Nontraditional factors such as level of allograft function, proteinuria, abnormal calcium and phosphorus metabolism, hypertriglyceridemia, hyperhomocysteinemia, anemia, systemic inflammation and oxidative stress also play a significant role. Weight-gain post-transplantation, averaging about 3 kg in the first year, is common and may contribute to cardiovascular risk. Multiple episodes of acute rejection have been associated with the development of post-transplantation cardiovascular disease, possibly reflecting inflammation associated with the rejection episode or treatment with high doses of immunosuppressants. Immunosuppressive drugs can affect both traditional and nontraditional risk factors [6]. Corticosteroids exert hypertensive and dyslipidemic effects, increase insulin resistance, and contribute to posttransplantation obesity. Adverse effects of CNIs (cyclosporine and tacrolimus) include hypertension, dyslipidemia, renal insufficiency and the development of new-onset diabetes. The TOR inhibitors cause of hyperlipidemia, proteinuria, anemia, and hyperglycemia. Although the effects of TOR inhibitors on homocysteine are unknown, these agents have been associated with increased levels of inflammatory markers, including C-reactive protein. Diabetes mellitus New onset of diabetes mellitus (NODAT) is considered a serious adverse event after transplantation and confers increased risks of cardiovascular morbidity, impaired long-term graft function, and decreased patient survival [6,9,10]. In a patient population already at substantially high risk for cardiovascular disease, pre-existing diabetes or NODAT increases the relative risk for ischemic heart disease over 2.5 fold compared with non-diabetic transplant recipients. According to USRDS data, NODAT is independently associated with a 60% greater risk of graft loss and an almost 90% greater mortality. Emerging evidence suggests that microvascular complications such as neuropathy, nephropathy, and retinopathy are accelerated in patients with NODAT, resulting in a significant increase not only in disease burden but also in health care cost. The incidence of NODAT increases continuously with time posttransplantation, and recent data suggest that the absolute incidence has risen over the last decade [6,9,10], possibly reflecting the epidemic of obesity. The incidence can vary between 2% and 50% the first 3 years after transplantation, depending upon the population studied and how diabetes

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mellitus is defined. Well-established non-modifiable risk factors include increased age, family history of diabetes mellitus, African American or Hispanic ethnicity, and hepatitis C infection. Lifestyle modification may influence risk factors such as body weight and hyperlipidemia. Commonly used immunosuppressive agents also substantially contribute to the development of NODAT. Corticosteroids are well known to cause peripheral insulin resistance. CNIs, especially tacrolimus, have been associated with impaired glucose metabolism, causing both decreased insulin production and increased insulin resistance. Newer data suggest that sirolimus, an agent often used as an alternative to CNIs, is also diabetogenic, possibly causing apoptosis of beta cells. Hypertension Management of hypertension poses a challenge in the kidney transplant recipient. Considering that an elevation in either systolic or diastolic blood pressure is an independent risk factor for allograft failure and increased mortality, it stands to reason that hypertension should be treated aggressively. However, almost 90% of transplant recipients are affected and up to one third do not have optimal control [6]. Surprisingly, there are no large, prospective, randomized controlled studies that demonstrate improved longterm outcomes by decreasing blood pressure in kidney transplant recipients. Likewise, the optimal target blood pressure for kidney transplant recipients is not well defined. The Kidney/Dialysis Outcomes Quality Initiative (K/ DOQI) clinical practice guidelines, the European Best Practice Guideline (EBPG) and the American Society of Transplantation (AST) have recommended different targets for blood pressure control. (K/DOQI targets 130/80 mmHg; EBPG targets less than 130/85 mmHg in patients without proteinuria and less than 125/75 mmHg in proteinuric patients; AST targets less than 140/90 mmHg.) Additionally, a number of studies indicate that hypertension is underdiagnosed by office blood pressure measurement in this patient population, and that ambulatory blood pressure monitoring may be a more sensitive tool. The causes of posttransplantation hypertension are diverse (Table 1). In the general population, individuals who fail to exhibit the normal nocturnal decrease in blood pressure (ie, ‘‘nondippers’’) have been found to be at increased risk for left ventricular hypertrophy and adverse cardiovascular outcomes. Additionally, persistent non-dipping status may be associated with a faster rate in decline of GFR and increased proteinuria in patients with CKD. Immediately following kidney transplantation, nocturnal hypertension (‘‘nondipping’’) is common and associated with use of CNIs [11]. Over the long term, the nocturnal blood pressure profile improves in a significant number of patients (up to 30% in some series). The mechanisms by which CNIs blunt the normal nocturnal ‘‘dipping’’ status of blood pressure are unclear.

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Table 1 Factors associated with hypertension after kidney transplantation Pre-existing hypertension Impaired allograft function Acute rejection Chronic allograft nephropathy Recurrent or de novo kidney disease Ischemia reperfusion injury Renal artery stenosis In the native kidneys In the transplanted kidney Persistent parenchymal disease in native kidneys Immunosuppressive medications Corticosteroids Increase renal sodium absorption Volume expansion Calcineurin inhibitors (cyclosporine O tacrolimus) Renal arteriolar vasoconstriction Sympathetic nervous stimulation Increased renal sodium absorption

Hyperlipidemia Hyperlipidemia occurs in approximately 60% to 80% of kidney transplant recipients and results from a multitude of factors [6]. Both pretransplantation dyslipidemia and posttransplantation immunosuppression contribute. Additionally obesity, hyperglycemia, insulin resistance, proteinuria, and treatment with beta-blockers or with diuretics all play a role. The mechanisms by which immunosuppressive agents cause dyslipidemia are largely unknown. Cyclosporine, and to a lesser extent tacrolimus, negatively impact the serum lipid profile. The TOR inhibitor sirolimus is well known to cause profound elevations in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides in a dose-dependent manner. However, despite an increase in Framingham risk score associated with adverse serum lipid profiles, cardiovascular event rates in patients taking sirolimus have been lower than expected [12,13]. The reason for this apparent paradox is unclear, but it could be related to intrinsic anti-atherogenic properties of the TOR inhibitors. Corticosteroids inhibit lipoprotein lipase and enhance HMG CO-A and free fatty acid synthase, ultimately resulting in clinically apparent hyperlipidemia even at the small doses used for maintenance immunosuppression. A number of small clinical trials and retrospective analyses have correlated posttransplantation dyslipidemia with long-term allograft dysfunction and loss, particularly among males. Moreover, the Assessment of Lescol in Renal Transplantation Study (ALERT), the largest study of its kind, suggested some benefit to lowering cholesterol levels in kidney transplant recipients [14]. ALERT was a multicenter, randomized, double blind, placebo-controlled

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study of 2102 renal transplant recipients who were randomized to fluvastatin (n ¼ 1050) or placebo (n ¼ 1052), and followed for 5 to 6 years. The study initially failed to show a statistically significant difference in the primary composite endpoint (ie, occurrence of a major cardiac adverse event, namely cardiac death, nonfatal myocardial infarction, or coronary intervention). However, a trend toward a decreased incidence of myocardial infarction and sudden death was observed in the fluvastatin group during the early study period and persisted to achieve statistical significance in post hoc analyses [15]. The NKF K/DOQI clinical practice guidelines for posttransplantation hyperlipidemia are based largely upon the National Cholesterol Education Program (NCEP) III guidelines used in the general population. NKF K/ DOQI mandates evaluation for dyslipidemia in kidney transplant recipients at baseline, 2 to 3 months after a change in treatment, and at least annually thereafter. Recommended targets are an LDL cholesterol of less then 100 mg/dL, non-high density lipoprotein of less then 130 mg/dL, and triglyceride level of less then 150 mg/dL. Interestingly, NCEP III advocates LDL reduction to a goal less than 70 mg/dL in patients in the general population at high cardiac risk. It is unclear if such a strategy is warranted in kidney transplant recipients, who have event rates approximately twice that of the general population. Malignancy As part of their role in preventing rejection, immunosuppressive agents impair the normal immune response. Whether by directly damaging DNA, interfering with DNA repair mechanisms, or disturbing immunosurveillance for neoplastic or virally infected cells, immunosuppression in part accounts for the cancer risk seen in kidney transplant recipients. Preexistent risk factors, such as the ‘‘uremic milieu’’ of ESRD or treatment with dialysis also may play a role. It is therefore not surprising that the incidence of cancer is greater in kidney transplant recipients than in the general population. The most common cancer posttransplantation is nonmelanoma skin cancer, with an almost 20-fold increased incidence in kidney transplant recipients as compared with the general population [15]. The incidence of cancers linked to viral infections are also increased after kidney transplantation and include Epstein-Barr virus (EBV)-associated non-Hodgkin’s lymphoma and human herpes virus 8-associated Kaposi’s sarcoma. Whether other cancers occur at increased rates is more controversial. Recent large registry analyses in the United States, Canada, and Australia reveal an increased risk of several neoplasms after kidney transplantation, many with more than a two to three fold increase compared with the general population [16–18]. The majority of these cancers are of known or suspected viral origin. For example, human papilloma virus has been associated with cancers of the tongue, mouth, vulva, vagina, and penis and may be an etiologic

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agent in some cancers of the eye, lip, salivary gland, and esophagus. Hepatitis B and C are linked to liver cancer. Not all immunosuppressive agents are the same in terms of cancer risk. Studies in animals demonstrate that the TOR inhibitors have antineoplastic properties, including inhibition of cell-to-cell adhesions required for metastatic growth and inhibition of tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) [19]. Furthermore, preliminary studies seem to indicate that patients receiving TOR inhibitor-based immunosuppression exhibit lower rates of malignancy than patients receiving other regimens. Recent reports have described regression of cutaneous Kaposi’s sarcoma with conversion to sirolimus from a cyclosporine-based regimen. Whether it is cost effective to apply the same cancer screening guidelines used in the general population to kidney transplant recipients remains unclear. In the absence of good data, most transplantation centers follow those guidelines to screen for common solid tumors. Ironically, there are no readily available population-based screening guidelines for the most common cancers occurring in transplant recipients (ie, skin cancer, lymphoma, Kaposi’s sarcoma, and kidney cancer), and there is a great need to develop such guidelines [20]. Particular attention should be placed on patients at highest risk, ie, patients positive for hepatitis B and C, EBV-negative recipients of organs from EBV-positive donors, and recipients infected with human papilloma virus. The benefits of antiviral therapies, including vaccinations, in preventing cancer after kidney transplantation is largely unknown. Likewise, the potential antineoplastic benefits of the TOR inhibitors require further attention in prospective studies. Bone disease Immunosuppression (particularly from corticosteroids) and secondary hyperparathyroidism are often acknowledged as major causes of bone disease posttransplantation. However, the condition is much more complex, and comprises a spectrum of metabolic alterations of bone remodeling [6,21,22]. Preexisting uremic osteodystrophy, which encompasses some combination of hyperparathyroidism, adynamic bone disease, osteomalacia, mixed bone disease, B2 microglobulin-associated amyloidosis, and diabetic osteopathy, certainly contributes. Other important underlying factors are poor renal function; hypercalcemia; hyperphospaturia and hypophosphatemia; and alterations of vitamin D metabolism. The main pathologic alterations in bone remodeling in the kidney transplant recipient consist of decreased bone formation and mineralization in the face of persistent resorption. Osteoblast number is decreased while apoptosis of osteoblasts and osteocytes is increased. New evidence implicates the growth factor, fibroblast growth factor-23 (FGF-23, or phosphatonin), in posttransplantation hypophosphatemia [22]. FGF-23 induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease.

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The contribution of hypophosphatemia to apoptosis of osteoblasts is unclear. Although cyclosporine has long been associated with loss of bone mineral density over time, the relative effect of tacrolimus has only recently been described. Both agents have been linked to high bone turnover in animal studies; however, their effect in humans is unclear as they are often used in conjunction with glucocorticoids. Conversely, many studies in kidney transplant recipients have shown a correlation between glucocorticoid cumulative dose and bone mineral density. Steroids increase osteoclastic resorption, decrease osteoblastic activity, decrease intestinal calcium absorption, and increase renal calcium wasting (thereby stimulating parathyroid hormone secretion). Localized osteonecrosis is a debilitating complication that can result from chronic glucocorticoid use. Clinically, transplant recipients experience a rapid decline in bone mineral density in the first 6 to 12 months posttransplantation, particularly in the lumbar spine [6,21,22]. The fracture rate of approximately 3% per year post transplantation is higher than that seen in patients with CKD stage V who are on dialysis, and up to four times higher than the rate observed in the general population. However, the decline in bone mineral density as assessed by dual x-ray absorptiometry in the transplant recipient does not necessarily correlate with fracture rate. Treatment options remain limited [6,21]. The K/DOQI and EBPG recommend serial bone mineral density measurement and close monitoring of serum calcium, phosphate, and PTH concentrations. The optimal level of parathyroid hormone in kidney transplant recipients is unknown. Likewise, there is a paucity of data regarding the efficacy of bisphosphonates and vitamin D analogs in the treatment of posttransplantation bone disease. Given the heterogeneity of the problem, and the concern for potential oversuppression of bone turnover with agents currently available, more studies are needed that can evaluate reduction of fracture risk. Therapy should be considered for those at high risk, such as those with severely low bone mineral density, history of fractures, or biopsy-proven disease. Chronic allograft nephropathy Renal allograft failure is a common cause of ESRD and accounts for up to 30% of patients on the waiting list for transplantation [6,23]. The most common cause of allograft failure after the first year post transplantation is a poorly defined entity referred to as chronic allograft nephropathy (CAN). Histopathologically, CAN is characterized by arterial intimal fibrosis, interstitial fibrosis, and tubular atrophy without evidence of any specific etiology. Glomerular capillary walls thicken with an occasional double-contour appearance, termed ‘‘transplant glomerulopathy.’’ Although there are no universally accepted diagnostic criteria, CAN is generally recognized by slowly progressive renal allograft dysfunction after 3 months

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posttransplantation in the absence of active rejection, acute drug toxicity, or another disease. Clinically, azotemia, proteinuria (occasionally in the nephrotic range), and worsening hypertension develop, which frequently lead to loss of the allograft. The pathogenesis of CAN is complex and multifactorial [6,23]. Both immune and nonimmune mechanisms of injury are implicated. Immune-mediated factors include HLA mismatch, prior sensitization, prior rejection, and chronic or subclinical rejection. Hypertension, glomerular hyperfiltration and hypertrophy, diabetes, hyperlipidemia, proteinuria, smoking, and obesity are important modifiable nonimmunologic etiologic factors. Early graft dysfunction, ischemia/reperfusion injury, CMV infection, chronic hypoxia, oxidative stress, and chronic CNI toxicity also may play a role. Donor factors (age, living versus deceased source, genetic factors, donor/recipient size mismatch, and comorbidities) can contribute as well. Greater than 90% of allografts demonstrate histologic changes consistent with at least mild CAN at one year post transplantation [6,23]. Disease severity (ie, the amount of interstitial fibrosis and tubular atrophy, the presence of sclerotic glomeruli and vascular change) correlates with late graft function and failure. There is no specific treatment for CAN. Rather, nonspecific treatment approaches include efforts to reduce urinary protein excretion, control hypertension and dyslipidemia, and maintain adequate immunosuppression. Conversion from a CNI-containing regimen to the TOR inhibitor sirolimus is associated with an improvement in short-term renal function, but adequately powered randomized trials are needed to ascertain if this strategy leads to long-term benefit [24]. Similarly, interest in CNI-free or CNI-minimization regimens to prevent the development of CAN is growing. Infectious diseases Infections after kidney transplantation follow a specific temporal paradigm [25,26]. The timetable for these infections can be roughly divided into three distinct periods (Fig. 2). The first month after transplantation is dominated by postsurgical infections including: infection of the surgical site, bronchopneumonia, urinary tract infection, and catheter-related infections. The offending organisms are generally bacteria or yeast. Common infections during this early period include: oropharyngeal candidiasis (thrush), bacterial and fungal urinary tract infections, intravenous catheter infections, and reactivation of mucosal herpes simplex virus (HSV) (oral, pharyngeal, genital) in seropositive patients. Onset of hepatitis B or C infection occasionally may appear in a fulminant form during this early period. The second period (months 2–6) harbors the opportunistic infections traditionally associated with transplantation and immunosuppression [25,26]. These include cytomegalovirus (CMV) infections ranging from a flu-like syndrome with fever, chills, myalgias and leukopenia, to the most

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Fig. 2. Classic timetable of infection after transplantation. HSV, herpes simplex virus; CMV, cytomegalovirus; EBV, Epstein Barr virus; VZV, varidella zoster; RSV, respiratory syncytial virus; PTLD, posttransplantation lymphoproliferative disease. (From Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741–51; with permission. Copyright Ó 1998, Massachusetts Medical Society.)

symptomatic forms of tissue-invasive CMV. HSV infections and infections resulting from other members of the herpes virus family also can occur during this period. These infections include varicella zoster virus, human herpes virus-6 and 7, and Epstein-Barr virus (sometimes associated with posttransplantation lymphoproliferative disease). Other infections occurring during this second time period include community-acquired respiratory viral infections (influenza, parainfluenza, respiratory syncytial virus, adenovirus), fungal infections (candidiasis, cryptococcal meningitis or pneumonitis, aspergillosis, mucormycosis, and endemic mycoses like histoplasmosis and coccidiomycosis), Pneumocystis jiroveci (formerly carinii) pneumonia, tuberculosis, and parasitic infections in endemic areas of risk. In the third period (beyond 6 months posttransplantation), the risk of infection is close to that of the general population. However, patients who require higher levels of immunosuppression because of poor graft function or rejection remain vulnerable to the opportunistic pathogens of the second time period. A few patients may get late CMV, or recurrent CMV [27]. BK polyoma virus infection has a predilection for the urinary tract and may cause renal allograft dysfunction over months to years if not detected

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by early screening [28]. Hepatitis B and C may cause a gradual onset of liver dysfunction and cirrhosis over several years, or may remain quiescent. A febrile renal transplant patient should be carefully evaluated for the above typical and atypical infections. Obtaining a history of remote and recent exposures, ill contacts, travel, and animal exposure are essential parts of the evaluation. Of note, serologic testing for antibodies can be falsely negative in transplant recipients and direct detection methods, such as PCR, are usually more helpful. The ideal time to update vaccines is before transplantation [29]. These should include vaccines for pneumococcus, hepatitis B, tetanus-diptheria, and varicella (if the patient is seronegative). Live vaccines (measles/ mumps/rubella [MMR], inhaled influenza, varicella, smallpox, oral polio, oral typhoid vaccines) are generally avoided after transplantation. Immunosuppression may blunt the response to killed or recombinant vaccines following transplantation. Nevertheless, most transplantation centers recommend yearly influenza vaccine, pneumococcal vaccination every 5 years, and creating a ‘‘circle of protection’’ around the patient by vaccinating household contacts and health care workers. Other important precautions include avoidance of undercooked meat or eggs, nonpasteurized dairy products, and open salad bars, especially during the first year post transplantation. Transplant recipients should also avoid exposure to reptiles and amphibians, bird droppings, cat feces, and construction sites. Travel-associated risks and prevention should be discussed with the transplantation team before such plans are made [30].

Medications Immunosuppressants Some combination of immunosuppressive medications is generally required for patients with functioning renal allografts, constituting a lifelong need for many kidney transplant recipients. As a corollary, noncompliance with immunosuppression is a major risk factor for late episodes of acute rejection. A variety of antilymphocyte antibodies are used immediately after the transplantation operation for ‘‘induction’’ therapy, but they fall beyond the scope of this review [31]. For long-term maintenance, most patients are treated with a combination of two or three immunosuppressants, representing different drug classes with unique mechanisms of action and toxicities. The molecular targets for the various classes of immunosuppressants are shown in Fig. 3. Most of the available agents are targeted to inhibit either activation or proliferation of T-cell lymphocytes, which are the major mediators of acute cellular rejection. Corticosteroids have multiple mechanisms of action accounting for immunosuppression, but their dominant effect results from down-regulating production of a number of pro-inflammatory cytokines via inhibition of

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Fig. 3. Schematic intracellular signaling events associated with T cell activation, organized according to 3 sets of signals – 1) antigen recognition, 2) co-stimulation, and 3) cell cycle progression. The major steps involved in T cell activation are shown, and the sites of action of immunosuppressive drug classes are shown in italics. AP, activator protein; CTLA4-Ig, cytotoxic T lymphocyte antigen 4-immunoglobulin; IL, interleukin; NFAT, nuclear factor of activated T cells; NFKB, nuclear factor K B; TCR, T cell receptor; TOR, target of rapamycin.

NF-kB. These agents have been employed to prevent and treat acute allograft rejection for more than 40 years. However, the well-known side effects of steroids have led to steroid-sparing regimens and, although somewhat controversial, complete withdrawal of these agents in low-risk patients has become the standard of practice in many transplantation centers [32]. The CNIs act by inhibiting the intracellular phosphatase, calcineurin, which normally plays an important role in the intracellular transduction of signals that form a link between antigen recognition by a T cell and nuclear transcription of IL-2 and other cytokines [33,34]. Thus, this class of agents blocks antigen-specific T cell activation (sometimes referred to as signal 1). The two available CNIs, cyclosporine and tacrolimus, bind to different intracellular receptors but share the same mechanism of action. Their toxicities vary to some degree. Both agents can cause acute and/or chronic nephrotoxicity. Cyclosporine more commonly causes hirsutism, gingival hyperplasia, hypertension, and hyperlipidemia. Tacrolimus more commonly causes neurotoxicity (mostly tremor) and hyperglycemia. Antiproliferative agents inhibit the division of activated lymphocytes by impairing the production of DNA or RNA. The two agents approved for use in kidney transplant recipients are azathioprine and mycophenolate mofetil (MMF). Both agents inhibit purine synthesis. However, MMF more selectively inhibits purine synthesis within lymphocytes and proved to be superior to azathioprine for the prevention of allograft rejection in clinical trials [35]. MMF is a pro-drug that is immediately metabolized to the active metabolite,

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mycophenolic acid. Enteric-coated mycophenolate sodium was recently approved for use and it has efficacy and toxicity comparable to MMF. The most common side effects of MMF are diarrhea and, less commonly, upper gastrointestinal symptoms such as nausea, vomiting, or dyspepsia. The drug is also myelosuppressive and has been associated with leukopenia, thrombocytopenia, and anemia. The gastrointestinal and hematologic side effects are dose-related and often respond to dose reduction. Azathioprine also can cause myelosuppression, but gastrointestinal side effects are uncommon. The TOR inhibitors comprise another class of antiproliferative drugs that inhibit cytokine-mediated cell cycle progression (signal 3). Sirolimus is currently the only TOR inhibitor approved for use in the United States, but a chemical congener, everolimus, is also available in other parts of the world [36,37]. Side effects common to each of these agents reflect their effects on signal transduction mediated by a number of cytokines and growth factors. These include impaired wound healing, myelosuppression (especially thrombocytopenia), and delayed recovery from acute tubular necrosis. Other side effects include edema, mouth ulcers, and proteinuria. Full activation of T cells requires not only antigen recognition, but another set of ‘‘costimulatory’’ signals mediated by ligands between the lymphocyte and antigen presenting cells (collectively referred to as signal 2). Currently, there are no drugs available that primarily inhibit costimulatory ligands, but several compounds are in development. The agents described above are used in a wide variety of combinations for maintenance immunosuppression. In the United States, the most popular combination consists of tacrolimus and MMF with or without low doses of corticosteroids [38]. With the availability of multiple immunosuppressant drugs and drug classes, conversion from one regimen to another has become quite common, either as part of a designed protocol, or whenever a patient develops intolerable side effects from a particular drug. Adjustments of immunosuppression should always be managed directly by the transplantation center. Other drug classes Prophylactic antibacterial antibiotics, antiviral drugs, and antifungal agents are often prescribed in the early months after transplantation. In some centers, prophylaxis for Pneumocystis jiroveci (formerly carinii) is continued for life. The preferred agent is trimethoprim-sulfamethoxazole, but aerosolized pentamidine, dapsone or atovaquone are options for patients who are allergic to sulfa. As noted above, hypertension, hyperlipidemia, diabetes mellitus, and osteopenia are common in kidney transplant recipients. No single class of antihypertensive agents has emerged as a clear favorite for first line treatment of posttransplantation hypertension. Given the prevalence of cardiovascular disease in kidney transplant patients, beta blockers are

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often used for their concomitant cardioprotective effects. Calcium channel blockers are also popular, in part because they mollify the renal vasoconstrictive effects of the CNIs. The use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers is controversial. They are often prescribed based on their concomitant renoprotective effects, but, to date, there has been little direct evidence that these agents positively affect the function or survival of a transplanted kidney [39]. Moreover, these agents cause anemia in a substantial minority of transplant recipients and, of course, can occasionally cause hyperkalemia or acute renal failure. Despite early concerns about a heightened risk of rhabdomyolysis in patients taking cyclosporine and HMG reductase inhibitors, the latter ‘‘statins’’ have now emerged as the drug class most commonly prescribed for posttransplantation hyperlipidemia [40]. Ezetimibe also has been found to be safe and effective. The pharmacologic management of diabetes mellitus after kidney transplantation is similar to that used in the general population. This complication of kidney transplantation, diabetes mellitus, is commonly managed by diabetologists or primary care physicians. The treatment of posttransplantation osteopenia is controversial because few randomized trials have been performed to test specific therapies [41]. In the absence of hypercalcemia, calcium supplements and Vitamin D are frequently prescribed. The bisphosphonates are also prescribed commonly, but they are effective mostly in patients with high-turnover bone disease and can sometimes cause adynamic bone disease. Drug/drug interactions A number of drugs interact with immunosuppressants either pharmacokinetically or pharmacodynamically, potentially altering the efficacy and safety of the immunosuppressive drugs. Cyclosporine, tacrolimus, and sirolimus are each metabolized by the cytochrome P450 IIIA (CYP3A), which is present in the gastrointestinal tract and the liver. Drugs that induce or compete with this enzyme system can dramatically decrease or increase the blood concentrations of these immunosuppressants, posing a risk of under-immunosuppression and rejection or enhanced side effects, respectively. The drugs that most commonly and most potently exhibit these interactions are listed in Table 2, but many more agents have occasionally been incriminated. CNI-mediated nephrotoxicity may be enhanced by any concomitantly administered nephrotoxic drug, but additive nephrotoxic effects have been demonstrated most clearly with amphotericin, the aminoglycoside antibiotics, and nonsteroidal antiinflammatory drugs. Metoclopramide and grapefruit juice may increase the absorption of the CNIs leading to higher blood concentrations. The interaction of CNIs and TOR inhibitors with many commonly used drugs demands constant attention. All new drugs should be introduced with care or after discussion with the transplantation center.

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Table 2 Drugs that commonly interact with calcineurin inhibitors and target of rapamycin inhibitors Drugs that decrease immunosuppressant concentrations by induction of cytochrome P450 Antituberculous drugs Rifampin Rifabutin Anticonvulsants Barbiturates Phenytoin Carbamazepine Drugs that increase immunosuppressant concentrations by inhibition or competition with cytochrome P450 Antifungal agents Ketoconazole Fluconazole Itraconazole Voriconazole Antibiotics Macrolidesa Erythromycin Clarithromycin Calcium channel blockers Verapamil Diltiazem Nicardipine Amlodipine Protease inhibitors (especially ritonavir) a

Azithromycin does not interact with these agents.

Summary The short-term outcomes of kidney transplant recipients have improved dramatically in the past 20 years, in large part resulting from the availability of more potent immunosuppressive drugs capable of preventing or treating acute allograft rejection. Ironically, side effects from these same immunosuppressants play a role in the long-term morbidity and mortality of this patient population. As kidney transplant recipients survive for longer periods of time with functioning allografts, primary care physicians will likely become more involved in their management, mandating at least a basic understanding of immunosuppression and its complications. References [1] Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341:1725–30. [2] Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998;9(Suppl 12):S16–23.

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[3] Toussaint C, Kinnaert P, Vereerstraeten P. Late mortality and morbidity five to eighteen years after kidney transplantation. Transplantation 1988;45:554–8. [4] Merion RM, Ashby UB, Wolfe RA, et al. Deceased-donor characteristics and the survival benefit of kidney transplantation. JAMA 2005;294:2726–33. [5] O’Connor KJ, Delmonico FL. Increasing the supply of kidneys for transplantation. Semin Dial 2005;18:460–2. [6] Djamali A, Samaniego M, Muth B, et al. Medical care of kidney transplant recipients after the first posttransplant year. Clin J Am Soc Nephrol 2006;1:623–40. [7] Kasiske BL, Guijarro C, Massy ZA, et al. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996;7:158–65. [8] Lindholm A, Albrechtsen D, Frodin L, et al. Ischemic heart disease: major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation 1995;60:451–7. [9] Crutchlow MF, Bloom RD. Transplant-associated hyperglycemia: a new look at an old problem. Clin J Am Soc Nephrol 2007;2(2):343–55. [10] Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new onset diabetes mellitus in renal transplant recipients. Transplantation 2007;83:1027–34. [11] Padiyar A, Rahman M. Ambulatory blood pressure monitoring: an argument for wider clinical use. Cleve Clin J Med 2007;74(11):831–8. [12] Blum CB. Effects of sirolimus on lipids in renal allograft recipients: an analysis using the Framingham risk model. Am J Transplant 2002;2:551–9. [13] Morales JM. Cardiovascular risk profile in patients treated with sirolimus after renal transplantation. Kidney Int 2006;92(Suppl):S69–73. [14] Fellstro¨m B, Holdaas H, Jardine AG, et al. Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Kidney Int 2004;66(4): 1549–55. [15] Jardine AG, Fellstro¨m B, Logan JO, et al. Cardiovascular risk and renal transplantation: post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) Study. Am J Kidney Dis 2005;46(3):529–36. [16] Villeneuve PJ, Schaubel DE, Fenton SS, et al. Cancer incidence among Canadian kidney transplant recipients. Am J Transplant 2007;7(4):941–8. [17] Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296(23):2823–31. [18] Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4(6):905–13. [19] Kauffman HM, Cherikh WS, McBride MA, et al. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transpl Int 2006;8:607–20. [20] Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/ AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370:59–67. [21] Weisinger JR, Carlini RG, Rojas E, et al. Bone disease after renal transplantation. Clin J Am Soc Nephrol 2006;1:1300–13. [22] Hamdy N. Calcium and bone metabolism pre and post-kidney transplantation. Endocrinol Metab Clin North Am 2007;36:923–35. [23] Wilkinson A. Protocol transplant biopsies: are they really needed? Clin J Am Soc Nephrol 2006;1:130–7. [24] Mulay AV, Cockfield S, Stryker R, et al. Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation 2006;82(9):1153–62. [25] Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338: 1741–51. [26] Rubin RH. Infection in the organ transplant recipient. In: Rubin RH, Young LS, editors. Clinical approach to infection in the compromised host. 4th edition. New York: Plenum Medical Book Company; 2002.

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[27] Singh N. Late-onset cytomegalovirus disease as a significant complication in solid organ transplant recipients receiving antiviral prophylaxis; a call to heed the mounting evidence. Clin Infect Dis 2005;40:704–8. [28] Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79:1277–86. [29] American Society of Transplantation. Infectious Disease Community of Practice. Guidelines for the prevention and management of infectious complications of solid organ transplantation. Am J Transplant 2004;4(Suppl 10):1–166. [30] Kotton CN, Ryan ET, Fishman JA. Prevention of infection in adult travelers after solid organ transplantation. Am J Transplant 2005;5:8–14. [31] Kirk A. Induction immunosuppression. Transplantation 2006;82:593–602. [32] Augustine JJ, Hricik DE. Steroid sparing in kidney transplantation: changing paradigms, improving outcomes, and remaining questions. Clin J Am Soc Nephrol 2006;1:1080–9. [33] Kahan BD. The era of cyclosporine: twenty years forward, twenty years back. Transplant Proc 2004;36(Suppl 2):91S–378S. [34] Fung JJ. Tacrolimus and transplantation: a decade in review. Transplantation 2004; 77(Suppl 9):S41–3. [35] Ciancio GJ, Miller J, Gonwa TA. Review of major clinical trials with mycophenolate mofetil in renal transplantation. Transplantation 2005;80(Suppl 2):S191–200. [36] Abraham RT. Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol 1998;10(3):330–6. [37] Augustine JJ, Hricik DE. Experience with everolimus. Transplant Proc 2004;36(Suppl 2): 500S–3S. [38] Meier-Kriesche HU, Li S, Gruessner RW, et al. Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant 2006;6(Suppl 5):111–31. [39] Opelz G, Zeier M, Laux G, et al. No improvement of patient or graft survival in transplant recipients treated with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers: a collaborative transplant study report. J Am Soc Nephrol 2006;17:3257–62. [40] Ozsoy RC, van Leuven SI, Kastelein JJ, et al. The dyslipidemia of chronic renal disease: effects of statin therapy. Curr Opin Lipidol 2006;17:659–66. [41] Palmer SC, Strippoli GF, McGregor DO. Interventions for preventing bone disease in kidney transplant recipients: a systematic review of randomized controlled trials. Am J Kidney Dis 2005;45:638–49.

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Management of Hypertension in the Outpatient Setting Domenic A. Sica, MD Clinical Pharmacology and Hypertension, Division of Nephrology, Virginia Commonwealth University Health System, 1101 East Marshall Street, Sanger Hall, Room 8-062, Richmond, VA 23298-0160, USA

Once the decision is made to begin pharmacologic antihypertensive therapy, several questions will invariably arise: Is nonpharmacologic therapy still indicated even when pharmacologic therapy has commenced? Is one drug class more or less appropriate than another in controlling blood pressure in differing patient types? How long should single-drug therapy be maintained before switching to a different therapeutic class or adding a second agent? Can a patient ever safely discontinue antihypertensive medications and, if so, how best is such a patient monitored? The etiology of long-standing hypertension is infrequently due to one factor alone. Not unexpectedly, monotherapy brings blood pressure to goal in little more than 50% of patients [1]. Furthermore, the initial choice of a medication is most times subjective, often based on nonscientific grounds, anecdotal experience, personal preference, and simple intuition. Vigorous advertising and promotions to both health care providers and, more recently, patients often lead to the use of therapies based on unfounded information rather than objective analysis. Many patients who fail to achieve goal blood pressure also are not fully compliant [2]. Thus, the issue of controlling blood pressure is not as straightforward as choosing the correct first drug or combination of drugs. A more sophisticated approach to medication-taking behavior is needed, which is the case for most chronic illnesses. The attentive clinician, concerned about optimizing outcomes for patients, brings focus, skills, and resolve to the challenge of optimizing adherence to a prescription as well as to making the correct diagnosis and properly evaluating the hypertensive condition. This article focuses on many of these issues. Recommendations presented

E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.05.002 primarycare.theclinics.com

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in this article should be tailored to a patient’s age, gender, ethnic background, and body habitus [3]. Initial workup for hypertension The objectives of the initial evaluation of hypertension are to establish the diagnosis and stage of hypertension. The evaluation should gather office and nonoffice blood pressure readings, determine the presence of target organ damage, assess the level of global cardiovascular disease risk, and produce a plan for individualized monitoring and therapy. The basic components of the initial evaluation include a thorough history and physical examination, including assessment of orthostatic blood pressure change; basic serum chemistries, including serum potassium (Kþ), creatinine, fasting glucose and lipid profile; urinalysis with microscopic evaluation and an albumin/creatinine ratio; an ECG; and a nonoffice (home, workplace) 24-hour ambulatory blood pressure determination to establish the pattern of hypertension (sustained, ‘‘white coat,’’ or ‘‘masked’’ hypertension) (see the section on home blood pressure monitoring below). The presence of hypokalemia is perhaps the most noteworthy aspect of screening blood tests performed in the patient with hypertension. Diseases marked by excess activity of the renin-angiotensin-aldosterone system are ones most commonly associated with the combination of hypokalemia and hypertension. However, the level of hypokalemia (if it occurs at all) in disease states, such as primary aldosteronism, is highly dependent on the level of sodium (Naþ) intake. In a significant number of patients with primary aldosteronism, the serum Kþ falls in the normal (oftentimes low-normal) range. Certain tests are not routinely recommended at the initial evaluation stage of the patient with newly developed hypertension. These tests that are not recommended at this stage include ECGs, because of cost; chest radiographs, because of limited sensitivity; renal imaging studies, because of limited sensitivity and specificity; and tests for plasma aldosterone/plasma renin activity. At this stage, cardiac output profiling is not recommended because of the wide variation observed in the population and questionable relevance to therapeutic planning. The initial evaluation is seldom complete at the conclusion of the initial visit. Patient counseling and education should be prominent features of the initial evaluation [4]. To determine the urgency of treatment, it is useful to establish whether there is a strong family history of end-organ disease. General well-being is difficult to assess on a first visit but vague constitutional symptoms are quite common in hypertension, as demonstrated by the fact the quality-of-life measures consistently improve when blood pressure is lowered with any of a number of antihypertensive agents [5]. A careful history documenting the use of prescribed and over-the-counter medications, including herbal products, vitamins, and nutriceuticals, is important in that several such preparations can increase blood pressure. Also, a thorough sleep history

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is essential in the newly hypertensive patient because sleep apnea and a range of other sleep disturbances are associated with the development of hypertension by the manner in which sleep architecture is distorted. Several aspects of the physical examination are fundamental to the evaluation of the newly discovered hypertensive patient. Blood pressure should be measured with an appropriately sized cuff and in both arms (the higher of the readings being used). Postural blood pressure change is best assessed by going from the lying to the standing position and should include notation of the change in heart rate with position change. A diagnosis of hypertension can be immediately established if the blood pressure is found to be extremely elevated (O180/110 mm Hg). Otherwise such a diagnosis should wait until blood pressure is found elevated on at least two occasions where white coat hypertension is highly unlikely. Once the diagnosis is made, therapy should be started with at least two agents within a matter of days. Fundoscopic examination is a part of the initial evaluation but is seldom abnormal in the early stages of hypertension. Cardiac, peripheral pulses, and abdominal examinations classically seek out evidence of vascular disease or cardiac decompensation. Periumbilical and flank bruits suggest the presence of renal artery stenosis, especially if there is a diastolic component to the bruit. Pulse palpation alone can be an unreliable physical examination sign and is best used in combination with objective measurements, such as determination of the ankle-brachial index or carotid Doppler’s, as a guide to a clinical management plan. Home blood pressure monitoring Conventional office blood pressure measurements are generally higher than home-based readings, particularly for systolic blood pressure [6,7]. Home blood pressure monitoring provides a sizeable number of readings and thus over time adds to the exactness of blood pressure determination in a given patient [7,8]. Home blood pressure monitoring is also of some value in the long-term follow-up of patients with white coat hypertension and the evaluation of treatment effect in patients with persistent hypertension [7–9]. The level of home blood pressure that best approximates a clinic blood pressure of 140/90 mm Hg is about 135/85 mm Hg. Although technical, economic, and behavioral issues have held back the widespread use of home monitoring in clinical practice, the ready availability of low-cost monitors with memory are likely to overcome these barriers. Such technologic advances are of some consequence because many patients will omit or fabricate home readings [10]. Thus, devices that have memory or printouts of the readings are recommended. The number of clinic visits may be reduced with home blood pressure monitoring, making it a potentially cost-effective means for the management of hypertensive patients. Studies have shown that adjustment of antihypertensive treatment based on home blood pressure measurements instead of office blood pressure readings leads to

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less-intensive drug treatment [11]. Although home blood pressure monitoring requires further validation, self-monitored readings are increasingly recommended as a complement to office-based readings. General guidelines Most current clinical guidelines primarily address the management of individual cardiovascular risk factors, such as hypertension, hypercholesterolemia, or diabetes. The guidelines give less emphasis on the need to collectively treat these disturbances. Accordingly, a better clinical approach to reducing cardiovascular disease risk would be based on an all-inclusive consideration of global (absolute) risk in individual patients. It would seem commonsense that global risk be used as the main determinant of who, when, and how much to treat. Accordingly, in some situations, low-risk patients with mildly elevated blood pressure levels would not be candidates for antihypertensive drug treatment whereas others at high risk but with lower blood pressure would emerge as treatment candidates [12]. The global risk approach, however, is in need of formal testing and is not consistent with the line of reasoning advanced by The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) [13]. Current guidelines recommend a goal blood pressure of 130/80 mm Hg in patients with hypertension and diabetes mellitus, chronic kidney disease (CKD), and high-risk coronary artery disease (CAD). Otherwise the level of blood pressure advised is less than 140/90 mm Hg. Need for 24-hour coverage The best long-term outcome for hypertensive patients is seen when antihypertensive therapy controls blood pressure from beginning to end of a 24-hour cycle of treatment [14]. Office-based readings are insufficient for determination of round-the-clock blood pressure control. Rather, home blood pressure monitoring is needed [14]. Drugs that work for 24 hours or longer are attractive because they minimize the impact of missed medication doses, which is not an uncommon occurrence in the general hypertensive population. In consideration of this, several antihypertensive drugs supply true 24-hour blood pressure coverage only with twice-daily dosing. The failure of a compound to consistently decrease blood pressure over 24 hours can relate to issues of drug half-life (pharmacokinetic and pharmacodynamic), biologic factors controlling whether a patient is a responder, or the drug formulation in use. Failure to maintain full effect for 24 hours subjects the patient to the full force of the next day’s early morning surge in blood pressure and an accompanying risk of early morning ischemic events [15]. The medication formulation administered is an important consideration in maintaining early morning blood pressure control, particularly as

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nighttime dosing is weighed. In considering nighttime medication dosing, clinicians should look at whether the peak medication effect overlaps with the natural overnight dip in blood pressure, increasing the likelihood of ischemic events. Alternatively, nighttime medication dosing can be of some use in increasing the likelihood of a nocturnal dip in blood pressure [16]. Blood pressure goals and the J-curve Vigorous treatment of hypertension, thereby bringing blood pressure down to levels once considered unsafe, is now recommended, particularly for patients with diabetes, CAD, or CKD. This approach has been opposed by studies that find aggressive lowering of diastolic blood pressure capable of triggering ischemic events, particularly if significant stenotic lesions exist in the coronary circulationdthe ‘‘J-curve’’ hypothesis. Many examples of the J-curve’s relationship to blood pressure, cardiovascular events, and noncardiovascular events reflect reverse causality, where underlying disease, such as poor left ventricular function, declining general health in the aged, and noncompliant arteries, is the basis for both the low blood pressure and the increased risk of both cardiovascular and noncardiovascular disease events [17]. In such cases, it would be prudent not to bring diastolic blood pressure below the low 80s mm Hg. Practically speaking, if systolic blood pressure is controlled to less than 130 mm Hg, there is marginal benefit and even the potential for risk in reducing diastolic blood pressure to less than 80 to 85 mm Hg. Alternatively, patients with wide pretreatment pulse pressures where diastolic blood pressure values are already below 80 to 85 mm Hg present a different management problem. In such patients (typically elderly) antihypertensive treatment should be intensified to prevent cardiovascular events when systolic blood pressure is not under control, at least until diastolic blood pressure reaches 55 mm Hg. However, a prudent approach is warranted in patients with concomitant CAD disease, in whom diastolic blood pressure should probably not be brought to less than 70 mm Hg [18]. Need to lower blood pressure gradually It is often recommended that blood pressure be gradually reduced to prevent abrupt and perhaps excessive reductions in organ blood flow (cerebral or coronary circulations). The rate of blood pressure reduction is rarely a problem in the young hypertensive patient, but in the older patient with long-standing hypertension, rapid blood pressure swings may be poorly tolerated because of diminished autoregulatory ability. Symptoms of cerebral hypoperfusion, such as dizziness, fatigue, and forgetfulness, may arise under such circumstances, particularly in the elderly hypertensive patient (normal cerebral autoregulation limits are typically in the 100–110 mm Hg mean arterial pressure range). Concern about an ‘‘excessive’’ blood pressure drop

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in the elderly or the otherwise vulnerable patient should not, however, be used as a reason to not seek recommended blood pressure goals within a relatively short time (weeks rather than months), since achieving quick blood pressure control offers meaningful benefits to the hypertensive patient at high cardiovascular risk [19]. Barriers to blood pressure control Barriers to blood pressure control can be classified into four categories: unavailability of care, including lack of insurance or the high cost of drugs (system issues); physician-controlled decisions about the diagnosis and treatment of hypertension (provider issues); patient nonadherence to a prescribed drug regimen or follow-up schedule (patient issues); and societal impediments to a healthy lifestyle (behavioral issues) [20]. Of these categories, provider issues may be the most underappreciated. A number of studies of hypertension control suggest that variation in treatment thresholds among individual physicians is the foremost factor in determining hypertension control rates. The rate at which physicians adopt recommended changes based on evidence-based findings can be quite slow and has been properly described as ‘‘clinical inertia’’ [21]. Professional organizations and regulatory agencies have implemented educational initiatives and quality improvement measures as well as pay-for-performance programs to improve hypertension control rates. Findings from such a pay-for-performance scheme in the United Kingdom suggest that generous financial incentives are, in fact, associated with high levels of achievement for aspects of care for hypertensive patients. However, the broad overall impact of such monetary incentives remains unclear and such gains may be attributable to other nonfinancial quality-improvement initiatives [22]. Lifestyle modifications Lifestyle modifications should address the overall risk of cardiovascular disease as they are implemented to change the pattern of blood pressure. Cardiovascular risk factors commonly cluster such that increased blood pressure is commonly seen in tandem with higher levels of cholesterol, triglycerides, and glucose. Such strategies should consist of preventing and managing obesity; requiring a suitable amount of aerobic physical exercise; avoiding diets high in Naþ, total fat, or cholesterol; maintaining recommended dietary intakes for Kþ, calcium, and magnesium; controlling alcohol consumption; and discontinuing cigarette smoking. The blood pressure reduction with any of these strategies ranges from 2 to 20 mm Hg with the most significant changes being observed with substantial weight loss and the implementation of an eating plan that restricts Naþ and encourages Kþ intake from nutritional foodstuffs. The latter is popularly achieved with the so-called Dietary Approaches to Stop Hypertension (DASH) eating

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plan, which relies on a diet high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein but with substantial amount of plant protein from legumes and nuts. This diet substantially reduces both systolic and diastolic blood pressure among hypertensive and normotensive individuals [23] and, as recently shown in women (based on a score that reflects adherence to the DASH-style diet), lowers the risk of coronary heart disease and stroke among middle-aged women during over 2 decades of follow-up [24]. Group efficacy considerations Most orally administered drugs lower blood pressure by 10% to 15% in the majority of patients with stage 1 or 2 hypertension and appear to have similar efficacy. For example, the Treatment Of Mild Hypertension Study, in which five drug classes (diuretic [chlorthalidone], b-blocker [acebutolol], peripheral a-blocker [doxazosin], calcium channel blocker [CCB] [amlodipine], and angiotensin-converting enzyme [ACE] inhibitor [enalapril]) were compared, showed a blood pressure–lowering response over 4 years that was virtually equal among the drugs tested [25]. Despite similar efficacy among classes of antihypertensive agents, individual patient responses may vary, depending in part on patient-specific determinants, such as ethnicity and age. For example, in the Veterans Administration Cooperative Trial, 1292 patients were randomly administered drugs from one of six antihypertensive medication classes (b-blocker [atenolol], ACE inhibitor [captopril], central a-agonist [clonidine], CCB [diltiazem], peripheral a-blocker [prazosin], or diuretic [hydrochlorothiazide (HCTZ)]). The CCB diltiazem worked best in blacks, the ACE inhibitor captopril worked best in young white males, and the b-blocker atenolol worked best in older white males [26]. The importance of securing hard end-point data for individual antihypertensive medications (and presumably medication classes) cannot be overstated. For example, a breakdown of the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that, despite similar blood pressure reduction for both chlorthalidoneand doxazosin-based regimens, doxazosin use was marked by a twofold higher cardiovascular disease event rate, primarily in the form of more frequent episodes of heart failure [27]. Such data, however, were confounded by study design issues particular to ALLHAT and do not support a blanket censure of this particular drug class, which remains an excellent drug class as add-on therapy in the patient with resistant hypertension [28]. The blood pressure–reducing effect of an antihypertensive medication is important only to the extent that it is followed by a measurable decrease in morbidity and mortality rates. Such hard end-point data are available for diuretics, ACE inhibitors, CCBs, and, to a much lesser degree, b-blockers [27,29–31]. An overview of placebo-controlled trials of ACE

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inhibitors showed that with only a modest reduction in blood pressure, these agents decreased the risk of stroke, coronary heart disease, and major cardiovascular disease events by 20% to 30% among high-risk patients chosen on the basis of cardiovascular disease or diabetes mellitus [29]. A similar overview of placebo-controlled trials with CCBs showed that these agents reduced the risks of stroke and major cardiovascular disease events by 30% to 40%. It has also been shown that total major cardiovascular disease events are reduced to a comparable extent in individuals with and without diabetes by regimens based on ACE inhibitors, CCBs, angiotensin-receptor blockers (ARBs), and diuretics/b-blockers. Thus, treatment with any commonly used regimen reduces the risk of total major cardiovascular disease events, with larger reductions in blood pressure producing larger reductions in risk [30]. This latter observation suggests that the initial drug choice is of token importance and that better blood pressure control is the primary determinant of superior outcomes [32]. Choice of drugs There are many drug options for the pharmacologic management of hypertension. The contemporary approach, suggested by JNC-7, recommends a thiazide-type diuretic as the first medication to be used in most stage 1 hypertensives without compelling indications for other drug therapy. In JNC-7, an ACE inhibitor, an ARB, a b-blocker, and a CCB were viewed as acceptable alternative therapies, particularly in the setting of compelling indications, such as heart failure, post–myocardial infarction, high CAD risk, diabetes, CKD, and recurrent stroke [13]. Countless opinions exist on how to choose the best first drug when beginning antihypertensive therapy. The practitioner’s selection of a drug to treat hypertension is most often based on the perception of its efficacy in lowering blood pressure and the likelihood of compliance-limiting side effects. In fact, efficacy does not differ meaningfully among the available drug classes. Thus, a ‘‘new start’’ antihypertensive should be based on the phenotypic characteristics of the patient together with those concomitant diseases that are present. An older, heavyset black male will ‘‘respond’’ better to diuretic or CCB monotherapy than to a b-blocker or an ACE inhibitor. However, this is not an all-or-none phenomenon with many blacks being reasonably responsive to an ACE inhibitor or an ARB [33]. The elderly respond equally well to the majority of the available drug classes with the possible exception of b-blockers [34]. Women and men respond equally well to most medication classes with the possible exception of CCBs, which produce greater blood pressure reductions in women than in men on what appears to be a pharmacokinetic basis [35]. The presence of concomitant medical conditions should bear on the manner in which hypertension is treated. For example, a patient with symptomatic CAD and hypertension or migraine headaches may benefit doubly from

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a treatment plan that includes either a b-blocker or a CCB. A logical choice in an elderly male with benign prostatic hyperplasia (BPH) and difficult-totreat hypertension would be a peripheral a-blocker in that these compounds diminish the symptoms of BPH while also effectively reducing blood pressure, particularly when added to multidrug antihypertensive regimens [28,36]. An ACE inhibitor or ARB would be an appropriate choice in a patient with hypertension, CKD, and proteinuria in that these compounds decrease urinary protein excretion and therein (amongst other mechanisms) the rate of CKD progression [37]. Conversely, antihypertensive medications may adversely affect concomitant disease states (eg, high-dose thiazide or loop diuretic therapy in patients with gout). A stepped-care approach to the treatment of hypertension entails the sequenced addition of medications on a pro forma basis. This timehonored approach has used a thiazide-type diuretic or a b-blocker as first-line therapy. However, lately, b-blocker monotherapy has fallen out of favor and ACE inhibitors, ARBs, and CCBs are increasingly looked at as acceptable first-step options. A substitution therapy approach replaces one antihypertensive drug class with another and is considered if the initial drug class falls short in lowering blood pressure or is associated with serious or annoying side effects. A substitution approach to therapy is best applied to stage 1 hypertension, as a single drug is frequently sufficient for blood pressure control. In stage 2 hypertension, multidrug therapy is more frequently needed. In this situation, even if the initial drug selected is only marginally successful in reducing blood pressure, there is no need per se to switch drug classes. Rather, the stepwise addition of other complementary antihypertensive medications is a practical approach. For example, in a nonresponder to either an ACE inhibitor or an ARB, the addition of a diuretic in many instances will allow goal blood pressure to be reached. Pharmacologic principles and dosing effects Dose-response effects exist for all classes of antihypertensive drugs, but blood pressure responses to dose titration are most evident with diuretics, sympatholytics, a-blockers, and CCBs. A major consideration in the pharmacodynamic dose–response relationship for an antihypertensive medication is the extent to which blood pressure counterregulatory mechanisms are set in motion by blood pressure lowering. Acute and chronic blood pressure reduction often activates an interlinked series of mechanisms to bring blood pressure back toward previously raised values. Reflex increases in cardiac output, peripheral vasoconstriction, and salt and water retention can arise from baroreflex-mediated activation of the sympathetic and reninangiotensin-aldosterone systems. These counterregulatory responses are dose-dependent and most regularly crop up with nonspecific vasodilating drugs (eg, hydralazine or minoxidil) or diuretics.

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It can prove quite difficult to approximate the extent to which counterregulatory systems are activated with antihypertensive medications. A reliable sign of such ‘‘pseudotolerance’’ is loss of previously established blood pressure control. In that regard, a 10% to 20% increase in heart rate induced by antihypertensive medication should prompt a lowering of the dose of the provoking agent, or the addition of a pulse rate–lowering compound (eg, b–blocker), or both. Peripheral edema with an accompanying gain in weight is an easily recognizable sign of sodium retention, which oftentimes is the basis for loss of blood pressure control in a previously well controlled patient. However, a lapse in control can still occur from volume expansion even in the absence of peripheral edema. If this is suspected, diuretic therapy can be started to bring about a small weight loss in the order of 1% to 2% of body weight. If diuretic therapy has already been initiated, the dose can be increased.

Drug classes: positioning and use Diuretics: first or second line Thiazide-type diuretics are useful therapies in the treatment of hypertension either as monotherapy or when administered adjunctively (even when given in doses as low as 6.25 mg of HCTZ) [38]. Accordingly, diuretics are extremely useful add-on therapies when nondiuretic antihypertensive treatments have produced plasma volume expansion. Salt-sensitive forms of hypertension, as in the patient with diabetes or renal impairment, can be very responsive to diuretic-based regimens. In the stage 1 hypertensive, thiazide diuretics lower blood pressure as well as most other drug classes [26]. Blacks and the elderly normally respond well to diuretic therapy but not necessarily better than nonblacks or younger patients. Both efficacy and outcomes data strongly supporting the use of diuretic therapy in the elderly are available from the Systolic Hypertension in the Elderly Program (SHEP) [39] and in blacks from ALLHAT [40]. The thiazide-type diuretic used in both SHEP and ALLHAT was chlorthalidone. The extremely long half-life of 40 to 60 hours for chlorthalidone clearly differentiates it from HCTZ, which has a much shorter half-life, ranging from 3.2 to 13.1 hours. This half-life difference is associated with a more extended diuretic effect for chlorthalidone and a significant difference in blood pressure reduction as compared with HCTZ. For example, the reduction in systolic blood pressure during nighttime hours (at a fixed dose ratio of 2:1 for HCTZ [50]/chlorthalidone [25]) has been shown to be 13.5 mm Hg (1.9 mm Hg) for chlorthalidone versus 6.4 mm Hg (1.7 mm Hg) for HCTZ, a difference that is highly significant [41]. These blood pressure and existing outcomes data with chlorthalidone suggest that this compound should be used more often for patients with hypertension.

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The dose–response relationship for blood pressure reduction with a thiazide-type diuretic, such as HCTZ or chlorthalidone, is shallow-to-flat at doses exceeding 25 mg/d [42]. This relationship has some importance in that much of the negative biochemical and metabolic experience with thiazide-type diuretics is seen with the very high doses (100 to 200 mg/d of HCTZ) that were once the custom. Metabolically negative side effects, such as hypokalemia, hypomagnesemia, glucose intolerance, and hypercholesterolemia, are uncommon with low-dose diuretic therapy (eg, 12.5 to 25 mg HCTZ once daily). Thus, the carryover of metabolic fear with diuretic therapy should not deter its use [43]. In general, loop diuretics do not reduce blood pressure as well as thiazide-type compounds when given as singledrug therapy, particularly if dosed once daily. Loop diuretics are most effective as antihypertensive agents when they normalize clinically evident volume-expanded states [44]. Aldosterone receptor antagonists: second or third line Although the most extensive antihypertensive treatment experience with aldosterone receptor antagonists (ARAs) exists with spironolactone, the ARA eplerenone is used with somewhat more regularity because of a cleaner side-effect profile. The onset of action for spironolactone is characteristically slow, with a peak response at 48 hours or more after the first dose. This may relate to a requirement for several days of spironolactone dosing in order for its active metabolites to reach steady-state plasma/tissue levels. The mg-for-mg blood pressure–lowering effect of eplerenone is not equivalent to that of spironolactone. For example, the blood pressure reduction with 50 mg of spironolactone twice daily is 1.3 to 2.0 times greater than that seen with eplerenone 50 mg twice daily (or 100 mg once daily) [45]. Spironolactone (and eplerenone) has been used both with and without a thiazide-type diuretic in the treatment of hypertension and most recently as add-on therapy for resistant hypertension [46–48]. The add-on effect of spironolactone occurs within days to weeks, persists for months, and is independent of ethnicity, plasma aldosterone values, and urinary aldosterone excretion. When spironolactone (12.5–50 mg/d) was added to a regimen of a diuretic, an ACE inhibitor, or an ARB, a mean fall in blood pressure of 21(20)/10(14) mm Hg (6 weeks) and 25(20)/12(12) mm Hg (6 months) was seen [47]. The benefit of aldosterone blockade in the overall population of patients with resistant hypertension suggests that aldosterone excess (relative or absolute) may be a more widespread cause of resistant hypertension than was originally believed [46,47]. Spironolactone contains elements of the progesterone molecule and its use can be accompanied by progestogenic and antiandrogenic adverse effects, such as painful gynecomastia and other sexual side effects [46,47]. Breast symptoms are dose-dependent and can include an increase in size (occasionally unilateral), the development of nipple or breast tenderness,

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or the appearance of discrete breast masses. Gynecomastia generally corrects upon discontinuation of the drug. However, the time required for reversibility can be lengthy, particularly if significant gynecomastia is present. Gynecomastia occurs much less frequently with eplerenone, and eplerenone can be safely substituted for spironolactone in the patient with gynecomastia [49]. Hyperkalemia (O5.5 mEq/L) can also occur with ARAs whatever their use. It develops most typically in the setting of either a reduced glomerular filtration rate or concomitant therapy with an ACE inhibitor or ARB [46,49]. The duration of the Kþ-sparing effect of spironolactone may persist for several days after its discontinuation, which differentiates it from the more short-acting ARA eplerenone [49]. Angiotensin-converting enzyme inhibitors: first or second line ACE inhibitors are considered a suitable first-step option in the treatment of hypertension in a wide range of patient types. The enthusiasm for the use of ACE inhibitors goes beyond their effects on blood pressure, since they are at best comparable with other drug classes, including diuretics, ARBs, and CCBs, for blood pressure control. In that regard, ACE inhibitors reduce morbidity and mortality rates in patients with heart failure, patients with recent myocardial infarctions, and patients with proteinuric renal disease [50,51]. Response rates with ACE inhibitors range from 40% to 70% in stage 1 or 2 hypertension, with level of Naþ intake and ethnicity influencing the overall effect. As such, ACE inhibitors are less effective as monotherapy in saltsensitive, low-renin forms of hypertension (eg, black and diabetic hypertensive persons). The low-renin state seen in the elderly hypertensive differs from other low-renin forms of hypertension in reflecting senescence-related changes in the renin-angiotensin-aldosterone system and not volume expansion. Accordingly, age per se does not limit the response to ACE-inhibitor monotherapy. Results from head-to-head comparison trials support the comparable antihypertensive efficacy and tolerability of the various ACE inhibitors when given at equivalent doses. Not all patients respond to ACE inhibitor therapy, but, for those patients who do, the dose–response curve for blood pressure reduction is steep at low doses only to flatten thereafter at higher doses. Thus, multiple-dose titrations of an ACE inhibitor are seldom warranted to gain better blood pressure control. The dosing frequency for an ACE inhibitor should take into consideration the highly individualized response patterns to these drugs. In the ACE inhibitor–treated patient who does not reach goal blood pressure with monotherapy, addition of a diuretic either as sequential therapy or in the form of a fixed-dose combination notably increases the effectiveness. The rationale for combining a diuretic with an ACE inhibitor is that diuretic-induced Naþ depletion activates the renin-angiotensin-aldosterone system and shifts blood pressure to a more angiotensin-II–dependent mode

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[38]. Even modestly natriuretic doses (12.5 mg/d) of thiazide-type diuretics further reduce blood pressure when combined with an ACE inhibitor. A b-blocker can also be given together with an ACE inhibitor, although the incremental effect on blood pressure reduction is generally inconsequential. b-Blockade in this combination blunts the reactive rise in plasma renin activity that accompanies ACE inhibition. Adding a peripheral a-antagonist, such as doxazosin, to an ACE inhibitor can further reduce blood pressure, although the basis for such additivity is uncertain. The blood pressure–lowering effect of an ACE inhibitor is also significantly enhanced with the addition of either a dihydropyridine or a nondihydropyridine-type CCB. ACE inhibitor use is not accompanied by either salt and water retention or an increase in heart rate. Side effects associated with ACE inhibitors include cough, angioedema, and a distinctive form of functional renal insufficiency [52]. Cough and angioedema are class-effect phenomena with ACE inhibitors. Thus, the occurrence of either of these side effects prohibits the use of any ACE inhibitor (particularly in the case of angioedema) [53,54]. Although ACE inhibitor therapy can reduce the glomerular filtration rate, these drugs are not inherently nephrotoxic. Thus, the occurrence of functional renal insufficiency with an ACE inhibitor does not preclude a patient from ACE inhibitor therapy per se unless high-grade bilateral renal artery stenosis exists. No specific level of renal function precludes ACE inhibitor use unless significant hyperkalemia (O5.5 mEq/L) has occurred [55]. Angiotensin receptor blockers: first or second line Angiotensin receptor blockers are suitable first-step options in a diversity of patient types. However, despite the inclusion of ARBs as a first-step therapy in practically all treatment guidelines, a number of formularies still limit their use to ACE inhibitor–intolerant patients. These restrictions arise from the fact that drugs in this class are at best comparable with diuretics, b-blockers, ACE inhibitors, and CCBs for blood pressure reduction while often costing considerably more. Also, although there are labeled indications for ARB therapy in patients with heart failure, patients with diabetes with renal disease/proteinuria, and patients following post–myocardial infarction treatment, algorithms for heart failure or diabetes do not routinely favor drugs in this class over ACE inhibitors [56]. Rather, ARBs are more often viewed as effective substitutes in an ACE inhibitor–intolerant patient. Response rates with ARBs range from 40% to 70% in stage I or II hypertension with Naþ intake and ethnicity having some bearing on the overall effect. In the interpretation of clinical trial results with ARBs, the mean reduction in blood pressure (which is normally significant) should be distinguished from the number of individuals who are poor, average, and excellent responders, which varies considerably in different studies. There are no predictors of the magnitude of the blood pressure reduction in response to an ARB. Certain patient groups are acknowledged as being

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generally more responsive (high-renin and young hypertensives) or less responsive (low-renin, salt-sensitive, volume-expanded individuals, such as the diabetic and the black hypertensive) to ARB monotherapy. However, the response to ARB monotherapy can be highly variable in black and diabetic patients, with some individuals in these groups experiencing significant reductions in blood pressure [57]. For the most part, the pharmacologic differences among the several compounds in this class are of little practical consequence including the ability of individual compounds to prevent new-onset diabetes in at-risk patients [58]. At high-end doses for drugs in this class, the excess of drug all but eliminates any compound-specific difference in receptor occupancy or elimination halflife. ARBs are pulse-rate neutral and do not trigger salt and water retention or sympathetic nervous system activation. They have a steep dose–response curve for blood pressure reduction at low- to mid-range doses; thereafter, the dose–response relationship curve is nearly flat, obviating multiple dose-titrations. Increasing the dose of an ARB typically does not add to its peak effect, but can prolong the response. All ARBs are indicated for once-daily dosing. Despite this, the effectiveness of an ARB may wane at the end of a dose interval, thereby necessitating a second dosing. This applies to all marketed ARBs with the exception of losartan, which does not reduce blood pressure as effectively as longeracting ARBs. The blood pressure reduction with an ARB can be improved with the addition of a diuretic given either as sequential therapy or as fixeddose combination therapy. Based on experience with ACE inhibitors, it can be expected that addition of a b-blocker to an ARB would have a minimal additional effect on blood pressure unless a significant decrease in pulse rate occurs and, by this, a blood pressure drop. Alternatively, adding a peripheral a-antagonist, a CCB, or an ARA to an ARB (with or without a diuretic) will incrementally reduce blood pressure [57]. ACE inhibitors and ARBs can be administered together, although only a modest additional blood pressure reduction should be expected [59]. In the patient with heart failure or proteinuria, additional benefits, including a reduction in proteinuria and an improvement in heart failure symptomatology, are derived from such combination therapy [60,61]. More recently, the ARB telmisartan was shown to be equivalent to the ACE inhibitor ramipril in patients with vascular disease or high-risk diabetes. The combination of the two drug classes was associated with more adverse events without an increase in benefit [62]. The increased likelihood of side effects with such combination therapy requires that such patients be more carefully followed [61,62]. Side effects are uncommon with ARBs. Cough is not seen with ARB therapy and angioedema is a rare occurrence [63]. An episode of functional renal insufficiency with an ACE inhibitor does not rule out future therapy with an ARB, unless high-grade bilateral renal artery stenosis exists. ARBs can be safely used in patients with moderate to severely advanced stages of CKD with hyperkalemia being less likely than is the case for ACE inhibitors [64].

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Calcium channel blockers: first or second line CCBs are a heterogeneous group of compounds, with distinctive structures and pharmacologic characteristics. The two major classes of CCBs are dihydropyridines and nondihydropyridines. Nondihydropyridines include verapamil and diltiazem. Verapamil and diltiazem reduce heart rate and cardiac contractility. Dihydropyridines can increase heart rate in a dose-dependent manner and have little, if any, effect on contractility [65]. The availability of CCBs in sustained-release delivery systems has both improved tolerance and simplified the use of these drugs. Heart failure occurs more commonly with CCB-based regimens than with regimens based on ACE inhibitors, diuretics, or b-blockers. Other than heart failure, however, there are no significant differences in total major cardiovascular events between regimens based on ACE inhibitors, diuretics, or b-blockers and regimens based on CCBs [29]. All patient subtypes are, to some degree, responsive to CCB monotherapy, including elderly and lowrenin, salt-sensitive, diabetic, and black hypertensive patients. CCBs have a steep dose–response curve for blood pressure reduction, which simplifies their use since there are no reliable predictors of the magnitude of the blood pressure reduction with a CCB. The degree to which blood pressure drops with a CCB is a function of the pretherapy blood pressure. Thus, the higher the blood pressure is when therapy begins, the greater the fall in blood pressure will be. Dihydropyridine CCBs can dose-dependently increase heart rate and, in so doing, diminish the accompanying blood pressure–lowering effect of these drugs. CCBs have a mild natriuretic effect, which explains why their blood pressure–lowering effect is independent of Naþ intake. First-step CCB therapy is of particular use if CAD, intermittent claudication, migraine, or Raynaud’s phenomenon coexist with hypertension [66]. If a CCB is required for blood pressure control in the presence of systolic dysfunction, a dihydropyridine CCB is preferred because nondihydropyridine CCBs, such as diltiazem and verapamil, have negative inotropic effects. Dihydropyridine CCBs also should not be used as monotherapy in hypertensive patients with CKD and proteinuria [67]. Verapamil or diltiazem are preferred monotherapies in the CKD patient with proteinuria. The negative renal effects of dihydropyridine CCB monotherapy in the CKD patient with proteinuria are probably reduced with the concurrent administration of an ACE inhibitor or an ARB [68]. Dihydropyridine CCBs are also useful as add-on therapy being effectively combined with b-blockers, ACE inhibitors, ARBs, or peripheral a-antagonists [38]. Nondihydropyridine CCBs can also be combined with these same drug classes, but their use with b-blockers is not routinely recommended. Diuretics can be combined with CCBs. However, the response therein is probably specific to the type of diuretic used and is not per se additive. Fixed-dose combination products containing the CCB amlodipine and an ACE inhibitor or an ARB are available (eg, benazepril–amlodipine,

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felodipine–enalapril, or trandolapril–verapamil or amlodipine–valsartan, and amlodipine–olmesartan) [38,69]. Most CCB-related side effects are class specific, with the exception of constipation and atrioventricular block, which occur most commonly with verapamil. CCB use, in general, can be associated with such side effects as polyuria, gastroesophageal reflux, or gingival hyperplasia. However, peripheral edema is the side effect that has the greatest impact on the use of these compounds. CCB-related edema is positional in nature and, as such, improves when a patient goes from the standing to lying position and typically disappears overnight only to recur the next day when a patient is more upright. Additional strategies for treating CCB-related edema include switching CCB classes (dihydropyridine to nondihydropyridine); reducing dosage; giving the medication later in the day; and adding a venodilator, such as a nitrate, an ACE inhibitor, or an ARB, to the treatment regimen. Diuretics may improve CCB-related edema, but at the expense of a reduction in plasma volume [70]. b-Blockers: second or third line The efficacy and side effect profile of b-blockers are both compound- and delivery system–dependent. b-Blockers reduce blood pressure without an accompanying decrease in peripheral vascular resistance and do so while maintaining a relatively flat dose–response curve. Cardioselective b-blockers are specific for the b1-receptor but only at low doses. One benefit of b1selectivity is a lower risk of paradoxical pressor effects during major stresses when compared with nonselective b-blockade. Nonselective b-blockade may be preferred in a hypertensive patient if concomitant illnesses, such as essential tremor or migraine, are present. b-Blockers have limited usefulness as monotherapy in certain hypertensive patient subsets, including blacks, the elderly, and those with diabetes. This limited utility together with the observed poor cardiovascular outcomes with b-blockers clearly has shifted these compounds to second- or third-tier status other than for select circumstances [71,72]. First-step b-blocker therapy is indicated for patients with a hyperkinetic form of hypertension, as in those with a heightened cardiac awareness profile or somatic manifestations of anxiety, such as tremor, sweating, and tachycardia [31,73,74]. b-Blockers are also complementary agents in subjects with tachycardic responses to drugs, such as dihydropyridine CCBs, or vasodilators, such as hydralazine or minoxidil. b-Blockers also have important primary roles in the treatment of angina pectoris, systolic and diastolic forms of heart failure, and in the post–myocardial infarction circumstance. When used for secondary prevention in patients after an acute myocardial infarction, cardioselective agents without intrinsic sympathomimetic activity seem to offer the best protection. Over the past decade, national and international guidelines have proposed that b-blockers be used on an equal footing with diuretics as initial

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therapy of hypertension. This preferred status was based on evidence documenting a reduction in morbidity and mortality rates with b-blocker therapy in hypertension. However, current review of these data finds scant evidence that b-blocker–based therapy, despite lowering blood pressure, reduces the risk of heart attacks or strokes. Much of the debate on the proper place that b-blockers should have in hypertension management has focused on how effective (or ineffective) the cardioselective b-blocker atenolol is both in the treatment of hypertension and in providing specific outcomes benefits. The demise of the b-blocker drug class (based on atenolol-related data) is premature and this drug class (and, in particular, the vasodilating b-blockers) still remains an effective therapy choice. b-Blocker–related side effects are not nearly as worrisome as once was believed, particularly if doses are maintained within reasonable boundaries. Higher doses of b-blockers can provoke salt and water retention, making diuretics a necessary adjunct therapy. Sudden discontinuation of a b-blocker, particularly when being given in high doses, may be followed by withdrawal symptoms that are adrenergically mediated. Therefore, a stepwise reduction in dose is advised, particularly in patients with active CAD. b-Blockers administered with the nondihydropyridine CCBs verapamil or diltiazem can cause sharp reductions in heart rate, which means that this combination be used with caution. Peripheral al-adrenergic–receptor blockers: third or fourth line al-Adrenergic–blocking drugs (al-blockers) reduce blood pressure with effectiveness comparable to that for other major drug classes. al-Blockers have also proven effective therapies for BPH-related symptoms. al-Blockers lower upright systolic and diastolic blood pressures more so than supine values [36]. a1-Blockers further reduce blood pressure when combined with nearly all antihypertensive drug classes and represents the only drug class that both improves lipid profiles and reduces insulin resistance. However, the latter two properties are not associated with a specific outcomes benefit and a modest decline in the use of a1-blockers has occurred coincident to the early termination of the doxazosin treatment arm in ALLHAT [27]. High-end doses of an a1-blocker can result in Naþ retention, volume expansion, and an attenuation of their blood pressure–lowering effect. Thus, diuretic therapy can be a useful add-on therapy with drugs in this class. Dizziness, headache, and drowsiness are frequent side effects with a1-blockers. In addition, orthostatic and first-dose hypotension can occur with these compounds, particularly in volume-contracted patients. Central a-agonists: third or fourth line Central a-agonists have a lengthy history in the treatment of hypertension. However, bothersome side effects have curtailed use of these compounds. Clonidine is the most commonly prescribed member of this class.

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A small dose of clonidine (0.1 to 0.2 mg twice daily) adds to the blood pressure–lowering effect of most other agents and can be reliably used in this way. Oral clonidine also has become a mainstay of therapy for hypertensive urgencies because of its ease of use and relative safety. Also, oral and transdermal clonidine transdermal clonidine have found alternative uses in the areas of smoking cessation, posttraumatic stress disorder, postmenopausal hot flashes, and alcohol and opiate withdrawal syndromes. Clonidine is available in a transdermal delivery system that has distinct therapeutic advantages but is limited in its use by issues related to cost and skin irritation. Transdermal clonidine is particularly useful in the management of the labile hypertensive patient, the hospitalized patient who cannot take medications by mouth, and the patient subject to early morning blood pressure surges. At equivalent doses, transdermal clonidine is more apt to precipitate salt and water retention than is the case with oral clonidine [75]. Dose titration of clonidine beyond 0.4 mg daily is frequently followed by compliance-limiting side effects, including fatigue, sleepiness, and decreased salivary flow (dry mouth). Dose escalation of clonidine often brings on salt and water retention. Thus, diuretic add-on therapy often aids the blood pressure–lowering effects of compounds in this class. Rebound hypertension occurs in some patients receiving oral clonidine if the drug is abruptly terminated. Patients particularly vulnerable to rebound hypertension are those with excessive adrenergic tone, individuals receiving high doses of clonidine, and those receiving concomitant b-blocker therapy that is continued as clonidine is discontinued. Rebound hypertension in susceptible patients can be avoided by frequent oral dosing of clonidine (three or four times daily) or by employing a transdermal delivery system. Combined a- and b-adrenergic–receptor blockers: third or fourth line Drugs in the class of combined a- and b-adrenergic–receptor blockers are nonselective b-blockers without intrinsic sympathomimetic activity and include labetalol and carvedilol. These compounds reduce peripheral resistance even with their b-blocking effect exceeding their a-blocking capacity. Compounds in this class have generally been reserved for the complicated hypertensive patient when an antihypertensive effect beyond b-blockade is sought. Intravenous labetalol has been effectively used to treat hypertensive emergencies. Carvedilol has been studied more extensively than labetalol from an outcomes perspective. It has also been shown to have a less adverse effect on glycemic control and to reduce urinary protein excretion more than metoprolol in hypertensive diabetic patients [76].

Step-down therapy The number and dosage of antihypertensive medications needed should be periodically re-examined if hypertension has been effectively controlled

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for at least 1 year. When a reduction in medications is being considered, clinicians should be sure therapies are stepped down in a deliberate yet progressive manner. Withdrawal from antihypertensive medication is most likely to be successful in patients with well-controlled hypertension who have been recently (within 5 years) diagnosed or treated, and who continue to adhere to lifestyle interventions involving weight loss and reduction in dietary Naþ intake.

Choice of drugs: first, second, and beyond A number of algorithms have been developed that offer straightforward guidelines for the treatment of hypertension. Treatment guidelines are most useful if a population-based approach to therapy is desired. Such guidelines are somewhat less useful for choosing the best first drug for an individual patient because each patient should receive customized therapy whenever possible. The findings from many clinical trials point to multidrug therapy being needed to reach goal blood pressure, particularly if goal systolic blood pressure values are less than 130 mm Hg. In addition, guidelines now suggest that, if blood pressure is greater than 20/10 mm Hg above goal, therapy should be initiated with two drugs. A practical approach to multidrug therapy is to use fixed-dose antihypertensive combinations as an alternative to the sequenced addition of two or three drugs [13].

Summary The treatment of the patient with hypertension on an outpatient basis can be approached methodically. This requires an understanding of the various antihypertensive medication classes and how they work together in various combination regimens. Engaging patients as active partners in their own health care is an important element to the management of the patient with hypertension. This is particularly the case relative to home blood pressure monitoring.

References [1] Burt VL, Cutler JA, Higgins M, et al. Trends in prevalence, awareness, treatment, and control of hypertension in the adult U.S. population: data from the health examination surveys, 1960–1991. Hypertension 1995;26:60–9. [2] Patel BV, Remigio-Baker RA, Mehta D, et al. Effects of initial antihypertensive drug class on patient persistence and compliance in a usual-care setting in the United States. J Clin Hypertens (Greenwich) 2007;9:692–700. [3] Cushman WC, Reda DJ, Perry HM, et al. Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med 2000;160:825–31.

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[4] Izzo JL, Sica DA, Black HR. Initial workup of adults with hypertension. In: Izzo JL, Sica DA, Black HR, editors. Hypertension primer. 4th edition. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 343–7. [5] Hansson L, Smith DH, Reeves R, et al. Headache in mild-to-moderate hypertension and its reduction by irbesartan therapy. Arch Intern Med 2000;160:1654–8. [6] Verberk WJ, Kroon AA, Kessels AG, et al. Home blood pressure measurement: a systematic review. J Am Coll Cardiol 2005;46:743–51. [7] Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 2005; 111:697–716. [8] O’Brien E, Asmar R, Beilin L, et al. European Society of Hypertension Working Group on Blood Pressure Monitoring. Practice guidelines of the European Society of Hypertension for Clinic, Ambulatory and Self Blood Pressure Measurement. J Hypertens 2005;23:697–701. [9] Staessen JA, Den Hond E, Celis H, et al. Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) trial investigators. Antihypertensive treatment based on blood pressure measurement at home or in the physician’s office: a randomized controlled trial. J Am Med Assoc 2004;291:955–64. [10] Mengden T, Hernandez Medina RM, et al. Reliability of reporting self-measured blood pressure values by hypertensive patients. Am J Hypertens 1998;11:1413–7. [11] Verberk WJ, Kroon AA, Lenders JW, et al. Home versus office measurement, reduction of unnecessary treatment study investigators. Self-measurement of blood pressure at home reduces the need for antihypertensive drugs: a randomized, controlled trial. Hypertension 2007;50:1019–25. [12] Giles TD, Berk BC, Black HR, et al. Expanding the definition and classification of hypertension. J Clin Hypertens (Greenwich) 2005;7:505–12. [13] Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. J Am Med Assoc 2003;289: 2560–72. [14] White WB. Importance of blood pressure control over a 24-hour period. J Manag Care Pharm 2007;13(8 Suppl B):34–9. [15] Patel PV, Wong JL, Arora R. The morning blood pressure surge: therapeutic implications. J Clin Hypertens (Greenwich) 2008;10:140–5. [16] Hermida RC, Ayala DE, Ferna´ndez JR, et al. Comparison of the efficacy of morning versus evening administration of telmisartan in essential hypertension. Hypertension 2007;50: 715–22. [17] Protogerou AD, Safar ME, Iaria P, et al. Diastolic blood pressure and mortality in the elderly with cardiovascular disease. Hypertension 2007;50:172–80. [18] Fagard RH, Staessen JA, Thijs L, et al. On-treatment diastolic blood pressure and prognosis in systolic hypertension. Arch Intern Med 2007;167:1884–91. [19] Jamerson KA, Basile J. Prompt, aggressive BP lowering in high-risk patients. J Clin Hypertens (Greenwich) 2008;10(1 Suppl 1):40–8. [20] Izzo JL, Sica DA, Black HR. Barriers to blood pressure control. In: Izzo JL, Sica DA, Black HR, editors. Hypertension primer. 4th edition. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 418–20. [21] Rose AJ, Shimada SL, Rothendler JA, et al. The accuracy of clinician perceptions of ‘‘usual’’ blood pressure control. J Gen Intern Med 2008;23:180–3. [22] Doran T, Fullwood C. Pay for performance: is it the best way to improve control of hypertension? Curr Hypertens Rep 2007;9:360–7.

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[23] Sacks FM, Svetkey LP, Vollmer WM, et al. DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med 2001;344:3–10. [24] Fung TT, Chiuva SE, McCullough ML, et al. Adherence to a DASH-style diet and risk of coronary heart disease and stroke in women. Arch Intern Med 2008;168:713–20. [25] Neaton JD, Grimm JH Jr, Prineas RJ, et al. The treatment of mild hypertension study: final results. J Am Med Assoc 1993;270:713–24. [26] Materson BJ, Reda DJ, Cushman WC, et al. Department of Veterans Affairs single-drug therapy of hypertension study: revised figures and new data. Am J Hypertens 1995;8: 189–92. [27] Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Hypertension 2003;42:239–46. [28] Wykretowicz A, Guzik P, Wysocki H. Doxazosin in the current treatment of hypertension. Expert Opin Pharmacother 2008;9:625–33. [29] Turnbull F. Blood pressure lowering treatment trialists’ collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–35. [30] Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure–lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005;165:1410–9. [31] Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–53. [32] Sica DA. Do pleiotropic effects of antihypertensive medications exist or is it all about the blood pressure? Current Cardiovascular Risk Reports 2007;1:198–203. [33] Sehgal AR. Overlap between whites and blacks in response to antihypertensive drugsHypertension 2004;43:566–72. [34] Messerli FH, Grossman E, Goldbourt U. Are b-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. J Am Med Assoc 1998;279:1903–7. [35] White WB, Johnson MF, Black HR, et al. Gender and age effects on the ambulatory blood pressure and heart rate responses to antihypertensive therapy. Am J Hypertens 2001;14: 1239–47. [36] Sica DA. Alpha1-adrenergic blockers: current usage considerations. J Clin Hypertens (Greenwich) 2005;7:757–62. [37] Sica DA. Angiotensin-converting enzyme inhibitors. In: Battegay E, Lip G, Bakris G, editors. Handbook of hypertension. 1st edition. New York: Marcel Decker, Inc.; 2005. p. 475–98. [38] Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: The cycle repeats. Drugs 2002;62:243–62. [39] SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the systolic hypertension in the elderly program (SHEP). J Am Med Assoc 1991;265:3255–64. [40] Wright JT Jr, Dunn JK, Cutler JA, et al. Outcomes in hypertensive black and non-black patients treated with chlorthalidone, amlodipine, and lisinopril. J Am Med Assoc 2005; 293:1595–608. [41] Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006; 47:352–8. [42] Flack JM, Cushman WC. Evidence for the efficacy of low-dose diuretic monotherapy. Am J Med 1996;101:53S–60S. [43] Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension 2006;48:219–24.

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[44] Sica DA, Gehr TWB. Diuretic use in stage 5 chronic kidney disease and end-stage renal disease. Curr Opin Nephrol Hypertens 2003;12:483–90. [45] Weinberger MH, Roniker B, Krause SL, et al. A selective aldosterone blocker, in mild-tomoderate hypertension. Am J Hypertens 2002;15:709–16. [46] Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49:839–45. [47] Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003;16:925–30. [48] Menard J. The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol 2004;217:45–52. [49] Sica DA. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev 2005;10:23–9. [50] Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adultdsummary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2005;112:1825–52. [51] Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43(5 Suppl 1):S1–290. [52] Schoolwerth A, Sica DA, Ballermann BJ, et al. Renal considerations in angiotensin converting enzyme inhibitor therapy. A statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation 2001;104:1985–91. [53] Vleeming W, van Amsterdam JG, Stricker BH, et al. ACE inhibitor–induced angioedema: incidence, prevention and management. Drug Saf 1998;18:171–88. [54] Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med 1992;117:234–42. [55] Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131–40. [56] Flaa A, Aksnes TA, Strand A, et al. Complications of hypertension and the role of angiotensin receptor blockers in hypertension trials. Expert Rev Cardiovasc Ther 2007;5:451–61. [57] Sica DA. Pharmacotherapy reviewdpart 2. Angiotensin-receptor blockers. J Clin Hypertens (Greenwich) 2005;7:681–4. [58] Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006;24:3–10. [59] Doulton TW, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 2005;45:880–6. [60] Kunz R, Friedrich C, Wolbers M, et al. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148:30–48. [61] Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Card Fail 2008;14:181–8. [62] ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–59. [63] Sica DA, Black HR. Current concepts of pharmacotherapy in hypertension: ACE inhibitor– related angioedema: Can angiotensin-receptor blockers be safely used? J Clin Hypertens (Greenwich) 2002;4:375–80. [64] Bakris GL, Siomos M, Richardson D, et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. Kidney Int 2000;58:2084–92.

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[65] Sica DA. Calcium channel blockers. J Clin Hypertens 2006;8:53–6. [66] Gradman AH. Treatment of hypertension with felodipine in patients with concomitant diseases. Clin Cardiol 1993;16:294–301. [67] Agodoa LY, Appel L, Bakris G, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. J Am Med Assoc 2001;285: 2719–28. [68] Segura J, Garcı´ a-Donaire JA, Ruilope LM. Are differences in calcium antagonists relevant across all stages of nephropathy or only proteinuric nephropathy? Curr Opin Nephrol Hypertens 2007;16:422–6. [69] Bakris GL. Combined therapy with a calcium channel blocker and an angiotensin II type 1 receptor blocker. J Clin Hypertens (Greenwich) 2008;10(1 Suppl 1):27–32. [70] Sica DA. Calcium-channel blocker peripheral edemadCan it be resolved? J Clin Hypertens (Greenwich) 2003;5:291–4, 297. [71] Goldstein S. b-Blockers in hypertensive and coronary heart disease. Arch Intern Med 1996; 156:1267–76. [72] Fonarow GC. Practical considerations of beta-blockade in the management of the post– myocardial infarction patient. Am Heart J 2005;149:984–93. [73] Sica DA. Old antihypertensive agentsddiuretics and b-blockersdDo we know how and in whom they lower blood pressure. Curr Hypertens Rep 1999;1:296–304. [74] Carlberg B, Samuelson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684–9. [75] Sica DA, Grubbs R. Transdermal clonidine: therapeutic considerations. J Clin Hypertens (Greenwich) 2005;7:558–62. [76] Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. J Am Med Assoc 2004;292:2227–36.

Prim Care Clin Office Pract 35 (2008) 475–487

Hypertensive Crises Christopher J. Hebert, MD*, Donald G. Vidt, MD Department of Nephrology and Hypertension, Cleveland Clinic, Suite A51, 9500 Euclid Avenue, Cleveland, OH 44195, USA

Hypertension is the most common reason for a physician office visit in the United States [1]. The primary care physician should therefore expect to see the occasional patient with very elevated blood pressure, defined as greater than 180/110 mm Hg. Expedited triage of such patients is necessary to identify the minority of patients that would benefit from acute reduction in blood pressure. Hypertensive crises are those situations in which markedly elevated blood pressure is accompanied by progressive or impending acute target organ damage. The discussion that follows addresses the assessment, treatment, and follow-up care for patients with very elevated blood pressure, with an emphasis on hypertensive crises. Definitions Patients presenting with very high blood pressuredblood pressure greater than 180/110 mm Hgdshould be triaged into one of three mutually exclusive groups. 1. Severe hypertension is present when blood pressure exceeds 180/110 mm Hg in the absence of symptoms beyond mild or moderate headache, and without evidence of acute target organ damage. 2. Hypertensive urgency is present when blood pressure exceeds 180/ 110 mm Hg in the presence of significant symptoms, such as severe headache or dyspnea, but no or only minimal acute target organ damage. 3. Hypertensive emergency is present when very high blood pressure (often O220/140 mm Hg) is accompanied by evidence of life-threatening organ dysfunction. Box 1 lists the important causes of hypertensive emergencies.

* Corresponding author. E-mail address: [email protected] (C.J. Hebert). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.05.001 primarycare.theclinics.com

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Box 1. Examples of hypertensive emergencies Acute ischemic or hemorrhagic stroke Subarachnoid hemorrhage Hypertensive encephalopathy Acute myocardial ischemia/infarction Acute heart failure Acute aortic dissection Eclampsia Head trauma Catecholamine excess states Beta-blocker or clonidine withdrawal Cocaine, phencyclidine hydrochloride use Pheochromocytoma crisis Hemorrhage Postsurgical Severe epistaxis

The term hypertensive crisis is used to indicate either a hypertensive urgency or emergency. There are two older terms that are notable. Malignant hypertension represents markedly elevated blood pressure accompanied by papilledema (grade 4 retinopathy). Accelerated hypertension is considered present if markedly elevated blood pressure is accompanied by grade 3 retinopathy, but no papilledema. However, the three numbered terms above usually suffice for the description of all clinical scenarios involving very high blood pressure. Epidemiology Among the 65 million Americans with hypertension, the minority have controlled blood pressure, with estimates falling between 38% and 44% [1,2]. Hypertensive crises, however, occur in less than 1% of individuals with hypertension [3]. Although crises are infrequent, very elevated blood pressure is a common clinical scenario facing the physician. In the United States, more that 250,000 emergency department visits in 2005 were attributed to the diagnosis of hypertension (International Classification of Diseases, Ninth Revision [ICD9] diagnoses 401.0, 401.1, 401.9), with 14% resulting in hospital admission [4]. Some have suggested that hospitalization for hypertensive emergency reflects upon the quality of ambulatory care (ie, an ambulatory care– sensitive condition) [5]. There are two ways in which an emergency department evaluation might indicate poor-quality ambulatory care. First, the treating physician may have failed to achieve good blood pressure control,

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resulting in less effective care [6]. Secondly, a patient with very elevated blood pressure may have been referred to the emergency department when office management was possible, making care less efficient. With high effectiveness and high efficiency being two key aims of high quality care [6], failure to achieve good blood pressure control and inappropriate referral undermine efforts to streamline and improve health care. An appropriate assessment of patients with very elevated blood pressure will identify the few patients requiring admission and acute reduction in blood pressure among the many who require initiation of oral medication on an outpatient basis and follow-up care. Bender and colleagues [7] studied 50 patients who presented to an emergency department and found that the most common reason precipitating the crisis was running out of medication. Furthermore, the average cost was $1543 per visit, which underscores the importance of effective primary care. Particularly common is rebound hypertension after abrupt discontinuation of clonidine or a beta-blocker [8]. This rebound hypertension is thought to be due to an acute increase in sympathetic outflow. Assessment A timely and focused history, physical examination, and select testing is important in the initial assessment of the patient with very elevated blood pressure. History The history should be completed in a timely manner and capture several key pieces of information. The physician should assess the duration and severity of hypertension. The relevant symptoms to address include headache, chest pain, dyspnea, edema, acute fatigue, weakness, epistaxis, seizure, or change in level of consciousness. Such symptoms as tachycardia, diaphoresis, and tremor may suggest pheochromocytoma, and thinning of skin and weight gain may suggest Cushing syndrome. Any history of comorbid conditions or end organ damage is important, such as left ventricular hypertrophy, chronic kidney disease, or prior stroke or myocardial infarction. Direct questioning regarding adherence to any prescribed antihypertensive medications is necessary, as well as recent use of such medications as oral contraceptives, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs, cyclosporine, stimulant/anorectic agents, and prednisone. The patient should be questioned for use of alcohol as well as recreational drugs, particularly cocaine, amphetamines, and phencyclidine hydrochloride. Physical examination The measurement of blood pressure should be performed with proper technique and, in the setting of diminished pedal pulses, should include

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both arms and at least one leg measurement. A fundus examination should be performed to assess for papilledema, hemorrhages, and exudates. A careful cardiovascular examination should include assessment of the jugular venous pulse, auscultation for abdomenal bruits, and assessment of peripheral pulses. A lung examination and assessment for dependent edema should be performed to estimate volume status. Finally, a neurologic examination, including assessment of mental status, is important. Testing In the emergency department setting, a limited but expeditious battery of tests should include a chemistry panel, urinalysis with microscopic examination of the sediment, and ECG. A chest radiograph is important if there is a suspicion of heart failure or pulmonary disease. A CT scan of the head is indicated if history or examination suggests a central nervous system disorder. In the office setting or with less severe elevations of blood pressure, clinical judgment should guide testing, but in all cases a careful history and examination are critical. In practice, emergency department evaluations often are lacking. For example, Karras and colleagues [9] observed care for patients with severely elevated blood pressure at four academic emergency departments. Serum chemistry was performed in only 73% of cases, ECG in 53%, and urinalysis in 43%. The goal should be a timely evaluation that includes the essential clinical tests.

Goals of treatment Proper triage prepares the physician to establish short- and long-term goals for the patient with very elevated blood pressure (Table 1). There is a distinct lack of trial evidence that patients with severe hypertension (without crisis) benefit from acute lowering of blood pressure, and it may be associated with risk. For example, short-acting nifedipine has been associated with severe hypotension, stroke, acute myocardial infarction, and death, and is no longer a part of the management of severe hypertension [10]. Although other oral medications for acute blood pressure reduction may not have such clear documentation of harm, the evidence of benefit is lacking, and the edict ‘‘first, do no harm’’ is advisable. Therefore, management of severe hypertension should include brief office observation (hours), initiation or resumption of oral antihypertensive medication, and arrangement for timely follow-up care, usually within 72 hours. For patients with hypertensive urgency, again clear evidence of benefit of acute lowering of blood pressure is lacking, but expert opinion [11–13] favors judicious acute treatment with an oral agent with rapid onset of action. The short-term goal is to reduce the blood pressure within 24 to 72 hours, and appropriate follow-up should be mandatory. For noncompliant patients,

Table 1 Triage of patients with very elevated blood pressure Hypertensive urgency

Hypertensive emergency

Blood Pressure Clinical features: symptoms

O180/110 mm Hg May be asymptomatic; headache

O180/110 mm Hg Severe headache, dyspnea, edema

Clinical features: findings

No acute target organ damage

Acute target organ damage usually absent, but may include elevated serum creatinine

Immediate goal

Lower blood pressure within days

Lower blood pressure within 24–72 hours

Treatment setting Medications

Outpatient Long-acting, oral

Follow-up

Within 3–7 days

Usually outpatient Oral medications with rapid onset of action; occasionally intravenously Within 24–72 hours

Often O220/140 mm Hg Chest pain, severe dyspnea, altered mental status, focal neurologic deficit Life-threatening target organ damage (eg, acute myocardial infarction, stroke, encephalopathy, acute renal failure, heart failure) Immediate blood pressure reduction; decrease by 15%–25% within 2 hours Inpatient, intensive care unit Intravenous medication

HYPERTENSIVE CRISES

Severe hypertension

As appropriate after hospital management

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resumption of prior medications may be sufficient. For untreated patients, initiation of long-acting agents is appropriate. Hypertensive emergency warrants admission to an intensive care unit and treatment with a parenteral agent. The short-term goal is to reduce the blood pressure by 15% to 25% within 4 hours. A reduction beyond 25% may exceed the autoregulatory capacity of the cerebrovascular circulation [14] and therefore elicit hypoperfusion, ischemia, and stroke. Pharmacotherapy For severe hypertension, initiation or resumption of long-acting antihypertensive medication is warranted. If immediate reduction of blood pressure is indicated (urgency), medications with rapid onset of action are preferred. Oral medications that may be appropriate include clonidine, (0.1–0.2 mg), labetalol (200–400 mg), or captopril (12.5–25 mg). Use of drugs with rapid onset carries two caveats. First, a large dose should be followed by a longer period of observation in the office or emergency department to assess for hypotension. Secondly, the effect of a drug with short onset of action (eg, clonidine) may decrease shortly after discharge to home, resulting in return of very elevated blood pressure. To avoid this occurrence, one can either continue dosing of the same drug as an outpatient, or begin a long-acting drug (eg, amlodipine, extended-release metoprolol, diuretic) in the office. Table 2 lists some commonly used oral agents in the treatment of hypertensive crises. Parenteral agents are indicated for some cases of hypertensive urgency and all cases of hypertensive emergency. Table 3 lists some commonly used intravenous medications. Table 2 Preferred medications for hypertensive urgencies Agent

Dose

Onset of action

Comment

Labetalol

200–400 mg po

20–120 min

Clonidine

0.1–0.2 mg po

30–60 min

Captopril

12.5–25 mg po

15–60 min

Nifedipine, extended release

30 mg po

20 min

Amlodipine

5–10 mg po

30–50 min

Prazosin

1–2 mg po

2–4 hours

Bronchoconstriction, heart block, aggravate heart failure Rebound hypertension with abrupt withdrawal Can precipitate acute renal failure in setting of bilateral renal artery stenosis Avoid short-acting oral or sublingual nifedipine due to risk of stroke, acute myocardial infarction, severe hypotension Headache, tachycardia, flushing, peripheral edema Syncope (first dose), tachycardia, postural hypotension

Table 3 Preferred medications for hypertensive emergencies Onset/duration of action (after discontinuation)

0.25–10.00 mg/kg/min as intravenous infusion; maximal dose for 10 min only

Immediate/2–3 min after infusion

Glyceral trinitrate

5–100 mg as intravenous infusion

2–5 min/5–10 min

Nicardipine

5–15 mg/h intravenous infusion

Verapamil

5–10 mg intravenous; can follow with infusion of 3–25 mg/h

1–5 min/15–30 min, but may exceed 12 h after prolonged infusion 1–5 min/30–60 min

Fenoldopam Hydralazine

0.1–0.3 mg/kg/min intravenous infusion 10–20 mg as intravenous bolus or 10–40 mg intramuscularly; repeat every 4–6 h

Enalaprilat

0.625–1.250 mg intravenous every 6 h

Parenteral vasodilators Sodium nitroprusside

2–5 min/2–4 h 1–5 min/15–30 min

1–2 min/10–30 min

Nausea, vomiting, muscle twitching; with prolonged use, may cause thiocyanate intoxication, methemoglobinemia acidosis, cyanide poisoning; bags, bottles, and delivery sets must be light-resistant Headache, tachycardia, vomiting, flushing, methemoglobinemia; requires special delivery systems due to the drug’s binding to polyvinyl chloride tubing Tachycardia, nausea, vomiting, headache, increased intracranial pressure, possible protracted hypotension after prolonged infusions Heart block (first-, second-, and third-degree), especially with concomitant digitalis or b-blockers; bradycardia Headache, tachycardia, flushing, local phlebitis Tachycardia, headache, vomiting, aggravation of angina pectoris

Renal failure in patients with bilateral renal artery stenosis; hypotension Bronchoconstriction, heart block, orthostatic hypotension First-degree heart block, congestive heart failure, asthma

Tachycardia, orthostatic hypotension

481

Parenteral adrenergic inhibitors Labetalol 10–80 mg as intravenous bolus every 10 min; up to 2 mg/min as intravenous infusion Esmolol 500 mg/kg bolus injection intravenously or 25–100 mg/kg/min by infusion; may repeat bolus after 5 min or increase infusion rate to 300 mg/kg/min Phentolamine 5–15 mg as intravenous bolus

!5 min/30 min 10 min intravenous/O1 h (intravenous); 20–30 min intramuscularly/ 4–6 h intramuscularly 15–60 min/12–24 h

Precautions

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Agent

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Sodium nitroprusside is very appropriate in the treatment of hypertensive emergencies because it is easily titratable, having an onset of action that is immediate and a duration of action only 2 to 3 minutes after discontinuation. It is a nonspecific vasodilator that has the same mechanism of action as endogenous nitric oxide. Adverse effects include nausea and vomiting, and thiocyanate intoxication with prolonged use is an important precaution. Despite these drawbacks, the drug is easily titrated and has become a mainstay of the management of hypertensive emergencies. When used in the setting of aortic dissection, concomitant use of a beta-blocker is important. Nitroglycerin improves coronary blood flow and is the drug of choice for hypertensive emergency associated with acute myocardial infarction when blood pressure is moderately elevated. It is a vasodilator of capacitance vessels more so than arteries, and is less potent than nitroprusside. Disadvantages include side effects, such as headache and vomiting, and tolerance with prolonged use is a limitation. Labetalol is commonly used for hypertensive emergencies, particularly aortic dissection. Its mechanism of action includes both alpha and beta blockade, and has a rapid onset of action. It can be continued orally on an outpatient basis, although it requires multiple doses per day. The disadvantages are those common to the beta-blocker class, including the potential for bradycardia, heart block, and bronchoconstriction. Esmolol is an intravenous beta-blocker that has very rapid onset of action along with short duration of action after discontinuation, making it particularly useful in the perioperative setting. It does not come in an oral form. Enalaprilat is an intravenous angiotensin-converting enzyme (ACE) inhibitor that has a fairly rapid onset of action. Like all ACE inhibitors, it carries the risk of acute renal failure in the setting of bilateral renal artery stenosis. Fenoldopam is particularly useful in the setting of renal insufficiency in that it has been shown to improve renal blood flow [15,16]. The drug acts as a dopamine receptor agonist and therefore causes renal as well as systemic vasodilatation. Like nitroprusside, it is easily titrated, but it is a much more costly drug. For hypertensive urgency, oral amlodipine or extended-release nifedipine may be useful if the goal is to lower the blood pressure within 72 hours. As mentioned previously, immediate-release nifedipine should be avoided because of risk of hypotension. Verapamil has a rapid onset of action and is available in both intravenous and oral forms, but carries a risk of heart block. Nicardipine is a calcium blocker without substantial risk of heart block, but tachycardia and the tendency toward prolonged action after discontinuation are limitations. Hydralazine is a direct vasodilator of arterioles and for years has been a useful drug in the management of hypertensive crises, particularly eclampsia of pregnancy. Its advantages include a rapid onset of action, intravenous and oral dosing, and a track record of safety in the setting of pregnancy.

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Limiting its use are several potential side effects, including reflex tachycardia, headache, and vomiting. The reflex tachycardia makes this drug generally undesirable for treatment of crises associated with acute coronary syndrome or acute aortic dissection. Phentolamine is a potent alpha-1 antagonist with a rapid onset of action that has traditionally been used in cases of catecholamine excess, such as pheochromocytoma crisis. Side effects can be problematic with this drug, particularly orthostatic hypotension, flushing, headache, and reflex tachycardia. Oral clonidine is a useful drug for hypertensive urgency due to its rapid onset of action. However, multiple doses of clonidine can be a setup for hypotension if the patient is not observed for a sufficient amount of time. The practice of clonidine loading has largely fallen out of favor. One small trial of clonidine loading among patients with severe asymptomatic hypertension found no benefit [17].

Assessment and management of selected hypertensive emergencies In addition to the general principles outlined above, the clinical features and management of several specific hypertensive emergencies deserve special attention. Neurologic hypertensive emergencies A neurologic hypertensive emergency is present if severe hypertension is associated with encephalopathy, stroke, subarachnoid hemorrhage, or acute head trauma. When neurologic findings, such as a focal deficit or altered mental status, are present, the physician should attempt to accurately place the case into one of the preceding four categories. A careful physical examination is important both for diagnosis and to establish the level of neurologic functioning at the time of presentation. The optic fundus and mental status must be examined, and the patient must be assessed for motor deficits and cerebellar dysfunction. Hypertensive encephalopathy is a manifestation of cerebral edema and is suggested by such symptoms as severe headache, nausea, vomiting, confusion, seizure, or coma. Papilledema is found on optic fundus examination, and rapid reduction of blood pressure is indicated. Sodium nitroprusside is the drug of choice, and a reduction in blood pressure by 20% to 25% over the first few hours is advisable. Stroke is typically diagnosed by history and examination indicating a focal neurologic insult along with corresponding abnormalities on brain CT or MRI. In such situations, watershed areas of brain parenchyma surrounding the stroke are dependent on perfusion pressure to remain viable. For that reason, acute and aggressive lowering of blood pressure may confer a risk.

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Severe hypertension resulting from head trauma (Cushing’s reflex) should be evident from the clinical presentation. The ideal target blood pressure in this setting is unknown. Blood pressure reduction should be accomplished cautiously and with close neurologic surveillance. Acute aortic dissection Aortic dissection is a life-threatening condition in which timely diagnosis and aggressive treatment of blood pressure are key. Severe hypertension and tachycardia are typically present, and efforts to reduce blood pressure and heart rate to reduce shear stress will decrease the likelihood of propagation of the dissection. Upon diagnosis, systolic blood pressure should be reduced to less than 120 mm Hg within 20 minutes. The drugs of choice are betablockers, such as labetalol or esmolol, as well as sodium nitroprusside. Acute coronary syndrome Acute coronary syndrome includes unstable angina and acute myocardial infarction. In these settings, an elevated adrenergic response is typical, leading to increased blood pressure and increased myocardial oxygen demand. The drugs of choice in these situations are intravenous nitroglycerin, which improves coronary perfusion, and beta-blockers. Acute pulmonary edema Treatment of acute heart failure with pulmonary edema requires drugs that decrease preload and left ventricular volume. Sodium nitroprusside and fenoldopam are good choices, along with a loop diuretic. Renal emergencies Measurement of serum creatinine and a urinalysis with examination of the sediment is important for all patients with hypertensive emergency. A renal emergency is present if new or acutely worsening renal dysfunction is present or if the urine sediment contains red cell casts or dysmorphic red cells. Fenoldopam is a strong choice of agent in this case due to its efficacy in reducing blood pressure along with its action to increase renal blood flow and urine output. Sodium nitroprusside and labetalol are also useful. A temporary reduction in glomerular filtration rate may occur with acute reduction of severely elevated blood pressure, even in crises of nonrenal causes. Short-term dialysis is sometimes necessary. Careful monitoring of renal function, electrolytes, and volume status is necessary throughout the clinical course. Adrenergic crises Examples of adrenergic crises include pheochromocytoma crisis, cocaine or amphetamine intoxication, and clonidine withdrawal. Drugs to consider

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in these cases include the pure alpha-blocker phentolamine (adding a beta-blocker if needed), the combined alpha-/beta-blocker labetalol, or clonidine in the case of clonidine withdrawal. Pregnancy Pregnancy-associated crises pose a challenge because many of the commonly used drugs for acute lowering of blood pressure are contraindicated in pregnancy. The drugs of choice include hydralazine, methyldopa, and magnesium sulfate. Beta-blockers or nifedipine are sometimes used in addition. Follow-up Studies suggest that patients treated for hypertensive crises often do not get adequate discharge instructions. Karras and colleagues [9] found that only 29% of such patients seen in four urban academic emergency departments received written instructions to follow up with a primary care provider. For many such patients, the risk attributable to ongoing poor control of blood pressure clearly outweighs the short-term risk of a transient rise in blood pressure. Prevention Hypertensive crises are largely preventable. Inadequate management of hypertension by the physician, poor adherence to therapy by the patient, and insufficient access to care are important factors leading to crises. Patients presenting with hypertensive crisis often have a history of poorly controlled blood pressure. Failure to intensify the treatment regimen in response to an elevated blood pressure in the office has been repeatedly correlated with poor control. More aggressive and effective execution of a treatment plan for hypertension is important in the effort to prevent crises. Another common scenario preceding a crisis is a patient discontinuing medications. Discontinuation of any antihypertensive medication can precipitate a crisis as the antihypertensive effect wears off. In addition, rebound hypertension can follow abrupt discontinuation of high-dose beta-blockers or clonidine. Poor access to care may be considered a system-level factor that contributes to the occurrence of hypertensive crises. Often a timely office visit or telephone call is all it takes to prevent a crisis. Pitfalls in office management of very elevated blood pressure A physician encountering a patient with very high blood pressure in the office or emergency department should be wary of several common pitfalls in assessment and treatment.

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The first pitfall is error in measurement of blood pressure. This can be due to any of several deviations from recommended technique, such as use of an ill-fitting cuff or omission of a brief rest period before measurement. A thorough discourse on the topic is provided elsewhere [18]. Particular attention should be given to the white coat effect, in which the patient’s blood pressure rises when in a medical setting, often due to anxiety about the blood pressure reading itself or about the examination in general. The physician then finds the blood pressure elevated and may assume it is normally this high, when the typical blood pressure is actually lower. This can lead to treatment based on overestimates of blood pressure. Measurement by a nonphysician provider or with an automated device with physician absent [19] can help avoid the confusion brought on by the readings that are possibly misleading because of the white coat effect. The next pitfall lies in treating the number. As discussed previously, the symptoms, physical examination, and findings on initial testing (laboratory tests, EKG, chest radiography) are more appropriate guides to decisionmaking than the blood pressure itself. Keep in mind that the clinical status of the patient rather than the level of blood pressure determines a hypertensive urgency or emergency. Another common mistake is to overestimate the benefit and underestimate the risk of acute lowering of blood pressure. Blood pressure should be acutely lowered if there is reason to believe there will be a benefit, such as in the case of an acute aortic dissection. Where the benefit is less clear, the physician should proceed with the approach of ‘‘first, do no harm.’’ Finally, after the urgency of the acutely elevated blood pressure passes, the physician should not underestimate the risk of chronic elevation of blood pressure. Consider the faulty logic of the following scenario: A patient presents to the office with a blood pressure of 190/112 mm Hg, without symptoms. The patient is medicated in the office to achieve a blood pressure of 170/100 mm Hg 3 hours later, and is discharged to home. The patient is then re-evaluated for this chronic condition 2 months later, at which time the blood pressure is still poorly controlled. In the majority of cases of patients with very elevated blood pressure, the patient has chronic hypertension, and the physician and patient should proceed accordingly to achieve good ongoing blood pressure control. References [1] Fang J, Alderman MH, Keenan NL, et al. Hypertension control at physicians’ offices in the United States. Am J Hypertens 2008;21:136–42. [2] Ong KL, Cheung BM, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999–2004. Hypertension 2007;49:69–75. [3] Gudbrandsson T. Malignant hypertension. A clinical follow-up study with special reference to renal and cardiovascular function and immunogenetic factors. Acta Med Scand Suppl 1981;650:1–62.

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[4] Agency for Healthcare Research and Quality. Available at: http://hcup.net.gov/HCUPnet. jsp. [5] Oster A, Bindman AB. Emergency department visits for ambulatory care sensitive conditions: insights into preventable hospitalizations. Med Care 2003;41:198–207. [6] Institute of Medicine. Crossing the quality chasm. Washington, DC: National Academy Press; 2001. [7] Bender SR, Fong MW, Heitz S, et al. Characteristics and management of patients presenting to the emergency department with hypertensive urgency. J Clin Hypertens (Greenwich) 2006; 8:12–8. [8] Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med 1990;323:1177–83. [9] Karras DJ, Kruus LK, Cienki JJ, et al. Evaluation and treatment of patients with severely elevated blood pressure in academic emergency departments: a multicenter study. Ann Emerg Med 2006;47:230–6. [10] Grossman E, Messerli FH, Grodzicki T, et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328–31. [11] Aggarwal M, Khan IA. Hypertensive crisis: hypertensive emergencies and urgencies. Cardiol Clin 2006;24:135–46. [12] Vidt DG. Hypertensive crises: emergencies and urgencies. J Clin Hypertens (Greenwich) 2004;6:520–5. [13] Moser M, Izzo JL Jr, Bisognano J. Hypertensive emergencies. J Clin Hypertens (Greenwich) 2006;8:275–81. [14] Strandgaard S, Paulson OB. Cerebral autoregulation. Stroke 1984;15:413–6. [15] Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993;95: 161–8. [16] Brienza N, Malcangi V, Dalfino L, et al. A comparison between fenoldopam and low-dose dopamine in early renal dysfunction of critically ill patients. Crit Care Med 2006;34:707–14. [17] Zeller KR, Von Kuhnert L, Matthews C. Rapid reduction of severe asymptomatic hypertension. A prospective, controlled trial. Arch Intern Med 1989;149:2186–9. [18] Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research. Hypertension 2005; 45:142–61. [19] Beckett L, Godwin M. The BpTRU automatic blood pressure monitor compared to 24 hour ambulatory blood pressure monitoring in the assessment of blood pressure in patients with hypertension. BMC Cardiovasc Disord 2005;5(1):18.

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Secondary Causes of Hypertension Sandra J. Taler, MD Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA

Secondary hypertension is uncommon in traditional primary care practice, yet it may cause major morbidity for a subset of patients. Depending on the conditions included, it may affect 5% to 10% of hypertensive patients. Investigation of all to detect these few would be costly and impractical and may exaggerate the risk to some patients without benefit, particularly because some secondary causes may not be correctable and others may be potentially treatable but at substantial risk. Nevertheless, for the few with a treatable secondary cause, detection and correction may be highly rewarding, even life prolonging. Knowledge of key clinical clues to secondary hypertension is essential to select which patients should be evaluated further and to what extent. This article provides an overview of the range of secondary causes, including key clinical features and appropriate diagnostic and treatment options. Details on the merits of surgical and other invasive interventions are beyond the scope of this discussion, and the reader is encouraged to refer these patients for subspecialty consultation and management.

Definition and approach Secondary hypertension is the presence of a specific condition known to cause hypertension. This condition may be the sole cause for hypertension in an individual, or a contributing factor in a patient who already has primary hypertension. A classification of secondary causes is shown in Table 1. Renal parenchymal disease, commonly termed chronic kidney disease (CKD), is the most common secondary cause, but urinary outlet obstruction should be considered. Renovascular disease occurs in young women as fibromuscular dysplasia and in older individuals because of atherosclerotic renal artery stenosis. Endocrine causes include primary aldosteronism, pheochromocytoma,

E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.001 primarycare.theclinics.com

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Table 1 Causes of secondary hypertension Renal Renovascular

Endocrine

Other

Renal parenchymal disease Ureteral or bladder outlet obstruction Renovascular hypertension Fibromuscular dysplasia Atherosclerotic disease Aortic coarctation Primary aldosteronism Pheochromocytoma Cushing’s disease Hypo- or hyperthyroidism Hyperparathyroidism OSA

cortisol excess, and thyroid or parathyroid abnormalities. In the current obesity epidemic, obstructive sleep apnea (OSA) is an increasingly common problem and may comprise sympathetic nervous system activation [1] and a relative aldosterone excess state [2]. Secondary hypertension may cause drug resistance, which is related to increased severity of the blood pressure (BP) elevation or to the presence of underlying hormonal abnormalities. Although the reported prevalence is 5% to 18% in referral hypertension practices [3–5], the author’s own experience suggests it may be more common, as noted in 31% of a group of 104 patients enrolled in a resistant hypertension treatment trial [6]. Further, reported prevalence rates vary widely depending on the extent of screening and the definitions used. Even with secondary hypertension, some individuals can be treated to goal BP levels using lifestyle changes and medication. For others, treatment of an identified secondary cause, even if feasible, does not resolve the hypertension. In most cases, unusual clinical features or resistance to effective therapy triggers the search for secondary hypertension. When making decisions regarding the extent of evaluation that is appropriate, the provider must consider the patient’s age, comorbidities, and long-term prognosis in addition to the efficacy of medical therapy; these are balanced against the risks for leaving the condition undetected and the risks for potentially invasive treatment. Here, the specific clinical questions to be answered may direct the extent of testing to be undertaken. Is the issue whether fibromuscular renovascular disease is present and may be treated with endovascular intervention or whether bilateral atherosclerotic disease is present and threatening renal functional viability? Selection of testing may change considerably depending on the clinical question and the potential for modifying therapy as a result. If the risks for intervention are prohibitive, it is best to avoid the use of complex diagnostic procedures. A patient’s response to medical treatment and tolerance of that treatment must also be considered. Because recent trends in primary hypertension management emphasize lifestyle changes and early initiation of drug treatment with limited

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laboratory investigation [7], many patients begin antihypertensive therapies without specific testing to exclude secondary causes. If medical therapy fails, the provider should then go back and expand the diagnostic testing to consider the presence of a secondary cause. In this context, the most common indication for secondary evaluation becomes the failure to achieve BP targets using escalating numbers and doses of medication [8]. In older patients, a progressive decline in renal function should prompt reconsideration of a secondary cause. Declining renal function in an elderly patient presents a difficult dilemma in which it may be reasonable to pursue a more invasive evaluation in the hope of preventing the major morbidity of kidney failure. For the patient unable to tolerate multiple attempts at medical therapy, a secondary evaluation may also be appropriate. The overriding goal of additional testing is to evaluate and correct potential contributing causes, and thereby improve BP response to the prescribed antihypertensive medications, perhaps resulting in fewer in number and lower dosages. Although this discussion focuses on rare causes of hypertension that are potentially curable if properly identified and corrected, it is important to remember that most patients who have secondary hypertension do not attain complete resolution even if a cause is determined. Clinical clues for secondary causes Secondary hypertension is more likely when there are atypical features of the patient’s history, clues on physical examination, or unexpected laboratory findings (Table 2). Although rare, these features suggest that a potentially curable form of hypertension may be present. The diagnosis of hypertension in a young person (younger than the age 30 years and especially without contributing features, such as obesity) merits a more aggressive evaluation, because the financial and medical costs of drug treatment are substantial over his or her lifetime, even if BP is well controlled. In this setting, early diagnosis may provide an opportunity for cure that may be lost later as the hypertension persists over time. Other historical clues include a more severe or accelerated hypertension course and the absence of a family history of hypertension. Specific drug intolerances may be a clue to a secondary cause. The development of hypokalemia that is disproportionate in severity to that anticipated, or the need for large amounts of potassium supplementation to maintain normokalemia, suggests excessive aldosterone production, whether primary or secondary. The development of acute renal failure with the introduction or dose increase of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker suggests the presence of severe bilateral renal artery stenosis. Specific symptom constellations also merit further investigation. These include hypertensive spells and lability suggesting pheochromocytoma, urinary obstructive symptoms (obstructive uropathy), and snoring with daytime hypersomnolence (OSA). The rapid onset of pulmonary edema

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Table 2 Atypical features suggesting secondary hypertension Historical

Possible causes

Early age of onset Severe or accelerated course Absent family history of hypertension Resistant hypertension

Any Any Any Any

Specific drug intolerances Marked hypokalemia while taking a diuretic medication Worsening hypertension after beta-blockade Acute renal failure after initiation or dose increase of ACEI, ARB

Primary or secondary hyperaldosteronism, corticosteroid excess Pheochromocytoma Renovascular hypertension

Symptoms Spells, lability, orthostatism Prostatism Snoring, daytime hypersomnolence Flash pulmonary edema Physical examination signs Cafe´ au lait spots, neurofibromas Cervical fat pad, moon facies, pigmented striae Thigh BP lower than brachial BP, continuous murmur over back Goiter or thyroid nodule Large neck, narrow pharynx with soft tissue crowding Abdominal systolic-diastolic bruit, multiple arterial bruits Large palpable kidneys Laboratory findings Hyperkalemia Hypokalemia Elevated serum creatinine Abnormal urinalysis Loss or blunting of nocturnal BP decrease Disproportionate target organ damage (cerebral lacunar infarcts, hypertensive retinopathy, left ventricular hypertrophy, renal failure)

secondary secondary secondary secondary

cause cause cause cause

Pheochromocytoma Urinary obstruction OSA Renovascular hypertension Pheochromocytoma Cushing’s disease Aortic coarctation Thyroid disease OSA Renovascular hypertension Polycystic kidney disease Renal parenchymal disease, urinary obstruction Renovascular hypertension, primary or secondary hyperaldosteronism Renal parenchymal disease, urinary obstruction, renovascular hypertension Renal parenchymal disease Any secondary cause Any secondary cause

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

(‘‘flash pulmonary edema’’) in a patient who has normal cardiac function may indicate tight bilateral renal artery stenoses. Physical findings are infrequent and require additional studies to confirm a diagnosis. Still, the presence of these signs should point to the need for

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further evaluation of the associated conditions (see Table 2). An examination for secondary causes should include thorough skin, cardiovascular, thyroid, and oropharyngeal examinations. Specific features include cafe´ au lait spots or neurofibromas (eg, pheochromocytoma, paraganglioma); moon facies; cervical fat pad and pigmented striae (Cushing’s disease); reduced thigh and, for some, left arm BP (aortic coarctation); redundant pharyngeal soft tissues with airway crowding and large shirt collar size (OSA); carotid or femoral bruits or an abdominal bruit (renovascular disease); and enlarged palpable kidneys (polycystic kidney disease). Laboratory abnormalities relate primarily to reduced or elevated serum potassium levels or to evidence for decreased renal function. Secondary hypertension is associated with disturbances in circadian BP rhythm by ambulatory blood pressure monitoring (ABPM), and thereby an increased risk for target organ damage [9]. The presence of target organ damage out of proportion to office BP levels suggests nocturnal hypertension and a potential secondary cause. Diagnostic evaluation If secondary hypertension is suspected, one should begin with a general evaluation encompassing multiple causes and then focus on contributing mechanisms based on abnormal test results. Beyond the basic laboratory tests advised by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [7], preliminary testing should include a noninvasive imaging study of the kidneys and renal arteries, along with hormonal screening for excess aldosterone, cortisol, and catecholamine states. It is important to distinguish renal parenchymal disease from renovascular hypertension to direct further testing appropriately. Secondary hypertension is traditionally classified by organ system into renal causes, endocrine causes, and other causes, including OSA (see Table 1). Renal parenchymal disease is the most common cause of secondary hypertension. A basic classification of renal diseases is included in Table 3. Although full coverage of renal diseases and their treatment is beyond the scope of this review, it is essential that the clinician recognize major types of renal disease in order to initiate early treatment and appropriate referral. A recent movement to have clinical laboratories report an estimated glomerular filtration rate (eGFR) concurrent with serum creatinine measurements should assist practitioners in recognizing renal function impairment (CKD) earlier, initiating renal protective measures, and making earlier specialist referrals [10]. Hypertension may be a presenting sign of renal disease and may be severe, even before a decline in renal function is evident. Further, aggressive treatment of hypertension in this setting may delay progressive renal function decline. Diabetic nephropathy is now the most common cause of end-stage renal disease, affecting 50% of those with diabetes over time [11]. Further, it

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Table 3 Broad classification of kidney diseases and appropriate testing options Renal parenchymal disease Manifestations

Confirmatory testing

Glomerular diseases

Serologic testing, ultrasound, renal biopsy

Tubulointerstitial diseases

Collecting system injury, including obstruction

Vascular disease, arterial

Vascular disease, venous Renal mass or masses

Hypertension, edema, hematuria, cellular casts, proteinuria Reduced renal function with or without urinary abnormalities (casts) Painful hematuria, urinary retention, overflow incontinence

Serologic testing, ultrasound, renal biopsy Ultrasound, urodynamic studies, CT imaging for nephrolithiasis, urinary supersaturation testing Ultrasound, CT, MRI (see text for limitations), arteriography

Hypertension, often severe without urinary abnormalities, decline in renal function if late or bilateral Edema, proteinuria, nephrotic Ultrasound, CT, MRI (see text syndrome for limitations), venography Ultrasound, CT, MRI (see text Pain related to pressure from mass lesion, obstruction, for limitations), biopsy or resection incidental finding on imaging study, may be asymptomatic

carries risk for multiple medical comorbidities, especially cardiovascular disease. Other glomerular diseases may also present with hypertension and proteinuria. With slowly progressive renal diseases, including interstitial diseases, hypertension may occur later in the disease course related to reduced efficiency of sodium and water handling. Parenchymal renal disease is characterized by elevated serum creatinine and, in some settings, active urinary sediment. Referral to a nephrologist for a renal biopsy may be necessary for definitive diagnosis. Renal outflow tract obstruction attributable to prostatic obstruction, a mass lesion, or complications of prior surgery should also be excluded before moving to invasive vascular imaging. Renal ultrasound is a practical first imaging study to visualize the renal parenchyma and the collecting system. Normal renal parenchymal imaging, the absence of hydronephrosis, and a negative urinary sediment test result suggest renal vascular disease; coupled with drug-resistant hypertension, this merits further vascular imaging. The choice of modality is currently limited to computed tomography angiography (CTA) requiring iodinated contrast or magnetic resonance angiography (MRA) using gadolinium, because most specialists would avoid the more invasive renal angiography unless other studies implicate significant and treatable arterial stenosis. Current concerns regarding the risk for nephrogenic systemic fibrosis (NSF), a life-threatening sclerosis of the skin and connective tissues [12,13], have reversed prior selection algorithms to favor CTA in patients who have renal

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insufficiency. This practice change further underscores the importance of careful consideration of the individual patient and the risk/benefit ratio of further testing before proceeding down this path. Contrast agent–induced renal failure is uncommon and can be prevented in part by using preprocedural saline hydration and N-acetylcysteine [14]. For most patients, it is generally reversible if it occurs, whereas NSF is irreversible and may be fatal. Significant renal vascular disease causing resistant hypertension or progressive renal dysfunction may respond well to renal revascularization, and for selected individuals, percutaneous or, less commonly, surgical intervention may salvage critical renal function [15]. Whether renal revascularization is a superior method for treatment of renovascular hypertension remains unproved, with large multicenter studies currently in progress [16,17]. Clinical features should guide the investigation of hormonal secondary causes. Primary hyperaldosteronism is increasingly recognized as a correctable cause for resistant hypertension; thus, screening should be considered early in the evaluation. Once regarded as rare, primary aldosteronism is reported in up to 20% of patients who have resistant hypertension [18,19]. In its classic form, primary aldosteronism refers to excess aldosterone secretion caused by an adrenal cortical adenoma. More commonly, no distinct adenoma is identifiable, but there is diffuse or nodular hyperplasia of both adrenal cortices. In this form, a positive relation between angiotensin II and aldosterone remains; however, it has a different set point, such that aldosterone is produced in relative excess [20]. Spontaneous hypokalemia, once considered a diagnostic requirement, is reported in approximately 30% of cases, likely those with greater severity. Most specialists begin with concurrent measurements of plasma aldosterone and plasma renin activity, preferably drawn in the morning when production is greater, although the sensitivity and specificity of this screen have not been well validated [21,22]. Using 0.5 ng/mL/h as the lowest threshold for renin measurement, an aldosterone-to-renin ratio (ARR) of greater than 20 is considered a positive screen for primary aldosterone excess but not sufficient for diagnosis. The diagnosis is made by a 24-hour urine aldosterone level greater than 12 mg in the setting of salt loading, demonstrating inappropriate aldosterone production in a sodium-replete state. It is important to remember that a single positive ARR is not diagnostic, nor does a negative ARR exclude the diagnosis of primary aldosteronism, even in the setting of an aldosterone-producing adenoma. Adrenal imaging should be withheld unless inappropriate aldosterone production is confirmed. The detection of an adrenal mass lesion may not correlate with the overproducing adrenal gland, and adrenal vein sampling is needed to confirm laterality before adrenalectomy. An obese patient who has resistant hypertension may have a relative aldosterone excess but fall short of the classic criteria for primary aldosteronism. Chemokines in visceral fat may stimulate the renin angiotensin aldosterone system, particularly in patients who have concurrent sympathetic activation from untreated sleep apnea [2].

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Once a diagnosis of primary aldosteronism is confirmed, lateralizing aldosterone production supports the diagnosis of an independent aldosterone-producing adenoma. Bilateral adrenal hyperplasia should be treated medically with an aldosterone receptor antagonist, such as spironolactone or eplerenone. For patients intolerant to these agents, amiloride may be effective. Some specialists require successful response to an aldosterone receptor antagonist before adrenalectomy to ensure that the correct diagnosis has been made. Pheochromocytoma is rare but should be considered in patients who have marked BP lability, particularly those with orthostatic hypotension, tachycardia, or spells. Fractionated plasma metanephrines have the highest sensitivity (97%) and are ideal for evaluation of hereditary pheochromocytoma states [23]. The levels are unrelated to episodic catecholamine release or production of metabolites at sites remote from the tumor mass, which may be particularly useful in patients who have hereditary pheochromocytoma and lack clinical signs or symptoms or who may harbor small tumors that release lower levels of catecholamines. Lower specificity (85%) means a lower likelihood of actually having pheochromocytoma, particularly in settings in which the prevalence is low, as in the patient who has hypertension or an adrenal incidentaloma. For those with sporadic pheochromocytoma, which is more likely seen in clinical practice, sensitivities of plasma metanephrines or urinary measurements are comparable (96%), but the urinary measurements more specific [24]. Increasing age is associated with a greater likelihood of false-positive fractionated plasma metanephrine measurements. Thus, negative measurements of fractionated plasma metanephrines and 24-hour urinary total metanephrines with catecholamines are effective in ruling out the diagnosis of pheochromocytoma. For patients undergoing evaluation for sporadic pheochromocytoma, particularly older hypertensive patients, 24-hour urinary metanephrine and catecholamine measurements are preferred to the more convenient plasma metanephrine measurement so as to provide adequate sensitivity with a lower rate of false-positive results. Once a diagnosis is made, the patient should be referred to an experienced endocrinologist for alpha- and then beta-receptor blockade before resection of the lesion. All patients who have hypertension should be evaluated for thyroid disease (hyperthyroid and hypothyroid states), particularly if their BP is not controlled. Directed testing of the adrenal cortisol axis is usually reserved for patients with clinical evidence of cortisol excess (eg, central obesity, pigmented striae, hyperglycemia) or for those with an incidentally discovered adrenal mass. An overnight dexamethasone suppression test is used for screening and excludes cortisol excess if negative. Positive testing should result in referral to an endocrinologist for localization of the tumor and removal. Epidemiologic evidence supports a link between OSA and hypertension. Potential mechanisms whereby OSA may contribute to hypertension include

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sympathetic activation, hyperleptinemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative and inflammatory stress, endothelial dysfunction, impaired baroreflex function, and effects on renal function. The Wisconsin Sleep Cohort Study demonstrated an independent doseresponse relation between sleep-disordered breathing at baseline and development of new hypertension 4 years later [25]. The odds ratio was graded with the severity of apneic frequency. In a recent case-control study of overweight or obese patients who had resistant hypertension, the diagnosis of OSA conveyed a 4.8-fold greater risk for resistant hypertension compared with body mass index (BMI)–matched subjects with treated and controlled hypertension [26]. The prevalence of resistant hypertension was directly related to the intensity of OSA by the apnea-hypopnea index. Others have shown a correlation between plasma aldosterone concentration and OSA severity (apnea-hypopnea index) in subjects who have resistant hypertension but not in those who have OSA without resistant hypertension [27]. The diagnosis of OSA requires a high index of suspicion combined with direct questioning, a focused examination, and confirmatory testing. The key to detection is to consider the diagnosis in every patient but particularly in those who have obesity and resistant hypertension. Symptoms primarily relate to chronic fatigue with daytime hypersomnolence in permissive settings. The physical examination may suggest the diagnosis, with a narrow oropharyngeal opening on direct oral examination as a result of crowding by a large uvula, tonsillar enlargement, or other soft tissue redundancy, in addition to the classic finding of a large neck (shirt collar size in a man). OSA-induced hypoxemia and increased upper airway resistance trigger a stress response manifested by chronically elevated circulating catecholamine levels [1]. Characteristically, patients show mild elevations in plasma and urinary metanephrines or catecholamine levels, which are low enough not to suggest pheochromocytoma strongly but are higher than normal ranges. Treatment of sleep apnea with continuous positive airway pressure (CPAP) often corrects the endocrine abnormalities and dramatically improves the fatigue symptoms. Whether treatment of OSA with CPAP fully corrects the contribution to resistant hypertension is unclear [28,29]. Less common secondary causes may present with subtle findings, and directed testing may be appropriate. At each step in the pathway, the clinician must decide whether the condition has been sufficiently excluded in the individual patient or whether more definitive testing is indicated. Such decisions should consider patient age, long-term prognosis, risks for leaving the condition undetected, risks for intervention, and adequacy of medical therapy. Role of ambulatory blood pressure monitoring As with the diagnosis of primary hypertension, misdiagnosis of resistant hypertension and estimates of severity may occur in the treated patient

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based on office BP measurements. Office or ‘‘white coat’’ hypertension may not extinguish with familiarity. Before embarking on a full evaluation for secondary causes, ABPM may be justified, using a 24-hour monitoring time [30] or an abbreviated method [31]. Analysis of nocturnal readings may be of particular utility in this setting, because several types of secondary hypertension are associated with absence or even reversal of the normal nocturnal BP decrease. A blunted or absent nocturnal BP decrease is characteristic of secondary forms, including renal parenchymal disease with reduced renal function, Cushing’s disease or posttransplant hypertension in the setting of exogenous corticosteroid use, OSA, renovascular hypertension, and primary aldosteronism [9]. The use of multiple home readings is increasingly favored as a more cost-effective modality but does not provide circadian or nocturnal information.

When to refer patients for more specialized consultation Decisions on referral depend largely on the comfort and experience of the treating practitioner. This article begins with a discussion directed to the level of the internist or subspecialist physician with expertise in the selection and use of multiple agents for the treatment of hypertension. Decisions regarding the extent of secondary evaluation require consideration of the likelihood of diagnosis, the patient’s overall health status and prognosis, and balancing the risks for intervention against the risks for missing a diagnosis. Referral is advised when these risks seem prohibitive, when there are questions regarding selection of the most optimal studies, or when there are questions about the extent of intervention to pursue when BP remains uncontrolled. Referral patterns vary with regional expertise. Resources include nephrologists (eg, renal parenchymal disease, renovascular hypertension, volume overload), pharmacists and pharmacologists (eg, drug interactions, regimen simplification, adherence), endocrinologists (eg, endocrine secondary causes, referral and interpretation of adrenal imaging, adrenal vein sampling), and sleep specialists for overnight polysomnography.

Summary The primary rationale for secondary hypertension evaluation is to achieve BP control more effectively and prevent morbidity and mortality related to the disease. Selection of patients for testing incorporates historical and clinical clues, previous treatment course, and comorbidities. Renal parenchymal disease, now termed CKD, is increasingly detected in an aging population. Renovascular disease is increasingly associated with impaired renal function and may not improve after high-risk interventions. Whether improvements in renal function may improve long-term survival merits

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further study. Although imperfect, the ARR has become the screening test of choice for primary aldosteronism. Prevalence rates of primary aldosteronism increase with severity of hypertension, and for many patients, aldosterone excess is attributable to bilateral adrenal hyperplasia. For these patients, the treatment is likely to be medical, incorporating an aldosterone receptor antagonist. The ideal test for pheochromocytoma depends on clinical suspicion and risk for hereditary disease. With the adoption of newer more sensitive assays, it is essential that the clinician understands their strengths and drawbacks. Plasma-free metanephrines are most sensitive and the best test for those at highest risk, as with hereditary pheochromocytoma. For sporadic pheochromocytoma, urinary metanephrines and fractionated catecholamines provide high sensitivity with fewer false-positive results. OSA is increasingly common in patients who have resistant hypertension and often remains unrecognized. Although treatment may improve cardiovascular prognosis, benefits to BP control are uncertain.

References [1] Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96(4):1897–904. [2] Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea and aldosterone: theory and therapy. Hypertension 2004;43:518–24. [3] Garg JP, Elliott WJ, Folker A, et al. Resistant hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens 2005;18:619–26. [4] Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med 1991;151:1786–92. [5] Martell N, Rodriguez-Cerrillo M, Grobbee DE, et al. High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension. Blood Press 2003;12: 149–54. [6] Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension 2002;39:982–8. [7] Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72. [8] Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51(6): 1403–19. [9] Polonia J, Santos AR, Gama GM, et al. Accuracy of twenty-four-hour ambulatory blood pressure monitoring (night-day values) for the diagnosis of secondary hypertension. J Hypertens 1995;13(12 Pt 2):1738–41. [10] Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification and stratification. Ann Intern Med 2003; 139:137–47. [11] United States Renal Data System, National Institute of Diabetes and Digestive and Kidney Diseases. USRDS 2007 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. [12] Grobner T. Gadoliniumda specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21(4):1104–8.

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[13] Grobner T, Prischl FC. Gadolinium and nephrogenic systemic fibrosis. Kidney Int 2007; 72(3):260–4. [14] Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agentinduced reductions in renal function by acetylcysteine. N Engl J Med 2000;343(3):180–4. [15] Safian RD, Textor SC. Medical progress: renal artery stenosis. N Engl J Med 2001;344: 431–42. [16] Cooper CJ, Murphy TP, Matsumoto A, et al. Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial. Am Heart J 2006;152(1):59–66. [17] Textor SC. Renovascular hypertension in 2007: where are we now? Curr Cardiol Rep 2007; 9(6):453–61. [18] Calhoun DA, Nishizaka MK, Zaman MA, et al. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002;40:892–6. [19] Eide IK, Torjesen PA, Drolsum A, et al. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens 2004;22:2217–26. [20] Lim PO, Jung RT, MacDonald TM. Is aldosterone the missing link in refractory hypertension?: aldosterone-to-renin ratio as a marker of inappropriate aldosterone activity. J Hum Hypertens 2002;16:153–8. [21] Tanabe A, Naruse M, Takagi S, et al. Variability in the renin/aldosterone profile under random and standardized sampling conditions in primary aldosteronism. J Clin Endocrinol Metab 2003;88:2489–94. [22] Montori VM, Schwartz GL, Chapman AB, et al. Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. Mayo Clin Proc 2001;76:877–82. [23] Lenders JWM, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427–34. [24] Sawka AM, Jaeschke R, Singh RJ, et al. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003;88:553–8. [25] Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleepdisordered breathing and hypertension. N Engl J Med 2000;342:1378–84. [26] Gonc¸alves SC, Martinez D, Gus M, et al. Obstructive sleep apnea and resistant hypertension*: a case-control study. Chest 2007;132(6):1858–62. [27] Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, et al. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 2007;131(2): 453–9. [28] Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003; 107(1):68–73. [29] Narkiewicz K, Kato M, Phillips BG, et al. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 1999;100(23): 2332–5. [30] Brown MA, Buddle ML, Martin A. Is resistant hypertension really resistant? Am J Hypertens 2001;14:1263–9. [31] Zachariah PK, Sheps SG, Ilstrup DM, et al. Blood pressure loadda better determinant of hypertension. Mayo Clin Proc 1988;63:1085–91.

Prim Care Clin Office Pract 35 (2008) 501–513

Resistant Hypertension Russell L. Silverstein, MD, FACP, FASNa, C. Venkata S. Ram, MD, MACP, FACCb,* a

Dallas Nephrology Associates, 13154 Coit Road, Dallas, TX 75240, USA Texas Blood Pressure Institute, Dallas Nephrology Associates, University of Texas Southwestern Medical Center, 1420 Viceroy Drive, Dallas, TX 75235, USA

b

Despite the high prevalence and heterogeneity of hypertension, blood pressure (BP) can be controlled to goal levels with effective therapy in many patients. However, in a small percentage of patients who have hypertension, the BP remains refractory to usual and customary therapeutic measures. In such patients who have so-called ‘‘resistant’’ or ‘‘refractory’’ hypertension, proper evaluation and assessment have to be undertaken to improve the BP control. There are some factors that may make hypertension control difficult in some patients. Therefore, it is necessary to identify possible etiologic reasons for the loss of BP control and to rectify them to achieve normotension. In addition to indicated work-up for secondary causes in selected patients, aggressive treatment (nonpharmacologic and pharmacologic) of hypertension is required to prevent excessive morbidity and mortality in this special subgroup of hypertensive patients. Resistant hypertension is somewhat uncommon when patients receive effective management of hypertension. A majority of patients with primary hypertension respond well to multiple antihypertensive drugs. Definitions vary, but hypertension is considered resistant if the blood pressure (BP) cannot be reduced below target levels in patients who are compliant with an optimal triple-drug regimen that includes a diuretic. The terms ‘‘refractory’’ and ‘‘resistant’’ are used interchangeably. In those patients with isolated systolic hypertension (ISH), refractoriness has been generally defined as a failure of multiple antihypertensive drugs to reduce systolic BP below 160 mmHg, but recent observations strongly indicate that the target level for systolic BP should be % 140 mm Hg. Whereas resistant hypertension may be still encountered in specialized referred hypertension centers, its prevalence in the general

* Corresponding author. E-mail address: [email protected] (C.V.S. Ram). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.03.002 primarycare.theclinics.com

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population of hypertensive patients is probably quite low; most patients with chronic uncomplicated hypertension respond to appropriate (combination) therapy. If a patient’s BP is not controlled with multiple antihypertensive drugs, but one of the drugs is not a diuretic, the patient’s condition should not be diagnosed as ‘‘resistant’’ hypertension. With increasing age and body weight, resistant hypertension becomes more common. Goal BP is defined as % 140/90 mmHg in general population or % 130/80 mm Hg in patients with diabetes or renal insufficiency, or with a urinary protein excretion O300 mg/24 hours (Table 1) [1]. An ‘‘optimal’’ dose may not necessarily equate to a ‘‘full’’ dose. An optimal dose is the highest dose tolerated by the patient or a dose affected by concomitant conditions such as chronic kidney disease, congestive heart failure, and diabetes. Volume control is a critical component of treating hypertension effectively. For whatever reasons, many patients are not treated with diuretics optimally; if a patient’s BP is not controlled on several drugs, but one of the drugs is not a diuretic, this would not meet the conventional definition of resistant hypertension. Since the true prevalence of resistant hypertension is not known, estimates are derived from observational and outcome studies. In the last National Health and Nutrition Examination Survey (NHANES), resistant hypertension was commonly identified [2]. In the Antihypertensive and Lipid Lowering Treatment To Prevent Heart Attack Trial (ALLHAT) after nearly 5 years of treatment, 27% of 33,000 subjects had resistant hypertension [3,4]. In the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial in individuals older than 55 years, 18% had resistant hypertension [5]. In the Valsartan Antihypertension long-term use evaluation (VALUE) trial, at least 15% of subjects had resistant hypertension after 30 months of therapy with three or more drugs [6]. While not representing typical clinical practices, the data from the ALLHAT provides an estimate of the prevalence of refractory hypertension in the community setting. In ALLHAT, 34% of the study participants had BPO140/90; most patients were on two medications, with 27% requiring three or more medications. Based on the five-year observations in ALLHAT, the authors estimate that the incidence of refractory hypertension was approximately 15%. In the CONVINCE trial, 18% of the patients had a BP level O 140/90 mm Hg on three or more medications. Patients who have diabetes Table 1 JNC VII classifications BP Classification

SBP mm/Hg

Normal Prehypertension Stage I hypertension Stage II hypertension

!120 120–139 140–159 R160

DBP mm/Hg and or or or

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

!80 80–89 90–99 R100

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are more resistant to antihypertensive drugs than nondiabetic subjects, thus requiring more antihypertensive drugs to achieve goal BP.

Causes of resistant hypertension The major causes of resistant hypertension are listed in Table 2. When a hypertensive patient demonstrates refractoriness to standard antihypertensive drug therapy, systematic management requires identification of possible etiologic factors. Before making abrupt drastic therapeutic changes, certain questions should come to the physician’s mind: Does the patient truly have ‘‘resistant’’ hypertension? Are there any patient/environmental factors? Does the patient have pseudoresistance? Are there adverse drug reactions or drug drug/food interactions? (Table 3) Does the patient have a secondary form of hypertension such as adrenal or renovascular hypertension? Are there any identifiable mechanisms (pressor) that are responsible for elevating the arterial BP despite anti-hypertensive drug therapy? Table 2 Causes of refractory hypertension Pseudoresistance ‘‘White-coat’’ hypertension Pseudohypertension in older patients Use of small cuff in obese patients Nonadherence to prescribed therapy Volume overload Drug-related causes Doses too low Wrong type of diuretic Inappropriate combinations Drug actions and interactions Sympathomimetics Nasal decongestants Appetite suppressants Cocaine Caffeine Oral contraceptives Adrenal steroids Licorice (as may be found in chewing tobacco) Cyclosporine, tacrolimus Erythropoietin Antidepressants Nonsteroidal anti-inflammatory drugs Concomitant conditions Obesity Sleep apnea Ethanol intake of more than 1 oz (30 mL) per day Anxiety, hyperventilation Secondary causes of hypertension (eg, renovascular hypertension, adrenal causes, and renal disease)

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Table 3 Drug interactions that may lead to resistant hypertension Angihypertensive Agents

Interacting Drugs

Hydrochlorothiazide Propranolol Guanethidine ACE inhibitors Diuretics All drugs

Cholestyramine Rifampin Tricyclics Indomethacin Indomethacin Cocaine Tricyclics Phenylpropanolamine

All drugs

Excessive alcohol consumption (more than 1 oz or 30 mL) clearly raises the systemic BP, sometimes to dangerously high levels. The authors have sometimes witnessed panic attacks and hyperventilation as possible causative factors for refractory hypertension. Similarly, chronic pain may aggravate BP levels. Pseudoresistance It is not uncommon to see patients whose clinic BP levels may be higher than the levels obtained outside the office setting, so-called ‘‘white coat’’ hypertension. Although white-coat hypertension is usually considered in the context of mild hypertension (Stage I), in some cases, resistant hypertension may be indicative of white-coat hypertension. Patients who may have refractory white-coat hypertension do not demonstrate target organ damage despite seemingly very high BP readings in the office or clinic. The disparity between the degree of hypertension and the lack of target organ damage can be supported by the measurement of serial home BP levels and or by obtaining ambulatory blood pressure (ABP) recordings [7–9]. Another possible source of erroneous BP measurement is a condition termed pseudohypertension, seen sometimes in the elderly individuals. Persistently high readings in the absence of target organ damage or dysfunction may indicate pseudohypertension. This condition is due to the fact that the hardened and sclerotic artery is not compressible, hence falsely elevated pressures are recorded – the Osler phenomenon [10]. Because of thickened calcified arteries, a greater pressure is required to compress the sclerotic vessels. There is little doubt that pseudohypertension does occur in older individuals, but its exact prevalence is not known. While some have advocated the use of intra-arterial BP determination as a means of accurately making the diagnosis of this aberration, the authors do not recommend this procedure to document pseudohypertension; it is simply not practical. A more common example of pseudoresistance is measurement artifact, which occurs when the BP is taken with a small cuff in people with large arm diameters [11]. With the patient in the seated position and the arm supported at heart level, the BP should be taken with an appropriate cuff size to ensure accurate

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determination. The bladder within the cuff should encircle at least 80% of the arm diameter. One has to be cautious, however, before dismissing an elevated reading as a measurement artifact, because patients with truly refractory hypertension experience a high rate of cardiovascular and other complications. Noncompliance Failure to follow a prescribed regimen is perhaps the most common reason not to achieve goal BP levels. There may be valid reasons for patients’ noncompliance such as side effects, costs, complexity of the drug regimen, and lack of understanding. Social, economic, and personal factors may also play a role in noncompliance. Noncompliance is a complex phenomenon that is not easily discerned or understood in clinical practice.

Volume overload Volume overload from any mechanism not only increases the BP but may offset the effectiveness of antihypertensive drugs [12]. Excessive salt intake and retention increases the plasma volume and causes resistance to antihypertensive drugs and can also raise the BP in some patients. The elderly and African American patients are particularly sensitive to fluid overload as are patients with renal insufficiency and congestive heart failure. Certain antihypertensive drugs such as direct vasodilators, antiadrenergic agents, and most of the nondiuretic antihypertensive drugs cause plasma and extracellular fluid expansion, thus interfering with BP control. Of all the nondiuretic antihypertensive drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium antagonists are least likely to cause fluid retention. Therapeutic responsiveness can be regained by: restricting the sodium intake; adding or increasing the dose of diuretic; and in some instances, switching to a loop-diuretic from thiazides. Drug-related causes Hypertension may be seemingly resistant if the antihypertensive drugs are used in suboptimal doses or when an inappropriate diuretic is used, eg, using a thiazide-type diuretic as opposed to a loop diuretic in patients with renal insufficiency, congestive heart failure, or in those who are taking potent vasodilators such as minoxidil or hydralazine. Inappropriate combinations can also limit their therapeutic potential. Adverse drug-drug interactions can raise the BP in normotensive as well as in hypertensive patients. Such adverse interactions (see Table 3) can occur as a result of alterations in drug pharmacokinetics or in pharmacodynamics of concomitant drugs administered for different indications. One typical example of an adverse drug interaction is between indomethacin and beta-blockers, diuretics, and ACE inhibitors. Tricyclic antidepressants (no longer widely used) have

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a significant interaction with sympathetic blocking agents. Hypertension associated with renal insufficiency is often difficult to treat; hypertensive patients with reduced renal function generally require concomitant therapy with a loop diuretic such as furosemide because the thiazide diuretics do not work very well in such patients. Of all the drugs listed in Table 3, the nonsteroidal anti-inflammatory drugs are important because of the frequency with which they are used in clinical practice. These drugs attenuate the vasodilatory actions of (intra-renal) prostaglandins, thus inhibiting natriuresis and causing volume expansion and resulting in BP elevation [13]. Hence, in patients with refractory or severe hypertension, nonsteroidal anti-inflammatory drugs should be avoided if possible. Estrogen as a component of oral contraceptive preparations may raise the BP, but hormonal replacement therapy has no significant adverse effect on BP. Concomitant conditions It has been reported (although not conclusively) that cigarette smoking can interfere with blood pressure control mechanisms [14]. Obesity often is a major factor in the genesis of refractory hypertension. Obstructive sleep apnea (OSA) is being increasingly recognized as a possible factor in the development of resistant hypertension [15]. Obstructive sleep apnea It is becoming increasingly clear that systemic hypertension is not only commonly encountered in patients with OSA. but it tends to be quite severe and resistant to therapy [16,17]. In patients with significant hypertension, sleep disturbances are common. The mechanisms of hypertension in OSA are likely complex: hypoxemia, hypercarbia, and enhanced activity of the renin-angiotensin system and sympathetic nervous system. Excessive (or inappropriately high) levels of aldosterone are associated with OSA-associated resistant hypertension [18]. Aldosterone and resistant hypertension Recent advances in hypertension research suggest a strong participation of aldosterone in the pathogenetic mechanisms contributing to resistant hypertension. A number of studies have documented a high prevalence of hyperaldosteronism in patients with truly resistant hypertension [19]. Aldosterone excess can increase the BP by conventional aldosterone-mediated effects occurring via volume expansion and sodium retention. However, the aldosterone BP connection may not be that simple; aldosterone may directly increase systemic vascular resistance and decrease vascular compliance. Aldosterone also augments arterial stiffness and inhibits nitric oxide. Thus, multiple actions of aldosterone not only cause volume expansion but also provoke vasoconstriction leading to BP elevation (Fig. 1) [20–22].

507

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Aldosterone

Kidney

Baroreceptor dysfunction Vasculature

Structural changes •Vascular Remodeling •Collagen •H20 and Na+ retention

Functional changes •Endothelial dysfunction •Vascular inflammation •Sympathetic tone

Systemic vascular resistance

Arterial stiffness

BP Fig. 1. Relationship between aldosterone and blood pressure regulation (From Duprez D. Aldosterone and the vasculature: mechanisms mediating resistant hypertension. J Clin Hypertens (Greenwich) 2007;9(1 Suppl 1):13–8; with permission).

Secondary causes of hypertension In a small percentage of patients with refractory hypertension, the underlying cause may be a secondary form of hypertension such as renovascular hypertension or other possible etiologies (Table 4). Patients with a secondary form of hypertension may present with drug resistant hypertension; the sudden loss of effectiveness of previously effective antihypertensive regimen should raise the suspicion of renovascular disease or other secondary forms of hypertension [23]. Management of refractory hypertension Rational management of refractory hypertension requires a careful approach based on the causative considerations described in the foregoing Table 4 Some examples of secondary forms of hypertension that may be resistant to conventional antihypertensive therapy Renovascular hypertension Primary aldosteronism Pheochromocytoma Hypothyroidism Hyperthyroidism Hyperparathyroidism Aortic coarctation Renal disease

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discussion. It should be re-emphasized that since uncontrolled hypertension can cause significant morbidity and mortality, effective therapeutic management should be implemented. An overall management approach should be based on careful evaluation and application of rational medical therapy. Assessment When a patient’s BP does not respond satisfactorily to appropriate therapy, one has to consider whether the patient has pseudoresistance due to: white-coat hypertension, pseudohypertension in the elderly, or a measurement artifact. In some individuals, therefore, it is appropriate to obtain home BP readings and/or 24-hour ambulatory BP recordings to document the degree of hypertension outside the medical setting [24]. Although the authors do not recommend 24-hour ambulatory BP monitoring (ABPM) routinely in the assessment of resistant hypertension, in selected patients based upon the clinical characteristics and the medical setting versus home BP measurements, 24-hour ABPM may be useful in confirming or excluding persistent hypertension. ABPM may help verify if the BP levels obtained in the medical setting represent the patient’s home BP readings [25,26]. Although useful in the diagnosis, follow-up, and management of resistant hypertension, there are no guidelines for the application and frequency of 24-hour ABPM in clinical practice. In obese individuals, BP should always be measured with a large cuff. Once the validity of the BP measurement is confirmed, it is critical to ascertain the patient’s adherence to the prescribed regimen; nonadherence to treatment must be considered before extensive and unnecessary evaluation is undertaken [27,28]. Any factors responsible for noncompliance should be identified and corrected, if possible [1,29,30]. The treatment should be simplified, if possible, to encourage patient participation. Often an open dialog with the patient and the family can reveal if noncompliance is the cause of treatment failure. Correction of volume overload is one of the key strategies in managing resistant hypertension. Excessive salt intake must be curtailed. Adequate diuretic therapy should be implemented based upon clinical circumstances. The dosage and the choice of the diuretic should be appropriately modified. Patients with concomitant congestive heart failure or renal insufficiency require optimal volume control to achieve adequate BP control. The doses of antihypertensive drugs should be titrated systematically to determine whether or not the patient is responding to the treatment. Drug interactions should be considered and eliminated in the treatment of hypertension. A complete list should be made of drugs that could increase the BP such as steroids, oral contraceptives, sympathomimetics, nasal decongestants, cocaine, and appetite suppressants. Patients should be counseled about alcohol consumption, weight control, salt intake, and regular physical activity. Conditions such as obstructive sleep apnea or chronic pain should be vigorously addressed.

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Secondary causes of hypertension such as those listed in Table 4 should be considered in the overall evaluation of patients with resistant hypertension. Based upon the clinical characteristics, renovascular hypertension should be pursued in patients with truly refractory hypertension. Other causes such as primary hyperaldosteronism, pheochromocytoma, Cushing’s syndrome, coarctation of aorta, and renal disease should be considered based on the clinical course, follow-up, and laboratory findings. If an underlying cause is found, it should be corrected, if possible, to permit better BP control. Patients with refractory hypertension do experience and suffer from a high degree of target organ damage [31,32]. Drug treatment of resistant hypertension When a correctable cause is not found, patients with refractory hypertension require aggressive and diligently considered drug therapy to control BP. The first step is to optimize the existing therapy either by increasing the dosages or by changing to different combinations and observing the patient for few weeks. In the event that BP still remains uncontrolled, effective diuretic therapy should be implemented. Assuming that the patient has failed to respond to conventional therapies, consideration should be given to the use of hydralazine or minoxidil (in conjunction with a beta-blocker and a diuretic). Because direct vasodilators cause significant reflex activation of sympathetic nervous system and fluid retention, their use should be accompanied by coadministration of a beta-blocker and a diuretic (usually a loop diuretic). The authors generally give a trial of hydralazine therapy before choosing minoxidil therapy. Occasionally, further reductions in the BP can be secured by adding a fourth agent such as oral or transdermal clonidine. In patients with advanced renal impairment, dialysis might be required for adequate control of BP. Recent observations suggest that in some patients with resistant hypertension, aldosterone levels may be inappropriately high; this may worsen BP control for these patients with classical primary hyperaldosteronism. Patients without the syndrome but who have relatively high aldosterone levels may present with resistant hypertension [33]. Thus, it seems reasonable to offer a trial of aldosterone antagonist therapy (as an add-on) for patients who have resistant hypertension [34]. As discussed in the introduction, aldosterone may play an important role in the pathogenesis of resistant hypertension [35,36]. Based upon the clinical course and laboratory data (hypokalemia, metabolic alkalosis), some patients who have resistant hypertension require work-up for primary hyperaldosteronism. If the diagnosis is confirmed (adrenal adenoma or hyperplasia), specific surgical or medical treatment is recommended. However, aldosterone is linked to resistant hypertension even in the absence of primary hyperaldosteronism. As a result, aldosterone blockade may be helpful in resistant hypertension with or without evidence of aldosterone excess. Low doses of aldosterone antagonists

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added to other antihypertensive drugs such as diuretics, calcium channel blockers, Angiotensin converting enzyme inhibitors, angiotensin receptors blocking agents, and direct renin inhibitors: each provide further and significant reductions in the BP. Therapy with aldosterone antagonists (spironolactone or epleronone) is strongly recommended as ‘‘add-on’’ therapy for resistant hypertension. The usual precautions with aldosterone inhibition (potassium and renal function) should be followed. The carefully-performed clinical studies cited above have confirmed the usefulness of adding an aldosterone antagonist for the management of refractory hypertension. Recent research findings suggest that aldosterone may play a possible contributory role in the pathogenesis of refractory hypertension. Whether this is a direct effect of aldosterone itself on the peripheral vascular resistance or is due to its humorally-mediated volume expansion is not clear. Aldosterone promotes vascular inflammation and vessel stiffness, which may contribute, in part, to its effects on systemic blood. Although, in a small number of selected patients, work-up for primary hyperaldosteronism is indicated, therapeutic response to aldosterone antagonists in refractory hypertension occurs irrespective of aldosterone levels. It also has been proposed that the pathogenesis of OSA may be explained by inappropriate vascular actions of aldosterone. Therefore, aldosterone antagonism may be an option in the management of OSA, in addition to the correction of underlying respiratory disturbance. OSA may be associated with refractory hypertension. Whether uncontrolled hypertension is due to obesity or due to OSA is hard to distinguish clinically. Nevertheless, correction of breathing disorders may be a necessary tool in the therapeutic management of refractory hypertension associated with OSA [37–39].

Summary In most patients with chronic primary hypertension, BP can be controlled with changes in lifestyle and with one or two drugs. In some patients, however, BP remains uncontrolled even on a three-drug regimen, including a diuretic. These patients have refractory or resistant hypertension. In the management of refractory hypertension, it is essential to determine the cause or causes that could be responsible for the failure of the patient to respond to an appropriate regimen. If an identifiable cause is not found or it cannot be corrected, suitable changes should be made in the treatment plan including effective diuretic therapy and proper use of potent classes of antihypertensive drugs such as direct vasodilators. With the pathophysiological and therapeutic concepts discussed above, the problem of refractory hypertension can be treated successfully in a systematic fashion and on a rational basis. In some (elderly) patients, isolated systolic hypertension (ISH) can be extremely resistant to optimal therapy. However, if the patient can tolerate sustained therapy, ISH should be treated as aggressively as possible, which

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will often require the use of multiple drugs. Ongoing research with endothelin antagonists tetrahydrobiopterin (a nitric oxide donor), and mechanical stimulation of carotid body will shed light on these evolving interventions in the management of resistant hypertension. Sadly, recent surveys point out that the dietary habits of adults in United States who have hypertension have actually worsened [40]. Yet this gives us one more national mandate to advocate and apply sound eating habits to lower BP control. Resistant hypertension may have less to do with the pathophysiology of the disorder and more to do with physician or patient behaviors. Too often physicians fail to intensify drug regimen to achieve lower BP goals and too often, patients do not adhere to their prescribed treatment. These trends must be urgently reversed. Perhaps online pharmacy data, electronic and ambulatory information systems could be applied, in the future, for the indentification of patients with resistant hypertension and for improving adherence and therapy intensification , which could result in improved BP control in our communities.

References [1] Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National Heat, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection. Evaluation and Treatment of High Blood Pressure. Hypertension 2003;41:1206–52. [2] Hyman D, Pavlik V. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med 2001;345:479–86. [3] The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to Angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97. [4] Cushman WC, Ford CE, Cutler JA, et al, for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heat Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393–404. [5] Black HR, Elliott WJ, Grandits G, et al, for the CONVINCE Research Group. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 2003;289:2073–82. [6] Julius S, Kjeldsen SE, Brunner H, et al. for the VALUE Trial. VALUE trial: Long-term blood pressure trends in 12,449 patients with hypertension and high cardiovascular risk. Am J Hypertens 2003;16:544–8. [7] Thibonnier M. Ambulatory blood pressure monitoring: when is it warranted? Postgrad Med 1992;91:263–74. [8] Veglio F, Rabbia F, Riva P, et al. Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension. Clin Exp Hypertens 2001;23(3): 203–11. [9] Verdecchia P. Using out of office blood pressure monitoring in the management of hypertension. Curr Hypertens Rep 2001;3(5):400–5. [10] Messerli FH, Ventura HO, Amodeo C. Osler’s maneuver and pseudohypertension. N Engl J Med 1985;312:1548–51.

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[11] Mejia AD, Egan BM, Schork NJ, et al. Artifacts in measurement of blood pressure and lack of target organ involvement in the assessment of patients with treatment-resistant hypertension. Ann Intern Med 1990;112:270–7. [12] Dustan HP, Tarazi RM, Bravo EL. Dependence of arterial pressure on intravascular volume in treated hypertensive patients. N Engl J Med 1972;286:861–6. [13] Fierro-Carrion G, Ram CVS. Nonsteriodal anti-inflammatory drugs (NSAIDs) and blood pressure. Am J Cardiol 1997;80:775–6. [14] Bloxham CA, Beevers DG, Walker JM. Malignant hypertension and cigarette smoking. Br Med J 1997;1:581–3. [15] Lavie P, Hoffstein V. Sleep apnea syndrome: a possible contributing factor to resistant hypertension. Sleep 2001;24(6):721–5. [16] Logan AG, Perlikowski SM, mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271–7. [17] Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. [18] Calhoun DA, Nishizaka MK, Zaman MA, et al. Aldosterone excretion among subjects with resistant hypertension and symptoms of sleep apnea. Chest 2004;125:112–7. [19] Calhoun DA, Nishizaka MK, Zaman MA, et al. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002;40:892–6. [20] Duprez DA. Role of the rennin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens 2006;24:983–91. [21] Duprez D, De Buyzere M, Rietzschel ER, et al. Aldosterone and vascular damage. Curr Hypertens Rep 2002;2:327–34. [22] Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension 2006;47:312–8. [23] van Jaarsveld BC, Krijnen P, Derkx FH, et al. Resistance to antihypertensive medication as predictor of renal artery stenosis: comparison of two drug regimens. J Hum Hypertens 2001; 15(10):669–76. [24] White WB. Expanding the use of ambulatory blood pressure monitoring for the diagnosis and management of patients with hypertension. Hypertension 2006;47:14–5. [25] Clement DL, De Buyzere ML, De Bacquer DA, et al, for the Office versus Ambulatory Pressure Study Investigators. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 2003;348:2407–15. [26] Kikuya M, Ohkubo T, Asayama K, et al. Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama Study. Hypertension 2005; 45:240–5. [27] Felmeden DC, Lip GY. Resistant hypertension and the Birmingham hypertension square. Curr Hypertens Rep 2001;3(3):203–8. [28] Nuesch R, Schroeder K, Dieterle T, et al. Relation between insufficient response to antihypertensive treatment and poor compliance with treatment: a prospective case-control study. BMJ 2001;323(7305):142–6. [29] Setaro J, Black H. Refractory hypertension. N Engl J Med 1992;327:534–47. [30] Eraker S, Kirscht J, Becker M. Understanding and improving patient compliance. Ann Intern Med 1984;100:258–68. [31] Cuspidi C, Macca G, Sampieri L, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens 2001;19(11):2063–70. [32] Moser M, Setaro J. Clinical practice. Resistant or difficult-to-control hypertension. N Engl J Med 2006;355:385–92. [33] Sartori M, Calo LA, Mascagna V, et al. Aldosterone and refractory hipertensio´n: a prospective cohort study. Am J Hypertens 2006;19:373–9. [34] Epstein M. Aldosterone blockade: an emerging strategy for abrogating progressive renal disease. Am J Med 2006;119:912–9.

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[35] Gaddam KK, Pratt-Ubunama MN, Calhoun DA. Aldosterone antagonists: effective add-on therapy for the treatment of resistant hypertension. Expert Rev Cardiovasc Ther 2006;4: 353–9. [36] Calhoun DA. Use of aldosterone antagonists in resistant hypertension. Prog Cardiovasc Dis 2006;48:387–96. [37] Wolk R, Somers VK. Obesity-related cardiovascular disease: implications of obstructive sleep apnea. Diabetes Obes Metab 2006;8:250–60. [38] Drager LF, Pereira AC, Barreto-Filho JA, et al. Phenotypic characteristics associated with hypertension in patients with obstructive sleep apnea. J Hum Hypertens 2006;20:523–8. [39] Norman D, Loredo JS, Nelesen RA, et al. Effects of continuous positive airway pressure versus supplemental oxygen on 24 hour ambulatory blood pressure. Hypertension 2006;47: 840–5. [40] Mellen PB, Gao SK, Vitolins MZ, et al. Deteriorating dietary habits among adults with hypertension. Arch Intern Med 2008;168(3):308–14.

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The Trend Toward Geriatric Nephrology Fasika M. Tedla, MD*, Eli A. Friedman, MD, MACP, FRCP (UK) Department of Medicine, Division of Renal Diseases, SUNY Downstate Medical Center, 450 Clarkson Avenue Box 52, Brooklyn, NY 11203, USA

There have been significant changes in the age distribution of the world population since Nascher [1] coined the term ‘‘geriatrics’’ in 1909. In contrast to 1900, when life expectancy in industrialized countries of the time was 45–50 years, life expectancy at birth for the world as a whole rose to 65 years at the beginning of the twenty-first century. This gain in longevity is even greater for developed nations, several of which attained life expectancy of over 80 years [2]. This demographic change is expected to have profound implications to health care policy and economic development [2]. Elderly individuals are not only going to continue increasing in number, but they will also comprise a progressively larger proportion of the total population. During the period between 2000 and 2030, the number of persons older than 65 years is projected to grow from 550 to 937 million worldwide, and from 35 to 71 million in the United States. Globally, this growth represents an increase from 6.9% to 12%, while, in the United States, the expansion in this age group will be from 12.4% to 19.6% [3]. The combination of reduced workforce and increased spending to care for the elderly is anticipated to impose a severe stress on existing medical, public health, and social service systems. Prevalence of chronic diseases is high in older individuals and appears to be increasing over recent decades. Based on analysis of data from the National Health and Nutritional Examination Survey (NHANES), Weiss and colleagues [4] found that 74.6% of women and 67.4% of men aged 65 years or older suffer from arthritis, diabetes, coronary heart disease, cerebrovascular accidents, or chronic lower respiratory tract disease, either singly or in various combinations. In addition, trend analysis of NHANES data showed that the prevalence of obesity and diabetes in older people has increased over time [5]. * Corresponding author. E-mail address: [email protected] (F.M. Tedla). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.04.001 primarycare.theclinics.com

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Similarly, chronic kidney disease (CKD) afflicts a large proportion of older persons. In a study by Coresh and colleagues [6], for example, 37.8% of individuals older than 70 years in the NHANES surveys of 1999 – 2004 had an estimated glomerular filtration rate (GFR) between 15–59 mL/ min. By contrast, the prevalence of an equivalent degree of CKD was only 0.7% in those aged 20–39 years. Recent studies that identified CKD as an independent risk factor for cardiovascular morbidity and mortality underscore the significance of these observations [7,8]. Considered in this article are: 1) the relationship of aging to renal pathology and physiology; 2) the historical context bearing on the current epidemiology of renal failure therapy; and 3) the clinical and ethical implications of managing an increasingly older patient population with CKD. Historical perspective In 1972, when the US Congress was debating the merits of federal financing of dialysis, the estimated total number of patients with CKD was only 55,000, of whom 25,000 were expected to require dialysis [9]. Viewed through the lens of a rapidly expanding dialysis population, these figures have been criticized for underestimating the number of patients with kidney disease and the accompanying cost of the end stage renal disease (ESRD) program. It is, however, important to put the discrepancy between the anticipated and actual number of Patients who have ESRD within the larger context of changes in practice patterns and the prevalence of risk factors for renal disease over the years. Confronted with the availability of a life-sustaining therapy, meager resources and an ever-increasing number of patients with ESRD, Scribner and his colleagues were forced to institute stringent patient selection criteria at the inception of maintenance dialysis [10]. An anonymous admissions and policy committee was charged with selection of patients for dialysis among a pool of candidates screened by a panel of nephrologists [11]. The selection process was aimed at extending the lives of patients with a reasonable potential to be rehabilitated and continue gainful employment. Only patients between 18 and 45 years of age who were employed, emotionally stable, and without significant comorbid conditions were, therefore, initially presented to the selection committee. It was estimated, even based on these strict criteria, that as many as a 75% of the patients eligible for dialysis were unable to receive dialysis prior to enactment of the legislation funding the treatment of ESRD under Medicare [12]. The emergence of such a rationing of therapy incited intense ethical discussions in the public and medical community that became the impetus for the development of biomedical ethics as a discipline and the passage of the 1972 Medicare legislation [10,13–15]. Together with federal financing of ESRD care, this ethical challenge resulted in the gradual relaxation of the original selection criteria. By 1984, just a little over a decade after the

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Medicare ESRD legislation, the total number of dialysis patients grew to more than 100,000. Specifically excluded in the early days of dialysis, patients older than 65 years and those with diabetes accounted for 24% and 17% of this total, respectively. Although sicker and older patients constitute a greater proportion of the ESRD population in the United States, the latest available data from the United States Renal Data System (USRDS) indicate that mortality rate in the first year of dialysis has remained stable, while mortality after the first year has declined in recent years. Five-year survival for those initiating ESRD care in the years 1996–2000 grew by 6.2% compared to incident patients in the period 1991–1995 [16]. It is difficult to attribute this trend toward improved survival to any specific measure because of changes in patient population, ESRD care, and overall medical care over time. However, close examination of the evolution of the various facets of ESRD care provides a useful backdrop to these observations. Dialysis The shortcomings of early dialysis technology and the clinical sequelae of prolonging life with maintenance hemodialysis became apparent shortly after the work of Quinton and colleagues [17] produced the external Teflonsilastic arteriovenous shunt that allowed repeated access to a patient’s circulation. Radio-cephalic arteriovenous fistulae, first described by Brescia and Cimino [18], and synthetic grafts soon replaced the Quinton-Scribner shunt, which was prone to infection, thrombosis, and dislodgement [19]. Close collaboration between clinicians, researchers, and industry resulted in the development of single-patient dialysis machines equipped with elaborate monitoring systems and proportioning pumps that make dialysate from concentrate [10,20]. In 1968, Kaplow and Goffinet [21] reported on transient neutropenia associated with dialysis. This was later found to be due to sequestration of leukocytes in the pulmonary microcirculation as a result of activation of complement by cellophane (CuprophaneÒ), the dialyzer membrane widely used at that time [22,23]. Innovations in membrane technology, though originally stimulated by a quest for better permeability, culminated in the availability of more biocompatible membranes that are being used today [24]. The high hydraulic permeability of these membranes, and the shorter dialysis times that soon became fashionable, required precision in fluid removal, a need met by the advent of volumetric control of ultrafiltration [25]. Another source of hemodynamic instability during hemodialysis was the accumulation of acetate in some patients who metabolized acetate at a rate slower than its diffusion into the body [20]. Eventually, bicarbonate-based dialysate, which had been abandoned because it fostered bacterial growth, was reintroduced . Dialysis facilities now adhere to rigorous quality control protocols to ensure the absence of bacterial and chemical contamination

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during the process of generating dialysate. Concurrent with the progress made in hemodialysis, there were similar advances in both techniques and equipments of peritoneal dialysis [10]. Interest in quantitatively defining the appropriate dose of dialysis grew out of early observations that intense dialysis prevented or improved uremic neuropathy [26]. Although subsequent studies characterized the desirable minimum dose of dialysis [27–29], it remains controversial as to whether more dialysis than currently prescribed, achieved by increasing either the frequency or duration of dialysis, provides additional benefit [30,31]. Large multicenter prospective trials are now in progress to determine whether the advantages of daily and nocturnal hemodialysis treatments noted in small studies might be generally applicable to all hemodialysis programs. The Frequent Hemodialysis Network (FHN) is comparing conventional in-center dialysis with either home nocturnal or in-center daily dialysis in two controlled trials that each randomize 250 subjects at clinical centers in the United States and Canada [32]. It is anticipated that the results of these studies will provide valuable information on the relationship of dialysis dose to clinical outcomes. Kidney transplantation The performance of the first successful kidney transplantation between identical twins in 1954 ushered in the modern era of transplantation [33]. Initial enthusiasm was, however, tempered by an inability to extend the transplant procedure beyond monozygotic twins until the introduction of azathioprine. Kidney transplantation using a combination of azathioprine and corticosteroids achieved allograft survival approaching 60% at one year, but it was associated with high rates of mortality and acute rejection. The introduction of cyclosporine in the 1980s revolutionized transplantation, resulting in significant reduction in rates of acute rejection and oneyear graft survival of over 80% [34]. Newer immunosuppressive agents, such as tacrolimus, sirolimus, mycophenolate mofetil, and antilymphocyte antibodies, have since been added to the immunosuppressive armamentarium. These agents further improved short-term graft survival, permitting transplantation across stronger immune barriers. Medical therapy in kidney disease The universally fatal outcome of renal failure thwarted investigation into the systemic complications of uremia until dialysis made prolongation of life feasible. Current understanding of the pathogenesis and treatment of renal osteodystrophy evolved from the unrecognized toxicity of aluminumcontaining antacids used to treat hyperphosphatemia. Failure to control persistent hyperparathyroidism by raising plasma calcium levels with vitamin D and calcium supplementation in part led to elucidation of

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vitamin D metabolism and the identification of aluminum-induced osteomalacia. As the role of deficiency of 1, 25 (OH)2 cholecalciferol and hyperphosphatemia in the development of renal osteodystrophy became clear, a host of phosphate binders and vitamin D analogues with less toxic side effects were developed [10,35,36]. Following the cloning of the human erythropoietin gene in 1985, treatment with recombinant erythropoietin revolutionized the quality of life of dialysis patients who no longer were burdened by the adverse effects of uremia and the risks of intermittent transfusions [37–39]. In parallel with changes in ESRD care, significant progress was made in slowing progression of CKD. Inhibition of the renin-angiotensin system was first shown to retard progression of diabetic nephropathy [40]. This finding was later replicated in both diabetic and nondiabetic nephropathies [41–45].

Kidney disease in the elderly The spectrum of disorders affecting the elderly is wide and different from that observed in younger individuals. In addition, age-related changes in renal structure and function have been described extensively. A thorough understanding of these changes is crucial to correct evaluation and management of elderly individuals by primary care physicians and nephrologists alike. Aging and the kidney Several structural and functional changes in the kidneys have been associated with aging, as reviewed in detail by Epstein [46]. It is important to point out that most of the studies investigating the effect of aging on the kidneys are cross-sectional in design, targeted institutionalized geriatric patients, used heterogeneous approaches to determination of comorbid conditions and renal function, and span a long period of time. As a result, their findings should be extended to other populations with caution. However, the totality of the available evidence allows making some generalizations. The overall effect of age-related renal changes is constriction of renal functional reserve similar to that noted in other organs with aging, a phenomenon aptly termed ‘‘homeostenosis’’ [47]. Table 1 summarizes these changes and alterations in other organ systems that are relevant to the care of the elderly patient with renal disorders. Structurally, the kidneys atrophy with age and renal cortical thickness decreases approximately 10% per decade after the age of 30 [46,48]. Kidneys from older individuals have a higher degree of glomerular sclerosis, interstitial fibrosis and atherosclerotic changes [46,49]. Renal plasma flow is not only reduced in the elderly, but also increases to a lesser extent in response to vasodilatory stimuli [49–51].

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Table 1 Age-related changes in the kidney and other relevant organ systems Affected structure/function Change

Clinical implication

Hemodynamics

Reduced renal plasma flow

Unclear

Glomerulus

Sclerosis, reduced GFR

Drug dosing, cardiovascular risk, fluid-electrolyte imbalance

Tubules and interstitium Sodium balance

Atrophy, fibrosis Reduced sodium conservation and excretion Reduced concentrating and diluting capacity

Water balance

Tendency to volume depletion and overload Tendency to dehydration and hyponatremia

Vasculature Compliance

Reduced

Poor compensation of volume changes

Myocardium

Reduced compliance

Tendency to pulmonary edema and hypotension Dependence on atrial contractility

Abbreviation: GFR, glomerular filtration rate.

Estimated glomerular filtration rate (eGFR) is one of the most commonly used measures of renal function. Accurate measurement of GFR using clearance of inulin or radioactive tracers is cumbersome and expensive. As a result, creatinine clearance or formulae have been used to estimate GFR in most clinical situations. Utilization of these estimation tools is especially important for evaluating elderly individuals because they may have significantly reduced GFR despite serum creatinine levels within the reference range. This occurs because muscle mass, which determines the rate of production of creatinine, declines with age. The recent trend by some clinical laboratories to report eGFR with serum chemistry is a welcome development in this regard. An alternative marker molecule, cystatin C, has been proposed as superior to creatinine when employed to estimate GFR. Current studies seek to discern whether creatinine or cystatin C is preferable as well as which formula may be best to convert the measured value into an eGFR [52,53]. At present, this issue is unresolved. Several investigators described a progressive decline in GFR with age [50,54–56]. Most studies found a reduction in eGFR of about 1 mL/min/ year after the age of 50 years unrelated to other comorbid conditions or reduction in cardiac function. By contrast, a longitudinal study of communitydwelling individuals showed 35% of subjects did not have reduction in eGFR over an observation period as long as 24 years [56], indicating that deterioration of eGFR is not an inevitable consequence of aging. Serum electrolytes and extracellular fluid volume are not affected by aging under basal conditions, but important age-related changes in renal

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adaptation mechanisms have been characterized. Older individuals require nearly twice as long to attain the same degree of sodium conservation when sodium is restricted, and they excrete less sodium with salt loading as compared with younger subjects [57,58]. Similarly, the ability to concentrate and dilute urine in response to water deprivation or water loading, respectively, is constricted in older individuals [59,60]. The mechanisms underlying these changes are not completely understood. It is unlikely that these changes are solely due to reduction in GFR because alterations in the metabolism of vasopressin and hormones in the rennin-angiotensin system have been described [46]. Clinically, the changes described above hamper the ability of the older person to adapt to fluctuations in fluid and electrolyte balance that younger patients tolerate without sequelae. This tendency is further magnified by age-related changes in other organ systems, especially the cardiovascular system. The reduced diastolic relaxation of the myocardium that is noted with aging predisposes elderly individuals to pulmonary edema with volume expansion and makes them more dependent on atrial systole for adequate diastolic filling. Aging is also associated with blunting of the heart rate response to exercise or volume depletion. This, in combination with diminished vascular reactivity and baroreceptor response, increases the risk of hypotension or syncope with less fluid loss than in younger subjects [61]. Acute renal failure Observational studies have shown that the age distribution of patients treated for acute renal failure (ARF) has changed over time such that ARF, previously associated with younger adults, is a common problem in elderly individuals. Illustrating this transition is a single-center retrospective study from England in which the average age of patients treated for severe ARF increased from 41 years in the 1950s to 61 years in the 1980s [62]. This trend is in part due to relaxation of criteria for referral and treatment of the elderly over time, although the high rate of ARF in older patients has been documented by other investigators. In a two-year, community-based prospective study, the incidence of ARF was found to progressively increase with age; those adults in the 80–89 year age group have an annual incidence of 949 per million as compared to 17 per million in adults under 50 years of age [63]. Similarly, Liano and Pascual [64] conducted a prospective, multicenter, city-wide study on the epidemiology of ARF among inpatients in Madrid and found that patients older than 64 years accounted for 48% of those who developed ARF. The causes of ARF in the elderly generally mirror those in younger individuals. While multiple factors contribute to the development of ARF in most patients, some causes may be more prevalent in older patients [65–67]. Pascual and Liano [66] compared the etiology and prognosis of ARF among three patient age groups: under 65 years, between 65 to 79 years, and older than 80 years. They found prerenal and postrenal causes of ARF to be more common in geriatric patients.

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Some forms of parenchymal renal disease also appear to occur with relatively high frequency in the elderly. Lameire and colleagues [65] reported that renal emboli or renal vascular thrombosis represented 8% of ARF in patients older than 65 years as compared to 1.6% in those aged 17–64 years. Nephrotoxic insult is another major cause, accounting for 66% of ARF in elderly patients who had normal renal function on admission in one study [67]. The spectrum of disorders identified in biopsy series, however, is different from that described above. This most likely reflects the indications elected for performing renal biopsy. In an analysis of 259 renal biopsies performed for evaluation of ARF in patients older than 60 years, the top two primary diagnoses were pauci-immune glomerulonephritis (31.2%) and interstitial nephritis (18.6%) [68]. Whether age, per se, impacts prognosis in ARF is controversial. Advanced age has been associated with increased mortality or inferior renal outcomes in some, but not all, studies [65,66,68–72]. It is important to note that most studies are small, retrospective and uncontrolled. They examined specific populations with ARF, such as those patients who underwent biopsies or surgical procedures, or those patients who were referred to a nephrologist. As a result, it is likely that their findings were influenced by the prognosis of the underlying disease process or selection bias rather than by age alone. The role of such confounding variables was highlighted by Pascual and Liano [66] in their prospective study. They replicated the findings of earlier studies that found no relationship between adverse prognosis and age even though older patients were less likely to receive dialysis than younger patients. In summary, ARF is common among the elderly and some causes of ARF are more frequent among older patients, probably reflecting the prevalent comorbid conditions and age-related renal changes in this age group. However, the available evidence does not support withholding of renal replacement therapy for ARF solely on the basis of advanced age. Chronic kidney disease Concern about the rapid expansion of the ESRD population prompted the National Kidney Foundation to develop guidelines for the definition and classification of chronic kidney disease according to uniform criteria, as shown in Table 2 [73]. Subsequent analyses of NHANES data according to these criteria have provided reasonable estimates of the burden of CKD in the adult United States population. Based on NHANES III, which was conducted from 1998 to 1994, the number of adults in the United States with some form of CKD was estimated to be 19.2 million [74]. Age was identified as one of the risk factors for CKD, with 11% of those older than 65 years without diabetes or hypertension having stage 3 or worse CKD. Comparison of the findings from this period to NHANES data from 1999–2004 showed that the prevalence of CKD is increasing, especially in those older than 70 years [6].

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Table 2 Stages of chronic kidney disease Stage

GFR in mL/min/1.73 m2

1 2 3 4 5

R 90 AND kidney damage 60–89 AND kidney damage 30–59 15–29 !15 or dialysis

Kidney damage is defined as either pathological abnormality or marker of renal injury such as abnormal blood tests, urine tests or imaging studies. Abbreviation: GFR, glomerular filtration rate. Modified from National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–266; with permission.

Aging of the population, however, did not appear to be the main factor responsible for this trend since increased prevalence of CKD was noted across all age strata, and the temporal pattern persisted after adjustment for age, sex, and race or ethnic composition. In contrast, further adjustment for diabetes, hypertension and obesity accounted for nearly all the observed difference, highlighting the importance of these risk factors in the development of CKD. Large observational studies have recently corroborated the findings of several earlier studies that linked CKD to high mortality, especially due to cardiovascular events [7,8]. Go and colleagues [8] compared outcomes between patients with estimated GFR R 60 mL/min/1.73 m2 and those with stage 3–5 CKD using data from a large health maintenance organization. They reported that patients in the latter group were older (mean age R 63 years) and had higher rates of pre-existing cardiovascular disease and risk factors for atherosclerosis. After adjustment for these and other variables, there was a graded increase in overall mortality, cardiovascular events, and hospitalization rates when eGFR fell below 60 mL/min/1.73 m2, and patients with stage 5 CKD had nearly six times more risk of death than the reference group. A similar association between reduced eGFR and adverse outcome was made by Anavekar and colleagues [7] in their study of survivors of myocardial infarction from the Valsartan in Acute Myocardial Infarction Trial. In their fully adjusted model, each reduction by 10 units below the reference eGFR of 81 mL/min/1.73 m2 was associated with 10% excess risk for mortality and nonfatal cardiovascular complications. The mean estimated GFR for the entire study population was 70.2 mL/min/1.73 m2, with 38.3% of subjects having an eGFR of at least 75 mL/min/1.73 m2. Patients in the lowest eGFR group (!45 mL/min/m2) were older (mean age of 73 years) and had the highest rates of hypertension, diabetes, and prior myocardial infarction. In addition, those in lower eGFR groups were less likely to have received aspirin, b-blocker, statins or undergone coronary revascularization.

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At present, it is unclear whether the observed association between CKD and cardiovascular mortality can be explained by aggregation of traditional cardiovascular risk factors, effects of the uremic state, or underutilization of proven therapies. Conversely, CKD may simply be a marker of the severity of cardiovascular disease. It is, however, important to note that all these factors may not be mutually exclusive; until further studies elucidate the exact relationships, the emphasis should be on controlling potentially modifiable risk factors in CKD patients. Dialysis and transplantation As mentioned earlier, the elderly constitute a significant part of the total ESRD population in the United States. The mean age at initiation of ESRD therapy rose from 52.8 years to 62.8 years between 1980 and 2005, as depicted in Fig. 1. According to the latest data from the USRDS, there were over 470,000 patients with ESRD at the end of 2005, of which a third were older than 65 years. In addition, the highest prevalence rate was for those aged 65–74 years at 5500 per million followed by a rate of 4800 per million for those 75 years and older. The high prevalence rate of ESRD in the geriatric age group is driven by a similarly high incidence rate, which until recently had been steadily rising [16]. Although overall mortality rates appear to have stabilized or improved over the last two decades, older age in ESRD is strongly associated with higher risk of mortality [16]. Among patients who have ESRD and are age 65 years or older, all-cause mortality has been reported to be three times that of patients aged 45–64 years and six times that in the general

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Fig. 1. Mean age of incident ESRD patients from 1980 to 2005. (Data from U.S. Renal Data System, 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.)

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population. Patients on dialysis make up a larger proportion of the mortality burden, with rates 4–7 times higher than that in transplant recipients. Two important factors help explain this difference in mortality between dialysis and renal transplant patients: the reality that transplant patients are a selectively screened and healthier group, and survival advantage due to renal transplantation. Wolfe and colleagues [75] compared mortality between patients on dialysis, those patients on the deceased donor transplant waiting list, and recipients of first deceased-donor renal transplants. Mortality was 49% lower in dialysis patients listed for transplants as compared with dialysis patients who were not listed. Transplant recipients, on the other hand, had a transient rise in mortality in the first 3–4 months following transplantation. However, this excess mortality was offset by survival advantage in subsequent months such that long-term mortality in transplant recipients is 68% lower than that in patients on the waiting list. At present, there is no age limit for renal transplantation within the United States. The survival advantage provided by transplantation has not been restricted to young individuals, although the number of years elderly individuals are expected to gain from transplantation diminishes with increasing age [75,76]. This is largely due to the higher burden of comorbid conditions in older patients. Oniscu and colleagues, reported on graft and patient outcomes of patients transplanted during the 10-year period between 1989 and 1999 in Scotland. They found that those older than 65 years had more cardiovascular disease, fewer rejections, higher rates of delayed graft function, and higher rates of transplantation with extendedcriteria donor kidneys. Compared with patients aged 18–49 years, the risk of mortality was more than four times higher in transplant recipients older than 65 years, who also were more likely to die with a functioning graft. Death with functioning graft (DWFG) has been identified as an important cause of graft loss. In an analysis of national registry data in the United States, DWFG accounted for 42.5% of all graft loss. Age at transplantation was the strongest predictor of DWFG, with those patients who were older than 65 years having mortality rates seven times higher than recipients aged 18–29 years [77]. Due to the long waiting time for a deceased donor kidney transplant and the high mortality of elderly dialysis patients, patients on the transplant waiting list older than 65 years are two or more times likely to die without getting transplant than those aged 20–44 years [16]. This has led some to suggest that older individuals may get more survival benefit if they receive an extended-criteria donor kidney than wait longer for a standard-criteria kidney [78]. There is currently an ongoing debate as to whether age should be a factor in allocation of kidneys to adult patients who have ESRD. Proponents of a system that allocates kidneys based on life expectancy after transplantation cite the aforementioned data to back their argument that such a system delivers scarce resources to those who would most benefit from them [79]. On the other hand, graft survival in older patients appears to be equivalent

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to that in younger individuals after adjustment for the impact of DWFG, as shown in Fig. 2. The subset of elderly transplant recipients who would gain significant benefit from renal transplantation, therefore, may be disadvantaged if older age is equated with poor long-term survival. In summary, the elderly make up a considerable proportion of patients who have ESRD and they carry a high burden of comorbidities and mortality. However, the outcome of treatment for ESRD is not universally grim in the elderly and until better prognostication methods become available, denial of treatment for older patients on the basis of age alone may not be appropriate.

Fig. 2. Death-censored deceased-donor (A) and live-donor (B) graft survival by age group of renal transplant recipients in the United States. (Data from U.S. Renal Data System, 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.)

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Summary It is apparent from the above discussion that elderly individuals do not make up a homogeneous group. While some processes that underlie senescence operate in all individuals, the rate of aging is different at the individual level and is, in part, influenced by coexistent disease states. Chronic kidney disease, acute renal failure, and end-stage renal disease affect a significant proportion of older persons. In addition, the prevalence of chronic kidney disease and end-stage renal disease continues to increase, driven largely by the rise in the incidence of diabetes and obesity. Physicians caring for elderly patients with renal disorders should be well versed in the age-related changes of vital organ functions and understand the gaps in the current body of knowledge. References [1] Nascher IL. Geriatrics. New York Medical Journal 1909;90:358–9. [2] United Nations. An aging world population. In: World economic and social survey 2007: development in an aging world. Available at: http://www.un.org/esa/policy/wess/ wess2007files/wess2007.pdf. Accessed January 31, 2008. [3] Center for Disease Control and Prevention. Trends in aging–United States and worldwide. MMWR Morb Mortal Wkly Rep 2003;52(6):101–4. [4] Weiss CO, Boyd CM, Yu Q, et al. Patterns of prevalent major chronic disease among older adults in the United States. JAMA 2007;298(10):1160–2. [5] Kramarow E, Lubitz J, Lentzner H, et al. Trends in the health of older Americans, 1970– 2005. Health Aff (Millwood) 2007;26(5):1417–25. [6] Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298(17):2038–47. [7] Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351(13):1285–95. [8] Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351(13):1296–305. [9] Rettig RA. Origins of the medicare kidney disease entitlement: the social security amendments of 1972. In: Hanna KE, editor. Biomedical politics. Washington, DC: National Academy Press; 1991. p. 176–214. [10] Blagg CR. The early history of dialysis for chronic renal failure in the United States: a view from Seattle. Am J Kidney Dis 2007;49(3):482–96. [11] Darrah JB. Moment in history. The committee. ASAIO Trans 1987;33(4):791–3. [12] Waterfall WK. Dialysis and transplant. Br Med J 1980;281(6242):726–7. [13] Friedman EA. Kolff’s contributions provoked the birth of ethics in nephrology. Artif Organs 1998;22(11):940–4. [14] Alexander S. They decide who lives, who dies: medical miracle puts moral burden on small committee. Life 1962;53:102–25. [15] Scribner BH. Ethical problems of using artificial organs to sustain human life. Trans Am Soc Artif Intern Organs 1964;10:209–12. [16] U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD), 2007. [17] Quinton W, Dillard D, Scribner BH. Cannulation of blood vessels for prolonged hemodialysis. Trans Am Soc Artif Intern Organs 1960;6:104–13. [18] Brescia MJ, Cimino JE, Appel K, et al. Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Engl J Med 1966;275(20):1089–92.

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[19] Kapoian T, Sherman RA. A brief history of vascular access for hemodialysis: an unfinished story. Semin Nephrol 1997;17(3):239–45. [20] Van Stone JC. Dialysis equipment and dialysate, past, present and the future. Semin Nephrol 1997;17(3):214–7. [21] Kaplow LS, Goffinet JA. Profound neutropenia during the early phase of hemodialysis. JAMA 1968;203(13):1135–7. [22] Craddock PR, Fehr J, Dalmasso AP, et al. Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 1977;59(5):879–88. [23] Craddock PR, Fehr J, Brigham KL, et al. Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 1977;296(14):769–74. [24] Cheung AK, Leypoldt JK. The hemodialysis membranes: a historical perspective, current state and future prospect. Semin Nephrol 1997;17(3):196–213. [25] Roy T, Ahrenholz P, Falkenhagen D, et al. Volumetrically controlled ultrafiltration. Current experiences and future prospects. Int J Artif Organs 1982;5(3):131–5. [26] Jebsen RH, Tenckhoff H, Honet JC. Natural history of uremic polyneuropathy and effects of dialysis. N Engl J Med 1967;277(7):327–33. [27] Lowrie EG, Laird NM, Parker TF, et al. Effect of the hemodialysis prescription of patient morbidity: report from the national cooperative dialysis Study. N Engl J Med 1981; 305(20):1176–81. [28] Gotch FA, Sargent JA. A mechanistic analysis of the national cooperative dialysis study (NCDS). Kidney Int 1985;28(3):526–34. [29] Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. Canada-USA (CANUSA) Peritoneal dialysis study group. J Am Soc Nephrol 1996;7(2):198–207. [30] Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347(25):2010–9. [31] Paniagua R, Amato D, Vonesh E, et al. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13(5):1307–20. [32] Suri RS, Garg AX, Chertow GM, et al. Frequent hemodialysis network (FHN) randomized trials: study design. Kidney Int 2007;71(4):349–59. [33] Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation of the human kidney between identical twins. JAMA 1956;160(4):277–82. [34] Morris PJ. Transplantation–a medical miracle of the 20th century. N Engl J Med 2004; 351(26):2678–80. [35] Sherrard DJ. Renal osteodystrophy. In: Henrich WL, editor. Principles and practice of dialysis. 3rd edition. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 381–92. [36] Andress DL. Vitamin D treatment in chronic kidney disease. Semin Dial 2005;18(4):315–21. [37] Lin FK, Suggs S, Lin CH, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A 1985;82(22):7580–4. [38] Eschbach JW, Egrie JC, Downing MR, et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316(2):73–8. [39] Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1989;111(12):992–1000. [40] Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med 1993;329(20): 1456–62. [41] Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12): 861–9.

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[42] Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345(12):851–60. [43] Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The angiotensin-converting-enzyme inhibition in progressive renal insufficiency study group. N Engl J Med 1996;334(15): 939–45. [44] Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN group (gruppo italiano di studi epidemiologici in nefrologia). Lancet 1997;349(9069): 1857–63. [45] Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361(9352):117–24. [46] Epstein M. Aging and the kidney. J Am Soc Nephrol 1996;7(8):1106–22. [47] Resnick NM, Rosa D. Geriatric medicine. In: Kasper D, Braunwald E, Fauci A, editors. Harrison’s Principles of internal medicine. 16th edition. New York: McGraw-Hill; 2005. p. 43–53. [48] Gourtsoyiannis N, Prassopoulos P, Cavouras D, et al. The thickness of the renal parenchyma decreases with age: a CT study of 360 patients. AJR Am J Roentgenol 1990;155(3): 541–4. [49] Fuiano G, Sund S, Mazza G, et al. Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int 2001;59(3):1052–8. [50] Davies DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 1950;29(5):496–507. [51] Mulkerrin EC, Brain A, Hampton D, et al. Reduced renal hemodynamic response to atrial natriuretic peptide in elderly volunteers. Am J Kidney Dis 1993;22(4):538–44. [52] Premaratne E, Macisaac R, Finch S, et al. Serial measurements of cystatin C are more accurate than creatinine-based methods in detecting declining renal function in type 1 diabetes. Diabetes Care March 4, 2008;31(5):971–3. [53] Gourishankar S, Courtney M, Jhangri GS, et al. Serum cystatin C performs similarly to traditional markers of kidney function in the evaluation of donor kidney function prior to and following unilateral nephrectomy. Nephrol Dial Transplant March 14, 2008, in press. [54] Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol 1976;31(2):155–63. [55] Danziger RS, Tobin JD, Becker LC, et al. The age-associated decline in glomerular filtration in healthy normotensive volunteers. Lack of relationship to cardiovascular performance. J Am Geriatr Soc 1990;38(10):1127–32. [56] Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33(4):278–85. [57] Epstein M, Hollenberg NK. Age as a determinant of renal sodium conservation in normal man. J Lab Clin Med 1976;87(3):411–7. [58] Luft FC, Grim CE, Fineberg N, et al. Effects of volume expansion and contraction in normotensive whites, blacks, and subjects of different ages. Circulation 1979;59(4):643–50. [59] Rowe JW, Shock NW, DeFronzo RA. The influence of age on the renal response to water deprivation in man. Nephron 1976;17(4):270–8. [60] Crowe MJ, Forsling ML, Rolls BJ, et al. Altered water excretion in healthy elderly men. Age Ageing 1987;16(5):285–93. [61] Ferrari AU, Radaelli A, Centola M. Invited review: aging and the cardiovascular system. J Appl Physiol 2003;95(6):2591–7. [62] Turney JH, Marshall DH, Brownjohn AM, et al. The evolution of acute renal failure, 1956– 1988. Q J Med 1990;74(273):83–104.

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[63] Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: results of a community based study. BMJ 1993;306(6876):481–3. [64] Liano F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid acute renal failure study group. Kidney Int 1996;50(3):811–8. [65] Lameire N, Matthys E, Vanholder R, et al. Causes and prognosis of acute renal failure in elderly patients. Nephrol Dial Transplant 1987;2(5):316–22. [66] Pascual J, Liano F. Causes and prognosis of acute renal failure in the very old. Madrid acute renal failure study group. J Am Geriatr Soc 1998;46(6):721–5. [67] Kohli HS, Bhaskaran MC, Muthukumar T, et al. Treatment-related acute renal failure in the elderly: a hospital-based prospective study. Nephrol Dial Transplant 2000;15(2):212–7. [68] Haas M, Spargo BH, Wit EJ, et al. Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 cases. Am J Kidney Dis 2000;35(3):433–47. [69] Gentric A, Cledes J. Immediate and long-term prognosis in acute renal failure in the elderly. Nephrol Dial Transplant 1991;6(2):86–90. [70] Cioffi WG, Ashikaga T, Gamelli RL. Probability of surviving postoperative acute renal failure. Development of a prognostic index. Ann Surg 1984;200(2):205–11. [71] Bullock ML, Umen AJ, Finkelstein M, et al. The assessment of risk factors in 462 patients with acute renal failure. Am J Kidney Dis 1985;5(2):97–103. [72] Pascual J, Orofino L, Liano F, et al. Incidence and prognosis of acute renal failure in older patients. J Am Geriatr Soc 1990;38(1):25–30. [73] National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1): S1–266. [74] Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey. Am J Kidney Dis 2003;41(1):1–12. [75] Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341(23):1725–30. [76] Oniscu GC, Brown H, Forsythe JL. How old is old for transplantation? Am J Transplant 2004;4(12):2067–74. [77] Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57(1):307–13. [78] Schold JD, Meier-Kriesche HU. Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis? Clin J Am Soc Nephrol 2006;1(3): 532–8. [79] Jassal SV, Krahn MD, Naglie G, et al. Kidney transplantation in the elderly: a decision analysis. J Am Soc Nephrol 2003;14(1):187–96.

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Classification and Epidemiology of Childhood Sleep Disorders Judith Owens, MD, MPH Brown Medical School, Division of Pediatric Ambulatory Medicine, Rhode Island Hospital, 593 Eddy Street, Potter Building, Suite 200, Providence, RI 02903, USA

Approximately 25% of all children experience some type of sleep problem at some point during childhood, ranging from short-term difficulties in falling asleep and night wakings, to more serious primary sleep disorders, such as obstructive sleep apnea. A number of studies have examined the prevalence of parent- and child-reported sleep complaints in large samples of healthy, typically developing children and adolescents; many of these have also further delineated the association between disrupted sleep and behavioral concerns. Sleep problems are even more prevalent in children and adolescents with chronic medical, neurodevelopmental, and psychiatric conditions. It is important to note that definitions of normal sleep patterns, sleep requirements, and sleep disorders in childhood must necessarily incorporate the wide range of normal developmental and physical maturational changes across childhood and adolescence, and cultural, environmental, and social influences.

Normal sleep patterns and behavior in childhood To define abnormal, problematic, or insufficient sleep in infants, children, and adolescents, it is important to have an understanding of what constitutes ‘‘normal’’ sleep in children. Definitions of normal sleep patterns and sleep requirements in childhood, and descriptions of sleep phenotypes, must necessarily incorporate the wide range of normal developmental and physical maturational changes across childhood and adolescence. Furthermore, cultural, environmental, and social influences, which profoundly influence children’s sleep in particular, must also be considered.

A version of this article originally appeared in Sleep Medicine Clinics, volume 2, issue 3. E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.003 primarycare.theclinics.com

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Surprisingly, however, there are relatively little large-scale epidemiologic data available that systematically define normal sleep and wakefulness patterns and sleep duration in the pediatric population. Most of the existing studies have used subjective, parent-report, retrospective, cross-sectional surveys in selected populations. Although cross-sectional studies yield important information regarding sleep in discrete age groups, by their nature they do not describe the evolution and persistence of sleep-wake patterns over time, nor do they help to elucidate the complex reciprocal relationship between sleep and cognitive-emotional development from the prenatal period through adolescence. There are even more limited data from studies using more objective methods of measuring sleep quality and duration, such as polysomnography and actigraphy, and many of these studies were conducted before the establishment of accepted sleep monitoring and scoring standards. Recognizing the limitations of the current knowledge base, epidemiologic studies do support several general trends in normal sleep patterns across childhood. As with most sleep behaviors, these trends reflect the physiologic-chronobiologic, developmental, and social-environmental changes that are occurring across childhood. These include the following: 1. A decline in the average 24-hour sleep duration from infancy through adolescence, which involves a decrease in both diurnal and nocturnal sleep amounts [1]. In particular, there is a dramatic decline in daytime sleep (scheduled napping) between 18 months and 5 years, with a less marked and more gradual continued decrease in nocturnal sleep amounts into late adolescence. 2. A gradual shift to a later bedtime and sleep-onset time that begins in middle childhood and accelerates in early to mid adolescence. 3. Irregularity of sleep-wake patterns characterized by increasingly larger discrepancies between school night and non–school night bedtimes and wake times, and increased weekend oversleep that typically begin in middle childhood and peak in adolescence. There is also some evidence to suggest that sleep patterns and behaviors in children and adolescents have changed over time. Several studies have not only shown that average sleep duration decreases across middle childhood and adolescence (in contrast to sleep needs, which do not dramatically decline), but that sleep duration in equivalent age groups has declined over time [1]. This trend seems to be related in school-aged children largely to later bedtimes and, in adolescents, to earlier sleep-offset and later sleeponset times. Variables affecting sleep patterns and behaviors in children The relative prevalence and the various types of sleep problems that occur throughout childhood must also be understood in the context of normal physical and cognitive-emotional phenomena that are occurring at

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different developmental stages. For example, temporary regressions in sleep development often accompany the achievement of motor and cognitive milestones in the first year of life. Similarly, an increase in nighttime fears and night wakings in toddlers may be a temporary manifestation of developmentally normal separation anxiety peaking during that stage. Parental recognition and reporting of sleep problems in children also varies across childhood, with parents of infants and younger children more likely to be aware of sleep concerns (and to bring them to the attention of their health care provider) than those of school-aged children and adolescents. Furthermore, the very definition of what behaviors constitute a sleep problem is often highly subjective, and is frequently determined by the amount of disruption caused to parents’ sleep. In addition to considering sleep disturbances within a developmental context, a number of other important child, parental, and environmental variables affect the type, relative prevalence, chronicity, and severity of sleep problems. In particular, it should be noted that sleep may function as a kind of barometer of a child’s physical and mental health. Child variables that may significantly impact sleep include temperament and behavioral style, cognitive and language abilities, individual variations in circadian preference, and the presence of comorbid developmental, medical, or psychiatric conditions. Parental variables include parenting and discipline styles; mental health issues, such as maternal depression [2]; medical issues; family stress; parents’ education level and knowledge of child development; quality and quantity of parents’ sleep; and differences between mothers and fathers in regards to perception of their child’s sleep [3,4]. Environmental variables include the physical sleeping environment (space, noise, perceived environmental threats to safety, sleep surface, room and bed sharing); family composition (number, ages, and health status of siblings and extended family members); and lifestyle issues (parental work status, competing priorities for time, household rules [5], and even socioeconomic status [household income [6]]). For example, a number of studies have now suggested a link between television viewing habits and sleep problems in children [5,7,8]. Furthermore, although many sleep problems in infants and children are transient and self-limited in nature, the common wisdom that children ‘‘grow out of’’ sleep problems in many cases is not an accurate perception. A number of studies have documented both the persistence and recurrence of infant sleep problems into early childhood [9]. A number of intrinsic and extrinsic risk factors (eg, difficult temperament, chronic illness, neurodevelopmental delays, maternal depression, family stress) may predispose a given child to develop a more chronic sleep disturbance. Finally, it is also important to consider the cultural, racial-ethnic, and family context within which sleep behaviors in children occur [10]. For example, co-sleeping of infants and parents is a common and accepted practice in many ethnic groups, including African Americans, Hispanics, and Southeast Asians, both in their counties of origin and in the United States.

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Rates of bed-sharing also vary widely in more ‘‘western’’ cultures, including the United States, in conjunction with such variables as socioeconomic status, maternal education, and family composition, whereas in more ‘‘traditional’’ cultures these factors do not significantly affect bed-sharing rates. In many more traditional societies, sleep is heavily embedded in social practices, and both the sleeping environment and the positioning of sleep periods within the context of other activities is much less solitary and less rigid than in more urbanized cultures. The relative value and importance of sleep as a health behavior, the interpretation of ‘‘problematic’’ versus normal sleep by parents, location of the sleep space and bedtime practices [11], and the level of acceptability of various treatment interventions (pharmacologic, behavioral, complimentary, and alternative strategies) for sleep problems are just a few additional examples of sleep issues that are impacted on by race-ethnicity and cultural and family values and practices. Impact of sleep problems Although a detailed description of the impact of disrupted or insufficient sleep on children’s health and well-being is beyond the scope of this article, any discussion of the epidemiology of pediatric sleep must underscore the importance of the relationships between sleep problems and mood, performance, and behavior. Many of the studies that have examined these complex relationships have sought to provide answers to such fundamental questions as how much sleep is needed by infants, children, and teenagers for optimal functioning; the minimum amount of sleep required at different developmental levels; the relative impact of other variables that may also affect sleep needs (eg, pubertal development) and patterns (eg, racial differences in napping); and how patterns of growth and development from infancy to adolescence are negatively impacted by insufficient sleep. In general, studies that have examined these relationships have used one of a number of different methodologies: (1) assessment of effects of experimental in-laboratory or at-home sleep restriction on mood, neuropsychologic test performance, and observed behavior; (2) evaluation of mood, behavioral, and academic problems in children with clinical sleep disorders (eg, obstructive sleep apnea, restless leg syndrome, periodic limb movement disorder); (3) examination of the impact of treatment of sleep disorders (pharmacologic, surgical, behavioral) on neurobehavioral measures; (4) identification of behavioral and academic dysfunction in ‘‘naturalistic settings’’ of children identified as poor sleepers or those with insufficient sleep; and (5) identification of sleep problems in populations of children with behavioral and academic problems (eg, hyperactivity-impulsivity, inattention) compared with typically developing control children. A number of studies have demonstrated that children for whom parents report sleep complaints are more likely to manifest not only increased subjective daytime sleepiness, but also moodiness, behavioral problems, and school and learning problems [12]. In one survey of sleep problems in

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elementary school-aged children, teachers reported behavioral evidence of significant daytime sleepiness in the classroom setting in 10% of their students [13]. Disrupted sleep patterns, including variability in sleep amounts and bedtimes, have been shown to predict less optimal adjustment in preschoolers [14]. Another study found a significant correlation between early rise times and self-reported difficulties in attention and concentration in fifth graders [15]. Because of their cross-sectional design, however, and the reliance on parental (or self) report for description of both sleep and behavioral variables in many of these studies, the results must be interpreted cautiously in terms of sleep as a causal or sole contributing factor. In similar survey studies, adolescents who reported disturbed or inadequate sleep were also more likely to report subjective sleepiness, mood disturbances, and performance deficits in both social and academic spheres [16,17]. Adolescents may be at increased risk for sleep disturbances and inadequate sleep for a number of biologic and environmental-psychosocial reasons, and studies have suggested that the lifetime prevalence of insomnia in random samples of adolescents may be as high as 11% [18]. The resultant decrease in total sleep time in adolescents has been associated in several studies with poorer grades in school, and depressed mood and increased anxiety. One study [19] that found an overall prevalence of significant sleep problems in about one third of the adolescents surveyed also reported an increased level of self- and parent-reported externalizing behavioral problems in the sleep-disturbed sample. Sleep problems are also a significant source of distress for families, and may be one of the primary reasons for caregiver stress in families with children who have chronic medical illnesses or severe neurodevelopment delays [20]. Furthermore, the impact of childhood sleep problems is intensified by their direct relationship to the quality and quantity of parents’ sleep, particularly if disrupted sleep results in daytime fatigue and mood disturbances, and leads to a decreased level of effective parenting [4]. Conversely, successful intervention not only has the effect of improving the sleep of the entire family, but may also aid parents in developing behavioral strategies that have the potential to generalize for use with daytime behavior problems. Empirical studies involving both normal and sleep-deprived pediatric populations (children with sleep disorders, adolescents, and so forth) have begun to describe the extent and the consequences of inadequate or disrupted sleep in children. Unlike adults, daytime sleepiness in children may not be characterized by such overt behaviors as yawning, complaining about fatigue, and so forth, but may rather be associated with a host of more subtle or even ‘‘paradoxical’’ (eg, increased activity) behavioral manifestations. These range from emotional lability, irritability, and low frustration tolerance (internalizing behaviors); to neurocognitive deficits (particularly those involving higher level executive functions, such as working memory, cognitive flexibility, and the ability to reason and think abstractly); to behavioral disinhibition (externalizing behaviors, such as increased aggression and

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impulsivity) [12]. In turn, functional deficits in mood, attention, cognition, and behavior may lead to performance deficits in the home, school, and social settings. Studies of sleep in children with primary behavior and learning problems have further supported an association between sleep and performance impairments. Finally, sleep problems in childhood may be an important precursor and potential early indicator of future anxiety, depression, and substance use disorders. More recent studies have also begun to explore potential links among sleep problems, insufficient sleep, and health problems [21]. One of the most potentially significant relationships from a public health perspective is that between short sleep duration and obesity in pediatric populations, a finding that has now been replicated in a variety of age groups in a number of different pediatric populations around the world [22–28], presumably mediated through effects on various metabolic systems and on patterns of hunger and satiety (glucose metabolism, insulin resistance, ghrelin and leptin levels). Additional health outcomes of inadequate or disrupted sleep in children include potential deleterious effects on the cardiovascular and immune systems, an increase in accidental injuries [29], and inappropriate consumption of alertness-enhancing substances, such as caffeine [30] and psychostimulants [31]. Empirical evidence indicates that children experience significant daytime sleepiness as a result of disturbed or inadequate sleep, and most studies suggest a strong link between sleep disturbance and behavioral problems. Behavioral manifestations of sleepiness in children not only vary with age and developmental level, but these behaviors may not be reliably interpreted as such by parents and other observers. Unfortunately, objective, reliable, and cost-effective measures of sleepiness and alertness that could be applied to large epidemiologic samples of children are currently largely lacking. In addition, there is little subjective parent-report or self-report data regarding sleepiness in children, although more recently daytime sleepiness measures for pediatric populations have been developed [32]. The few studies that have examined the prevalence of daytime sleepiness in large nonclinical samples of children have suggested that daytime somnolence is a common finding, even in school-aged children [33]. Classification systems for pediatric sleep disorders For a variety of reasons, it is often a challenge operationally to define ‘‘problem sleep’’ in children. The range of sleep behaviors that may be considered ‘‘normal’’ versus ‘‘pathologic’’ is wide, and the definitions often highly subjective. Researchers have taken a number of approaches to this issue; some use a priori definitions of disturbed or poor sleep, which are tailored for age and developmental level (eg, waking for longer than 30 minutes more than 3 times a week); some have relied on comparison with normative populations; and others have based the definition of sleep problems on what the parent subjectively identifies as problematic. More recent attempts to

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develop classification schemes for sleep-onset problems and night wakings in young children have used constructs related to specific sleep behaviors (ie, self-soothing and signaling) to predict the development of sleep problems [34,35]. Other authors have incorporated more concrete evidence of daytime sequelae (mood, behavior, academic performance) to quantify functional significance as part of the definition of problematic sleep in children. Some studies have included reports from other observers, including teachers, to avoid depending solely on parents’ awareness of, expectations for, tolerance of, and interpretation of the sleep and daytime behaviors. A number of studies in adolescents (and a handful in younger children) have included self-report measures of sleep quality, quantity, and perceived daytime impairment. The lack of consistent methodologies and standardized classification systems, however, which makes comparisons across studies problematic, underscores the need for a common nosology in terms of research definitions of sleep disorders. From a clinical rather than research perspective, significant sleep problems, like many behavioral problems in childhood, may best be viewed as more loosely occurring along a severity and chronicity continuum that ranges from a transient and self-limited disturbance to a disorder that meets specific standardized diagnostic criteria. Several clinical classification systems exist that are applicable to sleep problems in the pediatric population, including the International Classification of Sleep Disorders and the Diagnostic and Statistical Manual of Mental Disorders-IV. Some of the clinical sleep disorders described in the International Classification of Sleep Disorders, such as behavioral insomnia of childhood (sleep-onset association and limit-setting subtypes), are almost exclusively found in children, whereas others (eg, psychophysiologic insomnia) list diagnostic criteria that are intended to be applied to both adult and pediatric populations. This latter approach may not adequately capture developmental considerations and other factors unique to pediatrics (eg, the impact of sleep disorders on caregiver health and well-being), however, nor reflect the most common clinical presentations of these disorders when they occur in children. Any pediatric diagnostic classification system must acknowledge the validity of parental concerns and opinions regarding their child’s sleep patterns and behaviors, and the resulting stress on the family as primary in defining sleep disturbances in the clinical context. Furthermore, successful treatment of pediatric sleep problems in the clinical setting is highly dependent on these subjective parameters, such as identification of parental concerns, clarification of mutually acceptable treatment goals, active exploration of opportunities and obstacles, and ongoing communication of issues and concerns. Epidemiology of sleep in general pediatric populations The following discussion focuses on general sleep problems in children and on nonspecific presenting sleep complaints, such as bedtime resistance

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and night wakings; prevalence data regarding specific sleep disorders, such as obstructive sleep apnea, and behavioral sleep problems in childhood are found elsewhere in this issue. A number of studies examined the prevalence of parent- and child-reported sleep complaints in large samples of children and adolescents; many of these have also delineated the association between disrupted sleep and behavioral concerns. Most of these studies have used broad-based parent-report sleep surveys to assess for a variety of sleep problems, ranging from bedtime resistance to prolonged night wakings to parasomnias [36,37]. It should be pointed out that there are limitations to these types of data in addition to varying definitions of ‘‘problem sleep,’’ including difficulty in identifying daytime sleepiness-related behaviors, especially in younger children and limited information regarding possible confounding factors (comorbid medical conditions, medication use, and so forth). Parent-reports may overestimate or underestimate the prevalence of sleep problems. Furthermore, it should be emphasized that parental descriptions of sleep problems are not synonymous with the diagnosis of a sleep disorder, which can only be made in conjunction with a clinical evaluation and needs to meet specified diagnostic criteria. Approximately 25% of all children experience some type of sleep problem at some point during childhood, ranging from short-term difficulties in falling asleep and night wakings, to more serious primary sleep disorders, such as obstructive sleep apnea. Interestingly, these prevalence figures are quite consistent across different countries, and in the few studies that have conducted cross-cultural comparisons using a consistent methodology across populations [38]. Other studies have reported an overall prevalence of a variety of parent-reported sleep problems ranging from 25% to 50% in preschool-aged samples to 37% in a community sample of 4 to 10 year olds [13,39]. A more recent study of over 14,000 school-aged children [6] found sleep problems in 20% of 5 year olds and 6% of 11 year olds. Other studies have found a prevalence of sleeping difficulties in 43% of 8 to 10 year olds [40]. Many studies have examined the self-reported prevalence of sleep problems in adolescents; upward of 40% of adolescents also have significant sleep complaints [41] and 12% identified themselves as ‘‘chronic poor sleepers’’ [42]. Many of these studies have also documented a host of associated deficits in academic performance, social competence, and behavior problems [43]. Some of these studies have also suggested that there may be gender differences in rates and types of sleep problems in adolescents, and that sleep problems in this age group are highly likely to be persistent [31]. Studies that have used self-reports of sleep problems in older children have suggested that there may be a discrepancy between parental and child report, with parents less likely than the children to report sleep onset delays and night wakings. Finally, in studies that have asked health care providers to identify the prevalence of sleep problems in practice, rates of significant difficulties initiating or maintaining sleep across age groups vary, in one

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recent study comprising on average about 3%  7% of all practice visits [44]. In the IMS HEALTH National Disease and Therapeutic Index Survey of 2930 office-based practices in the continental United States, which uses diagnostic codes, 0.05% (5 in 10,000) of all pediatric visits were for sleep problems and 0.01% (1 in 10,000) were specifically for insomnia. It should be noted, however, that a number of studies suggest that practitioner-identified sleep problems may also underestimate prevalence [45]; in the Rona study, less than 25% of the school children with sleep problems had consulted a physician [46]. Several studies suggest that the prevalence of sleep problems in minority and poor children may be significantly greater [47], although not all studies have found this association [2]. Vulnerable populations, such as children who are at high risk for developmental and behavioral problems because of poverty, parental substance abuse and mental illness, or violence in the home, may experience double jeopardy as a result of sleep problems. Not only are these children at higher risk for developing sleep problems as a result of such conditions as chaotic home environments, chronic medical issues like iron deficiency anemia, and neglect, but they are also less likely to be diagnosed with sleep problems because of limited access to health care services. Finally, they are likely to suffer more serious consequences from those sleep problems than their less vulnerable peers. Epidemiology of sleep in special populations Because of the multiple manifestations of poor and insufficient sleep, the clinical symptoms of any primary medical, developmental, or psychiatric disorder are likely to be exacerbated by comorbid sleep problems. Furthermore, sleep problems themselves tend to be more common in those children and adolescents with chronic medical and psychiatric conditions. Conversely, improving sleep has the potential benefit of improving clinical outcomes. Sleep disturbances in pediatric special needs populations are extremely common. Estimates of sleep concerns in children with autism spectrum disorders, including Asperger’s syndrome, are in the 50% to 70% range [48,49]. Significant sleep problems have been reported to occur in 30% to 80% of children with severe mental retardation, and in at least half of children with less severe cognitive impairment. Significant problems with initiation and maintenance of sleep, shortened sleep duration, irregular sleeping patterns, and early morning waking have been reported in a variety of different neurodevelopmental disorders, including Angelman’s syndrome, Rett syndrome, Smith-Magenis syndrome, and William syndrome. Other studies have suggested that similar rates of sleep problems also occur in both younger and older blind children, with difficulty falling asleep and night wakings related to circadian disruption being the most common concerns.

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Sleep problems, especially in children with special needs, are often chronic in nature and unlikely to resolve without aggressive treatment. In addition, sleep disturbances in these children often have a profound effect on the quality of life of the entire family. These children also frequently have multiple sleep disorders occurring simultaneously or in succession. Higher degrees of cognitive impairment tend to be associated with more frequent and severe sleep problems. Psychiatric disorders, such as depression and anxiety, in children and adolescents with developmental delays and autistic spectrum disorders and medications used to treat these disorders (eg, atypical antipsychotics) may further contribute to sleep problems. Sleep disturbances often have a significant impact on the clinical presentation and symptom severity, and management of psychiatric disorders in children and adolescents. Virtually all psychiatric disorders in children may be associated with sleep disruption. Epidemiologic and clinical studies indicate that psychiatric disorders are the most common cause of chronic insomnia. Psychiatric disorders can also be associated with daytime sleepiness, fatigue, abnormal circadian sleep patterns, disturbing dreams and nightmares, and movement disorders during sleep. Use of psychotropic medications, which may have significant negative effects on sleep, often complicates the issue. Conversely, growing evidence suggests that primary insomnia (ie, insomnia with no concurrent psychiatric disorder) is a risk factor for later developing psychiatric conditions, particularly depressive and anxiety disorders [19]. Several studies have evaluated the prevalence of sleep problems in samples of children and adolescents with a variety of psychiatric disorders [19,50]. The results suggest an increase in a wide range of reported sleep disturbances in these mixed clinical populations, including parasomnias, such as nightmares and night terrors; difficulty falling asleep and frequent and prolonged night wakings; sleep-related anxiety symptoms (eg, fear of the dark); restless sleep; and subjective poor quality of sleep with associated daytime fatigue. Similarly, an association has been reported between Diagnostic and Statistical Manual of Mental Disorders-IV psychiatric disorders, including affective disorders, attention-deficit–hyperactivity disorder, and conduct disorder, and sleep problems in surveys of children and adolescents from the general population [13]. Studies of children with major depressive disorder, for example, have reported a prevalence of insomnia of up to 75% and severe insomnia of 30% and sleep onset delay in a third of depressed adolescents, although it should be noted that objective data (eg, polysomnography) do not always support these subjective complaints. Finally, reports of sleep complaints, especially bedtime resistance, refusal to sleep alone, increased nighttime fears, and nightmares common in children who have experienced severely traumatic events (including physical and sexual abuse) [51] may also be associated with less dramatic but nonetheless stressful life events, such as brief separation from a parent, birth of a sibling, or school transitions [52]. Sleep problems are not universally found in all children experiencing varying degrees of stress, and some authors

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have suggested [51] that such variables as level of exposure and physical proximity to the traumatic situation, previous exposure, and the opportunity for habituation to the stress may play important roles in either mitigating or exacerbating associated sleep disturbances. Other developmental considerations, such as the age and temperament of the child, and variables, such as the presence of parental psychopathology, also clearly have an important influence. Relatively little is currently understood about the interaction between sleep disorders and both acute and chronic health conditions, such as asthma, diabetes, and juvenile rheumatoid arthritis on either a pathophysiologic or behavioral level, although, particularly in chronic pain conditions, these interactions are likely to impact significantly on morbidity and quality of life [53–56]. Much of the information currently available regarding the types of sleep problems that occur in these children comes from studies of adults with chronic medical conditions or from clinical observations. A few recent studies have begun to examine the role of sleep disturbances in a number of chronic medical conditions of childhood, including sickle cell disease [57] and asthma [53], two disorders particularly common in high-risk and minority populations. Asthma in children has been associated with poorer subjective sleep quality, decreased sleep duration, increased nocturnal wakings with decreased sleep efficiency, and greater daytime sleepiness. The prevalence of sleep problems in children with asthma has been reported to be 60%. Asthma medications may also have adverse effects on sleep; for example, both theophylline and oral corticosteroids may cause significant sleep disruption. Other specific medical conditions that may also have an increased risk of sleep problems include atopic conditions (chronic allergy-mediated rhinitis, chronic sinusitis, atopic dermatitis [58]); chronic headaches (migraine and tension headaches); cancer; and chronic pain conditions, such as fibromyalgia and juvenile rheumatoid arthritis. The interaction between sleep and physical and emotional dysfunction in acute and chronic pain conditions, such as burns and juvenile rheumatoid arthritis, has also begun to be explored. A number of patient-related and environmental factors, such as family dynamics, underlying disease processes, comorbid mood and anxiety disorders, and concurrent medications, are clearly important to consider in assessing this bidirectional relationship of sleep disturbances and illness in children. In particular, the impact of hospitalization on sleep quality and quantity can be significant. Studies of adult inpatient populations have found reduced sleep time and sleep efficiency, particularly in intensive care settings, and increased awakenings, nightmares, early morning awakening, and more daytime sleep; up to two thirds of adult inpatients report some type of sleep disturbance [59]. Although there are relatively few similar studies of sleep disturbances in hospitalized children, prolonged sleep latencies, significantly later bedtimes, shortened sleep duration, and reduced napping have been described [60–66]. Factors contributing to sleep disturbance identified in studies of adult and pediatric inpatients include light and noise levels, sleep interruptions for medical monitoring and treatment and

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diagnostic procedures, circadian rhythm disruption, and alterations in normal home bedtime routine. In children with any medical, psychiatric, and neurodevelopmental disorder, sleep disturbances are likely to have a significant impact on both morbidity and quality of life. Effects of insufficient and disrupted sleep on physiologic functions, such as immune response and healing, on pain perception, and even on treatment compliance may compromise recovery in children with medical and psychiatric illnesses. Poor sleep and fatigue can contribute to problems with school attendance and performance, ability to concentrate, and neurocognitive function, and may be associated with depressive symptoms and reduced social and emotional functioning, and with caregiver fatigue and impaired mood. References [1] Iglowstein I, Jenni OG, Molinari L, et al. Sleep duration from infancy to adolescence: reference values and generational trends. Pediatrics 2003;111(2):302–7. [2] Bayer JK, Hiscock H, Hampton A, et al. Sleep problems in young infants and maternal mental and physical health. J Paediatr Child Health 2007;43(1–2):66–73. [3] Sadeh A, Flint-Ofir E, Tirosh T, et al. Infant sleep and parental sleep-related cognitions. J Fam Psychol 2007;21(1):74–87. [4] Boergers J, Hart C, Owens JA, et al. Child sleep disorders: associations with parental sleep duration and daytime sleepiness. J Fam Psychol 2007;21(1):88–94. [5] Adam EK, Snell EK, Pendry P. Sleep timing and quantity in ecological and family context: a nationally representative time-diary study. J Fam Psychol 2007;21(1):4–19. [6] Pagel JF, Forister BS, Kwiatkowki C. Adolescent sleep disturbance and school performance: the confounding variable of socioeconomics. J Clin Sleep Med 2007;3(1):19–23. [7] Owens J, Maxim R, McGuinn M, et al. Television-viewing habits and sleep disturbance in school children. Pediatrics 1999;104(3):e27. [8] Paavonen EJ, Pennonen M, Roine M, et al. TV exposure associated with sleep disturbances in 5- to 6-year-old children. J Sleep Res 2006;15(2):154–61. [9] Lam P, Hiscock H, Wake M. Outcomes of infant sleep problems: a longitudinal study of sleep, behavior, and maternal well-being. Pediatrics 2003;111(3):e203–7. [10] Jenni OG, O’Connor BB. Children’s sleep: an interplay between culture and biology. Pediatrics 2005;115(1 Suppl):204–16. [11] Milan S, Snow S, Belay S. The context of preschool children’s sleep: racial/ethnic differences in sleep locations, routines, and concerns. J Fam Psychol 2007;21(1):20–8. [12] Fallone G, Owens JA, Deane J. Sleepiness in children and adolescents: clinical implications. Sleep Med Rev 2002;6(4):287–306. [13] Blader JC, Koplewicz HS, Abikoff H, et al. Sleep problems of elementary school children: a community survey. Arch Pediatr Adolesc Med 1997;151(5):473–80. [14] Bates JE, Viken RJ, Alexander DB, et al. Sleep and adjustment in preschool children: sleep diary reports by mothers relate to behavior reports by teachers. Child Dev 2002;73(1):62–74. [15] Epstein R, Chillag N, Lavie P. Starting times of school: effects on daytime functioning of fifth-grade children in Israel. Sleep 1998;21(3):250–6. [16] Wolfson AR, Carskadon MA. Sleep schedules and daytime functioning in adolescents. Child Dev 1998;69(4):875–87. [17] Giannotti F, Cortesi F. Sleep patterns and daytime functions in adolescents: an epidemiological survey of Italian high-school student population. In: Carskadon MA, editor. Adolescent sleep patterns: biological, social and psychological influences. New York: Cambridge University Press; 2002. p. 132–47.

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[18] Johnson EO, Roth T, Schultz L, et al. Epidemiology of DSM-IV insomnia in adolescence: lifetime prevalence, chronicity, and an emergent gender difference. Pediatrics 2006;117(2):e247–56. [19] Morrison DN, McGee R, Stanton WR. Sleep problems in adolescence. J Am Acad Child Adolesc Psychiatry 1992;31(1):94–9. [20] Meltzer LJ, Mindell JA. Impact of a child’s chronic illness on maternal sleep and daytime functioning. Arch Intern Med 2006;166(16):1749–55. [21] Smaldone A, Honig JC, Byrne MW. Sleepless in America: inadequate sleep and relationships to health and well-being of our nation’s children. Pediatrics 2007;119(Suppl 1):S29–37. [22] Locard E, Mamelle N, Billette A, et al. Risk factors of obesity in a five year old population: parental versus environmental factors. Int J Obes Relat Metab Disord 1992;16(10):721–9. [23] Kagamimori S, Yamagami T, Sokejima S, et al. The relationship between lifestyle, social characteristics and obesity in 3-year-old Japanese children. Child Care Health Dev 1999; 25(3):235–47. [24] von Kries R, Toschke AM, Wurmser H, et al. Reduced risk for overweight and obesity in 5- and 6-y-old children by duration of sleep–a cross-sectional study. Int J Obes Relat Metab Disord 2002;26(5):710–6. [25] Sekine M, Yamagami T, Handa K, et al. A dose-response relationship between short sleeping hours and childhood obesity: results of the Toyama Birth Cohort Study. Child Care Health Dev 2002;28(2):163–70. [26] Agras WS, Hammer LD, McNicholas F, et al. Risk factors for childhood overweight: a prospective study from birth to 9.5 years. J Pediatr 2004;145(1):20–5. [27] Chaput JP, Brunet M, Tremblay A. Relationship between short sleeping hours and childhood overweight/obesity: results from the Quebec en Forme Project. Int J Obes (Lond) 2006;30(7):1080–5. [28] Chen MY, Wang EK, Jeng YJ. Adequate sleep among adolescents is positively associated with health status and health-related behaviors. BMC Public Health 2006;6:59–66. [29] Owens JA, Fernando S, McGuinn M. Sleep disturbance and injury risk in young children. Behav Sleep Med 2005;3(1):18–31. [30] Giannotti F, Cortesi F, Sebastiani T, et al. Circadian preference, sleep and daytime behaviour in adolescence. J Sleep Res 2002;11(3):191–9. [31] Bailly D, Bailly-Lambin I, Querleu D, et al. [Sleep in adolescents and its disorders: a survey in schools]. Encephale 2004;30(4):352–9 [in French]. [32] Drake C, Nickel C, Burduvali E, et al. The Pediatric Daytime Sleepiness Scale (PDSS): sleep habits and school outcomes in middle-school children. Sleep 2003;26(4):455–8. [33] Spruyt K, O’Brien LM, Cluydts R, et al. Odds, prevalence and predictors of sleep problems in school-age normal children. J Sleep Res 2005;14(2):163–76. [34] Gaylor EE, Goodlin-Jones BL, Anders TF. Classification of young children’s sleep problems: a pilot study. J Am Acad Child Adolesc Psychiatry 2001;40(1):61–7. [35] Gaylor EE, Burnham MM, Goodlin-Jones BL, et al. A longitudinal follow-up study of young children’s sleep patterns using a developmental classification system. Behav Sleep Med 2005;3(1):44–61. [36] Owens JA, Spirito A, McGuinn M. The Children’s Sleep Habits Questionnaire (CSHQ): psychometric properties of a survey instrument for school-aged children. Sleep 2000;23(8): 1043–51. [37] Bruni O, Ottaviano S, Guidetti V, et al. The Sleep Disturbance Scale for Children (SDSC): Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. J Sleep Res 1996;5(4):251–61. [38] Liu X, Liu L, Owens JA, et al. Sleep patterns and sleep problems among schoolchildren in the United States and China. Pediatrics 2005;115(1 Suppl):241–9. [39] Owens JA, Spirito A, McGuinn M, et al. Sleep habits and sleep disturbance in elementary school-aged children. J Dev Behav Pediatr 2000;21(1):27–36. [40] Kahn A, Van de Merckt C, Rebuffat E, et al. Sleep problems in healthy preadolescents. Pediatrics 1989;84(3):542–6.

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Infant Crying and Sleeping: Helping Parents to Prevent and Manage Problems Ian St James-Roberts, PhD, FBPsS Thomas Coram Research Unit, Institute of Education, University of London, 27/28 Woburn Square, London WC1H 0AA, UK

Impacts and costs of infant crying and sleeping problems Babies who cry a lot or are unsettled at night impact parents and health services in a variety of ways. First, because many parents find their baby’s crying or sleep-waking behavior hard to manage, these problems are troublesome for parents and costly for health services. For instance, in a national survey, 74% of American parents of infants 4 to 9 months old reported discussing infant night waking and fussing with pediatricians [1]. In the United Kingdom, the professional time devoted to discussing the problems with parents of 1- to 3-month-old infants costs the National Health Services about £66 million per year [2]. Second, less commonly and more alarmingly, prolonged crying may trigger shaken baby syndrome, resulting in infant brain damage or death [3,4]. Third, early crying and sleeping problems sometimes are the prelude to long-term disturbances in parent–child relationships and psychologic problems in school-aged children [5–7]. There is a need for evidence about the nature and causes of these problems and for these findings to be translated into services that support parents and babies cost effectively. This article summarizes the current understanding of infant crying and sleeping problems and the implications of this understanding for services and research, with a focus on the first months of infancy. The focus is on the amount and pattern of crying and sleep-waking rather than on indices of sleep type such as rapid eye movement sleep, because parents usually are unaware of these particulars [8]. Evidence is considered adequate when it stems from at least two studies from independent research groups (ie, includes replication). A version of this article originally appeared in Sleep Medicine Clinics, volume 2, issue 3. E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.004 primarycare.theclinics.com

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Distinguishing infant crying from sleep-waking behaviors and infant from parental problems Although crying and sleeping problems usually are not distinguished, they present differently, at different ages, often in different infants, and may well have distinct causes. Infant crying and parental concern about it peak at around 5 to 6 weeks of age, with most of the crying taking place in the daytime and particularly the evenings [9–11]. In contrast, infant ‘‘sleeping problems’’ occur mainly at night, after 3 months of age [12,13]. Most babies wake at night for feeding in the early weeks, and parents expect this awakening. Parents report that most babies begin to ‘‘sleep though the night’’ by about 12 weeks of age [14–16]. The failure to achieve this milestone, so that an infant continues to settle poorly or wake the parents at night after 12 weeks, accounts for most ‘‘infant sleeping problems’’ [13]. Emphasizing the distinctness of crying and sleeping problems, a recent randomized, controlled trial found that a behavioral program delivered by parents increased the number of infants who slept through the night by 12 weeks of age but did not affect 24-hour amounts of crying [17]. In addition to this separation of crying from sleeping problems, it is important to distinguish between the problem and the infant behavior that underlies it. Reviews of the evidence estimate that only about 1 in 10 infants taken by parents to professionals for infant crying problems has a food intolerance or other organic disturbance [18,19]. These parents generally are correct in judging that their babies cry more than average, but most infants who cry a lot in the first 2 months of infancy are healthy, put on weight normally, and do not have long-term disturbances [18,20]. Details about crying behavior are presented later in this article, but ‘‘infant crying problems’’ as a clinical complaint are characterized chiefly by parental alarm and concern about crying rather than by a pathologic infant condition [18,19]. Likewise, most infants who wake and disturb their parents at night beyond 3 months of age do not have general or long-term disturbances, other than continuing sleeping problems [21,22]. To a large degree, parental concern about infant night waking reflects Western cultural practices and norms [23,24]. This consideration does not downplay parental complaints, because parents who work Western office hours need to sleep at night themselves, and it is true that most Western infants over 3 months of age remain settled for long periods at night. Rather, the implication is that most infants who fail to develop this ability are in good health, so that the infant behavior needs to be distinguished from the largely parental problem. Emphasizing these distinctions, epidemiologic studies have found that most infants who have crying problems do not have sleeping problems (and vice-versa). Wolke and colleagues’ [22] epidemiologic study of 5month-olds found that 11% of infants had sleeping problems, 10% had crying problems, and only 5% had both types of problems; sleeping problems,

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rather than amount of crying at 5 months, predicted later sleeping problems. Similarly, Von Kries and colleagues [21] found that prolonged crying in the first 3 months was not associated with increased rates of sleeping or feeding difficulties. Earlier reports that crying babies sleep less per 24 hours probably result from inaccurate reports of parents of non-criers that exaggerate the amount these babies sleep because their parents are not aware of periods when they are awake but settled [25]. Lehtonen’s [20] review of follow-up studies of crying babies concluded that most slept normally at a later age. Likewise, Zuckerman and colleagues [26] found that infants who had only sleeping problems at 8 months did not have later behavior problems, whereas those who had chronic sleep problems continuing to 3 years of age were more likely to have additional behavior disturbances. These findings have two implications. First, the problem and the infant behavior underlying it both need to be assessed but should be considered separately. Second, two main groups of infants, and clinical phenomena, exist: infants who cry a lot in the day and evening in the first 2 months, and infants who fail to develop the ability to remain settled at night by 3 months of age. In addition, a much smaller third group of infants has organic disturbances [18,19]. Recent research has identified a group of infants who have multiple crying, sleeping, and other problems that persist after 3 months of age and who have extensive psychologic and family disturbances [5,21]. The nature and causes of these different behavioral and developmental pathways are examined separately later. Infant colic and the infant crying peaks Prolonged unexplained crying in early infancy traditionally has been attributed to gastrointestinal pain, as reflected in the term ‘‘infant colic’’ [27]. Recent studies have challenged this assumption and led to a reconceptualization. First, although prolonged crying can be caused by food intolerance and other organic disturbances during the first 3 months, these factors are absent in 90% of cases [18,19]. Furthermore, the evidence about the main organic conditions believed to cause cryingdgastroesophageal reflux disease and food allergydis equivocal. For gastroesophageal reflux disease, Heine’s [28] review concluded that ‘‘A direct causal relationship between acid reflux and colic therefore appears unlikely.’’ For allergic (atopic) disturbances, the recent evidence suggests a weak relationship but is unclear about its nature. Studying infants at familial risk of atopy, Kallioma¨ki and colleagues [29] found that infants who later showed eczema or asthma fussed (but did not cry) more at 7 weeks and cried more at 12 weeks, than infants who did not develop eczema or asthma. In contrast, Castro-Rodriguez and colleagues’ [30] prospective study of a large community sample found no association between physician-reported colic in early infancy and markers of atopy, asthma, allergic rhinitis, wheezing, and bronchial constriction from

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9 months to 11 years of age. Nor were rates of parental asthma or positive skin tests for allergy raised in infants who had colic. Heine’s [28] review concluded that colic is not usually associated with raised infant serum IgE or food-specific IgE levels. The most rigorous, randomized, controlled trial of the effects of a low-allergen diet for breastfeeding mothers found a much greater reduction in diary-measured infant fussing and crying in the week after mothers began a low-allergen diet than occurred in control-group infants [31]. The groups, however, did not differ at outcome in the proportions of infants who still had colic (defined as R180 minutes fussing/crying per 24 hours). Moreover, neither maternal ratings of their infant’s amount of crying at outcome nor of whether colic behavior was ‘‘improved, the same, or worse’’ differed between the treatment and control groups, suggesting that the low-allergen diet did not resolve the problem for parents. The implications of this complex evidence for identifying and treating organic colic cases is discussed further in the section ‘‘Helping Parents to Manage Infant Crying and Sleeping.’’ A second reason for reconceptualizing ‘‘infant colic’’ is that studies that have gone beyond clinically referred groups to include general community samples have found resemblances in crying behavior: babies in general have a crying peak in the first 2 months of infancy, with an evening clustering, followed by a marked reduction in crying by 12 weeks of age [9,11]. This peak also has been found in non-Western cultures, prompting the suggestion that it is a behavioral universal of infancy [9]. Most clinical cases seem to be at the extremes of the normal distribution, rather than a separate group. Further, the belief that the crying reflects pain has been disputed both by studies that have compared crying bouts acoustically and by a critical reexamination of the evidence that it is possible to tell the cause of crying from its sound [32,33]. Rather than ‘‘cry types’’ that reflect different underlying psychologic states (pain; hunger; anger) reliably, infant crying in the early weeks now is considered to be a graded signal that conveys the infant’s degree of distress but not the precise cause. Caregivers must work out the cause using experience and contextual information. It is thought that the chief features of early crying that disturb parents are its relative intensity (a high crying-to-fussing ratio), the prolonged length of the crying bouts, and the resistance of the crying to soothing techniques that usually stop babies from crying [34,35]. The unsoothability of the crying is thought to be its most salient feature, because it makes parents feel helpless and unable to manage [32]. Studies in which trained researchers have found such infants hard or impossible to soothe have confirmed that this unsoothability is an objective feature of the infants’ behavior [34,36]. Although the cause of these long and unsoothable crying bouts is uncertain, recent analyses have indicated that they probably are specific to early infancy [35]. Several researchers have argued that they are linked to the reorganization of brain systems that occurs at around 2 months of age, as reflex systems are replaced by cortical control of behavior [37,38]. In

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particular, the long and unsoothable nature of the bouts has been attributed to a temporary deficit in ‘‘responsivity,’’ so that infants are hyperreactive or unable to regulate (stop) crying once it has started [39,40]. Evidence for this hypothesis is so far equivocal, because parental diary reports show that 1- to 3-month-old infants who cry a lot have more crying bouts as well as longer ones [32,35]. Accurate separation of crying bouts, however, may require more precise measurements than allowed by the parental diary methods used so far. A further challenge is that the ‘‘neurobehavioral shift’’ at 2 months of age involves changes in several systems (eg, attention, sensory, circadian), in social abilities (eg, the emergence of social smiling [38]), and in electroencephalographic activity [41]. So far attempts to narrow down the neurophysiologic systems involved have not proved replicable; further research is needed to confirm this contemporary view of the causes of unsoothable crying in early infancy. In addition to changes to endogenous infant systems, prolonged crying in early infancy has been attributed to inadequate parenting. In particular, early intervention studies showed that both increasing and decreasing the parental response to the crying reduced its amount [42,43]. These studies have been criticized on methodologic grounds [44], but because intervention often quiets babies, reducing the overall amount of crying is neither difficult nor the point. Unless interventions address the prolonged unsoothable bouts that are the source of parents’ concerns, they are unlikely to resolve the problem. In principle, the optimal research method in this area involves randomized, controlled designs in which groups are assigned arbitrarily to alternative forms of parenting. In practice, two kinds of obstacle have been encountered. First, the findings have proved inconsistent. For example, supplementary carrying of the infant reduced crying preventively in one study [45] but not in two subsequent replication attempts that involved similar amounts of carrying [46,47], and supplementary carrying in response to crying proved ineffective as a treatment [48]. Second, these supplementation studies have achieved only modest changes in Western parents’ behavior, perhaps because parents resist changes in their modes of care. A recent randomized, controlled trial of the REST (Regulation, Entrainment, Structure, and Touch) nursing regimen for helping parents manage colic found benefits for parents [49,50] but used subjective maternal ratings of infant changes rather than validated measures of infant behavior, so it is not clear whether infant crying was reduced. Furthermore, mothers in the control group, who received much less support than the REST mothers, reported similar improvements, albeit of lesser degree. The value of professional consultations for parents is highlighted by Jordan and colleagues’ [51] randomized, controlled trial, which found that an infant mental health consultation for mothers was as effective as antireflux medication or a placebo prescription in reducing infant crying (with more than 90% of mothers in all three groups reporting that crying was improved). Fewer mothers receiving the

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infant mental health consultation were admitted to the hospital for cryingrelated stress, however. The REST and similar approaches seem to provide valuable support for mothers, but research is needed to uncover the nature of any effects on infant behavior and to evaluate the cost-effectiveness of these interventions. Comparative studies provide an alternative, if less methodologically robust, means of evaluating the consequences of parenting variables for infant crying. Two studies speak most directly to this issue. First, Hubbard and van Ijzendoorn’s [52,53] careful observations found no evidence that typical variations in how long Western parents took to respond to crying predicted the amounts infants cried at later ages. More rapid parental response in the first 9 weeks was associated with small increases in crying frequency in weeks 9 to 27, but the associations were modest and did not suggest any effect of early parental responsiveness on the amounts infants cried in later weeks. Second, by including much greater variations in parenting, a recent crosscultural study has shown quite different consequences for infant crying overall than for unsoothable crying bouts. The study compared parenting and infant crying longitudinally in three groups: London parents, Copenhagen parents (who were expected to be more responsive), and parents who elected before their babies’ birth to practice ‘‘proximal care.’’ This anthropological term was chosen to describe the key feature of this form of parenting, extensive infant holding, in contrast to the common Western practice of putting babies down [54]. Each of the groups included more than 50 infants, and infant and caregiver behavior was measured by validated behavior diaries. As expected, large group differences in parenting were found when the infants were 10 days and 5 weeks of age. Proximal care parents fed their babies more often than other groups (14 times, compared with 10–12 times, per 24 hours) and held their babies for an average of 15 to 16 hours per 24 hours, about twice as much as the London parents; the Copenhagen parents fell in-between. Proximal care parents coslept with their babies throughout the night much more often than either of the other groups. London parents had 50% less physical contact with their babies than the other groups, both when settled and when crying, and abandoned breastfeeding earlier. These differences in parenting were associated with substantial differences in amounts of infant crying. The London babies fussed and cried 50% more than both other groups at 10 days and 5 weeks of age. Fussing and crying declined at 12 weeks in all three groups but remained higher in London infants. In contrast, unsoothable crying bouts were equally common in all three groups. Likewise, at 5 weeks of age infant colic (defined as R 180 minutes fussing/crying per 24 hours) occurred equally often, in 5% to 13% of infants in each group. These latest findings need careful interpretation until they are confirmed by randomized, controlled trials, but they are consistent with a good deal of supporting evidence. First, Scho¨n and Keskivarra’s [55] similar study of

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Western parents practicing ‘‘natural parenting’’ found this approach to be associated with low amounts and, particularly, low frequencies of fussing/ crying. Previous Danish and African studies also have found that high amounts of body contact and responsive parenting are associated with low amounts of infant crying [56–58]. Second, Harlow and Harlow’s [59] primate study and Hofer’s [60] rat studies have documented infants’ preference for body contact. Hofer argues that early crying evolved as a reflex behavior that serves dual functions: a communicative function, which encourages maternal contact, and a homeostatic function that assists recovery from hypothermia. In turn, early parenting acts as an ‘‘external regulator’’ of infant physiologic homeostasis [60]. Similarly, Greenough and colleagues [61] argued that some infant brain systems are ‘‘experienceexpectant,’’ that is, presuppose the existence of environmental conditions that are evolutionarily typical. Third, the finding that variations in parenting do not prevent the bouts of unsoothable crying that occur in early infancy is consistent with the evidence cited previously that these crying bouts are specific to early infancy and are linked to endogenous neurodevelopmental changes at this age. In sum, the best available evidence strongly indicates, but does not yet confirm, that unsoothable crying bouts are common and specific to early infancy, are not affected by parenting, and probably are the result of neurodevelopmental changes that are a normal part of development. In contrast, overall 24-hour amounts of crying are substantially reduced when parents adopt methods of care that involve more physical contact and greater responsiveness. In a small number of cases, prolonged crying in the first 3 months can be caused by food intolerance and other organic disturbances. The implications of these findings for clinical practice are revisited later. Infant sleeping and sleeping problems Van Gelder [62] summarizes contemporary knowledge of sleep-wake mechanisms in adult mammals. There is extensive evidence that the brain’s suprachiasmatic nucleus provides the biologic clock on which sleep-wake and other circadian cycles are based. Environmental stimuli, particularly the effects of light through the photoreceptors in the eye, can reset the clock. Other environmental stimuli are less well understood, but dynamic interplay between a variety of external and endogenous regulatory influences probably is involved. Salzarulo and colleagues [41], for example, identify rising body temperature and rapid eye movement sleep as precursors of spontaneous waking in adults. A further finding of importance here is that older children and adults do not remain asleep at night for continuous periods of 8 or more hours. Rather, adult sleep involves brief awakening and resettlings, so that continuous sleep periods may not last more than 6 hours [23]. During the first 3 months of age, most infants pass from a pattern of short sleep-wake cycles more or less evenly distributed throughout the day

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and night to a pattern involving consolidation of sleeping into long periods at night and waking into the daytime [16,63,64]. Newborns have been said to lack day–night differences in sleeping and waking, but some parent-report studies have found more sleep at night within the first 2 weeks of age [65,66]. Studies involving even younger ages and other methods are needed, but infants may be predisposed to show rudimentary circadian sleep-wake organization from the first days after birth. So far, the crucial question of how this developmental progression takes place has yielded only a partial answer. Arguably the most seminal finding is that parents are not correct in reporting that 3-month-old infants ‘‘sleep though the night.’’ Infrared and light-sensitive video recordings have shown that infants, like adults, wake several times each night [63,64,67]. Most infants acquire the ability to resettle, but approximately a third, called ‘‘signalers’’ by Anders and colleagues [63], disturb their parents. As noted previously, this waking and signaling, rather than inadequate sleeping, is the core feature of the ‘‘infant sleeping problems’’ reported by parents. The methodologic implications of this evidence are worth noting, because objective methods, rather than parent reports, are required to measure infant sleeping behavior accurately. As with adults, it is likely that both endogenous and exogenous factors influence how this early process of sleep-wake consolidation takes place. Because waking before 3 months of age is thought to reflect the need for frequent feeding, nutritional processes probably are involved. For instance, infants’ stomachs may need to be large enough to contain sufficient milk to sustain a long period without feeding, which may explain why babies who are heavier at birth sleep through the night at a younger age [68]. Wright [69] has found that the amount of breast milk taken at each feeding is similar from birth to 4 weeks of age, but typical infants show a diurnal pattern by 8 weeks, taking the largest feeding at the beginning of each day, possibly in response to nighttime deprivation. By 4 to 6 months, the largest feeding occurs at the end of the day, suggesting that infants have adapted to anticipate the coming fast [69]. The implication is that learning influences behavioral organization after the first few postnatal weeks. The belief that feeding activities contribute to the sleep-wake pattern is supported by the consistent evidence that bottlefed infants remain settled for sustained periods at night and stop having a feeding between midnight and 6 AM at an earlier age than breastfed infants [26,69–71]. Although this disparity sometimes is attributed to differences in the constituents of the two milk types, particularly by parents [69], it is not clear that this is the case. Indeed, several lines of evidence suggest that exogenous factors associated with feeding may be more important sources of sleep-wake organization than milk constituents. First, two randomized, controlled trials have shown that breastfed infants whose parents adopt structured ‘‘behavioral’’ methods of care are more likely than other infants to remain settled at night by 12 weeks of age [17,72]. The second of these studies also found that

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the behavioral approach was particularly effective in promoting settled nighttime behavior at 12 weeks among infants who had a large number of breastfeedings (O 11/ 24 hr) in the first postnatal week. Second, there is evidence that cosleeping through the night (but not for short periods) is associated with persistent night waking [26,68,73]. In keeping with this finding, although both the proximal care and Copenhagen babies were breastfed more often than the London babies in the cross-cultural study described previously, proximal care babies (who typically coslept with parents throughout the night) were more likely to wake their parents at night at 12 weeks of age [17,72]. In summary, these studies provide robust, convergent evidence that exogenous environmental factors involved in parenting are important sources of individual differences in infant nighttime waking and signaling behavior by 12 weeks of age. Unfortunately, it is not yet known which factors are functionally important. At least five possibilities exist. First, McKenna [74] found that bed-sharing mothers and infants aroused more frequently (usually as a result of the other’s movement or sound) and spent significantly more time in lighter stages of sleep (stage 1 and stage 2), and less time in deeper stages of sleep (stage 3 or 4) than infants sleeping alone. The implication is that cosleeping might cause infants to wake more often. Second, the proximity of cosleeping infants and parents may lead parents to detect infant vocal and other cues more readily. Indeed, there is evidence that waking infants often spend time making low noises before a full cry [75]. Third, the behavioral approach to care described previously asks parents to maximize day–night differences in light and darkness as well as in social stimulation and play. It may be that these environmental cues help infants learn to set up a circadian sleep-wake organization, as happens with adults. Fourth, settling infants while awake may be important, because doing so may enable them to resettle autonomously on waking; infants who fall asleep in their parents’ arms may need to be held for resettling [64,73,76]. Settling babies while awake is one of the elements of the behavioral approach found to reduce night waking and crying described previously. Fifth, cosleeping may facilitate immediate feeding when babies wake, rewarding the waking, whereas separate sleeping arrangements may delay feeding. Burnham and colleagues [77] found that delayed parental response to night waking at 3 months predicted autonomous resettling at 12 months. Delaying feeding for a few moments to break the bond between waking and feeding is a further element of the behavioral approach described previously. These five potential mechanisms are not mutually exclusive, and several may be involved. At least three predicate learning, and the importance of learning for the development of settled nighttime behavior is supported by evidence that behavioral methods, which ignore waking and reward settled behavior, provide the most effective treatments for sleeping problems at older ages [24,78]. Although further research into the relative importance of these mechanisms is needed, the existing evidence base is sufficient to

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guide clinical practice. This evidence is revisited in the last section, ‘‘Helping Parents Manage Infant Crying and Sleeping.’’ In addition to parenting practices, it is likely that endogenous factors contribute to night waking in some 3- to 6-month-old infants. At older ages, 1% to 3% of children are thought to have sleep problems caused by organic parasomnias and ‘‘biomaturational disorders,’’ compared with a prevalence of 15% to 35% for sleep disorders arising from ‘‘psychosocial’’ causes [79]. It is reasonable to expect that a variety of biomaturational factors will contribute to night waking in early infancy and that a smaller group will have serious organic disturbances. Burnham and colleagues [77] found that high levels of quiet sleep at birth predicted which infants resettled at night at 12 weeks of age, suggesting that infant maturational characteristics play a part. Currently, however, there is no evidence base for distinguishing such cases or infants who have organic disturbances. There is a need for fine-grained, longitudinal research. Because behavioral methods are the preferred treatment even for neurodevelopmental cases [80], however, clinical practice need not wait upon more accurate data. Crying, sleeping, and other problems in infants over three months of age Beyond 3 months of age, there is growing evidence of a third and at least partly distinct group of infants who have multiple disturbances rather than crying or sleeping problems alone. For example, von Kries and colleagues [21] found that infants more than 6 months of age who cried a lot were 6.6 times more likely than other infants to have sleeping problems and 8.9 times more likely to eating difficulties, according to parental reports. These infants also tend to have far poorer outcomes than those who solely cry a lot or wake at night [6,7,81]. Wolke and colleagues [7] found a greatly increased prevalence of pervasive hyperactivity problems at school age in such cases when compared with case-control children. Similarly, Rao and colleagues [6] found that prolonged crying after 3 months of age (but not before 3 months) predicted hyperactivity, cognitive deficits, poor fine-motor abilities, and disciplinary problems when the children reached 5 years of age. Other studies have found a high rate of emotional and behavioral problems when crying or sleeping problems persist [26,81]. The persistence, nature, and severity of these problems suggest that organic disturbances may play a part in some of these cases, a speculation that is supported by Kallioma¨ki and colleagues’ [29] finding that crying beyond 12 weeks characterized atopic cases. Many of these infants’ parents, however, also have vulnerabilities, including a high rate of marital discord and maternal depression [81], which themselves are known to predict child problems at older ages [26,82]. At present, evidence about the prevalence of these older cases and the important question of whether their problems develop out of pre-existing crying or sleeping problems or from a distinct etiology is inadequate. A longitudinal study of 547 Canadian infants from birth to 6 months of age

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provides some information [83]. Using a definition of 3 or more hours of fussing and crying per 24 hours to define prolonged crying, this study found a prevalence of 24% at 6 and 6.4% at 12 weeks. About half the infants who cried a lot at 12 weeks had continued to do so since 6 weeks; in 3% of infants the onset of prolonged crying did not occur until 12 weeks of age or later. These figures need to be qualified by the methodologic limitations of this study, including the use of retrospective reports in a proportion of cases; also, it is not known how many of the infants had multiple problems. With these provisos, the findings suggest that half of infants who had prolonged crying at 12 weeks have an earlier onset, but in halfdperhaps 3% of infants overalldthe onset occurs at or after 12 weeks of age. Rao and colleagues [6] prospective study of problem criers found continuity beyond 12 weeks in 25% of cases. Few intervention studies have targeted this group specifically. An exception is Papousˇ ek and colleagues’ [81] Munich study, in which parents received an intervention program focusing on sensitive management of infant behavior. Although 93% of parents and infants were rated as ‘‘fully or partially improved’’ at the end of the program by a psychologist and pediatrician, at a follow-up assessment at 30 months of age, the infants in the program were reported by parents to be highly difficult and hard to control and to have high rates of sleeping and behavior problems. In summary, many of the infants who come to clinical attention because of prolonged crying, sleeping, and other problems after 3 months of age are reported by parents to have multiple problems; some families of such infants face multiple psychosocial adversities. These combined features are associated with more serious and long-term disturbances than are typical when infants have crying or sleeping problems alone. Although there are no accurate prevalence figures, the data suggest that problems start earlier than 3 months in about 50% of such infants, and in others the onset of problems is at or after 3 months of age, suggesting distinct etiologic pathways. The findings implicate parenting as a contributing factor in some cases, and this possibility is consistent with the understanding of the importance of parenting as a scaffold for older infants’ development [82] and the evidence that parenting programs can improve young children’s behavior [84]. The current data, however, neither distinguish the cases in which parenting is a factor nor indicate the sort of interventions likely to be most effective in these cases. Rather, the findings highlight the paucity of evidence about this group of infants and the need to make these issues a priority for research and clinical work. Implications for professionals: helping parents to manage infant crying and sleeping There is a longstanding debate in the research and popular literature about the relative merits of forms of parenting that respond to babies’ perceived needs, for example by breastfeeding on demand and cosleeping (often

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called ‘‘infant-demand’’ or ‘‘infant-led’’ care) and forms of parenting that seek to impose routines and constraints on babies’ behavior (‘‘routinebased,’’ ‘‘scheduled,’’ or ‘‘structured’’ care [85]). The evidence reviewed here goes some way toward explaining why this debate has persisted, because it indicates that neither of these parenting approaches is better overall; rather, they are associated with different benefits and costs. The clearest evidence, emerging both from comparative studies and randomized, controlled trials, is that structured care (as exemplified by parents following behavioral programs) leads infants to develop the ability to remain settled at night by 12 weeks of age. The best available evidence, not yet subjected to randomized trials, indicates that ‘‘infant-demand’’ care, exemplified by the frequent breastfeeding and high levels of responsiveness, holding, and cosleeping involved in proximal care, leads to low amounts of overall fussing and crying in the first 2 months of age but to waking and signaling at night that continues at and beyond 3 months of age. These findings, and the lack of evidence that most infants who cry a lot in the first 2 months or who wake and cry at night at 3 months are unwell or likely to have long-term problems, are empowering for parents. Rather than doing what is medically ‘‘best,’’ the findings suggest that parents can make informed choices. The aim here is to translate the evidence into guidance that health care professionals can give to parents to help them make such choices during early infancy. 1. Because there is no evidence that the bouts of unsoothable crying that occur in 1- to 3-month-old babies are affected by parenting, parents can be prepared for these episodes and reassured that they are not the parents’ fault. Anticipatory guidance also can emphasize that currently it is not possible to predict which particular baby will cry a lot. Variables such as gender, birth order, and method of feeding are poor predictors, and there currently are no reliable tests for predicting food intolerance. It follows that parents will need to choose the care approach that is most compatible with their goals and resources and make adjustments as necessary with experience. 2. The available evidence indicates that the main benefit of infantdemand care lies in the early weeks, when both proximal and Copenhagen forms of care are associated with 33% less overall fussing/crying than typically occurs among babies who receive conventional London parenting. When parents consider reduced fussing/crying a desirable goal, the choice between these two approaches involves balancing a number of benefits and costs, some of which are inadequately understood. Scho¨n and Silve´n [86], for instance, argue that proximal care methods have overall benefits, including shorter and less intense crying periods. Conceivably, cosleeping infants may not reach a full cry when they wake at nighttime for feeding, so that their parents are not as disturbed by feeding as much as non-cosleeping parents [87]. Unfortunately, there is a dearth of systematic research to confirm these benefits or to identify other costs. For example, there is

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some evidence that conflicts sometimes may arise at later ages when parents wish to stop cosleeping [54], but the conditions under which later problems do or do not happen are unknown. Some parents may find proximal care difficult to accomplish within the resources and constraints imposed by contemporary Western society. Notably, for instance, only 29% of proximal care mothers in the cross-cultural study described previously were employed before their babies’ births, compared with 57% of the London and 64% of the Copenhagen mothers. Parents also must keep in mind that continuation of cosleeping throughout the night to a later age has been linked repeatedly to continued infant night waking. Anticipatory guidance also should alert parents to the evidence about cosleeping and sudden infant death syndrome (SIDS), as discussed below in number four. Where parents find proximal care beyond their resources, a noteworthy finding in the cross-cultural study described previously was that Copenhagen parents’ care was as effective as proximal care in minimizing early crying and was as effective as London care in enabling infants to remain settled at night by 12 weeks of age. There is no evidence that cosleeping for short periods during the night, as practiced by Copenhagen parents, increases nightwaking problems. Many parents may wish to follow Copenhagen parents’ approach as a workable compromise between proximal and conventional Western care, and health professionals may wish to bring it to their attention. Unlike proximal care, the Copenhagen approach does not involve such continuous daytime carrying or nighttime cosleeping. 3. Where parents wish to prevent night waking and signaling after 12 weeks, there is strong evidence that introduction of structured parenting based on behavioral principles from about 6 weeks of age is likely to help. A noteworthy finding is that no benefits of this approach were apparent before 6 weeks of age. Important advantages are that this approach is effective with breastfed infants and that, unlike ‘‘extinction’’ and ‘‘controlled crying’’ methods used to treat infant sleeping problems after they have arisen, it does not involve leaving babies to cry. The elements of this approach are described more fully in the original publications [17,72], but in essence it comprises three steps. First, parents are advised to maximize the difference between daytime and nighttime environments by minimizing light and social interaction at night. Second, they are asked to settle a baby judged to be sleepy in a cot or similar place and to avoid feeding or cuddling to sleep, at nighttime. Third, once the baby is at least 3 weeks old, healthy, and gaining weight normally, they can begin to delay feeding when baby wakes at night, to dissociate waking from feeding. This dissociation is done gradually, using diaper changing or handling to introduce a delay, and does not involve leaving babies to cry. 4. Another consideration affecting parental choices is the controversy about the relationship between cosleeping and SIDS. Experts are divided in their interpretation of this evidence, with some concluding that cosleeping increases the risk of SIDS, even where parents do not show other risk

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factors such as smoking and alcohol consumption [88,89], and others concluding that cosleeping helps to keep infants in lighter stages of sleep and consequently may protect against SIDS [74]. Clearly, most parents will wish to choose a form of care that minimizes the risk of SIDS rather than care that minimizes sleeping problems. As Fleming and Blair point out elsewhere in this issue [90], however, there is no direct evidence to support a protective role for cosleeping. There is some epidemiologic evidence that cosleeping increases the risk of SIDS [88,89,91]. The Website for the Foundation for the Study of Infant Deaths (http://www. fsid.org.uk/babycare.html accessed 1 PM 09/02/2007) currently recommends that the safest place for a baby to sleep for the first 6 months is in a cot in the parents0 bedroom and recommends against sharing a bed with a baby, as does the American Academy of Pediatrics [92]. As Fleming and Blair also point elsewhere in this issue, however, the evidence about the risks of bed-sharing is far from conclusive because of the existence of confounding factors. Consequently, taking all this evidence into account, and providing infants settled in cots are placed on their backs or sides and monitored carefully, there is no reason to expect that using cots and a structured approach to infant sleeping after about 6 weeks of age will increase the likelihood of SIDS. 5. Where parents report an established infant crying or sleeping problem, the parental complaint, rather than the infant behavior, is the presenting phenomenon. Such complaints involve a subjective judgment, and parents vary in their knowledge and tolerance. Measurements that accurately assess infant behavior are an essential first step in understanding what the problem is. Instruments for measuring infant sleeping and crying have been developed for research and can be adapted for routine health service practice. Behavior diaries, such as the ‘‘Baby’s Day Diary’’ [45], are the most accurate method. Where parents cannot keep them, summary questionnaires such as the Crying Patterns Questionnaire can be used [93]. Questionnaire and diary methods also exist for measuring infant sleeping [80,94,95]. There is a need for cost-effectiveness research to evaluate the use of these procedures under routine health care service conditions. 6. Because some parents are particularly vulnerable to infant crying and night waking, collecting information to identify maternal depression, social supports, single parenthood, and other sources of parental vulnerability should be a core part of the primary work-up, so that services can be targeted toward need. 7. In about 1 in 10 cases, persistent crying in 1- to 3-month-old infants reflects an organic disturbance. Health services need effective means of identifying and treating these special cases. Gormally [18] and Treem [96], two pediatric members of an expert panel on infant crying and colic, recommended the following criteria for identifying organic cases:  High-pitched/abnormal sounding cry  Lack of a diurnal rhythm

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 Presence of frequent regurgitations, vomiting, diarrhea, blood in stools, weight loss, or failure to thrive  Positive family history of migraine, asthma, atopy, eczema  Maternal drug ingestion  Positive physical examination (including eyes, palpation of large bones, and neurologic, gastrointestinal, and cardiovascular assessment)  Persistence past 4 months of age Heine and colleagues [97] also recommend that gastroesophageal reflux should be diagnosed only in cases with feeding difficulties and frequent regurgitation (O 5 times daily). Where organic disturbance is suspected, parents again need to make choices about the benefits and costs of alternative actions. An important consideration is that no reliable tests are available to confirm atopic or gastroesophageal cases [28,29]. Consequently, confirmation requires dietary manipulations, which carry their own inconvenience and cost. Wolke [44] points to the advantages of breastfeeding and notes that manipulations of breastfeeding mothers’ diets to change their milk constituents are difficult to achieve in practice. Heine [28] identifies the need for expert supervision where breastfeeding mothers’ diets are restricted, so that this approach may be inappropriate where expertise is lacking. Further, as noted previously, there is little evidence that low-allergen diets for breastfeeding mothers produce changes in infant behavior that resolve the crying problem so far as parents are concerned. When babies are bottle fed formula, there is clearer, but not universally accepted, evidence that changes to a hypoallergenic formula can reduced crying in some cases [28]. Parents who favor this option need expert support. 8. Where no organic disturbances are found, the available evidence provides no basis for advising parents in general that changes in their method of care are likely to resolve crying problems in 1- to 3-month-old infants once the problems have arisen. This conclusion is particularly true of the prolonged, unsoothable crying bouts that seem to be central to parents’ concerns in early infancy. Instead, once organic disturbance has been considered, and the infant’s healthy growth and development has been confirmed, the focus of intervention should be on containing the crying and providing parents with information and support. Important elements advocated by an expert group are [98]  Examining the notion that crying means that there is something wrong with a baby of this age and introducing alternatives (eg, that the crying signals a reactive or vigorous baby).  Viewing the first 3 months of infancy as a developmental transition, which all babies go through more or less smoothly  Reassuring parents that it is normal to find crying aversive and discussing the dangers of shaken baby syndrome

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 Discussing ways of containing/minimizing the crying and highlighting positive features of the baby  Considering the availability of supports and the development of coping strategies that allow individual parents to take time out and ‘‘recharge their batteries’’  Empowering parents and reframing the first 3 months as a challenge that they can meet, with positive consequences for themselves and their relationships with their babies  Continuing to monitor infant and parents 9. Compared with infants who have only crying or sleeping problems, there is consistent evidence of poor long-term outcomes in cases with multiple behavior disturbances beyond 12 weeks of age. Unfortunately, the current data neither distinguish the cases in which organic or socialenvironmental explanations are most applicable nor indicate the sort of interventions most likely to be effective in these cases. Because there is evidence that interventions that target parenting are effective from about 6 months of age through the preschool period [84,99], programs of this kind may be considered as an important part of health care services. The chief implication of the findings in this area at present, however, is to highlight the paucity of evidence about this group of infants and to identify them and their families as a priority for health services and research.

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Bedtime Problems and Night Wakings in Children Melisa Moore, PhDa, Lisa J. Meltzer, PhDa, Jodi A. Mindell, PhDa,b,* a

CHOP Sleep Center, 34th Street and Civic Center Blvd., Philadelphia, PA 19104, USA b Department of Psychology, Saint Joseph’s University, Philadelphia, PA 19131, USA

Bedtime problems and night wakings in children are common complaints heard by general pediatricians and sleep specialists, affecting 20% to 30% of young children [1–7]. Bedtime problems and night wakings in children can significantly impact daytime functioning for both children and their parents, including daytime sleepiness, increased behavior problems, decreased neurocognitive functioning, and family stress [8–10]. In most cases, behavioral sleep problems do not resolve on their own [11,12], highlighting the need for preventive education, early identification, and intervention. Previous research has found behavioral treatments for bedtime problems and night wakings to be highly effective [13], improving not only sleep quality and sleep quantity, but also impacting other important parentand child-related outcomes, such as mood and behavior. This article reviews the presentation of bedtime problems and night wakings, empirically validated interventions, and challenges to treatment in both typically developing and special populations of children. Presentation of bedtime problems, night wakings, and nighttime fears Bedtime problems Bedtime problems include both bedtime refusal (eg, refusing to participate in aspects of the bedtime routine, to get into bed, or to stay in bed) and bedtime stalling (eg, attempting to delay bedtime with repeated requests for hugs, food or drink, stories, and so forth) [7]. Bedtime problems typically A version of this article originally appeared in Sleep Medicine Clinics, volume 2, issue 3. * Corresponding author. Department of Psychology, Saint Joseph’s University, Philadelphia, PA 19131. E-mail address: [email protected] (J.A. Mindell). 0095-4543/08/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.002 primarycare.theclinics.com

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begin with the developing independence of toddlers, but can continue or develop in preschoolers and school-aged children. Often children test the limits to determine boundaries and gain independence, both at night and during the day, which in most cases is developmentally normal. At bedtime, however, these behaviors can be more difficult for parents to deal with and can result in inconsistent bedtime routines or rules that change with the child’s requests. If this occurs, bedtime problems may worsen. With regular sleep routines and appropriate bedtime limits, children can learn to fall asleep quickly and independently. Night wakings Night wakings are most common in infants and toddlers, but can also occur in older children. Typically, night wakings are caused by negative sleep associations, although physiologic causes must be ruled out (eg, reflux, obstructive sleep apnea). Sleep associations develop when children learn to fall asleep under certain conditions (eg, parent present, being rocked) or with certain objects (eg, bottle, blanket) [14]. When the condition or object is not present the child may have difficulty falling asleep, at bedtime and following normal nighttime arousals. Although some associations may be positive and promote independent sleep (eg, stuffed animal or pacifier), negative associations (eg, lying with or rocking a child) that require the presence of another person, most often a parent, are problematic [14]. Normative night wakings occur throughout the night [15], but a child who has a negative sleep association at bedtime needs this same association to return to sleep following each night waking [16]. Bedtime problems and night wakings co-occur if a negative sleep association develops in response to inconsistent limits. For example, a child may make repeated requests for attention at bedtime, with the parent eventually staying with the child until he or she is asleep, forming a negative sleep association. The child becomes unable to fall asleep or return to sleep without the parent’s presence, and during normative night wakings, the parent must return to the child’s room to lie with him or her for the child to return to sleep. Nighttime fears Most children experience nighttime fears (73.3% of children ages 4–12), but these are considered to be normal features of development [17,18]. Cognitive development in young children, primarily increased creativity, imagination, and an awareness that bad things can happen, contributes to these fears. The presence of a parent or older sibling at bedtime typically alleviates children’s fears at night, but also may result in a negative sleep association. It is important to discuss these fears with the child during the day, but it is also important to maintain consistency with regard to bedtime routines to promote a developmentally appropriate level of independence and prevent more serious bedtime problems.

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Classification and prevalence Most empiric research on behavioral sleep problems and interventions has not been conducted using strict diagnostic definitions. Rather, studies have used a multitude of definitions to designate bedtime problems and night wakings, from parental identification of their child experiencing a sleep problem to more empirically based definitions, such as a child waking three or more nights a week. No studies have classified children according to the designation of the recent International Classification of Sleep Disorders, 2nd edition [19], which has included difficulty falling asleep independently or frequent night wakings to be primary symptoms in behavioral insomnia of childhood (BIC). The International Classification of Sleep Disorders, 2nd edition [19] defines three subtypes of BIC based on the behavioral etiology of the bedtime problem or night waking: (1) BIC sleep-onset association type, (2) BIC limit-setting type, and (3) BIC combined type. BIC sleep-onset association type is most often seen in infants and toddlers (ages 6 months–3 years), although it can occur at any point during childhood or adolescence [19]. Negative sleep associations contribute to prolonged sleep onset or frequent night wakings. In contrast to sleep-onset association type, children with BIC limit-setting type are often described by their caregivers as refusing to go to bed or attempting to delay bedtime with repeated requests [14,19]. BIC limit-setting type occurs most commonly in toddlers, preschoolers, and school-aged children [20]. If bedtime routines and rules are not clear and consistent, and parents have difficulty enforcing limits, BIC limit-setting type can occur. BIC combined type typically occurs when a negative sleep association develops in response to nonexistent or inconsistent limits. Because bedtime problems and night wakings often coexist, many prevalence studies do not treat them as separate disorders and the prevalence of each specific problem is difficult to ascertain. In cross-sectional studies, 20% to 30% of young children are reported to have bedtime problems or frequent night wakings [1–3,6]. In addition, frequent night wakings are one of the most common sleep concerns in children over 6 months, with 25% to 50% of children waking at night [7,21]. As stated, with regard to specific diagnoses, BIC limit-setting type occurs primarily in toddlers and preschoolers (10%–30%) and school-aged children (15%) [20].

Assessment A comprehensive assessment of both sleep patterns and daytime functioning is needed to evaluate bedtime problems and night wakings [16]. One approach is to guide a family through a ‘‘typical’’ 24-hour period to assess factors that may impact both nighttime sleep and daytime sleepiness. This provides information about the child’s sleep schedule (eg, bedtime and wake time on weekdays and weekends); bedtime routines (nighttime activities,

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bedtime stalling or refusal, sleep-onset latency); parental responses to child behaviors at bedtime and following night wakings (limit setting, reinforcement); parental knowledge and beliefs about sleep (eg, keeping the child awake longer leads to sleeping through the night); social and environmental context (eg, cosleeping, parental presence at bedtime); symptoms of physiologic sleep disorders (eg, snoring, sleep terrors); and daytime functioning (eg, sleepiness, napping schedule, irritability). Additional questions about the impact of the child’s sleep problems on the family and a discussion of the type and duration of strategies previously used is helpful in treatment planning. Finally, psychosocial information about significant life events is needed (eg, birth of a sibling, marital conflict) because these events may impact sleep and result in the development of sleep problems. Along with information provided by parents in a history, additional information may be collected using sleep diaries that track bedtime; sleep-onset latency; frequency and duration of night wakings; morning wake time; and naps (frequency, duration, and timing). It is recommended that a 2-week baseline diary be completed to provide sufficient information about sleep patterns [22]. Objective information about sleep patterns may be provided by actigraphy. Actigraphs are electronic activity monitors that are typically worn on the child’s wrist, providing measures of sleep patterns for an extended period of time (eg, 3 days–2 weeks). In addition to providing a picture of the child’s sleep patterns, actigraphy provides valid estimates of total sleep time, sleep interruptions, and times of sleep onset and offset [23–25]. Behavioral treatments for bedtime problems and night wakings Behavioral interventions have been empirically validated for the treatment of bedtime problems and night wakings. A recent American Academy of Sleep Medicine review of 52 studies investigating behavioral interventions for bedtime problems and night wakings reported that 94% of studies demonstrated clinically significant effects [13]. Empirical evidence from controlled group studies using Sackett criteria for evidence-based treatment provided strong support for unmodified extinction and preventive parent education, and additional support for graduated extinction, bedtime fading and positive routines, and scheduled awakenings [13,26]. These treatments are based on principles of learning and behavior, including reinforcement. Such interventions rely on parent training to impact changes in the parent’s behavior, which facilitate changes in the child’s behavior [13]. The primary goal of behavioral strategies is for children to develop positive sleep-related associations and self-soothing skills to fall asleep at bedtime and return to sleep following night wakings independently. Although the treatment strategies are straightforward, implementation is affected by multiple factors. One crucial element of behaviorally based treatments is parental consistency. Because these treatments can be stressful for parents, interventions should be tailored to the specific family and when

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possible, ongoing support should be provided to maximize the chances of successful follow through [27]. Extinction Extinction or ‘‘crying it out’’ is one of the earliest behavioral interventions studied for bedtime problems and night wakings, and continues to be recommended today [13,28]. Extinction involves putting the child to bed at a consistent time and ignoring the child’s negative behaviors (while monitoring for safety and illness), until a designated wake-up time. Negative behaviors that should be ignored include yelling, crying, and tantrums. The first known study of unmodified extinction (also called systematic ignoring) for bedtime problems and night wakings was conducted by Williams [28] with a toddler whose duration of crying decreased after consistent ignoring by her parents. Since that time, three randomized, controlled studies [27,29,30] and several smaller studies and case reports [27,31,32] have been conducted, providing strong empirical support for extinction. One randomized, controlled study found that extinction was more effective at reducing parental report of night wakings than a control group and worked faster than scheduled awakenings [29]. Another similar study compared an intervention delivered by a therapist (including a consistent bedtime, bedtime routine, and extinction) with a written information–only group and a wait-list control group [27]. Both intervention groups (written information and therapist support) demonstrated improvements over the control group; however, no differences were found between the intervention groups. Finally, extinction alone has been compared with extinction plus sleep-enhancing medication (trimeprazine) and extinction plus placebo [30]. Results showed that extinction was effective in all groups, with those in the extinction plus medication group showing the fastest response. When compared with untreated controls, significant improvements were maintained at 6 and 30 months for the intervention groups [30]. Parental consistency is essential for success, yet most parents find their child’s prolonged crying to be stressful; the standard approach to extinction may be difficult for some parents. If parents respond to yelling and crying after a period of time, the child’s negative behavior is reinforced with attention, increasing the likelihood of the behavior continuing. Parents should be advised about the likelihood of an ‘‘extinction burst’’ or brief reemergence or worsening of negative behaviors at some later date. Although this is a normative part of the extinction process, parents may perceive this as evidence that the intervention is not working. Graduated extinction As an alternative to unmodified extinction or the ‘‘cry it out’’ method, graduated extinction was developed. Graduated extinction involves ignoring the child’s negative behaviors (eg, crying and yelling) for a specified duration

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before briefly checking on the child. The time between checks should be based on parental tolerance of the child’s crying, and the child’s age and temperament. The period of time between checks can be fixed (every 3 minutes); can increase on a given night (3 minutes, then 5 minutes, then 10 minutes); or can increase over a week (3 minutes Monday, 5 minutes Tuesday, 10 minutes Wednesday). Following the ignoring period, the parent briefly checks on the child and provides reassurance but minimizes attention. Both randomized, controlled studies of graduated extinction [33,34] and case reports and within-subjects studies have supported graduated extinction [7,31,35,36]. Adams and Rickert [33] compared graduated extinction with positive bedtimes and with a control group. In the graduated extinction group, parents were told to keep their child’s established bedtime and ignore negative behaviors (eg, tantrums) for a set amount of time (based on the child’s age and the length of time the parents believed they could ignore the child). After the ignoring period, parents were told to comfort their child for a maximum of 15 seconds. In this study both graduated extinction and positive bedtime routines were significantly more effective at reducing bedtime tantrums than controls. There were no significant differences between the intervention groups. A recent randomized, controlled study of 3 to 6 year olds evaluating the use of the bedtime pass [34] found this to be an effective modification of graduated extinction. In this study, children were given a card (bedtime pass), which could be traded in for a visit from a caregiver or one trip from their room. After the bedtime pass was used, caregivers were instructed to ignore negative, attention-seeking behaviors from the child. Results demonstrated less frequent calling and crying out and shorter time to quiet in the intervention group compared with controls. These gains were maintained at 3 months, and parent satisfaction was high with this treatment. Positive routines and faded bedtime Positive routines with a faded bedtime is an alternative to extinction for the treatment of bedtime problems and frequent night wakings [33,37]. Proponents of positive routines suggest that although extinction eliminates negative behaviors, it does not provide positive behaviors to take their place [33]. Positive routines involves collaborating with parents to determine the child’s bedtime, based on when they would naturally fall asleep. Parents then create a bedtime routine involving a few quiet activities lasting 20 minutes in total [13,33]. Delaying bedtime is used to ensure a rapid sleep-onset latency that is paired with a positive association with bedtime. Once the association between the positive routine and rapid sleep association is in place, the child’s bedtime is moved 10 to 15 minutes earlier every few nights until the desired bedtime is reached. The linking of positive bedtime activities with bedtime and sleep onset is believed to eliminate bedtime problems, helping the child to develop self-soothing skills and fall asleep independently.

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Although less extensive than the literature on extinction and graduated extinction, at least three studies have found positive routines to be beneficial in the treatment of bedtime problems or frequent night wakings [33,37,38]. In the only study of positive routines to include a control group, Adams and Rickert [33] compared positive routines with graduated extinction and with a control group in 36 toddlers and preschoolers. Positive routines involved moving the child’s bedtime to a time the child would more naturally fall asleep. Before bedtime, the parent and child would complete four to seven calm, pleasurable activities together. If the child began to tantrum, the parent was to end the activities and tell the child that it was time for bed. Additionally, the child’s bedtime was gradually moved earlier until it reached the desired bedtime. In this study, both positive routines and graduated extinction were significantly more effective than the control group; however, they were not significantly different from each other. Scheduled awakenings If children wake during the night at predictable times, scheduled awakenings can be an effective treatment option. This interventions involves parents recording the time and number of spontaneous night wakings to determine a baseline [39,40]. The next step is for parents to wake their child and provide their typical response to night wakings (feeding, rocking, patting on the back) until the child returns to sleep at predetermined times during the night. The length of time between scheduled awakenings is gradually increased, which is thought to increase the length of time between spontaneous night wakings [13]. At least four studies have been conducted with scheduled awakenings [39–41], including one study with a control group [29]. Rickert and Johnson [29] found that scheduled awakenings were significantly more effective than a control group and as effective as extinction, although extinction worked more quickly. Although results may be seen in days with extinction, scheduled awakenings may take several weeks [13]. Additionally, scheduled awakenings may be more complex to implement, because parents consistently have to wake their child at least once every night. Further, this intervention is not applicable to children with bedtime struggles. Parent education and prevention Before the development of bedtime problems and night wakings, parental education and prevention has been shown to be an effective intervention [13,35,42]. Through written material or in-person education (individual or group), parents are taught how to help their child develop self-soothing skills. Prevention and education efforts have also focused on positive sleep habits, including a consistent sleep schedule, appropriate bedtime routine, and responses to normal developmental changes.

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Studies of parent education demonstrate that compared with controls, infants whose parents were part of a sleep intervention obtained more nighttime sleep and had less frequent night wakings [13]. Multiple studies have been conducted showing that short interventions (one to four sessions) greatly impact infant sleep [42–46], although longer-term outcomes from such studies are not available. Wolfson and colleagues [46] randomly assigned first-time parents in child birthing classes to a sleep education group (two classes before childbirth and two classes after childbirth) or a control group. According to parent diary, 72% of 3-week-old infants ‘‘slept through the night’’ as compared with 48% in the control group. A study by Pinilla and Birch [43] found that by 8 weeks, 100% of infants in a parent education intervention slept through the night as compared with 23% of controls. Fewer sessions may be effective, as demonstrated by Adair and coworkers [45], who incorporated written sleep information into two routine well-child visits. St. James-Roberts and coworkers [44] found less robust effects than Pinilla and Birch [43] when using a written format; however, the difference in numbers of infants who slept through the night was still 10% more than those in the control group. These findings suggest that face-to-face contact may be an important element of parent education interventions. Nighttime fears interventions A recent review of the treatment literature for nighttime fears found that most studies used cognitive behavioral techniques, such as desensitization, positive self-talk, positive imagery, reinforcement, relaxation, and desensitization [17]. Although it is difficult to determine the efficacy of any specific component because most studies used a combination of techniques, most of the 29 studies demonstrated a reduction of nighttime fears after a few sessions. One key component of cognitive behavioral interventions, as found in a small study by Ollendick and colleagues [47], is behavioral reinforcement. When children were rewarded for making steps toward sleeping independently and confronting their fears, much larger treatment gains were made. Nightmares may also contribute to the development of nighttime fears [48]. To help a child learn that they are objectively safe, it is important to promote appropriate coping skills, including sleeping independently. Following a nightmare, parents should return their child to bed and provide reassurance that the dream was not real. It is important for parents to model calm behavior and to provide reassurance with limited attention at night. A more in-depth discussion of the nightmare can be deferred until the next day [16]. To reduce the potential for future nightmares, sufficient sleep and avoidance of frightening books, movies, and television are recommended. Many parents are concerned that nighttime fears are a symptom of a more serious psychologic problem. Typically, when more severe anxiety disorders (posttraumatic stress disorder, generalized anxiety disorder, phobias, or separation anxiety) are present, symptoms are also seen during the daytime. When nighttime fears

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persist or cause significant distress to the child and family, psychologic assessment and intervention are recommended. Treatment challenges Although behavioral treatments for bedtime problems and night wakings are effective, there are a number of barriers that may result in nonadherence to treatment recommendations. Behavioral treatments, such as extinction and graduated extinction, rely on behavioral principles, including schedules of reinforcement. Parent inconsistency results in an interval or unpredictable reinforcement schedule, which in turn maintains the unwanted behavior. When parents report that ‘‘they have tried everything,’’ it is important to assess for how long they tried each treatment approach. Unlike medications, behavioral interventions take several days to several weeks to implement, and parents may give up prematurely if not apprised of this factor. While monitoring for safety, it is crucial that parents select an approach (in collaboration with a clinician) and systematically adhere to that approach for several weeks. To improve consistency, it is important that parents understand the rationale for the behavioral intervention and the specifics of implementation. One factor that may improve adherence to behavioral treatments is determining the appropriate timing for sleep training, so it does not coincide with any life stressors. Individualizing the treatment plan also helps to prevent the inconsistencies that can lead to poor outcomes. Furthermore, family and environmental issues can contribute to difficulties in treatment implementation. Parental mental health challenges and limitations in basic parenting skills can result in an inability to develop and implement treatment strategies. Other children in the home or parents who are shift workers can make it difficult for families to follow through on any strategies that may result in sleep disruption to others. Furthermore, home environment issues can be challenging, such as child needing to share a bed or bedroom with other family members. Special populations of children Developmental disorders Children with developmental conditions, such as autism spectrum disorders (ASDs), may be at increased risk for bedtime problems and night wakings compared with typically developing children. In fact, 44% to 83% of children diagnosed with ASDs have a sleep problem as determined by actigraphy or parent report [49–51]. The most common problems reported are difficulty falling asleep, inability to sleep independently, frequent and lengthy night wakings, early morning wakings, and less total sleep time [51–54]. Although research in this area is limited, sleep problems in children

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with ASDs have been shown to relate to more energetic, excited, and problematic daytime behaviors [50]. Moreover, in this population total sleep time has been shown to be related to both social skills and stereotypic behaviors [55]. Although the implementation of behavioral interventions may be challenging, studies have shown that parents of children with ASDs prefer behavioral approaches to sleep-enhancing medications, although pharmacologic interventions are offered more frequently than behavioral interventions [54,56,57]. A recent survey of various behavioral approaches found that at least 50% of parents perceived most interventions as helpful [58]. The same study demonstrated that between subgroups of children with ASDs (mentally retarded versus not mentally retarded), the effectiveness of each behavioral intervention might differ [58]. Attention-deficit–hyperactivity disorder Children with attention-deficit–hyperactivity disorder (ADHD) have been reported to have more bedtime problems (eg, longer time to sleep onset and bedtime resistance) than children without ADHD; however, this remains a controversial issue [22,59]. Although parents of children with ADHD may report more bedtime problems [60–64], recent reviews of objective evidence have not demonstrated increased bedtime resistance or time to sleep onset in children with ADHD [65,66]. One potential explanation is that longer time to sleep onset is related to medications for ADHD [67]. In addition, sleep problems may be caused by a comorbid psychiatric disorder (eg, oppositional defiant disorder) rather than the ADHD. Furthermore, it is possible that parents may overreport the severity of both daytime and sleep-related behavior problems in a negative halo effect [61]. Behavioral interventions for bedtime problems and nightwakings in children with ADHD are promising, with at least one case series [68] and one small study [69] showing feasibility and parent satisfaction. Early implementation of behavioral treatment is critical, because sleep disturbance can exacerbate symptoms of ADHD [70,71]. Summary Bedtime problems and night wakings in children are extremely common, and the treatment literature demonstrates strong empiric support for behavioral interventions. Empirically validated interventions for bedtime problems and night wakings include extinction, graduated extinction, positive routines, and parental education. Although parent report of bedtime problems and night wakings may be higher in children with ASDs and ADHD, behavioral interventions for sleep difficulties can be important first steps in improving both sleep and daytime functioning. Most children respond to behavioral interventions, resulting not only in better sleep for the child, but also better sleep and improved daytime functioning for the entire family.

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