Respiratory Physiology: The Essentials

r Structure and Function How the Architecture 01the LungSubserves Its Function

Blood-Gas Interface Airways and Airflow Blood Vessels and Flow

Stability of Alveoli Removal of Inhaled Particles

We begin with a short review of the refationships between structure and function in the fungoFirst we look at blood-gas interface where the exchange of the respiratory gases occurs. Next we look at how oxygen is brought to the interface through the airways, and then how the blood removes the oxygen from the lung. Finally two potential problemsof the lung are briefly addressed: how the alveoli maintaintheir stability, and how the lung is kept clean in a polluted

environment.

The lung is for gas exc ha nge . Its prime fun ct ion is to a llow oxygen to move fro m the air into the venous blood and carbon dioxide [Q move o ut. The lun g does

other jobs too. It metabo lizes some compounds, filters unwanted mater ials from the c ircul ation, an d acts as a reservo ir for blood. But its cardin al fun ction is to C X~ change gas, and we shall therefo re beg in a t th e blood -gas interface where the gas excha nge occurs.

Blood-Gas Interface

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Oxy gen and carbon dioxide move between air and blood by simple diffusion, that is, from an area of high to low partial pressure, * much as water runs downhill. Pick's law of diffusion states that the am oun t of gas that moves acro ss a sheet of t issue is proportional to the area of the sheet but inversely proporti onal to its thickness. The blood- gas ba rrier is exceedingly thin (Figure I-I) and h as an area of be tween 50 and 100 square meters. It is therefore well suited to its funct ion of gas exchange. How is it possible to obtain such a prodigious surface are a for diffusion inside the limited thorac ic cav ity?This is done by wrapping the small blood vessels (cap illaries) around an en ormo us number of small air sacs called alveoli (Figure 1-2). There are abou t 300 mill ion alveo li in the hu man lung, eac h abou t 1/3 mm in diam eter. If th ey were spheres," their to tal surface area would be 85 square me ters, but the ir volume only 4 liters. By co ntrast , a single sph ere of this vo lume wo uld have an int ern al surface area of on ly 1/100 square mete r. Thus, the lung gene rates this large diffusion area by be ing divided in to myriad un its. Gas is brough t to one side of the blood-gas interface by airways, an d blood to the othe r side by blood ,'essels.

Airways and Airflow T he a irways consist of a se ries of bra nching tubes wh ich be co me n arrower, sho rter, and more numerous as th ey penetrat e deeper in to the lun g (Figure I ~J) . T he trachea divides in to righ t and left main bronchi, which in turn d ivide in to 10' bar , then segme nta l bronchi. This process co n tin ues down to the tenninal bran, chioles, wh ich are the sma llest a irways without alveo li. All of these bronch i make up the conducting airways. T h eir function is to lead inspired air to th e gas ex , ch an ging regions of the lung (Figure 1,4). Beca use the co nduct ing airways con, tai n no alveo li and therefore take no part in gas exc hange, the y const itute the ana tomic dead space. Its volume is about 150 ml. The termin al bro nch ioles divide into respiratory bronchioles, whic h h ave oc casional alveoli budding from their walls. Finally, we come to the alveolar dU ClS , wh ich are completely lined with alveoli. This alv eo lated region of the lung where the gas exc ha nge occ urs is known as the respiratory zone. T h e portion of lun g dis, Figure

la r w a t Th e eryth r t lo n), a pla sm a a nd a ~

1.-_

* The part ial pressure of a gas is found by mu lriplving its concentrat ion

t

by the to ta l pressure. For example, dry air has 20.93% 0 ,. Its partia l pressure (Po) at sea level (barom etric pressure 760 mm Hg] is 20.93/ 100 X 760 = 159 rom Hg. When air is inhaled into the upper airways, it is war med and moistened, and th e wate r vapo r pressure is th en 47 mm Hg, so tha t the tot al dry gas pressure is only 760 - 47 = 713 mm Hg. The Po , of inspired air is therefore 20.93/ 100 X 713 = 149 mm Hg . A liq uid exposed to a gas un til equ ilibration take s plac e h as th e same parti al pressure as the gas. For a more complete description of th e gas laws, see App endix A. Th e alveoli are not sphe rical hut polyhedral. No r is th e whole of their surface available for diffusion (see Figure 1, 1). These numbers are th erefore only approx imate .

Structure and Function

3

Figure 1-1. Elect ro n microg raph showing a pulmona ry capill ary (C) in the alv eolar wall. Note the extremel y th in blood -gas barri er of abo ut 0.3 u rn in some pl aces. The large arrow ind icates the diffusi on pat h fro m alveolar gas to th e interio r of t he eryt hrocyte (ECI and includes t he lay er of surfactant (not shown in th e preparation ), alve olar epitheli um (EP), interst it ium (IN), capill ary endoth elium (EN), and pl asm a. Parts of stru ctura l cell s call ed fibroblasts (FBI, baseme nt membrane (8M ), and a nu cleu s of an endot helia l cell are also seen.

Figure 1-3. Cas awa y, allov 'r-:; ol es t o be s~~ "

tal

to

a te rm u

tan ce from "

Figure 1-2. Sect ion of lu ng showing m any alveo li and a sma ll bronchio le. Th e pu lm onary capil lar ies run in t he w alls of the alv eo li (Figure 1-1). The holes in t he alve olar walls are the pores of Kahn.

but th e respir 3 liters durine During i drawn in to"

tion of the J intercost al of the thorax. ~ flow. like war

Structure and Function

5

Figure 1-3. Cast of the airwa y s of a human lu ng. The alveoli hav e been pruned

aw ay, allowing t he con ducti ng airwa ys from t he trach ea to the termina l bro nchioles to be seen.

tal to a termi nal bronc hiole forms an ana tomical un it called the acinus. The d isranee from the terminal bronchiole to the most distal alveolus is only a few mrn, but the respiratory zone makes up most of the lung, its volume being about 2.5 to 3 liters dur ing rest. During inspirati on, th e volume of the th oracic cavity increases and air is drawn into the lung. The incr ease in volume is brought about par tly by contraction of th e diaph ragm, wh ich causes it to descend, and partly by the actio n of th e int ercostal muscles, which raise th e ribs, thu s increasing the cross-sectional area of the thorax. Inspired air flows down to about the terminal bronchio les by bulk flow, like water th rough a hose. Beyond that point, the combined cross-sectiona l

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Figure 1-4. Id eali zat io n of th e hum an air wa y s according to We ibel. Note th at th e f irst 16 gene ratio ns (2) m ake u p t he condu cti ng airway s, and t he la st 7, t he respi rat or y zo ne (o r the t ran sitional and respir ato ry zo ne) .

area of th e airways is so enormous because of the large number of branc hes (Figure 1-5) that th e forward velo city of the gas becomes small. Diffusion of gas within the airways then take s over as the domin ant mech anism of vent ilation in the respiratory zone. The rate of diffusion of gas molecules within the airways is so rapi d and th e d istances to be co vered so short that differences in conc en tration within the acinus arc virt ually aboli shed with in a second. However, because the veloc ity of gas falls rapidly in the region of the ter mina l bronc hioles, inhaled dust frequently sett les out there.

Airways • • • •

Divided into a conducting zone and a respiratory zone Volume of the anatomic dead space is about 150 ml Volume of the alveolar region is about 2.5-3.0 liters Gas movement in the alveol ar region is chiefly by diffusion

Figure 1·5. aarea of t he a' f o rward ve toer th e resptraro vent ilat io n.

The lunc resting breat ml, for ex trast, a ch i vo lum e. The pres ing normal ' the airwav-

7

Structure and Function

500 I I I I I I I I I I I I I I I I

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Airway generation

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Figure 1 ~ 5 . Diag ram t o show t he ext rem ely rap id increase in tota l cross-sect ional a rea of t he ai rway s in t he respirato ry zone (co m pare Figure 1-4). As a resu lt, th e fo rw ard velocity of t he gas du ri ng in spirati o n bec o m es ve ry sma ll in t he region of th e respir ato ry bron chi ol es, and gaseous diffusio n beco mes th e ch ief m od e of ve nti latio n.

The lung is elastic and returns passively to its preinspiratory volume during restin g breat hing, Ir is remarkably easy to disten d. A normal brearh of about 500 rnl, for example, requ ires a disten ding pressure of less th an 3 em water. By contrast, a chi ld's balloon may need a pressure of 30 em water for the same cha nge in volume. The pressure required to move gas through the airways is also very small. During normal inspira tion , an air flow rate of 1 liter/sec requires a pressure drop along th e airways of less than 2 ern water. Compare a smoker's pipe whic h needs a pressure of about 500 ern water for the same flow rate.

Blood Vessels and Flow T he pulmonary blood vessels also form a series of branching tubes from the pulmonary artery to th e capillaries and baek to the pulmonary veins. In itially, th e arreries, veins, and bronch i run close together, but toward the periphery of the lung, t he ve ins move awa y to pass bet ween the lobules, whereas the art eri es and bronchi travel toget her do wn th e cent ers of th e lobules. The capillaries form a dense network in the walls of the alveoli (Figure 1-6 ). The d iameter of a capillary

8

Chapter 1

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500p. Figure 1-6. View of an alveolar wa ll (in t he frog ) showing the dense netwo rk of capill arie s. A sm all art ery (left) and ve in (ri g h t) can also be seen. The indi vi du al capi llary seg m ents are so short th at t he blood form s an almost co nt in uou s sheet.

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segmen t is about 10 u rn, just large eno ugh for a red blood cell. The lengths of the segmen ts are so short th at the dense network forms an almost co nr in uous shee t of blood in the alveolar wall, a very efficien t arrangement for gas exchange. A lveolar walls are not oft en seen face on, as in Figure 1,6 . The usual, thin microscopic cross section (Figure 1-7) shows th e red blood cells in th e capillaries and emphasizes the enormous exposure of blood to alveolar gas, with only th e th in blood-gas barrie r in terveni ng (compa re Figure IvI}, The ext reme thinn ess of th e blood- gas barri er mean s th at th e capillaries are easily dam aged . Increasing th e pressure in the ca pillaries to h igh levels or in flat ing the lung to h igh vo lumes, for example, can raise the wall st resses of th e capillaries to the point at whic h ultrastru ctural cha nges can occur. The capillaries then leak plasma an d even red blood cells in to the alveolar spaces. The pulmonary arte ry receives the whole output of th e right heart , but th e resistance of the pulmon ary circuit is aston ishingly small. A mean pulmo nary arterial pressure of only about 20 ern water (about 15 mm Hg) is required for a flow of 6 liters/rum (the same flow th rough a soda straw ne eds 120 cm water). Each red blood cell spends about 3/4 sec in the capillary network and during thi s time probably traverses two or th ree alveoli. So efficient is the ana tomy for

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frn C(

fairlv

T clance

Structure and Function

rk of idua! sheet.

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Fig u re 1 ~7 . M icros cop ic sectio n of d og lun g showing capi ll aries in t he alveo lar wa lls. Th e bloo d-gas ba rr ier is so th in th at it can not be id ent ified here (compare Figure 1 ~ 1). This sect ion w as pr ep ared f rom lu n g t hat w as rapidl y frozen w hi le b e~ ing pe rfu sed ,

gas excha nge tha t th is brief tim e is sufficien t for virtually complete equilibrat ion

of oxygen and carbon dioxid e between alveo lar gas and capillary blood. The lung h as an additiona l blood system, the bron ch ial circulation , wh ich supplies the conducting airways do wn to about the terminal bro nch ioles. Some of th is blood is carried away from the lung via the pulmonary veins and some enters the systemic circulation . The flow thro ugh th e bronchial circulation is a mere fract ion of th at through the pulmona ry circulation, and the lung can funct ion fairly well with out it, for exa mple, followin g lung transplantati on . T o con clude th is brief acco un t of the function al ana tomy of the lung, let us glance at two special problems th at th e lung has overcome.

Blood Vess els • • • •

Who le of the output of the right heart goes to the lung Diamete r of t he capillaries is about 10 ..... m Thickness of much of the blood-gas barrier is less than 0.3 u rn Blood spends about 3/4 sec in the capillaries

Stability of Alveoli T he l ung can he regarded as a collect ion of 300 million bubbles. each 0.3 mm in

diameter. Such a struc ture is inherently unstable. Because of the surface tension of the liquid lining th e alveoli, relatively large forces develop tha t tend to collapse alveoli. Fortu nately, some oft he cells lin ing th e alveoli secrete a material called surfactant, which dramatically lowers the surface tension of th e alveola r lining layer (see C ha pter 7). As a consequenc e, th e stab ility of the alveoli is enor mously inc reased . although collapse of small air spaces is always a potential problem and frequentl y occurs in disease.

Removal of Inhaled Particles

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W ith its surface area of 50 £01 00 square met ers, the lung presents th e largest surface of th e body to an in creasingly host ile environmen t. Various mechanisms for dealing wi th inhal ed part icle s h ave been developed (see C hapt er 9). Large part i-

cles are filtered out in the nose. Sma ller particles th at deposit in the conduct ing airways are removed by a moving sta ircase of mucu s th at conti nuall y sweeps dehris up to the epiglott is, where it is swallowed . The mucus, secreted by mucous glands and also by goblet cells in the bronch ial wall s, is propelled by millions of

tiny cilia, which move rhythmicall y under norm al conditions but are paralyzed by some inhaled tox ins. T he alveoli have n o ci lia , and part icles that deposit there arc engulfed by large wandering cells ca lled macrop hages. The foreign material is th en remov ed from th e lung via th e lymphat ics or the blood flow. Blood. ce lls such as leukocytes also participat e in th e defense rea ction to foreign materia l.

QUESTIONS For each question. choose the one best answ er. 1. Wh ich of t he following statements about th e blood-gas barrier of the human lung is FALSE ' A. Mu ch of the blood-gas barrier has a thickness of less than 0.3 I'm . B. The total area of the blood-gas barrier exceeds 50 square meters. C. Most of th e area of the alveolar wa ll is occupied by capillaries. D. If the pressure in the capillaries rises to unphysiologically high levels. the blood-gas barrier can be damaged. E. Oxygen crosses the blood-gas barrier by act ive transport. 2. W hen oxygen moves through the thin side of th e blood-gas barrier from the alveolar gas to the hemog lobin of the red blood cell it traverses the fo llow ing layers in order: A. Epithelial cell, surfactant. interstitium, endothelial cell. plasma, red cell membrane. B. Surfactant, epithelial cell. interstiti um. endothelial cell. plasma. red cell membrane.

Structure and Function

11

C.

3.

Surfactant . endo the lial cell. interstitium. epith elial cell. plasma. red cell membrane. D. Epithelium, interstitium, endothelial cell, plasma, red cell membrane. E. Surfactant. epithelial cell. interstitium. endoth elial cell. red cell membrane. What is the P0 2 (in mm Hgl of moist inspired gas of a climber on the summit of Mt. Everest (assume barometric pressure is 247 mm Hql? A. 32

B. 42 C.

52

D. 62 E. 72 4.

5.

6.

Wh ich of the fo llowing statements about the airw ays of the hum an lung is FALSE? A. The volume of the conduct ing zone is about 150 ml. B. The volume of the rest of the lung during resting conditions is about 2.5--3.0 liters. C. A respiratory bronchiole can be distinguished from a terminal bronchiole because the former has alveoli in its walls. D. On the average there are about 3 branchings of the conducting airways before the first alveoli appear in th eir w alls. E. In the respiratory bronchioles the predominant mode of gas flow is diffusion rather than convection. W hich of t he fo llowing statem ents abo ut t he blood vessels of th e human lung is FALSE? A. The pulmonary arteries form a branching pattern which matches that of the airways. B. The average diameter of the capillaries is about 50 u rn. C. Most of the surface of the alveoli is covered with capillaries. D. On t he average blood spends about 3/4 sec in the capillaries. E. The mean pressu re in t he pulmonary arte ry is only about 15 mm Hg at rest. W hich of the follow ing statements about t he removal of inhaled dust in the lung is FALSE? A. Very small particles are f iltered out by the nose. B. Particles that deposit on the airways are removed by the mucus escalator. C. The escalato r is propelled by mi llions of tiny cilia. D. The mucus comes from m ucous glands and goblet cells in the bronchial walls. E. Particles that reach th e alveoli are engulfed by macrop hages.

r Ventilation How Gas Gets to the Alveoli

Lung Volumes Ventilation Anatomic Dead Space

Physiologic Dead Space Regional Differences in Ventilation

We now look in more detail at how oxygen is brought to the blood-gas barrier by the process of ventilation. First lung volumes are briefly reviewed. Then total ventilationand alveolar ventilation, that is the amountof fresh gas getting to the alveoli, are discussed. The lung that does not participate in gas exchange is dealt with under anatomic and physiologic deadspace. Finallythe uneven distribution of ventilation caused by gravity is introduced.

The next three chapters concern how inspired air ge ts to rhc alveoli, how gases cross the blood-gas interface, and how they are removed from the lung by th e blood. These func tions are carried out by ventilation , diffusion , and blood flow, respectively. Figure 2-1 is a highly simplified diagram of a lung. The various bronchi that make up the conduct ing airways (Figures 1-3 and 1-4) arc now represented by a single tube labeled anatomic dead space. This leads into the gas-exchanging region of the lung, which is bounded by the blood-gas int erface and th e pulmonary capillary blood. W ith each inspirat ion, about 500 ml of air enter the lung (tidal l'Olume). Note how small a proportion of the total lung volume is represented by

13

Tidal volum e

500 ml

-1-

Anatom ic dead space 150 ml

Tota l ven tilation

7500 ml /mi n

Frequency 15/min

1-----\:- ----..

Alveolar ventilation 5250 ml/min

Alve olar gas 3000 ml

.;. = 1

»> Pulm ona ry cap illary blood 70 ml

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Pulmonary blood flow 5000 ml/ min

Figure 2-1. Dia gra m of a lung showing ty pi cal vo lumes and fl ow s. Th ere is co nsiderable v ariat io n aro un d these va lues .

8

__ ____ __________~_P aper

t

Total 6

lung

capacity

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Sp irom eter

Vital capac ity

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Pen

volume

2

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Fun ctional residual Residual

capacity

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__________ _t

volume

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Figure 2-2. Lung vo lumes. Note that th e tota l lung capacity, functio nal resi d ua l capa city . and resid ual vo lume can not be measu red w it h th e sp irometer.

15

Ventilation

the anatomic dead space. A lso note the very small volume of capillary blood compared with th at of alveolar gas (co mpare Figure 1-7).

Lung Volumes Before look ing at th e moveme nt of gas into th e lung, a brief glance at th e sta tic vo lumes of th e lung is helpful. Some of these can be measured with a spiromete r (Figure 2-2). During exha lation, the bell goes up and the pen down, marking a movin g chart. First, normal breathing can be seen (tidal volume). Next th e subjec t tonk a maximal inspirat ion and followed this by a maxima l exp iration. The exha led volume is ca lled th e vital capacity.. H owever, some gas remai ned in the lung after a maximal exp iratio n; thi s is th e residual volume. The volume of gas in the lung after a norm al expiration is the functional residual capacity. Neithe r th e functi onal residual capacity nor th e residual volume can be measured with a simple spirometer. However, a gas dilution technique can be used as shown in Figure 2-3. The subjec t is con nec ted to a spiromete r containing a known concentration of hel ium, which is virtually insoluble in blood . A fter some breaths, th e helium concent rations in the spirometer and lung become the same. Because no helium h as been lost, the amoun t of helium present before equi libration (concentration times volume ) is:

and equals th e amoun t after equilibration:

c, X

(V, + V,)

From thi s:

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Before equ ili brat ion

After equi libration

Figure 2-3. Measu rem ent o f th e f unctional residu al capa city by hel ium d ilution.

16

Chapter 2

Figure 2-4. M easurem ent of fu nct ional

re s idua l capaci ty (FRC) wit h a bod y plethysmograph. W hen the subje ct makes an in spirat ory effort agai nst a closed air w ay, he sli ghtly increase s th e vo lume of hi s lung, air wa y pre ssur e decrea ses, and bo x pres su re in creases. From Boyl e' s law, lung vo lu me is obtain ed (see t ext ). PV =K

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In practice, oxygen is added to th e spirometer during eq uilibra tion to make up for th at consumed by the subjec t, and also carbon dioxide is absorbed. A no the r way of measuring t he fun cti onal residual capacity (FRC ) is with a bod y plethysmograph (Figure 2-4) . This is a large airti ght box, like an old teleph one booth, in wh ich the subject sits. A t the end of a normal ex pirati on, a sh utt er closes the mouthp iece and th e subject is asked to make respir ato ry efforts. As th e subject tries to in ha le. he (or she) expands th e gas in h is lungs, and lung vo lume in creases, and th e box pressure rises beca use its gas vo lume decrea ses. Boyle's law states that pressure X vo lume is con sta nt (at constan t temperature). Therefor e, if th e pressures in the box before and after the in spiratory effort are PI and Pz, respecti vely, V I is th e pre -Insplracorv box volume and t1V is th e cha nge in volume of the box (or lun g), we can write:

PI VI = P, (V I - Ll.V) Thus Ll. V can be obta ined. Nex t, Boyle's Law is applied to the gas in the lun g. N ow:

P, V z = P4 (V z + Ll.V ) wh ere p} and P4 are th e mouth pressures before and after th e inspiratory effort. and V z is the FRC. Thus FRC can be obta in ed. The body plethysmograph measures the total vo lu me of gas in the lung, incl ud ing any tha t is trapped behi nd closed airways (an exa mp le is sh own in Figure 7~9) and that th ere fore does not co mmun ica te with the mou th. By contr ast, the h elium d ilut ion method measures only communicating gas, or vent ilated lung volume. In young n ormal subjec ts, these volumes a re virtually th e same , but in pat ients with lun g disease, the venti lated vol ume may be considerab ly less than the tot al volume because of gas t rapped behind obst ruct ed airways.

Ventilation

17

Lung Volumes • Tidal volume and vital capacity can be measured with a simple spirometer • Total lung capacity, functiona l residual capacity and residual volume need an additional measurement by helium dilution or the body plethysmograph • Helium is used because of its very low solubi lity in blood • The body plethysmograph depends on Boyle's Law PV=K at constant temperature

Ventilation

ze up

stan t are rs the

Suppose the volume exhaled with each breat h is 500 ml (Figure 2- \) and there are 15 breat hs/min . Then th e tota l volume leaving the lung each minute is 500 X 15 = 7500 ml/min. Th is is known as the total ventilation. T he volume of air en te ring the lung is very slightly greater because more oxygen is taken in than car bon dioxide is given out. However, not all the air that passes the lips reaches the alveolar gas compartmen t where gas exchange occurs. O f each 500 ml inhal ed in Figure 2-1, 150 ml remain behind in the anatomic dead space. Thus, th e volume of fresh gas en te ring the respiratory zone each min ute is (500 - 150) X 15 or 5250 ml/min. This is called th e alveolar ventilation and is of key importan ce because it represent s th e amount of fresh inspired air ava ilable for gas exchange (strictly, the alveolar ventila tion is also measured on expiration, but the volume is almost the same.) T he to tal ventilat ion can be measured easily by having the subject breathe through a valve box th at separates the inspired from the expired gas, an d collecting all th e expired gas in a bag. T he alveolar venti lation is more difficult to de, rerm ine. O ne way is to measure the volume of the anatomic dead space (see below) and calculate th e dead space ven tilation (volume X respiratory frequen cy). T his is then subtracted from the total ventilation. We can summarize thi s con veniently with symbols (Figure 2 ~5 ). Using V to denote volume, and the subscripts T , D, and A to denote tidal, dead space, and alveolar, respecti vely:

+ VA * Vi) . n + VA · n

VT = V" therefore, effort,

VT . n =

where n is the respiratory frequency. lung,

Therefore, where V mean s volume per unit time, VE is expired total ventilat ion , and Vn and \ 1A are the dead space and alveolar ven tilations, respectively (see Ap pend ix A for a summary of symbols).

can, ted

* Nore that VA here means the volume of alveolar gas in the tidal volume, not the total volume of alveolar gas in the lung.

VA= VE - Vn A difficulty with this method is that the anatomic dead space is not easy to measure, alt hough a value for it can be assumed with little error. N ote that alveolar vent ilation can be increased by raising either tid al volume or respirator y frequency (o r both). Incr easing tidal vo lu me is ofte n mo re effec ti ve because th is rei duces the proport ion of each breath occupied by th e ana tom ic dead space. Another way of measuring alveolar ventilation in normal subjects is from the concen trat ion of CO 2 in expired gas (Figure 2; 5). Because no gas exch ange occur s in the ana to mic de ad space, th ere is no C O 2 there at the end of inspirat ion (we can neglect the small amount of CO 2 in the air.] T h us, because all th e expired CO 2 comes from th e alveolar gas, % CO ,

,n

100 wher e \1<:0 2 means the volume of CO 2 exha led per uni t time.

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VA = .

too

Vco , X ---':~::::-% CO,

T he % CO,jl OO is often ca lled the fract iona l co ncentrat ion and is denot ed by Fcor Thus, th e alveolar ven tilation can be obtained by dividin g th e COl output by th e alveolar fractional conc en tration of thi s gas. Note that the partial pressure of C O , (denot ed Pco, ) is propo rt ional to the fract ional concen tration of the gas in th e alveoli, or PC O l = Fco z X K wher e K is a constan t.

Therefore,

Figure 2-5. The tidal v olume (VT ) is

a mi xt ur e o f gas f rom the anato m ic de ad space (Vol and a co nt ribution fro m th e alve olar ga s (VA)' Th e co ncentra tio ns of CO 2 are shown by the dots. F, fraction al co ncentr atio n; I, inspired; E, expi red. Com pare Figu re 1-4.

F,

FE

19

Ventilation

Because in normal subjects th e Pet)1 of alveo lar gas and arterial blood are virtually identical, th e arte rial r eX); can he used rodeterm ine alveolar ven tilation . The relation betwee n alveolar vent ilation and Pc"o z is of cruci al importance. If the alveolar ventilati on is halved (and COl produ ction remains unchanged ), for ex~ ampl e, the alveolar and arter ial pet)z will double.

Anatomic Dead Space T h is is the vo lume of the conducting airways (Figures 1-3 and 1-4), The normal value is about 150 rnl, and it increases with large inspirations because of the traction or pull exerted on th e bronchi by the surrounding lung parenchyma. The dead space also depends on the size and posture of th e subject. T he volume of th e anatomic dead space can be measured by Fowler's method. The subjec t breat hes through a valve box. and th e sampling tube of a rapid n itw gen analyzer continuously samp les gas at th e lips (Figure 2 ~ 6A ) . Followin g a single inspiration of 100% O 2 , the N2 concen tration rises as the dead space gas is increasingly washed out by alveolar gas. Fina lly, an almost un iform gas conce ntration is seen representing pure alveolar gas. This ph ase is often called the al veolar "plateau," altho ugh in normal subjects it is not quite flat, and in pat ien ts with lun g disease it may rise steeply. Expired volume is also recorded. The dead space is found by plott ing N z concentration against expired volume and drawin g a vert ical line such that area A is equal to area B in Figure 2F6B. T he dead space is th e volume exp ired up to the vert ical line. In effect , th is method measures the volume of the conducting airwaysdown to th e midpoint of th e tran sition from dead space to alveolar gas.

Physiologic Dead Space Another way of mea suring dead space is Bohr's method, Figure 2-5 shows that all th e expired CO 2 comes from th e alveolar gas and none from the dead space. T herefore, we can write

VT , FE =VA, FA now,

VT = VA + VD

the refore,

VA = VT - VI)

substituting when ce

VT ' FE= (VT - VD) , FA

=

W e saw earlier tha t th e part ial pressure of a gas is proportion al to its concen trution . Thus,

PA COI

-

PF..( X1Z

PAco ,

(Bohr equation )

20

Chapter 2

A

Start of inspiratio n

~

80

...c

End of expiration

0

~

.~

C c

"c

40

t

Alveolar

0

c ~

z

N2 meter

~

0

ltli ~ ' 'If' '

plat eau

Start of expiration

0

10

5 Time (sec)

,"

B

...c .!2

40

'§ C

"co 0

o ~

z

0

0

0.4

0.6

0.8

Expired volume (liters)

Figure 2-6. Fow ler's met hod of measuring t he anato m ic dead space w it h a rapid N 2 an alyz er. A shows that fo llowing a test in sp irat io n of 100% O 2 , t he N 2 co ncen tration rises durin g ex piration to an almost level " p lateau " represen ting pure alveolar gas . In B, N 2 co ncent rat ion is plott ed against expi red volume, and the dead space is t he vo lume up to th e vertical dashed li ne, w hich m akes th e areas A and B equ al.

where A and E refer to alveolar and mixed expired. respectively (see A ppend ix A ). The normal rat io of dead space to tidal volume is in th e range 0.2 to 0.35 during rest ing breathin g. In no rma l subj ects, the P CD 2 in alveola r gas and that in arteria l blood are virt ually iden t ical so th at the eq uat io n is therefore often written

VD VT

Paco z - PEe"'o z Paco,

21

Ventilation

i 'v e ntilation • Total vent ilation is tidal volume x respiratory frequency • Alveolar ventilation is the amount of fresh gas getting to the alveoli, or

IV, - Vol

X

n

• Anatomic dead space is the volume of the conducting airwavs, about 150 ml • Physiologic dead space is the volume of gas that does not eliminate CO2 • The two dead spaces are almost th e same in normal subjects, but the physiologic dead space is increased in many lung diseases

It should he not ed that Fowler's and Bohr 's methods measure somewhat differen t th ings. Fowler's method measures the volume of the conducting airways down to th e level where th e rapid dilution of inspired gas occurs with gas already in the lung. This volume is determined by the geometry of the rapidly expanding airways (Fig; ure 1-5), and because it reflects the morpho logy of th e lung, it is called th e anatomic dead space. Bohr's method measutes the volume of th e lung that does not eliminate CO 2, Because this is a functional measurement , th e volume is called the physiologic dead space. In normal subjects, the volumes are very nearly the same. However, in patients with lung d isease, the physiologic dead space may be considerably larger because of inequality of blood flow and vent ilation with in th e lung (see Chapter 5).

Regional Differences of Ventilation So far we have been assuming that all regions of the normal lung ha ve th e same ven tilation. However, it has been shown that the lower regions of th e lung ventilate bett er th an do the upper zones. T his can he demonstrated if a subject inhales radioactive xeno n gas (Figure 2; 7) . When the xenon-133 en ters the

133Xe ----+

100

Radiation

counters

~~ ~

w

E "0

80

'1'

60

~ c ,2

40

">

]1

E w >

20

a

t Lower

zone

I Middle zone

I Upper

zone

Distan ce

Figur e 2-7. Measureme nt of regio nal differences in v ent ilat ion w it h radi oacti ve xenon. When the gas is inh aled, it s radiation can be detected by cou nters outsi de th e chest. Note th at t he vent ilat ion decrease s from the lo we r to upper regi ons of

t he upr igh t lung.

coun ting field , its radiation penetra tes th e che st wall and can be recorded by a bank of co unt ers or a radiation camera. In this way, the volume of the inhaled xeno n going to various regions can be de termined. Figure 2-7 shows the results obtai ned in a series of normal volunteers using th is method. It can be seen th at ventilation per un it volume is greatest near t he bottom of the lung an d becomes progressively small er toward the top. O th er measuremen ts sho w th at whe n th e subjec t is in th e supine posit ion, th is difference d isappears with the result th at apical and basal ven tilat ions become the same. H owever, in that posture, the ventilat ion of the lowermost (pos te rior ) lung exceeds that of the uppermost (anterior) lung. A ga in in the lateral position (subjec t on his side) the dependent lung is best venti lated . The cause of th ese regional d ifferences in vent ilati on will be dealt with in Ch apter 7.

QUESTIONS For each question, choos e t he one best answe r. 1. All of the follow ing can be measured w ith a simple spirom eter and sto pwatch EXCEPT: A. Tidal volume. B. Functional residual capacity. C. Vital capacity . D. Total ventilation. E. Respiratory f requency . 2. All of the follow ing statements about the pulm onary acinus are true EXCEPT: A. All the oxygen uptake occu rs in the acini. B. Percentage change in volume of t he acini during inspiration exceeds t hat of th e whole lung. C. Volume of the acini is greater than 90% of t he tota l volume of the lung at FRC. D. Each acinus is supplied by a term inal bronchiole. E. Acini at the base of the upright human lung at FRC are larger than those at th e apex. 3. In a measur ement of FRC by helium-dilution , the original and final helium concentra tions were 10 and 6%, and the spirom eter volume was kept at 5 liters. Wh at was the volum e of th e FRC in liters? A. 2.5 B. 3.0 C. 3.3 D. 38 E. 5.0

23

Ventilation

4.

A patient sits in a body plethysmograph (body box) and makes an expiratory effort against his closed glottis. What happens to the followi ng: pressure in the lung airways. lung volume. box pressure. box volum e?

Airway

Lung

Box

Box

Pressure

Volume

Pressure

Volume

l l

t

A.

B.

c.

r

D.

i

E. 5.

r

r

r

l l i l l i l

l

r l

r l

If CO2 production rem ains constant and alveolar ve ntilation is increased three-fold, the alveo lar Pee- afte r a steady state is reached w ill be w hat per· centage of its former value? A. 25

B. 33 C. 50 D. 100 E. 300 6.

In a meas urem ent of physiologic dead space using Bohr's method the alveo-

lar and m ixed expired Pco, w ere 40 and 30 mm Hg. respectively. W hat wa s the ratio of dead space to tidal volume? A. 0.20

B. 0.25 C. 0.30 D. 0 35 E. OAO

r

Diffusion How Gas Gets Across the Blood-Gas Barrier

of Diffusion ion and Perfusion it at ions gen Uptake Along the , mo nary Capillary eas urernent of Diffusing Capacit y

Reaction Rate s with Hemoglobin Interpretation of Diffusing Capacity for CO CO2 Transfer Across the Pulmonary Capillary

=- now consider how gasesmove across the blood-gas barrier by diffusion.

the basic laws of diffusion are introduced. Next we distinguish between z ~sion - and perfusion-limited gases. Oxygen uptake along the pulmonary z ary is then analyzed, and there is a section on the measurementof _ ~"s "'g capacity using carbon monoxide. The finite reaction rate of oxygen -- ,emog/obin is convenientlyconsidered with diffusion. Finally there is a _ '3~ reference to the interpretation of measurements of diffusing capacity, and _iss ble limitations of carbon dioxide diffusion. ="57

-=

~~

chapter, we looked at how gas is moved from the atmosphere to the r in the reve rse directio n . W e now come to the tr ansfer of gas across the '"= barrier. This process occurs by diffusion. O n ly 60 years ago, some ph ys-- .. beli eved that the lung secreted oxygen into th e capillaries, that is, the

25

.

Vgas

A

OC

T · 0 · (P,- P2)

IY

....tl T hickness Figure 3-1. Diff usio n t hro ugh a t issue shee t. The amou nt of gas t ran sfer red is propo rt io nal to the are a (A I, a d iffusi o n const ant (0) , and th e di ff er ence in partia l p ressure (P,- P2), and is inver sely propo rti onal t o th e t hic kness (T). The constant is proportion al t o th e gas solu bility (Sol) but inv ersely pr op ortiona l to t he squ are root of it s mo lecular w eight (M W ).

oxygen was mo ved from a region of lo wer to one of h igh er part ial pressure . Su ch a proce ss was th ought to occur in th e swim bladder of fish, and it requires energy. But more accurate measuremen ts sho wed th at thi s does not occur in the lung and th at all gases move across the alveolar wall by passive diffusion .

Laws of Diffusion Diffusion through tissues is described by Fick's law (Figure 3-1). T his sta tes that the rate of tran sfer of a gas through a sheet of t issue is propo rtional to th e ti ssue area and th e d ifference in gas partial pressure be tween th e two sides, and in versely proportional to th e tissue th ickn ess. As we have seen, the area of the blood-gas bar rier in th e lung is enormo us (50 to 100 square meters), and the th ickness is on ly 0.3 u rn in many places (Figure 1 ~ 1), so the dim en sions of the harrier are ideal for diffusion. In addition , th e rat e of tran sfer is proport ional to a diffusion con stant wh ich depends on th e properti es of the t issue and the particu lar gas. T he constant is proportion al to the solubility of the gas and inversely pro po rtional to

the squate toot of the molecular weight (Pigure 3- 1). This means tha t CO , d iffuses abou t 20 ti mes mo re rapidly than does Oz thro ugh tissue sheets because it has a much h igh er solubility but not a very d ifferen t molecu lar weight.

Fick's Law of Diffusion • Rate of diff usion of a gas through a tissue slice is proportional to the area but inversely proportiona l to t he thickness • Diffusion rate is proportional to the partial pressure difference • Diffusion rate is proport ional to the solubility of the gas in the tissue but inverse ly proport ional to t he square root of t he molecular w eight

Diffusion

27

Diffusion and Perfusion Limitations - ppose a red blood cell enters a pulmonary capillary of an alveolus which concains a foreign gas such as carbon monoxide or ni trous oxide. How rapidly will the part ial pressure in the blood rise ? Figure 3-2 shows th e time courses as the red clood cell moves th rough th e cap illary, a process that takes about 3/4 sec. Look first at carbon monoxide. \Vhen t he red cell enters the capillary, carbon mon oxIJ e moves rapidly across the extremely thin blood-gas barrier from the alveolar gas int o the cell. As a result , the content of carbon monoxide in the cell rises. How; ever. because of the tight bond that forms be t ween car bon monoxide and hemoglobin within the cell, a large amount of carbon monoxide can be taken up bv the cell with almost no increase in part ial pressure . T hus, as the cell moves through rhe ca pillary, th e carbon monoxid e part ial pressure in the blood hard ly changes, so th at no appreciable back pressure devel ops, and th e gas conti nues to move rapidly across th e alveolar wall. It is clear, therefore. that the amount of car; bon monoxide th at gets into the blood is limited by the diffusion propert ies of th e Hood-gas barrier and not by th e amount of blood available' The tran sfer of ca tton monoxid e is th erefore said to be diffusion limited. Cont rast th e time course of nitrous oxide. W hen thi s gas moves across th e alveolar wall in to the blood, no combina tion with hemoglobin take s place. As €I result, the bloo..i has nothing like th e avidity for nitro us oxid e tha t it has for car; ron monoxide, and the part ial pressure rises rapidly. Indeed, Figure 3-2 shows tha t the part ial pressure of ni trous ox ide in the blood has virt ually reached that of the alveo lar gas by the time the red cell is only one-tent h of the way along the capillary. After th is poin t, almost no ni trous ox ide is transferred . T h us, the amount of th is gas take n up by the hlood depends ent irely on the amount of ava il; able blood flow and not at all on th e d iffusion properties of the blood-gas barrier. The transfer of n itrous oxide is th erefore perfusion limited. W hat of Oz? Its time cour se lies between those of carbon monoxide and ni trous oxid e. Oz combines with hemoglobin (unlike nit rous oxide) but with nothing like th e avidity of carbon monoxide. In other words, th e rise in partial pres; sure when O r enters a red blood cell is much greater th an is the case for the same number of molecules of carbon monoxid e. Figure 3-2 sho ws that the Po, of th e red blood cell as it enters the capillary is already about four-tenths of th e alveo lar value because of th e Oz in mixed venous blood. U nde r typical resting cond itions, the capill ary Po, virtually teaches th at of alveolar gas when the ted cell is about one-th ird of the way along the capillary. U nder these conditions, O 2 transfer is perfusion limited like nitrous oxide. However, in some abnor mal circumstances when the diffusion propert ies of th e lung are impaired, for example, because of th ickening of the blood-gas barrier, the blood Po, does not reach the alveolar value by th e end of the capillary, and now th ere is some d iffusion limitat ion as well.

* Th is introductory description of carbon monoxide tran sfer is not completely accurate because of th e rate of reaction of carbon mon oxide with hemoglobin (sec later).

Start of capillary

~

Alveolar ---+

A

End of capillary

~

co o

.25

.50

.75

Time in capillary (sec) Figur e 3·2. Upta ke of car bo n monoxi de, nit rous oxi de, and O2 along t he pul -

mona ry capill ary . Note that t he bl ood partial pre ssur e of nitrou s o xide virt uall y reaches t hat of alveolar ga s very early in the capil lary so t hat t he transfer of th is gas is perfu sio n limited. By cont rast, the part ial pressure of carbo n mon oxi de in th e blood is alm ost un chan ged so that its t ran sfer is di ff usion limited. O2 tr an sfer ca n be pe rfus ion limit ed or partl y diffusion lim it ed, dep ending on the conditi ons.

A more detailed analysis sho ws that whether a gas is d iffusion limited or not depen ds essentially on its solubility in th e blood -gas barrier compared with its "solubility" in blood (actu ally th e slope of th e dissociation curve; see Chapter 6) . For a gas like carbon monoxide, the se are very differen t, whereas for a gas like nitrous oxide, they arc the same. An an alogy is the rate at which sheep can enter a field th rough a gate. If the gate is narrow but the field is large, th e number of sheep that can en ter in a given time is limited by the size of the gate. However, if bot h th e gate and the field are small (or both are big) th e nu mber of shee p is limit ed by the size of the field.

Oxygen Uptake Along the Pulmonary Capillary Let us take a closer look at the uptak e of O 2 by blood as it moves through a pulmonary capillary. Figure 3-3A shows that th e PO z in a red blood cell entering the capillary is norm ally about 40 mm Hg. Across the blood-gas barrier, only 0.3 u rn away, is the alveolar P Ol of 100 mm Hg. Oxygen floods down this large pressure gradient, and the Po z in th e red cell rapidly rises: indeed, as we have seen , it very nearly reaches th e Po, of alveolar gas by th e time th e red cell is only one-th ird of

29

Diffusion

- .. way along the capillary. Thus, und er nonnal circumstances, the difference in :-""\.. between alveolar gas and end-capillary blood is immeasurably small-a mere rraction of a mm Hg. In other words, th e diffusion reserves of the normal lun g are ~ rrnous. \J;;rith severe exe rcise, the pulmon ary blood flow is greatly increased, and the urne normally spen t by th e red ce ll in rhe capillary, abo ut 3/4 sec, may be red uced · 0 as little as one-th ird of thi s. Therefore, th e time ava ilable for oxygenation is ~5 , but in norm al subjects breath ing air there is generally st ill no measurable fall m end-capillary Pa r However, if th e blood-gas barrier is markedly thicken ed cv disease so th at oxygen d iffusion is impede d, th e rat e of rise of P02 in th e red Nood ce lls is correspon dingly slow, and the PO l may n ot reach that of alveolar gas

A

'"

I

~

50

Grossly abnormal

t

Exercise

o"-_ _- L o B 50

- ' -_

.25

_

---J

.50

y Alveolar - - - - -- -- - - - - --.:;;-...- _

-

-

.75

-

-

-

'"

I

E E

t

rE OL-

Exercise -'-

o

.25

Grossly abnormal

--'.50

--' .75

Time in capillary (sec) Figure 3-3. Oxy gen time courses in the pulmona ry capi llary w hen diff usion is normal and abno rma l (f or example. becau se ofthicke ning of t he blood-gas barri er by di sease). A shows ti me co urses w hen th e alveolar P02 is no rmal. B shows slo we r oxy genation w he n the alveo lar P02 is abnormally low. Not e that in both cases, severe exe rci se red uces the time available for oxy genatio n.

before th e time available for oxygena tion in th e capillary h as run out. In thi s case, a measurable differen ce bet ween alveolar gas and en d-ca pil lary blood for P 0 2 may occur. A nothe r way of stressing th e diffusion properties of the lun g is to lower t he alveo lar Pa z (Figure 3-3B). Suppose th at thi s has been red uced to 50 mm Hg, by the subjec t either going to hi gh alt itud e or inhal ing a low O 2 mixture. Now, although the Po , in th e red cell at the sta rr of the cap illar y may on ly he about 20 mm Hg, th e partial pressure d ifferen ce respo nsible for driving the O 2 across the blood -gas ha rriet has been reduced from 60 rnrn Hg (Figure 3-3A) to only 30 mm Hg, O 2 therefore moves acro ss more slowly. In add ition, th e rat e of rise of Po , for a given inc rease in O 2 co nc entra tion in the bloo d is less th an it was becau-se of th e steep slope of the O 2 d issoci at ion curve whe n the P 0 2 is low (see C hapt er 6) . For bot h of these reasons, therefore, the rise in Po , along the capillary is relati vely slow, and failure to reach th e alveo lar P 0 2- is more likely. Thus, severe exe rcise at very high altitude is one of th e few sit uat ions where diffusion impairment of O 2 transfer in no rmal subjects ca n be convinci ngly demonstrated. By the same token, patients with a thi cken ed blood- gas barrier will be most likel y to show ev idence of diffusion impairm ent if they breathe a low oxygen mixt ure, especially if th ey exercise as well .

Diffu sion of Oxygen Acros s the Blood-Gas Barrier • At rest the P0 2 of the blood virt ually reaches that of t he alveolar gas after 1/3 of its ti me in the capillary • Blood spends only 3/4 sec in the capillary at rest • On exercise the time is reduced to perhaps 1/4 sec • The diffusion process is challenged by exercise, alveolar hypox ia, and thickening of the blood-gas barrier

Measurement of Diffusing Capacity W e ha ve seen th at oxygen tran sfer in to th e pulm onary capillary is normally limited by th e amoun t of blood flow available, altho ugh under some circumstanc es d iffusion limi tation also occ urs (Figure 3 ~2). By cont rast, th e transfer of carbon mon oxide is limited solely by diffusion, and it is there fore the gas of choice for measuring the d iffusion properti es of the lung. At one time O 2 was employed under hypoxic condit ions (Figure 3 ~3 B) , but th is tech nique is n o longer used. The laws of diffusion (figure 3 ~ 1) state that th e amoun t of gas transferred across a sheet of tissue is proport ional to th e area, a diffusion constant, and th e difference in partia l pressure, an d in versely proportional to t he thickness, or

.

A

Vgas = - . D· (P, - P, ) T Now for a complex structure like the blood-gas barrier of the lung, it is nor possible to measure the area and th ickness duri ng life. Instead, th e equati on is rewritten Vgas = DL · (P, - P, )

Diffusion

31

_ ur ement of Diffusing Cap acity

:

: ::-on monoxide is used because the uptake ot t his gas is diffu sion-lim ited t'T'a' diffu sing capacity is about 25 ml.min r l.mrn Hg - 1 .; ..IS ng capacity increases on exe rcise

is called the diffusinl; capacit)'of thelung and includes the area, thickness, _ - sion properties of the sheet and th e gas concerned. Thus, the diffusing .... lo r carbon monoxide is given by _

L.

OL

=

Veo PI - P,

P and P2 arc the partial pressures of alveolar gas and capillary blood, rcspec Bu as we have seen (Figure 3 ~ 2 ), the part ial pressure of carbon monoxide in rv blood is extremely small and can generally he neglected . Thus,

01

.

= -

Veo-

Peco

rds. the diffusing capacity of the lung for ca rbon monoxide is th e volume n monoxide transferred in milliliters per minute per mm Hg of alveolar r rC::':'Ufe .

-.. frequen rlv used rest is the singlebreach method, in which a single inspiration me mixture of carbon monoxide is made and the rate of disappearance of "'11 monoxide from the alveolar gas dur ing a IOvscc brcath ho ld is calculated , ..usually done by measuring th e inspired and expired conce n tration s of carnoxide with an infrared an alyzer. The alveo lar concen tration of carbon xide is not constant during th e breath holding period, but allowance can be : r thar. Helium is also added to th e inspired gas to give a measurement of lurne by dilution. e normal value of the diffusing capacity for carbon monoxide at rest is - : - ml : min - 1 . mm Hg- 1, and it increas es to two or three times th is value .. ercise because of recru itment and d isten sion of pulmonary capillaries (sec «er 4).

Reaction Rates With Hemoglobin we ha ve assumed that all the resistance to th e movemen t of O 2 and CO rche barrier bet ween blood and gas. However, Figure 1-1 shows that th e ncrh from th e alveolar wall to th e cen ter of a red bl<:XXI cell exceeds that 'all itself, so that some of the d iffusion resistan ce is locat ed withi n th e cap~ in addition, the re is anothe r type of resistance to gas transfer tha t is most ien tly discussed with diffusion, that is, th e resistance caused by the finit e : reaction of O 2 or CO with hemoglobin inside the red blood cell. ben 02: (or CO) is added to blood, its combina tion with he moglobin is quite -eina well on the way to completion in 0. 2 sec. However, oxygenation

~~

J

occurs so rapidly in the pulmonary capillary (Figure 3-3) that even thi s rapid reaction sign ifican tly delays the loading of 0 , by the red cell. T hus, the uptake of 0 , (or CO) can be regarded as occurring in two stages: (1) diffusion of 0 , through the blood-gas barrier (including the plasma and red celt interior); and (2) reaction of the O 2 with hemoglobin (Figure 3 ~4 ). In fact, it is possible to sum the two resultan t resistances to pro duce an overall "d iffusion" resistance.

W e saw that the diffusing capacity of the lung is defined as DL = Vgas!(P j - P,) , th at is, as the flow of gas di vided by a pressure difference. Thus , the inverse of DL is pr essur e d ifferen ce d ivi ded by flow an d is therefore anal ogous to electrical resistance. Consequen tly, the resistance of the blood -gas barr ier in Figure 3A is shown as l/D lvh wh er e M means membrane . Now the rate of reaction of O 2 (or CO) with hemoglobin can be described by 8, wh ich gives the [ate in ml per minute 0£02 (or CO) wh ich co m bine with 1 ml of bloo d per m m lIg partial pressure of 0 , (or CO). This is analogous to the "diffusing capacity" of 1 mlof blood and, whe n mu ltiplied by the volume of cap illary blood (VJ , gives th e effective "d iffusing capacity" of th e rate of reacti on of O 2 with hemoglobin. Again its in verse, 1/(8' VJ , describ es th e resistance of th is react ion . W e can add the resistances offered by the membran e and the blood to obtain the total diffusion rcsisranee. T h us, th e comp lete equation is

1 !i,

DL In practi ce, the resistances offered by the membrane and blood co mpo ne nts are approx imately equal, so th at a redu ction of capillary blood volume by disease can . reduce the diffusing capacity of the lun g. e for co is reduced if a subject breath es a h igh 0, mixture , because the 0, competes with th e CO for hemoglobin. As a result , the measured diffusing capac ity is reduced by O 2 breath ing. In fac t, it is possible to sepa rately determine OM and V c by measuring the diffusin g capaci ty for CO at different Po , values.

Alveolar wall

Figure 3-4 . The d iffus ing capacity of th e lun g (Dd is m ade up of two compon ent s, th at d ue to t he d iffu si on process itself and th at attri bu t abl e to t he ti me take n for O2 (o r CO) t o react w it h hemog lo b in.

33

io n Rates of O2 and CO with Hemoglobin <eection rate of O2 is fast but because so little time is available in the capilsrv. this rate can becom e a limit ing factor - e resistance to th e uptake of O 2 att ributable to reaction rate is probably ut the same as that due to diff usion across the blood-gas barrier - "'e reaction rate of CO can be altered by changing the alveolar POz. In this 'ay the separate contri butions of the diffusion properti es of the blood-gas carr er and the volume of capillary blood can be derived.

Int erpret at io n of Diffusing Capacity for CO dear that the measured diffusing capacity of th e lung for CO depend s not on the area and th ickness of the blood-gas barrier but also on the volume of .J in the pulmona ry capillaries. Furthermore, in the d iseased lung, the meacemen t is affected by the distri but ion of diffusion propert ies, alveolar volume, cap illary blood . For th ese reasons, the rerm transfer facto r is somet imes used - racularlv in Europe ) to emphas ize th at th e measurement does not solely recr th e d iffusion propert ies of t h e lung.

CO2 Transfer Across the Pulmonary Capillary ha ve seen that diffusion of COz through tissue is about 20 times faster tha n 0 ; 0, beca use of th e much higher solubility of CO 2 (Figure 3-1). A t first ' . the refore, it seems un likely tha t CO 2 elimination could be affected by dif'Il di fficult ies, and indeed thi s h as been th e genera l belief. However, the rc- '" 01CO, with blood is complex (sec Chapter 6) , and although the re is some certa in ty about th e rates of the va rio us reactions, it is possible th at a d ifference n end-capillary blood and alveolar gas can develop if the blood -gas barrier seased . ~

ESTIONS -:::::

qu est ion, choose the one bes t answer.

_sO ng Fick 's law of diff usion of gases t hrough a t issue slice, if gas X is 4 - ..... as as soluble and 4 times as dense as gas Y, what is t he ratio of the : ":":usion rates of Y to X?

0.25 _. 0.5 2

J. 4 _

8

- "" exercising sub ject breath es a low co ncent rati on o f CO in a steady state. :. t:18 alveolar Pco, is 0.5 mm Hg and t he CO upta ke is 30 ml.min 1, w hat is tr e diff using capacity of t he lung for CO in ml .mm r l .mrn Hg- ' ?

20

_ _ _

~_

30

C. 40

3.

D. 50 E. 60 In a normal person, doubling the diffus ing capacity of the lung wo uld be

expected to:

4.

A. B.

Decrease arterial Peo2 during resting breathing. Increase resting oxygen uptake w hen the subject breathes 10% oxygen.

C. D.

Increase the uptake of nitrous oxide during anes thesia. Increase the arte rial P0 2 during resting breathing.

E.

Increase maximal oxygen uptake at extreme altitude.

A subject inhales several breaths of a gas mixture containing low

concentrations of carbon monoxide and nitrous oxide. W hich of the follow ing statem ents is FALSE? A. The partial pressures of carbon monoxide in alveolar gas and endcapillary blood wi ll be virt ually the same. B. The partial pressures of nitrous oxide in alveolar gas and end-capillary blood wi ll be virtually the same. C. Carbon monoxide is transferred into the blood along the whole length of t he capillary. D. Almost all of the nitrous oxide w ill be taken up in the early part of the capillary. E. The uptake of carbon monoxide can be used to measure the diff using capacity of the lung. 5. All of the follow ing statements about the diffu sing capacity of the lung are t rue J:XCEPT: A. It is best measured with carbon monoxide because this gas diffuses very slowly across the blood-gas barrier. B. Diffusion-limitation of oxygen transfer during exercise is more likely to occur at high altitude than sea level. C. Breathing oxygen reduces t he measured diffu sing capacity for carbon mono xide compare d with air breathing.

D. It is decreased by removal of one lung. E. It is decreased in pulmonary fib rosis whi ch t hickens t he blood-gas barrier. 6. All of the follow ing wo uld be expected to reduce the diffu sing capacity of the lung for carbon monoxide EXCEPT: A. Emphysema whic h causes loss of pulmonary capillaries. B.

Asbestosis which causes thickeni ng of the blood-gas barrier.

C. Pulmonary embolism which cuts of f the blood supply to part of the lung. D. E.

Exe rcise in a norma l subject . Severe ane mia .

en.

r

~QOQ

Blood Flow and Metabolism How the Pulmonary Circulation Removes Gas From the Lung and Alters Some Metabolites

Pressures Within Pulmonary Blood Vessels Pressures Around Pulmonary Blood Vessels Pulmonary Vascular Resistance Measurement of Pulmonary Blood Flow Distribution of Blood Flow

Active Control of the Circulation Water Balance in the lung Other Functions of the Pulmonary Circulation Metabolic Functions of the lung

" We now turn to how the respiratory gases areremovedtrotn the lung. First the pressuresinside andoutsidethe pulmonary bloodvessels are considered, and then pulmonary vascular resistence is introduced. Next we look at the measure-

ment 01 totalpulmonary blood flow andits uneven distribution caused by gravity. Active control 01 the circulation is then addressed10110wed by fluid balance in the lung. Finally othertunctions 01the pulmonary circulation aredealt with, particularly the metabolic lunctions 01the lung. . .mg.

The pulmonary circulat ion begins at th e main pulmonary artery, which receives me mixed venous blood pumped by th e righ t ventricle. This artery th en branches successively like the system of airways (Figure 1-3), and, indeed, the pulmonary eries accompany th e airways as far as the termin al bronchioles. Beyond tha t, the y break up to supply the capillary bed which lies in th e walls of the alveoli

35

(Figures 1-6 and 1-7). T he pulmon ary capillaries form a dense net work in the alveo lar wall wh ich makes an exc eed ingly effic ient arrangeme nt for gas exchange (Figures I - I , 1-6, and 1-7). So rich is th e mesh th at some ph ysiologists feel that it is misleading to talk of a network of individual capillary segmen ts and prefer to regard the capillary bed as a sheet of flowing blood interrupted in places by posts (Figure 1-6), rather like an underground parking garage. T he oxygenated blood is th en collected from the capillary bed by the small pulmonary veins tha t run hetween th e lobules and even tually uni te to form the four large veins (in h uman s), whic h drai n into the left atrium. At first sigh t, this circulation appears to be simply a small version of th e svs(ernie circu lation which begins at the aorta and ends in th e righ t atrium. H owever, there are impo rtan t d ifferences betwee n the two ci rcu lati ons, and co nfusion frequently results from attempt s to empha size similarities between them.

Pressures Within Pulmonary Blood Vessels

..• The pressures in th e pulmonary circulation are remarkably low. The mean pressure in the main pulmon ary art ery is only about 15 mm Hg; the systolic and dtasrolic pressures are about 25 and 8 mm Hg, respectively (Figure 4 ~ 1). The pressure is th erefore very pulsat ile. By con trast, the mean pressure in th e aorta is about 100 mm Hg- about six times more than in the pulmonary art ery. T he pressures in th e right and left atr iums arc not very dissimilar-about 2 and 5 mm Hg, respectively. Thus, the pressure differences from inlet to outlet of th e pulmon ary and systemic systems are abo ut (15 - 5) = 10 and (100 - 2) = 98 mm Hg, respect ively-a factor of 10. In keeping with these low pressures, the walls of th e pulmonary. artery and its branc hes are remarkably thi n and conta in relat ively I{~tle smooth muscle (t hey

Mean =~]g Artery

2%

80

Pulmo nary

Vein

Artery

Systemic

25/

Cap

-

Mean = 100

120/

0

12%

RV

LV

RA

LA

2

5

Cap

20

Vein

Figure 4-1. Compa rison of pressur es (mm Hg) in the pulmon ary and syst em ic circulations . Hyd rostatic diff eren ces modi fy these.

e easily mistaken for veins ). T his is in striking con trast to th e systemic circulan where the arteries generally have th ick walls and the arterioles in part icular ve abundan t smooth muscle. ---_. Th;r~;~s for th ese difference s become clea r whe n th e funct ion s of th e tw o circulations are comp ared. T he systemic circulation regulates the supply of blood [ various organs, including t hose wh ich may be far above th e level of th e heart he upstretched arm, for example) . Bycontrast, th e lung is requ ired to accept the whole of the cardiac out put at all tim es. It is rarely concerned with directi ng blood from one region to ano th er (an excepti on is localized alveo lar hypoxia, see below), and its arterial pressure is therefore as low as is cOllsisten t with lifting blood to the to p of th e lun g. This keeps the worKoFilleright he art as small as is feasible for efficient gas exch an ge to occur iMh;-f~~.- ---- The pressure within [he pulmonary capillaries is uncerta in. The best evidenc e suggests that it lies about h alfway between pulm onary arterial and veno us pressure, and probably tha t much of th e pressure drop occurs within the ca pillary bed itself. Certa in ly th e distribut ion of pressures along the pulmonary circulation is tar mo re symmetrical th an in its systemic co un te rpart , where most of the pressure drop is just upstre am of the capillaries (Figure 4-1) . In addit ion, th e pressure with in the pu l m~:mary ca pillaries varies consjderablv througho ut the lung. because of hy~rostat Cc eifects-i~e below) . ,.,

Pressures Around Pulmonary Blood Vessels The pulmonary capillaries arc unique in tha t they arc virtually surrounded by gas ( Figures I- I and 1-7). It is tru e that th ere is a very thin layer of epithelial cells lin in g th e alveoli, but th e cap illaries receive lit tle support from th is and, co n sequen tly, arc liable to collapse or d istend, depend ing on th e pressures within and around them. The latter is very close to alveolar pressure. (The pressure in the alve o li is usuallvclosero atmosphe ric pressure: indeed , during breathhold ing with the glottis open , the two pressures are identical.) U nd er some spec ial conditions, the effective pressure around the capillaries is redu~ced bythe surface tension of the fluid lining the alveo li. But usually, theeffecti ve pressure is alveo lar pressure} and when thi s rises above the pressure inside th e capillaries, they -c(; llaps~-Thc pr~§sure diff<.;r!';nce betwee n the .in sid e and outside of th e cap illaricsis often called th e transmural pressure. W hat is the pressure aro und th e pulm on ary arteries and veins? This can be considerably less than alveolar pressure . A st he lung expand~these larger blood vessels are pu lled open by th e radial tr acti on of the clastic lung parenchy ma wh ich surrounds them (Figures 4-2 and 4~3) . Consequen tly, th e effect ive pressure around th em is 100\'j in fact th ere is some ev idence tha t thi s pressure is even less th an the pressure around the who le lung (Intrapleural pressure) . T his paradox can be explained by the mechanical advantagcthat devc10ps when a relat ively r igid structure like a blood vessel or bronchus is surrounded by a rapidly expanding elastic mat er ial sll~h-as lung parenchyma. In any even t, oorh- tk arter-ies an d veins' increaseth eircaliber as the.::::::;:lungexpands. --. -_ _-_.-' , ...

.

t Alve~eOlar~esseIS t

t

y

y

y

y

A

A

A

A

t

t

t

t

~

Extra-alv eolar vessels

Figure 4-2. " Alveo la r" and " ext ra-alv eola r" v essels. Th e f irst are mainly th e cap-

.

illari es and are exp osed to alveolar pressure. Th e seco nd are pulled o pe n by the radi al tra ct io n of the surro undi ng lung parench y m a, and the eff ect ive pressu re aro un d t hem is th erefore low er than alv eolar pressu re.

T he beh avior of th e cap illaries and the larger blood vessels is so differe nt they are often referred to as alveolar and ex tra-alveolar vessels (Figure 4, 2). A lveolar vessels are exposed to alveolar pressure and incl ude the cap illaries and th e sligh tly larger vessels in the corners of the alveolar walls. Their ca liber is determined hy the relat ionship between alveolar pressure and th e pressure within them. Exrra-a lveolar vessels include all th e arteries and veins that run through th e lung parenc h yma. The ir caliber is greatly affected by lung volume beca use th is determ ines the ex panding pull of the parenchyma on their walls. The very large vessels near the hil um are outside the lung substance and are exposed [0 intrapleural pressure .

Figure 4-3. Secti o n of lu ng sho w ing m any alv eo li and an ex t ra-alveo lar v esse l (i n t hi s case, a sm al l vei n) w it h its peri vascu lar sheath .

A lv eo lar and Extra-Alveolar Vessels • Alv eolar vessels are exposed to alveolar pressure and are compressed if this increases • Extra-alveolar vess els are exposed to a pressure less t han alveolar, and are pulled open by the radial traction of the surrounding parenc hyma

Pulmonary Vascular Resistance :. i , useful to descr ibe the resistan ce of a syste m of blood vessels as follows:

Vascular resistance

=

in pu t pressure - output pressure blood flow

-:hi ~

number is certain ly no t a complete descri ption of the pressure -flow prope ries of the system. For example, th e n umber usuall y de pend s on the magnitude of th e blood flow. Nevert heless, it ofte n allows a helpful co mparison of different circulat ions o r the same ci rculat ion under different conditions. \Ve h ave seen th at the to ta l pressure d rop from pu lmo nary artery to left atrium in the pulmo nary c irculat ion is o n ly some 10 mm Hg aga inst abou t 100 mm l-lg tor th e syste mic circulat ion . Because the blood flows through the two circ ulat ions are virtually identical , it follows that the pulmonary vascular resistance is o n ly ne-ren th that of the syste mic ci rcul ati on. The pul monary blood flow is about 6 u ers/mm so that, in numbers, th e pulmonary va scula r resista nce = (15 -5)/6 or about 1.7 mm Hg · lircr- 1 • min." The hi gh resistance of the syste mic circu lation 5 largely caused by very muscula r art er iole s which allow the regulat ion of blood .~ w to various organs of the body. T h e pulmonary circulat ion has no such vessels and appea rs to h ave as Iow a resistan ce as is compat ible with distr ibuting th e -""'1 in a thin film over a vast area in the a lveo lar walls. A lthough the normal pulmonary vasc ular resistance is extrao rd ina rily sma ll, it sa remarkable facili ty for becom ing eve n smaller as the pressure with in it rises. Figure 4 ~4 shows tha t an increase in eithe r pulmonary art eria l o r venous pressure causes pulmonary vasc ular resistance to fall. T wo mec ha n isms arc respo nsible for chis. U nder normal conditions, some ca pillaries are e ithe r closed , or o pen but . -uh no blood flow. As the pressure rises, t he se vessels begin to co nduc t blood, th us lowe ring the o verall resistance. T h is is te rmed recruitmenr (Figure 4~ 5) and is apparcn tlv the ch ief mechanism for th e fall in pulmonary vascular resistance that ~curs as th e pulmon ary ar tery pressure is raised from low levels. T h e reaso n wh y some vessels arc unperfused at low perfu sin g pr essures is no t fully understo od bu t perhaps is caused by random differen ces in the geo me try of the co mplex net work Ficure 1 ~3) , which result in preferen tia l channels for flow. .Ar hi gh er vascular pressures, widening of individual capillary segmen ts oc curs. This increase in ca liber, or distension, is hardly surprising in view of the very th in me mbrane whi ch separates th e ca pillary from th e alveo lar space (Figure 1-1 ). Disten sion is pro ba bly ch iefly a ch ange in shape of the cap illar ies from near-flat tened -: -- - .. ---- -_ :-_ ~.-

. ---~ _ . -

~-

Ca rdiologists sometimes express pulmona ry vascular resistance in the units dyne ' sec ' em- 5• The normal value is then in th e region of 100.

c

300

~

8 N

I

E £

"oc

200 Increasing arterial pressure

1Jl ·in ~

:;; "5 o

'"'">

100 Increasing venous pressure

e-

'"s0:

". "

E

"5 Q.

0" - - -- -"-- - ---'--- --' 10

20

30

40

Arterial or venous pressu re (em H20 )

./

Figure 4-4. Fall in pu lmonary va scular resi stance as the pu lm ona ry arte ri al or ve nou s pre ssure is raised. Whe n th e art eri al pr essu re w as changed, th e v eno us pressure was hel d co nstan t at 12 em w ater, and w hen the ve nou s press ure w as chang ed, the arte rial pressure was held at 37 em w ate r. (Data from an exci sed animal lun g prep aratlo n.)

to more circular. There is evidence that th e capillary wall strongly resists stretch-

ing. Dis tension is appare ntly the predom inant mechani sm for th e fall in pul mon ary vascular resistance at relatively h igh vascular pressures. However, recruitmen t an d d istension often occur together. Another important dete rmina n t of pulmonary vascular resistan ce is lung velume. The caliber of rhe extra -alveolar vessels (Figure 4-2) is det ermined by a balan ce between various forces. As we have see n, they are pulled open as the

Figure 4-5. Recrui tm ent (ope ni ng of prev io usly cl osed vessels ) and di st ensi on [i ncrease in calib er of vessels). Th ese are th e tw o mechanism s fo r t he decrease in pulmo nary vascular resistance that occurs as vasc ular pressure s ar e raised.

lung expands. As a result, the ir vascular resistance is low at large lung volumes. O n the ot her hand , th eir walls contain smooth muscle and clastic tissue, whic h resist d istension and te nd to reduce t he ir calibe r. C on sequently, t hey have a high resistance when lung vo lume is low (Figurc 4 ~ 6 ) . Indeed, if the lung is completely col lapsed. the smooth muscle tone of these vessels is so effective that the pulmonary artery pressure ha s to be raised several ce ntimeters of water above downstream pressure before any flow at all occurs. T his is called a critical opening pressure.

Is the vascular resistance of the capillaries influenced by lung volume ?This de pends on whe the r alveolar prcssure changes with respect to the pressure inside the capillaries, that is, whethe r the ir transmural pressure alters. If alveolar pressure rises with respect to capillary pressure, the vessels tend to be squashed , and their resistance rises. This usually occ urs whe n a normal subject takes a deep inspiration , because the vascular pressures fall. (The heart is surrounded hy in trapleural pressure, which falls on inspiration.) However, the pressures in the pulmona ry circulation do nor rema in steady after such a maneuver. An additio nal factor is that the caliber of the capillaries is reduced at large lung volumes because of ~tre tch infm;dconsequen t rh tnning of th e ~lveolar walls. Thus, even if the transmural pressure of the cap illaries is nor changed with large lung inflati ons, their vascular resistance increases (Figure T iJ)-. - -' Because of the TO re of smoo th muscle irt determ in ing the caliber of the extraalveolar vessels, d rugs that cause con traction of the muscle increase pulmonary vascular resistanc e. These include serotonin, histamin e, and norep inephrine .

o Extra-alveolar vessel

120 C

Capillary

:§ 0

t

N

:r: E

100

Em u c;

~ ·in t'! <;;

0

80

~

==0 == a ~

j

"""

"3 u m ~

>

60 50

100

150

200

Lung volume (ml) Figu re 4-6. Effect of lun g v o lu m e on pu lm on ary v ascu lar resista nce w hen t he t ransm u ral pressure of the cap illaries is held co nstant . At low lung v o lu mes, resista nce is hig h becau se t he ext ra-alveo lar vessels beco m e narrow . At hig h v o lum es, .t he cap illaries are st retched, and th eir cali ber is redu ced . (Data f ro m an anim al lo be preparation .)

Pulmona ry Vascular Resistance • • • •

Is norm ally very small Decreases on exercise because of recruitment and disten tion of capillaries Increases at high and low lung volumes Increases with alveolar hypoxia because of constriction of small pulmonary arteries

These drugs are part icularly effective vasoco nstr icto rs when the lung volume is low and th e expanding forces on th e vessels are weak. Drugs that can relax smoo th muscle in the pulmonary circulation include acet ylch oline and isoprot erenol.

Measurement of Pulmonary Blood Flow It.,'

."

",, I'

The volume of blood passing thro ugh th e lungs each min ute (Q ) can he calculated using th e Fick principle . T his sta tes that th e O 2 consumption per minute (VOl) is equal (0 the amount of O l taken up by the blood in the lungs per minut e, Because the 0 1 conce ntration in th e blood en tering the lungs is evo) and that in ~ th e blood leaving is C
Vo ,

=

Q (Cau, - G o,)

or VOl

Q= -:=--,,=C~)l

-

eVO l

VOl is measured by collecting the expired gas in a large spirometer and measuring

its O 2 conce nt rat ion. Mixed venous blood is ta ken via a catheter in the pulmonary artery, and arterial blood by punct ure of th e brach ial or radial artery. I'ul mon ary blood flow can also be measured by th e ind icator dilution te chniq ue in which a dye or other indicator is injected into the venou s circu latio n and its concentration in arte rial blood is recorded. Bot h th ese methods are of great importanc e, bur they will not be considered in more detail here because they fall with in the province of cardiovascular physiology.

Distribution of Blood Flow So far, we have been assuming tha t all parts of the pulmonary circ ulation behave iden ticall y. However, considerable inequality of blood flow exists with in the hu man lung. This can be shown by a modification of th e radioactive xenon method that was used to measure th e distribution of ven tilation (Figure 2 ~ 7). For the measuremenr of blood flow, the xenon is dissolved in saline and injected into a peripheral ve in (Figure 4~7 ). When it reach es the pulmona ry ca pillaries, it is evolved into alveo lar gas beca use of its low solubility, and the d istribution of radioactivity can be measured by counters over the chest during hrea th holding. In th e upright h uman lung, blood flow decreases almost linearly from bottom to top, reaching very low values at th e apex (Figure 4 ~7 ) . T his d istrib ution is

150

Radiation counters

"C

s

50

iii

, Bottom

OLL-

o

Top

---'--5

---'--10

---'-15

---'-- -' 20

25

Distance up lung (cm) Fig ure 4-7. M easurem ent of t he di str ibution of blood fl ow in the upright human lung, using radioacti ve xen on. The dissolv ed xen on is ev olved into alv eolar gas fro m th e pu lmonary cap il laries. The un it s of blood fl ow are such th at if flow we re unif orm , all valu eswo uld be 100. Note the small fl ow at th e apex.

affected by change of posture and exercise. When the subject lies sup ine, the apical :one blood flow increases bur the basal zon e flow remains virtually unchanged, with th e result th at th e distribut ion from apex to base becomes almost uniform . However, in th is posture, blood flow in the poste rior {lower or dependent) regions of the lung exceeds flow in th e ante rior parts. Measuremen ts on subjects suspended upside down show that apica l blood lIow may exc eed basal flow in this posit ion. O n mild exe rcise , both uppe r and lower zone blood flows increase, and the region al differen ces becom e less. The uneven d istribut ion of blood flow ca n be explain ed by the hydrostati c pressure differen ces within the blood vessels. If we consider th e pu lmon ary arterial system as a con tinuous co lumn of blood , the differe n ce in pressure bet ween the top and bottom of a lung 30 em high will be about 30 em wat er, or 23 mm Hg. This is a large pressure difference for such a low-pressure system as the pulmon ary circulat ion (Figure 4-1 ), an d its effects on regiOnal blood tlo~' areshown in Fig~ ure-q-B. T here may be a region at the top of the lung (zone I) where pulmon ary artcrial pressure falls below alveolar pressure (norma lly close to at mospheric pressure ). If this occ urs, the cap illaries are squashe d flat , and no flow is possible. T h is :one 1 does ncr occ ur un der normal conditions beca use the pulmonary arte rial pressure is just sufficien t to raise blood to th e top of th e lung but may be present II the arterial pressure is reduced (following severe hemorrh age, for exa mp le) or if alveolar pressure is raised (during positive pressure ven tilatio n). This ven t ilated but unperfused lung is useless for gas ex ch ange and is called alveolar dead space.

Alveol ar

~

Pa ~Pv

I '----" I Arterial Venous

.'

~,

;.

Zon e 3 Pa > P", > PA

Figure 4-8. Ex plan atio n of th e u nev en di stributio n of blood fl ow in the lu ng, base d on the p ressu res affecti ng t he cap illa ries .

Farther down th e lung (zone 2) , pulmonary arterial pressure inc reases bec ause of the hydrosta tic effect and now excee ds alveolar pressure. However, veno us pressure is still very low and is less th an alveolar p ressure, and thi s leads to remarkablc pressure -flow cha ract eristics. Unde r these cond it ions, blood flow is determ ined by the difference between arterial and alveo lar pressures (nor the usual art erial-veno us pressure difference ). In deed , ven ous pressure ha s no influen ce on flow unless it exc eeds alveolar pressure. This behavior can be modeled with a flexible rubber tube inside a glass chamher (Figure 4~9) . W hen chamber pressure is grea ter th an downstr eam pressure, the rubber tube collapses at its downstream end, and the pressure in the tube at th is poin t limi ts now, The pulmonary capillary bed is clearly very d ifferent from a rubber tube. Ne vertheless, the ove rall beh avior is similar and is often called the S tarling resistor, sluice, or waterfall effect. Because arterial pressure is increasing down the zone but alveolar pressure is the same th roughout the lung, the pressure difference respo nsible for flow increases. In add ition, increasing recruitmen t of capillaries occurs down th is zone. In zone 3 , veno us pressure now exceeds alveolar pressure, and flow is determine d in the usual way by the arrerial-veno us pressure difference. The increase in blood flow down thi s region of the lung is apparen tly caused chiefly by distension of the capillaries. T he pressure withi n them (lying hetween arte rial and venous) increases do wn th e zone while th e pressure outside (alveolar) remains constan t. T h us, th eir tran smural pressure rises and, indeed, measuremen ts show that their mea n width increases. Recruitmen t of previously closed vessels may also play some part in th e increase in blood flow down this zone.

r----Jl::::~ A

Figu re 4-9. Tw o Star lin g resisto rs, each co nsisti ng of a th in ru bb er t u be inside a container. When cham ber pr essu re exceeds downstream pressure as in A, flow is independent of downstream pressur e. How ever, w hen do w nst ream pr essur e ex ceeds cha mber pr essu re as in B, flow is dete rmi ned by t he upstream -downstream difference.

The sche me shown in Figure 4 ~8 summarizes th e role played by the capillaries in deter min ing th e distri bution of blood £10\,,', A t. low lung volumes, th e resistan ce of the extra-alveo lar vessels becom es impo rtant, and a reduction of regional blood rlow is seen , start ing first at the base of the lun g, where the paren ch yma is least expanded (see Figurc 7-8). This region of reduced blood flow is sometimes called zone 4 and can be exp lained by th e n arrowin g of th e extra-alveo lar vessels, wh ich occurs whe n th e lung aro und th em is poorly inflated (Figure 4-6). There are othe r factors causing une ven ness of blood flow in th e lun g. In some an imals, some regions of the lung appear to h ave an intrinsically higher vascular resistance. There is also evide nc e th at blood flow dec reases along the acinus with pet iph eral pans less well supplied with blood . Some measurements suggest that the periphe ral region s of th e whole lung receive less blood flow th an the central regions. Finally, th e com plex , partl y random arrangeme n t of blood vessels and capillaries (Figure 1-6) causes some inequality of blood flow.

Active Control of the Circulation \Ve hav e seen that passive facto rs dominate the vascular resistance and the distribution o( flow in the pulmonary circu lati on under normal conditions. Howeyer, a remarka ble act ive response occ urs when th e POz of alveo lar gas is reduced. This is known as hypoxic pulmonaT)' vasoconstriction andconsists of con traction of smooth muscle in the walls ofthe small arterioles in th e hypoxic region. T he pre~ cise mechani sm of th is response is not kn own, but it occurs in excised isolat ed lung and so does not depend on cent ral ner vous connecti on s. Excised segmen ts - pulmon ary artery can be sh own to con stric t if the ir en vironment is made hvpoxic so th at it may be a local act ion of th e hypoxia on th e artery itself O ne h ypoth esis is th at cells in the perivasc ular tissue release some vasoconstricto r substance in response to hypoxia, but an intensive search for th e med iato r h as not

.'

~ ."

...

'"

heen successful. Interest ingly, it is the Po , of the alveolar gas, not the pulmonary arte rial blood , th at ch iefly derenn in es.. . t. h-;; response. This can b e proved by perfusing a lung wirh blood of a high Po , while keeping rhe alveolar Po , low. Unde r these cond itio ns the respo nse occurs. The vessel wall presumably beco mes hypoxic through diffusion of oxygen over the very shor t distance from th e wall to the surrounding alveoli. Recall th at a small pulmonary artery' is very closely surrounded by alveoli (comp are th e proximity of alveoli to the small pulmo nary vein in Figure 4-3) . The stimulus-response curve of th is constr ict ion is very nonlinear ( Figure 4-10 ). \X1h en the alveolar po ! is alte red in the region above 100 mm Hg, little ch ange in vascular resistance is seen. However, when the alveolar Po ~ is reduced below approximately 70 mm Hg, mark ed vasoconstriction may cc curvand at a very low Po , the local blood flow may be almost abolished. The mechan ism of h ypoxic pulmon ary vasoconstrict ion rema ins obscure in spite of a grea t deal of research. Rece n t studies suggest that in h ibit ion of volt agegated pot assium ch annels and membrane depolarization may be involved, lead; ing to increased calcium ion concen trat ions in th e cytoplasm. A n in crease in cytopl asmic ca lcium ion co ncen trat ion is the major trigger for smooth muscle co n trac tion . End otheliurn-der ived vasoact ive substances play a role. N itr ic ox ide (l"O) has been shown to be an endo the lium-de rived relaxing facto r for blood vessels. Ir is formed h om Largin in e via catalysis by end othelial N O syn thase (eN O S) and is a fina l com mon pathway for a variety of biological processes. NO act ivates soluble guanylate cyclase and increases the syn thesis of guanosine 3',5' ~ cyclic mono phosph are (cyclic G MP), whic h leads to smoo th muscle relaxat ion.

.

100

•

80

ec

. 0 0

60

~

g

40

"0

0 0

OJ 20

a

50

100

150

200

300

500

Alveolar P02 Figure 4-10. Eff ect of redu cing alve o lar P 0 2 o n pu lm on ary bl o od f low. (Data from ane sth eti zed cat .l - - --

irors of NO synt hase augment hypoxic pulmon ary vasoconstriction in cal preparations, and inhaled NO reduces hypoxic pulmonary vasoconst ricm h umans. The required inh aled concentration of i'0 is ext remely low c t 20 ppm), and the gas is very roxie at h igh conce ntrations. Disruption of c. -OS gene has been shown to cause pulmonary hypertension in an imal

""k

. ulrnon arv vascular endothelial cells also release pote nt vasoconstr ictors as endorhelin- I (ET -l) and thromboxane A, (TXA,) . Thei r roles in I r hysioloJ::Y and disease are the subject of inten se study. Blockers of enneli n recepto rs have been used clin ically to treat patien ts with pulmon ary -rerrensio n . Hvpoxic vasoco nstric tion has th e effect of d irecting blood flow away from hv- regions of lung. T hese regions may result from bronchial obst ruction, and ... vert ing blood flow the deleterious effec ts on gas exchange are reduced. At _ altitude, generalized pulmonary vasoconstric tion occu rs, leading to a rise in nary arte rial pressure. But probably the most importan t situation in which , mechanism operates is at birth . During fetal life, the pulmon ary vascular re-AnCe is very high, part lv because of hypox ic vasoconst riction, an d only some orthe cardiac output goes th rough th e lungs (see Figure 9,5). When the first Ah oxygenates the alveoli, th e vascular resistan ce falls dramatically because of ion of vascular smoot h muscle, and the pulmonary blood flow increases usly. Jroer active responses of the pulmonary circulat ion have been described . A blood plI causes vasoconstriction, especiall y when alveolar h ypoxia is pre-. There is also evidenc e th at th e auto nomi c nervous system exerts a weak -01. an inc rease in sympathetic outflow causing stiffening of the walls of the na ry arteries and vasoconstriction.

" 'YPoxic Pulmonary Vasoconstriction • Alveolar hypoxia constricts small pulmonary arteries Probably a direct effe ct of the low P02 on vascular smoo th muscle Cr tical at birth in the transition from placental to air breathing Directs blood flow away from poorly vent ilated areas of the diseased lung in ' ''e adult

Water Balance in the Lung ;e only 0.3

urn of tissue separates the capillary blood from the air in th e lung _ e 1- 1), the problem of keeping th e alveoli free of fluid is critical. Fluid exec across the capillary endo thelium is believed to obey Starling's law. T he e rend ing to push fluid out of the capillary is the capi llary h ydrostatic pressure .;: the h ydrostatic pressure in the in terst itial fluid, or Pc - Pi. The force te nd, _ . fu ll fluid in is the colloid osmoti c pressure of th e proteins of the blood mi char of the protein s of the interstitial fluid, or 7Tc - 'ITt- This force depends on

the reflection coefficien t IT, which ind icates the effectiveness of th e capillary wall in preve n ting the passage of protei ns across it. Thus, net fluid out = K[(P, - P;) - a (", - " ;)]

"

'.

where K is a con stan t called the filtra tion coefficient. U nfortu na tely, the practical use of th is equation is limited because of our ig~ noranc e of many of the va lues. The colloid osmot ic pressure wit hin th e capillary is about 28 mm I-Ig. The capillary h ydrostat ic pteSSUle is probab ly about halfway between arterial an d veno us pressure but is much h igher at the bottom of t he lung th an at th e top. The colloid osmotic pressure of the in terstitial fluid is not known but is about 20 mm Hg in lung lymph . However, thi s value may be h igher than that in the int erstitial fluid around the capillaries. The in terstitial h ydrostatic pressure is unknown , but some measuremen ts sh ow it is substan tially below atmosphe ric pressure. It is probable that the net pressure of th e Sta rling equation is outward, ca using a small lymph flow of perhaps 20 ml/hr in human s under normal cond itions. W he re does fluid go when it leaves the cap illaries?Figure 4-11 sh ows th at fluid whic h leaks out into th e int erst itium of the alveolar wall trac ks thro ugh the in terstitial space to th e perivascular and peribronch ial space with in the lung. Numerous lympha tics run in th e perivascular spaces, and th ese help to transport th e fluid to the h ilar lymph nodes. In addition, the pressure in these perivascular

,.• I,

Alveolar space

® Interstitium Capillary

Alveolar wall

CD

~-------------------....

Bronchus

Perivascular space Figure 4-11. Tw o pos sible pat hs for f lu id th at m ove s out of pul mon ary capi ll aries. Flui d t hat enters the int erst itium ini tia lly fin ds it s wa y in to th e perivascula r and pe ribron chia l spa ces . Later fl uid may cross th e alve ol ar wa ll , fil ling alveolar spaces.

spaces is low, thu s forming a natural sump for the dra inage of fluid (compare Figure 4 ~ Z ) . The earliest form of pulmona ry edema + is characterized by engorgement of these peribronchi al and perivascular spaces and is known as in terstitial edema. The rare of lymph flow from the lung increases considerably if th e capillary prcs~ sure is raised over a long period. In a later stage of pulmonary edema, fluid may cross th e alveolar epithel ium into the alveolar spaces (Figure 4-11 ). W hen this occurs, the alveoli fill with fluid one by one , and because they are then un ventilated, no oxygenation of the blood passing through th em is possible. What prompts fluid to start moving across into the alveolar spaces is not known, but it may be th at th is occurs when th e maximal draina ge rate th rough th e inte rstitial space is exceeded and the pressure the re rises too high. Fluid that reach es the alveolar spaces is actively pumped out by a sod ium, pot assium, AT Pase pump in epithelial cells. A lveolar edema is much more serious than in terstitial edema because of the int erference with pulmona ry gas exchange.

Other Functions of the Pulmonary Circulation The chief functio n of th e pulmonary circulation is to move blood to an d from th e blood-gas barr ier so that gas excha nge ca n occur. However, it ha s ot her importan t func tions. O ne is to act as a reservoir for blood. W e saw th at th e lung has a rcmarkable ability to reduce its pulmonary vascular resistan ce as its vascular pres~ sures are raised thr~h th e mech an isms of recruitmen t and disten sion (Figure 4~5) . The same mechanisms allow the lung to increase its blood volume with relativelv small rises in pulmon ary arterial or venous pressures. This occurs, for example, whe n a subject lies down after standing. Blood then drains from th e legs in to th e lung. Another function of th e lung is to filte r blood. Small blood thrombi are removed from the circulation before they can reach the brain or other vita l organs. Man y wh ite blood cells are trapped by the lung and later released, although th e value of this is not clear.

Metabolic Functions of the Lung T he lung has importan t metabolic funct ions in add ition to gas exch an ge. A nuruber of vasoact ive substanc es are metaboli zed by the lung (T able 4-1). Because th e lung is th e only organ except th e heart that rece ives the whole circulation. it is un iquely suited to modifying blood-borne substan ces. A substan tial fraction of all the vascular end ot helial cells in the body are located in th e lung. T he meta bolic functions of the vascular end othelium are only briefly dealt with here because man y fall within the province of pharmacology.

T

For a more exte n sive discussion of pulmonary edema, sec the co mpa nion volume, JB West: Pulmonary Pathophysiology- The Essentials , cd 6. Baltimore. Lippincott Wil liams & Wilkins, 2003.

Table 4-1. Fate of Substances in the Pulmonary Circulation Sub stance

"

." .iI

Peptides Ang iote nsin I Angiotensin II Vasopressin Bradykinin Amines Seroto nin Norepinephrine Histamine Dopamine Arachidonic acid metabolites Prostaglandin E2 and F2a Prostag landin A, Prostacyclin IPGI,) Leukot rienes

Fate

Converted to angiot ensin II by ACE Unaffe cted Unaffe cte d Up to 80 % inactivated Almost co mpletely removed Up to 30% remove d Not affected Not affected Almost complete ly remo ved Not affected Not affe ct ed Almost completely removed

The on ly known example of biological activatio n by passage th rough th e pulmonary circulat ion is th e conve rsion of the relatively inactive polypeptide, an giotensin I, to th e poten t vasoconstr ictor, angiotensin II. The latt er, which is up to 50 time s more ac tive th an its precursor , is unaffected by passage th rough th e lung. The conversion of angiotensin I is catalyzed by th e enzyme, angiotensin . convert ing enzyme or AC E, which is located in small pits in the surface of th e cap illary endo thel ial cells. Man y vasoactive substances are completely or parti ally inactivated d uring pas· sage through the lung. Bradykinin is largely inact ivated (up to 80% ), an d the en zyme respon sible is angiote nsin-convert ing enzyme, ACE. The lung is the major site of inact ivation of serotonin (5· hydroxytrypramine) , but th is is not by enzvmati e degradat ion, but by an uptake and storage process (T able 4-1). Some of the seroto nin may he transferred to platelets in th e lung or stored in some other way and released du ring an aphylax is. The prostagland ins E lo Ez, and FZn are also inactivate d in th e lung, which is a rich source of th e respons ible enzymes. No repinephrine is also taken up by th e lung to some extent (up to 30%). Histami ne appears not to be affected by th e in tact lung but is readily inact ivated by slices. Some vasoactive mat erials pass th rough th e lung withou t sign ifican t gain or loss of act ivity. These include epine ph rine, prostaglandins A l and A ZI angiotensin II, and vasopressin (ADH). Several vasoactive and bronchoactive substances are metabolized in the lung and may be released in to th e circulation under certain condi tions. Importan t among these at e the arach idonic acid metabolites (Figure 4-12). Ar achi donic acid is formed through the act ion of the enzyme phospholipase A z on phospho lipid bound [0 cell membranes. T here are two major syn thetic pathways, the ini tial reacti ons being cata lyzed by the enzymes lipoxygen ase and cyclooxygenase, respectively. The first produces th e leukotrienes wh ich include th e medi ator mi g. inally described as slow-reacting substa nce of anaphylaxis (S RS-A ). T hese com-

1~

Membrane-bou nd phospholipid

-7

Phospholipase A,

Arachidon ic acid

Lipoxygenase

Leukotrienes

~

Cyclooxygenase

Prostaglandins, Thrc mboxana A 2

Figure 4-12. Two pathwa ys of arach id onic acid me ta bo lism . Th e teu kot ne nes are g enerated by t he Iipoxy gena se pat hw ay, w hil e t he p ro staglan din s and t hro m bo xane A 2 com e from th e cyclo oxyge nase path w ay .

rounds cause airway constr ict ion an d may h ave an important ro le in asth rna." O ther leukorrienes arc in volved in inflammatory respon ses. The prostaglandins are potent vasoconstrictors or vasodilators. PGE2 plays an importan t role in the fetus because it helps to relax the pa tent d uctu s arteriosus. Prostaglandins also affect platelet aggrega tion and are ac t ive in other syste ms such as the kallikrein -k in in clo tti ng casca de. T h ey also rnav h ave a role in th e bronchoc onstrict io n of asth ma . T he re is also evidence tha t the lung plays a ro le in th e clotting mechani sm of blooJ under normal and abno rmal conditions. For example, th ere are a large nu mbe r of mast cel ls con ta in ing hepar in in th e in tersti t ium. In addition , the lung is ab le to sec rete spec ial immunoglobulin s, particular ly IgA , in the bron chial rnucus wh ich con tribute to its defen ses again st infect io n . Synthet ic func tio n s of the lung include th e syn thesis of phos pholipids such as dipalmirovl phospharidvlcholin e, wh ich is a compone nt of pulmo nary surfactant (see C ha pter 7). Prot ein syn thesis is also clear ly important because co llagen and elas tin for m the struc t ural framework of th e lung. U nde r some co nditio ns, proteases are app aren tly liberared from leukocytes in th e lung, ca using breakdown of collagen an d elastin , an d th is may result in emphysema. A nothe r sign ificant area is carbo h ydrate rn etebolisrn , especially th e elabor at ion of mucopolvsaccharides of bronch ial mucus.

QUESTIONS For each question, choose th e one best answer. 1. The ratio of total syste mic vascular resistance to pulmo nary vascular resistance is about : A. 2 : 1 B. 3 : 1 C. 5 : 1 D. 10 : 1

E. 20 : 1 :i:

For more details, see JB West: Pulmonary Pathophysiology- T he Essentials, cd 6. Hait i more, Lippinco tt \V ill iams & Wilkins, 2003.

2.

All of the following statements about the ext ra-alveolar vess els of the lung are true EXCEPT: A. They are pul led open by radial traction of alveolar wall s. 8 . They tend to be narrowed by smooth mus cle and elast ic tissue in t heir w alls. C. They are exposed to alveolar pressu re. D. On the arterial side they constrict in response to alveolar hypoxia. E. Their caliber is increased by lung inflation. 3 . A patient w ith pulm ona ry vascular disease has me an pulmo nary arterial and venous pres sures of 55 and 5 mm Hg, resp ect ively, w hile the cardiac output is 3 liters per min ute . W hat is his pulmonary vascular resistance in rnm Hg . titer " . min .

4.

5.

A. B. C D. E.

05

A

2.5

1.7

2.5 5

17 In a norm al subject all of the following contr ibut e to the fall in pulmonary vascular resistance on exercise EXCEPT: A. Increase in pulm onary arterial pressure. B. Increase in pulmonary venous pressure, C. Recruitm ent of pulrnonarv capillaries. D. Distension of pulmonary capillaries . E. Alveolar hypoxia. In a me asurem ent of cardiac out put usi ng the Fick Principle the O 2 concentrations of mixed ve nous and arterial blood are 16 and 20 mi · 100 m t". respect ively, and the O 2 consumption is 300 ml m in- ' . The cardiac output in liters ' m in - 1 is:

B. 5 C. 7.5 D. 10 E. 75 6 . In zone 2 of the lung all of the fol low ing statements are true EXCEPT: ~ A. Arterial pressure exceeds alveolar pressure . \. - B. Alveolar pressure exceeds venous pre ssure . C. Arterial pressu re exceeds venous pressu re. D. Blood flow is determ ined by arter ial pres sure mi nus alveo lar press ure. E. Blood flo w is determ ined by arterial pressure mi nus ve nous pressu re. 7 . Pulmonary vasc ular res istance is reduced by: A. Removal of one lung. B. Breath ing a 10% oxygen m ixtur e. C. Exhaling from func t ional residual capacity to residual volume . D. Acu tely increasing pulmona ry venous press ure. E. M echanically venti lating the lung wit h posit ive pressure.

8. All of the following stateme nts about hypoxic pulmonary vasoconstriction are true EXCEPT: A. It depends more on the P 0 2 of mixed venous blood than alveolar gas. B. It is important in the transition f rom placental to air respiration. C. Its mechanism involves K+ channels in vascular smooth muscle. D. It partly diverts blood f low from poorly ventilated regions of diseased lungs. E. It is reduced by inhaling low concentratio ns of nitric oxide. 9. If the pressure in the capillaries and interstitial space at the top of the lung are 3 and 0 rnrn Hg, respectively, and the colloid osmotic pressures of the blood and inters titial fluid are 25 and 5 mm Hg, respecti vely, wh at is th e net pressure in mm Hg moving fluid into the capillaries?

A

17

B.

20

C. 23 D. 27 E. 33 10. The metabolic funct ions of the lung include all of the foll owing EXCEPT: A. Convert ing angioten sin-1 to angiotensin-2. B. Inactivating bradykinin, C. Removing serotonin .: D. Removing leukotri enes. E. Generating erythropo ietin.

Ve ntilation-Perfusion Relationships How Matching of Gas and Blood Determines Gas Exchange

gen Transport from A ir to -"'SS ues

ventilat ion sion t ent ilat ion-Perfusio n Ratio _ ect of Altering the entilation-Perfusion Ratio a Lu ng Unit . nal Gas Exchange in the ng

Effect of Ventilation-Perfusion Inequality on Overall Ga s Exchange Distributions of VentilationPerfusion Ratios Ventil ation-Perfusion In equality as a Cause of CO 2 Retention Measurement of VentilationPerfusion Inequality

- 's chapter is devoted to the primary function of the lung, that is gas exchange. ~rst a

theoretical idea! lung is considered. Then we reviewthree mechanisms

, ypoxemia including hvpoventitetion, diffusion limitation and shunt. The difficult concept 01 ventilation-perfusion inequalityis then introduced, and to illusrrste this the regional differences of gas exchange in the upright human lung are described. Then we examine how ventilation-perfusioninequality impairs overet;gas exchange. It is emphasizedthat this is true not only 01 oxygen but 3 so carbon dioxide. Methods of measuring ventitstion-pettusion inequality are ___ _ _ _ . en briefly discussed.

So far we h ave cons idered the movement of air to and from the blood-gas interface, th e diffusion of gas across it, and th e movement of blood to and from th e barrier. It would be na tural to assume th at if all these processes were adequate , normal gas exchange with in th e lung would be assured. Unfortuna tely, th is is not so because the matching of ventilation and blood flow with in various regions of the lung iscritical for adequat e gas exchange. Ind eed. mismatch ing of ventilation and blood flow is responsible for most of the defecti ve gas exchange in pulmonary d iseases. In th is section we shall look closely at the importan t (but difficult ) subject of h ow the relation s between ventilation and blood flow det ermi ne gas exc hange. First, however, we shall exa mine two relati vely simple causes of impairmen t of gas exch ange- hypoventilati on and sh unt. Because all of the se sit uations result in hypoxemia , th at is, in an abnormally low PO z in arterial blood. it is useful to take a prelimin ary look at normal O 2 transfer.

Oxygen Transport From Air to Tissues Figure 5 ~ 1 shows how th e Po , falls as the gas moves from the atmosphe re in whic h we live to the mitochondria where it is ut ilized. The POz of air is 20.93% of th e total dry gas pressure (th at is, excluding water vapor). At sea level, th e barometric pressure is 760 mm Hg, and at the body temperatu re of 37°C, the water vapor pres~ sure of moist inspired gas (wh ich is fully saturated with water vapor) is 47 mm Hg. Thus, the Po, of inspired air is (20 .93/ 100) X (760 - 47 ) or 149 mm H g (say 150). Figure 5-1 is drawn for a h ypotheti cal perfect lung, and it shows th at by th e time the 0 , h as reached th e alveoli, the Po, ha s fallen ro abo ut 100 mm Hg, that is, by one- th ird. This is because th e POz of alveolar gas is determin ed by a balance

150

Air Lung and blood

r»

I

E E

100

,

;or Perfect

,f

•. --")f-------... ----. . ----50

Hypoventilati on

Tissues

a Atmosphere - - - - - - --

--+_ Mitoch ondria

Figure 5-1. Schem e of t he O2 partial pressure s from air to t issues. The soli d li ne shows a hyp oth eti cal perfect sit uation, and t he bro ken li ne depicts hypoventi lati on. Hypoventilation depresses the P02 in the alv eolar gas and, therefo re, in th e tissu es.

"""'''''''.'f1 rwo processes: the removal of 0, by pulmonary capillary blood on the replenishment by alveolar ventilation on the othe r. ......v, alveolar ventil .ulon is not contin uous hut is breath -by-breath . Howc fluctuation in alveo lar Po z with each breath is only about 3 mm Hg, bee tidal volume is small compared with th e volume of gas in the lung, so ress can be regarded as conti nuous.} T he rate of removal of O 2 from the ( _ ~ verned by the O 2 consumption of the tissues and varies lit tle under rest_ =Jlditi? ns. In practice, the refore, th e alveolar POz is largely determined by ) ~ el ot alveolar ven tilation. T he same applies to the alveolar Peo 2' wh ich is ly about 40 mm Hg, "ben the systemic arterial blood reach es the tissue capillaries, O 2 diffuses to tochondria whe re th e Po , is much lower. The "tissue" Po z probably differs ierably throughout the body, and in some cells at least, th e Po z is as low as - H~. However, the lung is an essential link in th e chain of O, transport, an d rease of Po z in arterial blood must result in a lower tissue Po z' othe r things rs: equal. For the same reasons, impaired pulmonary gas excha nge causes a rise ;."an:l. and its continual

-;ue

Peo,.

r Cau ses of Hypoxemia • - vpoventit atton

--.. ;fusi on limitation

S

unt

entitation-perf usion inequality

Hypoventilation e have seen th at th e level of alveolar POz is de termined by a balance between rate of removal of 0 , by the blood (which is set by the metabo lic demands of tissues] and the rate of replenishment of Oz by alveolar ven tilation . T hus, if alveolar ventilation is abnormally low, the alveolar PO z falls. For similar rea'. th e PC-D, rises. This is known as hypoventilation (Figure 5-1). Ca uses of h ypoven tila tion includ e such drugs as morphine and barbiturates . h depress th e cent ral dr ive to the respiratory muscles, damage to the chest lor paralysis of the respiratory muscles, and a high resistance to breathing (for mple, very den se gas at great depth underwater) . Hypoven n lanon always .:aI.." O an increased alveolar and, the refore, arterial Pear The relationship be-eeen alveolar ventilation and PCOl was derived on p. 18:

Pc o ,

Veo,

= - V·-xK A

.ere Vco~ is th e CO 2 production , VA is the alveolar ventilation , and K is a conscant. This·mean s th at if the alveo lar ventila tion is halved, the PCOl is doub led, " ...lOCe a steady state has been established.

The relat ionship between th e fall in POz and the rise in Pco, that occurs in hypoventilation can be calcul ated from th e alveolar gas equation if we know th e compos ition of inspired gas and th e respirator y exchange ratio R. The lat ter is given by th e CO, ptoduc tion/O , consumpti on and is de termined by the metabolism of th e tissues in a steady state. It: is sometimes known as the respiratory quot ient . A simplified form of the alveo lar gas equa tion is

PAo,

P ALU z

=

Plo z - - -R-

+F

whe re F is a small correc tion factor (typically abou t 2 mm Hg), which we can ig-

C note. This equation shows that if R has its normal value oi~Jhe fall in alveo-

lar P02 is sligh tly greater than is the rise in Peo2 J uring hypoventilation. T he full version of th e equat ion is given in Appendix A. Hypovemilation always reduce s the alveolar and art erial P0 2 except when th e subject breathes an enriche d O 2 mixtu re. In th is case, the added amount of O 2 per breath can easily make up for th e reduced flow of inspired gas (t ry question 3 on p. 72).

.: ,II

Hypoventilation • Always increases the Peo;? • Decreases the POz unless additional Oa is inspired • Hypoxemia is easy to reverse by adding O 2

~S

1

Sho uld alveo lar ventilation be suddenly increased (for exampl e, by voluntary hyperven til ation), it may take several minu tes for th e alve ola r Po z and Peo 2to assume their new steady state va lues. T h is is because of the different O 2 and CO 2 stores in th e bod y. The CO2 stores are much grea ter tha n the O2 stores because of th e large amoun t of CO, in the form of bicarbona te in the blood and interstitial fluid (see C ha pter 6). T her efore, the alveola r Pe a , takes longer to co me to equilibrium, and during the nonsteadv state. the R value of expired gas is high as th e CO2 sto res are washed out. Opposite changes occ ur with th e onset of h vpoventilat ion .

Diffusion Figure 5-1 shows th at in a perfect lung, th e PO z of arterial blood would be th e same as that in alveolar gas. In real life, th is is not so. O ne reason is that although the Po, of th e blood rises closet and closet to th at of alveolar gas as the blood traverses the pulmonary capillary (Figure 3-3) , it can never quite reach it. U nde r normal cond itio ns, the POz difference betwe en alveolar gas and end-capillary blood resulting from incomplete d iffusion is immeasurably small but is shown schematically in Figure 5 ~2 . As we have seen, th e difference can become larger during exercise, or when the blood-gas barrier is th ickened. or if a low O 2 mixture is inhaled (Figure 3-3B).

150

Air

1~?C9 G "j cal

rn

I

E E

100

Art

N

0

o,

50

Diffusion Shunt

Tissues

a ) Mitochondria

Atmosphe re

Figure 5-2. Schem e of O 2 transfer from air to tissues show ing the dep ression of art erial P02 caused by diffusion and shunt',

Shunt Another reason why the POl of arterial blood is less th an that in alveo lar gas is shunted blood. Shunt refers ro blood rhar en ters rhe arrerial system wirhour going rhrough ventilated areas of lung. In the normal lung, some of the bronch ial art ery blood is collected by the pulmonary veins after it has perfused th e bronchi and its 0 ;2 has bee n partly deple ted. A nother source is a small amount of coronary venous blood which drains directly into rhe cavity of the left vent ricle thro ugh the Thebesian veins. The effect of the addition of th is pootly oxygenated blood is to depress the arterial POr So me patie nts have an abnormal vascular connection be; [ween a small pulmona ry artery and vein (pulmonary arteriovenous fistula). In patients with heart disease, there may be a direct additio n of veno us blood to ar-

terial blood across a defect between the right and left sides of the heart. W hen the shunt is caused by the addirion of mixed venous blood to blood drain ing from the capillaries, it is possible to calculate the amount of the shunt

rlow (Figure 5-3) . The total amount of 0 , leaving the system is th e total blood rlow QT mult ipl ied by the 0 , concentration in the art erial blood C ao " or QT X Cae,. This must equal the sum of the amounts of 0, in th e sh unt ed blood, Qs X C vo" and end-c apillary blood, (QT - Qs) X C c' 0,. Thus,

QT X C ae,

=

Qs X eva ,

+ (QT - Qs) X Cc'o ,

Rearranging gives

CC 0 2 - Cao 2 Cc o 2

Cvo 2

The 0 , conc en tra tion of end-capillary blood is usually calculated from the alveo lar P0 2 and the oxygen dissoc iation curve (see next chapter).

AS

CC'0 2 - Ca02

aT

CC'02- CV02

Figure 5-3. Me asureme nt of shunt flow. The oxygen carri ed in th e arterial blood equa ls the sum ofth e oxyg en carr ied in t he capillary blood and that in th e shunt ed

blood (see text).

"

'",.

W he n the sh unt is caused by blood tha t does not have the same O 2 concentration as mixed veno us blood (for example, bronchi al vein blood), it is gene rally not possible to calc ulate its true magnitude. However, it is often useful to calculate an "as if" sh unt, that is, what th e sh unt would be if the observed depression of ~ / arterial O z concen tration were caused by the add itio n of mixed venous blood . 'I:-- A n important feature of a sh unt is that th e hypoxemia cannot be abolished by giving th e subject 100% 0, to breathe. This is because the sh unted blood that bypasses ven tilated alveoli is never exposed to the higher alveola r POz so tha t it continues to depress th e art erial P O l' Howeve r, some elevation of the art erial P0 2 occurs because of the 0, added to th e capillary blood of vent ilated lung. Most of the added 0 , is in the dissolved form, rathe r tha n attached to hemoglobin, because the blood th at is perfusing ventilated alveoli is nearly fully saturated (see next cha pte r) . G iving the subject 100% O 2 to breathe is a ~sensitive mea'suremen r of shunt because whe n the P0 2 is h igh, a small depression ofa rteri al O a conce n tration causes a relativel y large fall in P 0 2 due to th e almost flat slope of th e 0 , d issociation curve in th is region (Figure 5-4). A sh unt usually does not result in a raised Pcoz in arte rial blood , even tho ugh the shunted blood is rich in COz. The reason is tha t th e chemorecep tors sense any elevation of arterial PCOz and they respond by increasing the ventilatio n. This reduces the Pco , of the unsh un ted blood until the arterial Pcoz is no~l. Indeed , in some patien ts with a shunt, th e arte rial Peo z is low because the hypoxemia increases respiratory driv e (see C hap ter 8).

11

Shunt r.:~ ~

• Hypoxemia responds poorly to added inspire d O2 2 is inspired, the arterial P0 2 does not rise to the expected level- a useful diagnostic test • If the shunt is caused by mixed venous blood. its size can be calculated from the shunt equation

• Wh en 100% O

O2 dissociation curve

~~~-~~~~~~~~~~~~~~~~~~~~~~~~ - ---~•} •• •,,, , E

15

s

~ ,,""'' , , , , , ,,', • ,,

•• ••, ,

c .Q 10

,,

"§

"go s

•,

,, ,, •,

,, ,, ,,

o

" 5

-o

200

~--

400

--600

Figure 5-4. Depression of arte ria l P02 by shunt during 100% O2 breathing . Th e additio n of a sma ll am ou nt of shunted bloo d w ith its lo w O2 co ncentrat io n greatly reduces the P02 of arteri al b lo od . This is becau se the O2 di ssociation curve is nearjv fl at when the P 0 2 is very hig h.

The Ventilation-Perfusion Ratio So far we have considered three of th e four causes of hypoxemia: hypoventilat ion, diffusion, and shunt. W e now come to th e last cause, which is both the cornmonest and th e most difficult to understand, namely, ven tilation-perfusion inequality. It turns out th at if ven tilat ion and blood flow are mismat ch ed in various regions of the lung, impairment of both 0 , and CO, transfer results. The key to understanding how th is happens is th e ventilation -perfusion ratio. Consider a model of a lung unit (Figure 2-1) in which the uptake of 0 , is being mimicked using dye and water (Figure 5-5) . Powdered dye is continuously poured into the un it to represen t th e addi tion of O 2 by alveolar ventilation. Water is pumped continuously th rough th e unit to represent th e blood. flow which removes the O 2, A stirrer mixes th e alveolar con ten ts, a process normally accomplished by gaseous diffusion . The key question is: wha t determin es the concen tration of dye (or O 2 ) in th e alveolar compartment and, th erefore, in th e eft1uen t water (or blood )? It is cle ar that borh the rat e at whi ch the dye is added (ve n tilat ion) and tn~'~ ta te at whic h wate r is pumped (bl ood flow) will affect the co nc en tra tion of dye in the mode l. What may no t be int uitively cle ar is th at the conc en tra tion of dye ./

Powdered dye V

"~y':0o;0

~

"0 :-.:

... .. . ... ... .. ... . o

Concentrati on

via

Water

a- -_) -----'

:\\ 0

0

00"¥"O".. •

0

•

"

•

0

• 0° • •

_ ' ----'0' - ' -

0

•

•

~::

0

•• ° '----,--

•• • •

~

Figure 5-5. M ode l to il lustrat e how t he ve nt ilatio n-perfus io n rat io determ in es t he P02 in a lung un it. Pow dered dye is added by v enti lat io n at th e rate V and rem ov ed by blo od f low Q t o repres ent t he f actors co ntrolling alveo lar P02' Th e concentrat io n of dye is giv en by V/ Q.

is determined by th e ra ti o of th ese ra te s. In other wor ds, if d ye is added at the rate of V gm . min - 1 and wate r is pumped th rou gh at Q liters ' min - 1, the concen tr ation of dye in th e alveolar compa rt ment and effluen t wate r is VIQ gm . liter- J • "lIn exactl y the same way, th e concen trati on of O 2 (or bet ter, Po z) in any lung unit is det ermined by the rat io of ventilat ion to blood flow, and not only O 2 but CO 2 , N 21 an d any other gas th at is presen t under steady state cond itions. T his is th e reason why th e ventilation-perfusion ratio plays such a key role in pulmonary gas exchange.

Effect of Altering the Ventilation -Perfusion Ratio of a Lung Unit Let us take a closer look at th e way altera tions in the ven tilation-perfusion ratio of a lung unit affect its gas excha nge. Figure 5-6A shows th e POz and Peo z in a uni t with a normal ven tilation-perfusion ratio (abo ut I- see Figure 2-1). The inspired air has a Po, of 150 mm Hg (Figure 5-1) and a P= , of zero. The mixed venous blood entering th e uni t has a Po, of 40 mm Hg and P= , of 45 mm Hg. The alveolar Po, of 100 mm Hg is derermined by a balance between th e addition of 0, by ventilation and its removal by blood flow. The normal alveolar P= , of • 40 mm Hg is set similarly. N ow suppose that the ven tilation-perfusion ratio of [he unit is gradually reduced by obstrucring its vent ilation, leaving its blood flow unch an ged (Figure 5-6B). lr is clear that rhe 0, in th e unit will fall and rhe CO, will rise, although

O2 = 150 mm Hg

A

~~~~--,

::;

CO,= 45

J ,Y"'f' '''"'

a,v1

1

0 2 = 150

CO,= 40 0 2= 4~0!J-.~~=-l---..

"'" ? ,-

".

c

1

O2 = 100

O 2 = 40

CO 2 = 45

"

C

\ V\ :.(

.J

CO 2 = 0

B

2(

C02= 0

"'"

Decreasing

Increasing

VA/a

VA/a

Fig ure 5-6. Effec t of alte ring th e ve nti lation-p erfusion rati o o n th e a lu ng un it .

P02

and Pee, in

th e relat ive cha nges of these two are not immediately obvious." However, we can easily predic t what will even tu ally h appe n when the ventilation is completely abolished (v en tilation-perfusion rati o of zero ). Now th e O 2 an d CO2 of alveo lar gas an d end- cap illary blood must he the same as those of mixed venous hlood. (In practice, comp let ely ob stru cted un its eve n tually co llapse, but we can n eglect such long-term effec ts at the mo ment.) Note that we are assuming that wh at h appen s in one lung un it ou t of a very large n umber does not affect the co mpos ition of the mixed venous blood , Suppose instead that the vent ilat ion-perfusion rat io is increased by grad ually obstruct in g blood flow (Figure 5-6C) . No w th e 0, rises and the CO, falls, even wa lly reaching the co mpo sit ion of inspired gas when blood flow is abolished [ven t ilat ion -perfusion rat io of infinity). T h us, as the ventilation- perfusion rat io of the unit is alte red, its gas co mpos it ion approac hes that of mixed venous blood or inspired gas. A co nve nie nt way of dep icting th ese changes is to use the 0 2-C02 d iagram (Pigure 5-7) . In this, POz is plott ed on th e X axis, and Peo z is plotted on th e Y axis. First, locate the normal alveo lar gas composition, point A (Po, = 100, Pco , = 40) . If we assume that blood equilibrates with alveo lar gas at the end of the capillary (Figure 3-3), th is point can equa lly well represent the end-capillary blood. Next find the

* The alveolar gas equation is not applicable here because the respiratory exchange ratio is not constant . The appropriate equation is

IIA ~ 8.63 . R . Q

(Cao, - Cvo,)

~ o

50 rn

I

v~ o - - t - -_ _-:~ Dec reasing

E E

'itAI Q

Normal

A

i s o

50

100

L~ I

150

.

"

Figure 5-7. OTCOZ diagram showing a venti lation-perfusion ratio line. The POz and Pee, of a lung unit move along thi s line f rom th e mi xed veno us point to the insp ired gas point I as its ventilation -perfu sion ratio is increased (compa re Figure 5-6).

'""

mixed veno us point v (Po, = 40, Peo, = 45). The bar above v means "mixed" or "mean." Fina lly, find the inspired point I (POI = 150 , Pc o , = 0 ). Also, note the sim ilarities betwe en Figures 5-6 and 5 -7.

v

I'

..'

~

T he line joining to I passing through A shows the cha nges in alveolar gas (and end-capillary blood) composition that can occur when the ventil ation. perfusion ratio is eithe r dec reased below normal (A ~ 'V) or increased above normal (A -e 1). Indeed, thi s line indicates all the possible alveolar gas compositions ·n a lung that is supplied with gas of composition I and blood of composition v. For example , such a lung co uld not contain an alveolus with a POz of 70. and Pcoz of 30 mm Hg, because th is poi nt does no t lie on the ventilatio n-perfusio n line. However, this alveo lar co mposition could ex ist if the mixed veno us blood or inspired gas were changed so that the line then passed through this point.

D

Regional Gas Exchange in the Lung The way in which the ventila tion-perfusion ratio of a lung unit determines its gas

exchange can be graphically illustrated by looking at the differences tha t occur down the upright lung. We saw in Figures 2~ 7 and 4-7 that ventilation increases

slowly from top to bottom of th e lung and blood flow increases more rapidly (Figure 5-8 ). A s a consequence , the ventilation-perfusion ratio is abnormally high at

th e top of the lung (where the blood flow is minimal) and much lower at th e bottom. We can now use these regional differences in ventilat ion-perfusion ratio on an

O,·CO, diagram (Figure 5-7) to depict th e resultin g differences in gas exchange. Figure 5-9 shows the upright lung divided into imaginary horizontal "slices," each o f wh ich is located o n the ventilation -perfusion line by its own ve ntilationperfusion ratio. This ratio is high at the apex so that thi s point is found toward

the right end of the line, while the base of th e lung is to the left of normal (com-

.15

3


E

.Q

Blood flow

.10

~

"@ c 2 .2

-0 >

'"

c '"

~

'e

~


Vent ilation

-0

'"E

C.

C

0

0

<=

$

.05

E Rib number Bottom

Top

5

4

2

3

Fig ure 5·8 . Distrib ut ion of v enti lat io n and bl ood flow down t he uprig ht lu ng (co m par e Fig ures 2-7 and 4-7). No te that t he ve nti lation-pe rf usion rat io de creases do w n th e lu ng.

-------"",

60

,

l

,

,

-.

,

,, ,, ,

"\,

40

E

E

(L8

"",,, ,,

20

,,

:1

o 40

60

80

100

120

140

Po.,. mm Hg Figure 5-9. Result of co m bi ning t he patt ern of v ent ilatio n-pe rf usio n rat io ineq uality sho w n in Fig u re 5-8 w ith th e effects of t hi s on gas exc ha nge as shown in Figu re 5-7. Note tha t th e hi g h ventil atio n-perf usio n ratio at th e apex results in a high P02 a nd low PC02 the re . Th e o p po s ite is seen at th e base.

pare Figure 5-7) . It is clear that th e POI of th e alveoli (ho nzonral axis) decreases markedly down the lung, while the Pcoz (vertic al axis) increases much less. Figure 5;10 illustrates the values that can be read off a diagram like Figure 5-9. (Of course the re will be variat ions betwe en ind ividuals; the chief aim of this approach is to describe the princi ples underlying gas excha nge.) Note first that th e volume ofthe lung in th e slices is less nea r the apex th an th e base. Ventilation is less at the top tha n the botto m, but the differen ces in blood flow are more marked. Co nsequently, th e ventilation-perfusion ratio decreases down th e lung, and all rhe d ifferen ces in gas exchange follow from th is. Note tha r th e PO, ..---changes by over 40 rom Hg, while the difference in Pco, between apex and base I is much less. (In ciden tally, th e high PO, at the apex probably accounts for th e preference of adult tube rculosis for this region because it provides a more favor, .able environm ent for this organism.) T he variation in P N 2 is, in effect, by default because th e total pressure in th e alveolar gas is th e same throughout the lung. The region al differences in POz and Pe o l imply d ifferences in the end-capillary concentrations of th ese gases, which can be obtained from the appropriate

-*' -' I L

Vol

(%)

VA

Q I (I/ min)

I I

VA/Q P"" Pc"" PN2 0 2 !c0 2 (mm Hg)

," .

.07

3.3

132

/

I

I

28

553 20 .0

,, ,, ,

/

.82

,.

,

1.29 0.63

,,

,

~

-, --

-

••

89 -~~-

42

7.51

4

I 42

\ \ \ -,

••

\ 582 19.2

"V

-~ -

:=: .. - -

8

\

, • ••

\ •-, \

leo,

in out (ml/min)

1"\

,,

•• ,•

•, 13

r<

\

/ .24

O2

(ml/ l00 ml)

,r--. 7

pH

cone.

49

":. - - - - ~

7.39

-- -~ ... ,

,

60

39

-, ,,

J

Figure 5-10. Regional differen ces in ga s exchang e dow n the nor m al lu ng. Only th e apica l and basal v alue s are show n fo r cl arity.

Ventilatio n-Perfusion Relationships

67

in~

- arion curves (C hapter 6). Note the surprisingly large d ifferen ce th e lung, whic h reflects th e considera ble variation in PUl z of th e bl&xi. min imal con tribution to overall O 2 uptake made by the apex can be mainly ~ ted to the very low blood flow there. The difference in CO, output be- fY{ apex an d base is much less because th is can be sho wn to bernore closelv re-: J _~ LO \" ent iia t io n_~_A s a result, th e respiratory exchange ratio (C 0 2 output/Oz .e) is higher at the apex th an at the base. O n exercise, when the d istribution flow becomes more Uniform , the apex assumes a larger sha re of the Qz -'£r-

\

e.

Effect of Ventilation-Perfusion Inequality on Overall Gas Exchange th e regiona l differences in gas excha nge discussed above are of int erest, importan t to the body as a who le is whe the r uneven ventilation and blood arrect the overall gas exchange of the lung, th at is, its ability to rake up O 2 put out CO2 , It turns ou t th at a lung with ventilatio n-perfusion inequality is and CO2 as a lung that is uniformly ven tilate d able to transfer as much - perfused. ot he r th ings being equal. O r if the same amounts of gas are be ing srerred (because these are set by the metabolic demands of th e body), the lung ventilation-perfusion inequality can not maint ain as h igh an arterial POz or -an art erial Pco, as a homogeneous lung, again other things being eq ual. "he reason wh y a lung with uneven ven tilation and blood flow has d ifficulty .., na ting arterial blood can be illustrated by looking at the d ifferences down cpn aht lung (Figure 5-11). Here the Po, at th e apex is some 40 mm Hg h igher at the base of the lung. However, th e major sha re of th e blood leaving the ., comes from the lower zones, where the POz is low. This has the result of dessing the art erial POZ" By con trast, the expired alveolar gas comes more uniI~- from apex an d base beca use th e differences of ven tilation arc much less th ose for blood flow (Figure 5-8). By the same reasoning, th e arte rial Pco , . be eleva ted because it is hi gher at th e base of the lung than at the apex 10 ,-,"re 5-10) . .An additional reason why uneve n vent ilation and blood flow depress th e aral Po , is sho wn in Figure 5-12. This depicts thr ee groups of alveoli with low, - .....-alai, and h igh ven rtlation-perfuslon ratios. The O z conc en trations of the efm blood are 16, 19.5, and 20 ml . 100 ml" , respecti vely. As a result, the ts with th e hi gh ventilation-perfusion ratio add relatively little oxygen to th e - ood. compared with th e decrement caused by the alveoli with the low vent ila.... vi -perfusion ratio. Thus, th e mixed ca pillary blood has a lower O 2 conce n trarhan th at from un its with a normal ven rilarion- perfusion ratio. This ca n be expla ined by the non linear sha pe of th e oxygen dissociation curve, which means mar, although un its with a high ven rilation- perfusron ratio have a relatively eh POz' th is docs not increase th e oxygen conc en tra t ion of t he ir blood very uch. T h is add itiona l reason for the depression of Po , docs not apply to the el... -arion of th e Pcoz because the CO 2 dissociation curve is almost linear in th e rkin g ran ge.

a,

Figure 5-11. Depressi on of the arteri al P 0 2 by ve ntilatio n-pe rfus io n in equ ality . In this diag ram of t he upri ght lu ng, only two gro ups of alveoli are shown, on e at th e apex and ano the r at the base. The relativ e sizes of th e airways and blood ve ssels ind icate th eir relat ive ventilations and blood flows . Becau se most o f the blood co mes fro m the poo rly oxygenate d base, depression of th e blood P02 is inevita ble.

"

The net result of these mechanisms is a depression of the arterial Pa z below that of the mixed alveolar POz- the so-called _alveolar~arterja L O~= In th e normal upright lung, this difference is of trivial magnitude, being only about 4 mm Hg due to ventilation-perfusion inequa lity. Its development is described here only to illustrate how uneven ven tilation and blood flow must result in depression of the arterial Po zf In lung diseasej th e lowering of arterial Po z by th is mechani sm can be extre me.

!

0 2concentration 14.6 16 .0

19.5

20 .0

Figure 5-12. Additiona l reaso n for the depression of arterial P 0 2 by m ismat ching of v entilation and blood flow. Th e lung units w it h a high ventilation-perfusio n ratio add relati v ely little oxy ge n to the blood, com pared w it h th e dec reme nt caused by alveo li wi t h a low ventilatio n-perf usio n rati o.

Distributions of Ventilation-Perfusion Ratios ; , possible to obtain inform at ion abo ut the distrib uti on of ventilation-p erfusion ~ in pat ien ts with lung disease by infusing into a periphera l vein a mixture of - k ed ine rt gases h avin g a ran ge of solub ilit ies, and measur ing the concentra.'lI'l5- of th e gases in arterial blood and exp ired gas. T he details of this technique roo complex to be described h ere, and it is used for research purposes rather in the pulmonary fun ction labora to ry. The technique returns a distribut ion -en n lan or; an d blood flow plotted against vent ilation-perfusion rat io with 50 . ;. -enpartrnenrs equally space d on a log sca le. r i-gure 5-1 3 sho ws a typical result fro m a young norm al subject. Note that h e ven t ila tion and bl ood flow go to compa rtmen ts close to th e no rmal entilat ion -perfusion rati o of abo ut 1.0, and, in part icular, there is no blood flow - e unven t ilated comp artment (shunt). The distributions in patients with lung sease are ofte n very different. An exa mp le from a patient with ch ron ic brontis and emphysema is sho wn in Figure 5-14. Note that altho ugh much of the entilation and blood flow go to co mpart ments with vent ilatio n-perfusion ratios - ar normal, conside rable blood flow is going to compa rtme nts with ven tilat ionrerfusion ratio s of between 0.03 and 0.3. Blood from the se units will be poorly ~nated and will depress the arter ial P~ . There is a lso excess ive ventilat ion ~ - lung units with ven ulati on-perfusion ratios up to 10. These un its are ineffici ent - e iminat ing CO2, T h is part icular pa tient had arterial hypoxemia but a nor mal srte rial PC02 (see bel ow ). O t he r patterns are seen in ot h er types of lung disease.

,

,

1.5

+- Ventilation Blood flow --..

0 .5

No shunt

,/ , , .j o L+/~--:~--+-~~;;--='-~~--:::! 10 .0 100 .0 o 0.0 1 0 .1 1.0 Ventilation -pe rfusion ratio

e 5-13 . Distribution of ve ntila tio n-perfus io n ratios in a yo u ng normal subote the narrow di spersi on an d absence of shunt.

~

J

, "

0.6

0.4

0 .2

,-

No shunt

,(

o

0 .0 1

0 .1

1.0

10 .0

100 .0

Ventilation-perfu sion ratio

Figure 5-14. Distributi o n of v ent ilat io n-pe rf usio n rat ios in a pa tie nt w it h chronic bronchitis and emphys em a. No te part icu larly the bl ood fl ow to lung u nit s w ith very low venf ila tio n-pert usi o n ratio s.

. ,.\ J.. , ~

Ventilation-Perfusion Inequality as a Cause of CO 2 Retention Imagine a lung that is uniformly ven tilated and perfused and tha t is transferring normal amoun ts of O 2 and CO 2 _ Suppose that in some magical way, th e match ing of ven tilation and blood flow is suddenly d isturbed wh ile everyth ing else rem ains un cha nged. What happens to gas exchange ? It transpires th at th e effeet of this "pure" vent ilatio n-perfusion inequality (t hat is, everyth ing else held consta n t) is to reduce both the O2 upt ake and CO, output of the lung. In other words, th e lung becomes less efficien t as a gas excha nger for bot h gases. Hence, mismatching ven tilation and blood flow must cause bot h hypoxemia and hypercapnia (CO, retent ion ), other thi ngs being equal, However, in pract ice, patients with und oubted ven tilation-perfusion mequality often have a normal arte rial Pear T he reason for this is th at whe neve r the che morece ptors sense a rising Pe o z' the re is an increase in ven tilatory drive (C hapter 8). The consequen t increase in vent ilation to the alveoli is usually effective in return ing the arterial Peo l to normal. However, such patient s can only main tain a normal PCOz at th e expense of this increased ven tilation to their alveoli; th e ventilation in excess of what they would norma lly require is sometimes referred to as wasted ,,-'entilarion and is necessary beca use the lung un its with abnormally high ven tilation -perfusion ratios are inefficien t at eli mina ting CO2 , Such un its are said to constitute an alveolar dead space.

entilat ion-Perfusio n Inequality The vent ilation-pe rfu sio n rat io (VA/OJ dete rm ines the gas exc hange in any 5 ngle lung unit • Regional difference s of VA/Q in the upright hum an lung cause a pattern of reg:onal gas exchange :.JQ inequality im pairs the uptake or elimination of all gases by t he k:ng A tho uqh t he elim inat ion of CO is im paired by VA/a. inequality, this can be corr ected by increasing the vent ilation to t he alveoli By contrast, t he hyp oxem ia resul ting fr om VA/Oineq uality cannot be efiminated by increases in vent ilation Toe diffe rent behavior of the two gases results fro m th e different shapes of ~ rj e i r dissoci at ion cu rves

~n ile

the increase in ven tilation to a lung with ven rilation-pcrfusion in lity is usually effective at reducing the arterial Pe o zl it is much less effective - Increasing th e arterial P Ol" The reason for the differen t beh avior of th e two . lies in the sha pes of the CO, and 0 , dissocia tion curves (Chapter 6) . The '- :: dissociation curve is almost straigh t in the physiological range, with th e rc~ that an increase in ventilation will raise the CO 2 output of lung units with ~ high and low ven tilat ion-pe rfusion ratios. By contrast, the almost flat top of ~ 0 :: dissociation curve means tha t only un its with moderatel y low ven tilationcerfusion ratios will benefi t appreciably from th e inc reased ven tilation. Those su rs that are very high on th e d issociation curve (h igh ven tilation-perfusion ra- I increase the O 2 conc entra tion of their effluent blood very litt le (Figure 5- 12). 5C units which have a very low ventilation-perfusion ratio continue to put out -sood with an O 2 concentration close to th at of mixed venous blood. The ne t re'lc is that the mixed arterial Po z rises only modestly, and some h ypoxemia always mains.

M easurem ent of Ventilation-Perfusion Inequality row can we assess the amount of ventilation-perfusion ineq uality in diseased

......'1gs! Radioactive gases can be used to define topographica l differences in vcnti-

' ion and blood flow in the norm al uprigh t lung (Figures 2-7 and 4-7), but in st pat ien ts large amounts of inequality exist between closely adjacent units, .mJ th is can not be d istinguished by coun ters over th e chest. In practice, we rum - ") ind ices based on the resulting impairmen t of gas exchang e." One useful measurement is the altJeolar-arterial POz difference, obtained by sub- acti ng the arte rial P 0 2 from the so-called "ideal" alveolar POr The latt er is the which the lung would have if there were no ven tilation- perfusion inequality

For more details of th is difficult subject, see }B West: Pulmonary PathophysiologyTM Essenrials, ed 6. Baltimore, Lippincott W illiams & Wilkins, 2003.

•

and it was exchanging gas at the same respiratory exchange ratio as the reaIl ung. It is derived from the alveo lar gas equation:

PAco, PAa, = PIo , - - R- + F The arterial PaJ! is used for the alveolar value. An exa mple will clarify this. Suppose a patient who is breathing air at sea level

has an arte rial Po, of 50 mm Hg, an arterial Pco, of 60 mm Hg, and R is 0.8. Co uld the art erial hypoxemia be explained by hypoventilation ? From the alveo lar gas equation, the ideal alveo lar POz is given

PAa, . J'

....

, ~

by

60 = 149 - 0.8 + F = 74 mm Hg

where the inspired Po, is 149 mm Hg and we ignore the small factor F. Thus, the alveolar-arterial Po, difference is approximately (74 - 50) = 24 mm Hg. T his is abnormally h igh, and indicates that there is ven tijat ion -pertusion inequality. Ad ditio nal information o n th e measurement of ventilatio n-perfusion inequal-

iry can be found in Chap ter 10.

QUESTIONS For each Question, choose the one best answer.

1. A climber reach es an altitude of 4500 m (1 4,800 ttl where the baromet ric

. ".

pressure is 447 mm Hg. The P0 2 of moist ins pired gas (i n mm Hg) is: 47

A. B C. D. E.

63 75 84 98 2. A man w ith normal lunqs and an arterial PC02 of 40 mm Hg takes an overdose of barbiturate w hich halves his alveolar ventilation but does not change

his CO2 out put. If his respiratory exchan ge ratio is 0.8, 'wh at w ill be his arts rial P0 2 (i n mm Hgi approximate ly? A. 40 B. 50 C. 60 D. 70

E. 80 3. In the situation described in Guestion 2 how much does the inspired O2 concentration (%1 have to be raised to return the arterial P0 2 to its original leve l?

A. 7 B. 11 C. 15 D. 19 E. 23 4.

A pat ie nt w ith normal lungs but a right-to-Ieft shu nt is found at cat hete rization to have oxyg en concentrations in his arterial and mixed venous blood of

. " and 14 ml . 100 ml"" , respectively . If t he 0 , conc entr ation of the blood ",aving the pulmonary capillaries is calculated to be 20 mi · 100 rnl" , w hat 5 his shunt as a percentage of his cardiac output?

23 _ . 33 43 ) . 53 _. 63 , a climber on the summit of Mt. Everest (barometric pres sure 247 mm Hg) 1), his 3 eolar Peo, (in mm Hg) cannot be any higher t han:

-naintains an alveolar POz of 34 mm Hg and is in a steady state (R $:

)

~. 5 3. 8

C. 10

_.

D.

12

_.

15

~

patient w ith severe chronic obstructive pulmonary disease, w hich causes marked ventilation-perfusion inequality, has an arterial POz of 50 mm Hg and an arterial Peoz of 40 mm Hg. The Peoz is normal despite the hypoxemia because: A. Ventilation-perfusion inequality does not interfere with CO2 elimination. B. Much of the CO2 is carried as bicarbonate. C. The formation of carbonic acid is accelerated by carbonic anhydrase. D. CO, diffuses much faste r th rough tiss ue th an 0 , . E. The 0, and CO, dissociatio n curves have differ ent shapes. 7. The apex of the upr ight hum an lung com pared w ith the base has a: A. Higher Po, . B. Higher ventilation. C. Low er pH in end-capillary blood . D. Higher blood f low . E. Smaller alveol i. 8, If the ventilation-perfu sion ratio of a lung unit is decreased by partial bronchial ob struct ion w hile the rest of the lung is unaltered, the aff ected lung unit will show : A. Increased alveolar Po, . B. Decreased alveolar Peo2' C. No change in alveolar PN,. D. Rise in pH of end-capillary blood. E. Fall in oxygen uptak e. 9. A patient w ith lung disease w ho is breathing air has an arterial Po, and Peo, of 49 and 48 m m Hg, respectively, and a respiratory exchange ratio of 0.8. The approximate alveolar-arterial difference for P0 2 (in mm Hg) is: A. 10 B. 20

C. 30 D. 40 E. 50

~

I

Gas Transport by the Blood How Gases Are Moved to the Peripheral Tissues

Acid-Base Status

en : ssolved O 2

Respiratory Acidosis

- iem c q lo bin :", Dissociation Curve

Resp ira tory Alkalosis M etabolic Aci do sis

Dioxi de

=O:! Car riage

M etabolic Alka losis

Blood-Tissue Gas Exchange

:0. Dissociation Curve

e rJ OW consider the carriageof the respiratory gases, oxygen andcarbon xide, by the blood. First we look at the oxygen dissociationcurve including e actors that affect the oxygen affinity of hemoglobin. Then we turn to carbon _ "de which is carried in the blood in three forms. Next we consider the acidase status of the blood and the four principal abnormalities: respiratory acidos and alkalosis, and metabolic acidosis and alkalosis. Finallywe briefly look at -.55 exchange inperipheral tissues.

Oxygen .. carr ied in the blood in two forms: disso lved and combined with J obin .

, ~

76

Chapter 6

Total O2 ---+-r:

__J.------

100

t

22 18

80

60

E o o -

14

:§.

10

.~

c;

o

C

40

g

6

20

8

s

Dissolved 02 ~ . ~ "'f-- 2 ----~--------------------~-----------

20

40

60

80

100

600

Po, (mm Hg)

Figure 6-1. O2 di ssociation curve (so lid line) for pH 7.4, P C0 2 40 m m Hg, and 3rc The t otal blood O2 con centrat io n is also show n f or a hem ogl obin con cent ration 15 gm · 100 ml " ? of blood .

Dissolved O2 ./

This obe ys Henry's law, th at is, the amount dissolved is proportion al to th e par tial pressure (Figure 6-1). For each mm Hg of Po, there is 0.003 rnl O, . l ro rnl" of blood (sometimes writte n 0.003 vol %). Thus, normal arterial blood with a P of 100 mm Hg con tains 0.3 ml 0 , . 100 ml- 1 • It is easy to see th at th is way of transporting O 2 must be inadequate . Sur that th e card iac output during stren uous exercise is 30 liters . min -I . Beca arterial blood con tains 0.3 ml 0 , . 100 ml - ' blood (t hat is, 3 ml 0, . Iirer " blood) as dissolved 0 " th e roral amount delivered to the tissues is only 30 X 3 = 90 mi · min - I. However, the tissue requirements may be as hi gh as 3C\."\: O 2 • min - I. C learly, an additional method of transporting O 2 is required.

Hemoglobin Heme is an iron-porph yrin compound, and th is is joined to th e protein glob wh ich consists of four polypepti de chains. The cha ins are of two types, alpha beta, and differenc es in th eir amino acid sequences give rise to various type-s human hemoglobin. No rmal adult hemoglobin is known as A. Hemoglobin F (;eta l) makes up part of the hemoglobin of the newborn infant and is gradually replaced over the first year or so of postnaral life. Hemoglobin S (sickle) has valine instead of glut amic acid in th e beta chains. This results in a shift in th e dissociation curve to the right . but , more importa nt, the deoxygena ted form is poorly : • uble and crysta llizes within the red cell. As a consequence, th e cell sha pe ch anges. from biconc ave to crescent or sickle sha ped with increased fragility and a ten-

.mcy to th rombus formatio n. Man y ot her variet ies of hemoglobin ha ve now ree n described , some with bizarre O 2 affin ities. For more informa ti on about ., • moglobin, consult a textbook of biochemistry. . _.annal hemoglobin A can have its ferrous ion oxidized to the ferric form by -arious drugs and chemicals, including nitr ites, sulfonamides, and aceta n ilid. -:-his ferric fonn is known as methem oglobin . There is a congen ital cause in which :he enzvrnc meth emoglobin reductase is deficien t within the red blood cell. An • er abnormal form is sulfhemoglobin. These compounds arc not useful for O 2 carriage.

.

O2 Diss ociat io n Curve 0: forms an easily reversible combination with hem oglobin (Hb) to give oxvhemoglobin: O 2 + Hb ~ HbO z. Suppose we rake a n umber of glass con tainers tonomerers), each containing a small volume of blood, and add gas with various concent rations of 0 ,. After allowing time for the gas and blood to reach equilibrium, we measure th e Po z of th e gas an d the O 2 conc en tration of the blood . Knowing that 0.003 ml 0, will be dissolved in each 100 ml of blood/mm Hg Po" 'e can calculate the 0 , combined with Hb (Figure 6-1). Note that th e amoun t 0 1 carried by the Hb increases rapidly up to a POz of about 50 mm Hg, but above that the curve becomes much flat ter. The maximum amount of 0, that can be combined with Hb is called th e 0 , capacity, T h is is when all th e available binding sites are occupied by 0 " It can be measured by exposing the blood to a very high Po, (say 600 mm Hg) and subtracting th e dissolved 0 ,. One gram of pure Hb can combine with 1.39* ml O j and because normal blood has about IS gm of Hb . 100 ml- I , the 0 , capac ity is about 20.8 ml 0 , . 100 ml- I of blood, The O 2 saturation of Hb is the perce ntage of the available bindi ng sites that have O 2 att ached, and is given by

or

0 , co mbined with H b 0 , capacity

X

100

The 0 , sat urat ion of arte rial blood with Po, of 100 mm H g is about 9 7.5%, while that of mixed venous blood with a Po , of 40 mm Hg is about 75%. The change in Hb from the fully oxygena ted sta te to its deoxygen ated sta te is accompan ied by a conformationa l cha nge in the molecule. The oxygenated form is the R (relaxed) state, while the deoxy form is the T (tense) sta te. It is important (0 grasp the relat ionsh ips between P O l ' O 2 saturation, and 0 2conc entration (Fig. ure 6·2). For example, suppose a severely anemic pati ent with an Hb conc en trarion of on ly 10 gm : 100 ml- l of blood has normal lun gs and an arte rial Po, of 100 mm Hg. This panem's O j capac iry will be 20.8 X 10/ 15 = 13.9 ml- 100 ml- I , The patien t's O 2 saturation will be 97.5% (at norm al pH, Pe o z• and tempe rature), but

* Some measurements give 1.34 or 1.36 ml. The reason is that under the normal conditions of the body, some of the hemoglobin is in forms such as methemoglobin that can, no t combine with O z.

"

r,

'I " "

~

r

30 ,c Hb = 20

E

100

0 0

-g

,c Hb = 15

20

......~._------------

.~

"ao

c

a

(HbCO = 33%)

c

a

c

~

100

10

\ . Hb = 10

c;

~

0

0

30

60

90

120

r 0

~

~

;;;

50

00 ~

0

50

u

0

50

.0

I

o

0

PO, (mm Hg)

Figure 6-2. Effects of an emia and polycyt hemia on O2 co nce ntratio n and saturati on . In add it ion , t he broken line shows the O2 dis sociati on curve w he n one-th ird of th e norma l hem oglobin is bound t o CO. Note that the curve is shift ed to the left .

"

th e 0 , combin ed with Hb will be only 13.5 ml . 100 ml - I Dissolved 0 , will contribute 0.3 ml, giving a to tal 0, concentration of 13.8 ml . 100 ml- ' of blood. In gene ral, th e oxygen concen tration of blood (in ml 0 , . 100 ml- ' blood ) is given by Sat ) ( 1.39 X Hb X 100

+ 0.003 Po ,

where Hb is th e hemoglobin concen tra tion in gm ' 100 rol- t , Sat is th e percen tage saturation of the hemoglobin , and POz is in mm Hg. T he curved shape of th e O 2 dissociat ion curve has several physiological advantages. The flat upper portion means th at even if the P Ol in alveolar gas falls somewha t, loading of 0 , will be little affected. In addition, as the red cell takes up 0 , along the pulmonary capillary (Figure 3-3), a large parrial pressure d ifference between alveolar gas and blood con tin ues to exist when most of th e O 2 has been tran sferred. As a result , the diffusion process is ha stene d. The steep lower part of the dissoc iat ion curve means that the peripheral tissues can withdraw large amounts of O 2 for only a small drop in capillary PO r This mainten an ce of blood POz assists the diffusion of O 2 into the tissue cells. Because reduced Hb is purple, a low arte rial O 2 saturation causes cyanosis . However, this is not a reliable sign of mild desatu rarion because its recogn ition depe nds on so many variables, such as lighting conditions and skin pigment ation . Because it is th e amoun t of reduced Hb th at is important , cyanosis is often marked when polycyth emia is presen t but is difficult to detect in ane mic pat ient s. T he O 2 dissociation curve is shifted to th e right, i.e.. the O 2 affinity of Hb is reduced, by an increase in H + concen tration, PCO l , temperature, and the con-

1 00 ~ 200 3~~o % Sat 100

o

Temp

Pa,

100 100

80 %

Sat 60

Pco, Pa, 100 7.6 100~ 7.2

40

0;';

S;t

7.4

20

a 20

40

60

80

, ~

pH p

a,

100

100

Po, {mm Hg)

Figure 6-3. Rig htward shift of th e O2 dissociati on curve by increase of H+, P~02' tem perat u re, an d 2,3-d ip ho sphog lycera te (DPG) .

-,

'•. ,I

•

f

cen tration of 2.3-d iphosphog lyceratc in the red cells (Figure 6-3 ). Opposite changes shi ft it to the left. Most of th e effect af Pcco ,. which is known as th e Bahr effect, ca n be attributed to its ac t ion o n H + co nc en tra t ion . A righ tward sh ift means more unload ing of O 2 at a given PO z in a tissue capillary. A simple way to remember these sh ifts is th at an exercising muscle is ad d, hypercarbic , and hot, and it benefits from increased unl oading of O 2 from its capillaries. The en viron ment of the Hb with in th e red cell also affects the O 2 d issociation curve. A n increase in 2.3-diphosphoglyce rate (DPG) . which is an end-product of red cell metabolism, shifts the curve to the righ t. A n increase in conce n tration of th is material occurs in ch ronic hypo xia, for example . at high alti tude or in the presence of chron ic lung disease. As a result, the unl oading of O 2 to peripheral rissues is assisted. By con rrast, stored blood in a blood ban k may be depleted of

Oxygen Dissociation Curve • Useful "anchor" points : POz 40, SOz 75% ; P02 100, SOz 97% • Curve is right-shifted by increases in temperat ure, Pcoz, H+, 2.3 DPG • Small addition of CO to blood causes a left shift

2,3-D PG, an d un load ing of 0 , is therefore impaired. A useful measure of the position of the d issociat ion curve is the

PO l

for 50% O 2 saturation. T h is is known as

th e Pso. 111C normal value for hu man blood is about 27 mm Hg. Carbon mon oxide interferes with the O 2 tr ansport functio n of bloo d by corn-

bining with Hb to form carboxyhemoglobin (COHb). CO has about 240 times th e affinity of O 2 for H b; th is means that CO will combine with the same amount of Hb as O 2 when th e CO partial pressure is 240 times lower. In fac t , the CO di s-

sociation curve is almost iden tical in shap e to the O 2 dissociation curve of Figure 6-3, except tha t the Fc o axis is greatl y comp ressed. For examp le, at a f'c o of 0. 16 mm Hg, 75% of the Hb is combined with CO as COHb. For this reason, small amounts of CO can tie up a large proportion of the Hb in the blood , thus makin g it unavailable for O 2 carriage. If th is happens, the H b concentration and P01 of blood may be normal, but its O 2 concen tration is grossly reduced. T he pre sence of :J~;; "-'~J!

COHbalso sh ifts th e 0 , dissociation curve to the left (Figure 6-2) , thus int erfering with the unl oading of 0 ,. T h is is an additiona l feature of the toxic ity of CO.

Carbon Dioxide CO2 Carriage CO 2 is carried in th e blood in t h ree forms : di ssolved , as bicarbonate, and in com-

bination with proteins as carbamino compounds (Figure 6-4 ). Dissol'ved COb like 0 21 obeys H enry's law, but CO2 is about 20 times more solub le th an Oz. As a result, dissolved CO 2 plays a sign ificant role in its carriage in 100%

'-7", 5

i.

30

90

HCO,

60

5 Dissolved 0% '---=---l Arte rial blood

10

Venous-arterial differe nce

Figure 6-4 . The first colum n shows t he p ropo rtions o f th e to t al CO 2 co nce ntrat ion in art erial blood . The seco nd column shows th e pro portions t hat ma ke up the ve no us-a rte ria l difference,

? CO2

Dissolved

?

Dissolved

~ . ~ "~,%

CO 2

CO 2 + H20 _

~

~ C. ~

(J

%

.j.

m 3

H2CO,

~ _

HCO,

H'J

HCO,

CINa"

~:-

"6

HHb

Hb-} Hb0 2

O2

O2

O2

~

O2 H2O

H2O Tissue

Plasma

Red blood cell

Fig ure 6 ~5 . Scheme of the uptake of CO 2 and liberation of O 2 in system ic ca pillar-es. Exactly opposite ev ents occur i n the pulmon ary capilla ries.

tha t abour 10% of rh e gas rhar is evolved into the lung from rhe blood is in the dissolved form (Figure 6-4). Bicarbonate is formed in blood by the follow ing sequence: CO , + H 20

CA

H, C0

3 ""

H+

+ HCO ,

The first reaction is very slow in plasma but fast with in the red blood cell because of the presence there of rh e enzyme carbonic anhydrase (CA). The seco nd reaction, ion ic dissociation of carbonic acid, is fast without an enzyme. When the co ncentration of these ions rises with in the red cell , HC0 3" diffuses out but H+ canno t easily do this because the cell membrane is relative ly impermeable to cations. Thus, to maintain electrical neutrality, CI- ions move into the ce ll from th e plasma, rhe so-called chloride shift (Figure 6-5). The movemenr of ch loride is in acco rdance with the G ibbs-Donnan equilibrium. Some of the H + ion s liberar ed are bound ro reduced h emoglobin;

H~,+ 0, -re C' Thi s occu rs because reduced Hb is less acid (that is, a bener proton acceptor} than rhe oxygenared form. Thus, rhe presen ce of reduced Hb in the peripheral blood help s with th e loading of CO " whi le rhe oxvgenation that occurs in the pulmonary capillary assists in rhe unloading. The fact th at deoxygenarion of rhe blood increases its abili ry ro carry CO 2 is kn own as rhe Haldane effect. Th ese events associa ted with the uptake of CO2 by blood increase the osmolar content of the red ce ll, and, consequently, water ente rs the cell, thus increasing its volume. When rhe cells pass through rhe lung, rhey sh rink a little. H + + HbO , "" H \ (J -t-

Carbamino compounds are formed by th e combination of CO 2 with terminal amine groups in blood proteins . The most important protein is th e globin of hemoglobin : H b ·NH, + CO, -.= Hb ·NH ·C O OH, giving carbamino hemog lobin . This reacti on occurs rapidly with out an en zyme, and reduced H b can bind more CO, as carbamino-hemoglobin tha n H bO , . Thus, again unloading of 0, in periphe ral capillaries facilitates th e loadin g of CO" while oxygenation has the oppos ite effect. T he relat ive con tributions of th e various forms of CO 2 in blood to the total ( CO 2 conc en tration are summarized in Figure 6;4 . Note th at th e great bulk of the CO 2 is in the form of bica rbona te. The amount dissolved is small, as is that in the form of carbamino- hemoglobin. However, these proporti on s do not reflect t he changes that take place when CO, is loaded or unloaded by the blood . Of the to tal veno us-arter ial d ifferen ce, abo ut 60% is attributable to HCO j , 30% to car; bamino compounds, and 10% to dissolved CO, .

CO2 Dissociation Curve

,

,.'

..

T he relat ionship between the Pco, an d the tota l CO, conc en tration of blood is shown in Figure 6;6. Note th at the CO2 dissociation curve is much more linea r than is the O 2 dissoc iation curve (Figure 6;1). Note also that the lower the sat uration of Hb with Oz , th e larger th e CO 2 concentra tion for a given Pc o , . As we have seen, this Haldane effect can be explaine d by th e bett er ab ility of reduced Hb to mop up th e H + ions produ ced when car bon ic acid dtssoc iares, and the greater faci lity of redu ced Hb to form carbamino -he moglobin. Figure 6~ 7 sho ws that the CO 2 dissociation cu rve is considerab ly steeper than th at for 0 , . For example, in the range of 40 to 50 mm Hg, the CO, conccn tra-

60

-I

40

.§ "§

c

1l

8

20

8 o

20

40

60

80

CO2 partial pressure (mm Hg) Figure 6-6. CO2 di ssociati on curves for blood o f different O2 sat uratio ns. Not e t hat oxygenate d blood carries less CO2 fo r t he sam e P C0 2' Th e inset shows t he " phv siological" curve between arterial and mixed ve nous bl ood.

83

Gas Transport by the Blood

60

a

.~

50

E ::=-

40

1l E co 0

"

0 ~

0 ":: =

CO2

30

o.s

20

o"

10

02

O
o

20

40

60

80

100

O2 and CO 2 partial pressure (mm Hg)

Figure 6·7. Typical O2 and CO2 dissoc iatio n curves plotted w ith t he same scales. l ate that th e

CO 2 curve is muc h steeper.

[ion changes by about 4.7 , compared with an 0 1 concentration of on ly about 1.7 mlllOO m!. This is why the Po , difference between art erial and mixed ve n ous blood is large (typically about 60 mm Hg) but the Peo , difference is small (about 5 mm Hg).

Carbon Dioxid e Dissociation Curve • CO2 carried as: dissolved, bicarbonate, carbamino • CO2 CUNe is steeper and more linear than the O 2 curve • CO2 curve is right-shifted by increases in S02

Acid-Base Status Th e transport of CO, has a profound effect on the acid-base status of the blood

and rhe body as a whole. The lung excret es over 10,000 mEq of carbon ic acid per day compared with less tha n 100 mEq of fixed acids by th e kidn ey. Therefore, bYJ -altering alveolar ventilation and thus the e limination of CO 2 , the body has great control overIt;;~ id~base balance . Th Ef siiDJed wll f be treated only briefly here because it overlaps th e area of ren al physiology. The pH resulting from the solut ion of CO , in blnod and the consequen t dissociation of carbonic acid is given by the Henderson-Hasselbalch equation. It is derived as follows. In the equation H,CO J

""

H+

+ HCO l

the law of the mass an ion gives the dissoc iation co nstant of carbon ic acid K,.:, as (W ) X (HCO l

(H,CO,)

)

Because the concentration of carbonic acid is proportional to the co ncentrati of disso lved carbon dioxide, we can change the constant and write (W) X (HCO l )

(CO, ) Taking logarithms log KA

= log (H+) + log

(HC O , ) (CO, )

whence

(HCO, )

. _

- log (H+) = - log KA

+ log (CO, )

,., ~

·,1,

-'":l

Because pH is the negative logarithm

(HCO,) pH = pKA

+ log (CO,)

Because CO, obeys Hen ry's law, th e CO, concent ration (in mmol/liter) can replaced by (Pc'Oz X 0.03 ). The equat ion the n becomes plI = pKA

+ log

(H CO,) 0.03 P , eo

The value of pKA is 6.1, and the norma l HCO , concentration in arte rial blood 24 rnmohlu er. Substituting give s pH

Therefore,

= 6.1 + log

24 0.03 X 40

= 6.1 + log 20 = 6.1 + 1.3 pH = 7.4

N ote that as lon g as the ratio of bicarbonate concentration to (Pa.::h X O.C~ remains equal to 20, the pH will remain at 7.4. The bicarbonate concenrrati

determined ch iefly by the kidney and the Pco, by the lung. The relationships bet ween plI, Pe o l . and HC0 3 are co nveniently shown a Davenpor t diagram (Figure 6-8) . T he two axes show HCO , and pl-l, and lin of equal P<"''Oz sweep across the diagram. N ormal plasma is represented by po int A .

The line CAB shows the relat ionsh ip between HCO , and pH as carbon ic acid is added to whole blood, that is, it is part of the titrat ion curve for blood and is called the buffer line . The slope of th is line is steeper than that measured in plasma separated from blood because of the presence of hemoglobin, which has an additional buffering action. The slope of the line measured on whole bloo d in ti rro b usually a littl e different from that found in a patient because of the buffering ac tion of the interstitial fluid and ot he r body tissues.

85

Gas Transport by the Blood

A 50

'2 0-

40

W

.s 1M

0

30

0 I

"'E

w ro

20

ii:

10

6.8

7.0

7 .2

7.4

7 .6

7.8

8 .0

pH units

B

.. •

60

I

I

40

'a. w

.s

30

1M

0 0 I

"'Ew

20

.!'l 0-

10

.

7.1

7.4 Acidosis

7.7 Alkalosis

• pH

Figure 6-8 . Davenport diagram showing the relationships among HCO"3, pH, and Peo2. A shows the norm al buffer line BAC. B shows t he changes occurring in respiratory and m etabolic acidosis and alkalosis (see text). The vertical distan ce betwee n buffer lines is the base excess.

If the plasma b icarbon at e conc ent ration is altered by th e kidney, the huffe line is d isplaced. A n increase in bicarbonate conce nt rat ion displaces th e buffe line upward as sho wn. for exa mple. by line DE in Figure 6~8 . In this case, the excess is increased and is given by the vert ical distance between the two butte lines DE and BAe. By cont rast, a reduced bicarbonate conce n tration displac the buffer line downward (line G F). and there is now a negative base excess,

base deficit. The ratio of bicarbonate to P= , can be d isturbed in four ways: both Peo, an bicarbonate can be raised or lowered. Each of t hese four distu rbances gives rise t a characteristic acid-base cha nge.

Respiratory Acidosis

-.

. ..... - -",l

,"

.J!

This is caused by an increase in Pe o l which reduces th e HC0 3"/P co z rat io and th us depresses the pH. This corresponds to a movemen t from A to B in Figure 6~ 8. Whenever the Pco- rises, th e bicarbonate must also increase to some exrent because of dissociatio n of th e carbon ic acid produ ced. This is reflected by rh left up ward slope of the blood buffer line in Figur e 6-8 . However. rh ratio HC0 1 /Peo z falls. CO 2 rete n tion can be caused by h vpovenril ar ion ven tilation- perfusion inequality. If respiratory acidosis persists. the kidney responds by conserving HCO l . It is prompted to do th is by th e increased Peo, in the renal tubular cells, which the excrete a more acid urine by secreting H + ions. The H + ions are excreted H zP0 4" or N H~; th e HCO l ions are reabso rbed. The result in g in cre ase in plasma HCO , then moves the HCO , /Pc o , rat io bac k up toward its norma level. T h is corresponds to t he movement from B to D along the line Pco. = 6C mm Hg in Figure 6~8 and is known as compensated respirawry acidosis. T vpical eve n ts would be

24

+ log 0.03 x 40

~

6.1 + log 20

28 pl-l ~ 6.1 + log 0.03 x 60

~

6.1

pH = 6.1

33

pH = 6.1

+ log 0.03

X

60 ~ 6.1

= 7.4

(N ormal

+ log 15.6 = 7.29 (R espiratory acidosis

+ log 18.3 = 7.36 (Compensated respiratory acidosis

The renal compensation is typically not complete. and so the pH doe s not full return to its normal level of 7.4. The extent of the renal compensation can be determined from the base excess. th at is, the vert ical distance between the butter lines IlA and DE.

Respiratory Alkalosis T h is is caused by a decrease in Pe o z• wh ich increases th e HCO l /Pc'Oz rat io and th us elevates the pH (movemen t from A to C in Figure 6~ 8) . A decrease in Po:>: is ca used by h yperven tilation, for example, at h igh altitude (see C h apter 9). Re-

n al compensation occurs by an incr eased excretion of bicarbonate, th us returning the HCO j /P co , rati o back toward normal (C to F along th e line Pco, = 20 mm Hg) . A fter a prolonged stay at high alti tude, the renal compensation may be nearly complete . There is a negative base exce ss, or a base defici t.

Metabolic Acidosis In th is con text, "metabolic" means a primary change in HCO ~, that is, th e numerator of th e Hend erson -H asselba lch equation . In metabolic acidosis, th e ratio of HCO j to Pco , falls, th us depressing th e pH. The HCO j may be lowered by the accumulation of acid s in th e blood , as in uncon trolled diabetes mellitus. or after tissue h ypoxia, wh ich releases lactic ac id. The correspond ing ch ange in Figure 6-8 is a movement from A toward G. In thi s instance, respirato ry compensation occ urs by an increase in ven tilation that lowers th e Peo l and raises th e depressed HCO j /Pe GI rat io. The stimulus to raise the ventilat ion is ch iefly the action of H + ions on th e peripheral chemorecepto r> (Chap ter 8). In Figure 6-8, th e point moves in th e direct ion G to F (altho ugh not as far as F). T here is a base deficit or negative base excess.

M et abo lic Alkalosis Here an increase in H CO j raises th e HCO"J/PCU I rat io and , thus, the pH . Excessive ingestion of alkalis an d loss of acid gastr ic secret ion by vomit ing are ca uses. In Figure 6 ~8 , t he movement is in th e direction A to E. Some respirator y compensation sometimes occurs by a reduction in alveolar vent ilation th at raises the Peo ,. Poi nt E then moves in th e direction of D (altho ugh not all th e way). However. respiratory compen sation in met abolic alkalosis is often small and may be absen t. Base excess is increased. Note th at mixed respirato ry an d metabol ic distur bances often occur, and it may the n be difficult to un ravel the sequence of eve n ts.

Four Types of Acid-Base Disturbances

HCO, pH = pK + log 0.03 Peo, Primary

Compensation

Acidosis Respiratory M eta bolic

Peo" HCO, 1

HCO" Peo, 1

Alkalosis Respiratory Metabolic

J.

Pco, 1

HCO,

HCO"

oft en none

Blood-Tissue Gas Exchange 0 , and CO, move between the syste mic ca pillary blood and the tissue cells by simple d iffusion , just as th ey move bet ween the capillary blood and alveolar gas in the lung. We saw in C hap ter 3 that the rate of transfer of gas th rough a tissue sh ee t is pro port ional to th e tissue are a and th e difference in gas part ial pressure between the two sides, and inversely proport iona l to the th ickness. The thickness of the blood -gas barrier is less than 0.5 p.rn, but th e distance between open capillaries in resting muscle is on the order of 50 u rn. During exercise, when the O 2 consumption of the muscle increases, add itional capillaries open up. th us reduc ing the d iffusion d istance and increasing the area for diffusion . Because CO2 d iffuses about 20 time s faster th an 0 , thro ugh tissue (Figure 3- 1), elimination of CO, is much less of a problem than is 0, delivery. The way in which the PO z falls in tissue between adjacent open capillaries is shown sche matically in Figure 6-9. As the 0, diffuses away from the capillary, it is consumed by tissue, and the Paz falls. In A , the balance between O 2 consumption and delivery (determined by th e capillary Po, and the int ercapillary dist ance) results in an adequ ate PO z in all the tissue. In B. th e int ercapillary distance or the O 2 consumption has been increased until the PO z at one point in th e tissue falls to zero. This is referred to as a critical situat ion . In C , there is an an oxic region where aerob ic (that is, O 2 utilizing) metabolism is impossible. U nder th ese conditions, the tissue turn s to anaerobic glycolysis with the formation of lactic acid. There is evidence tha t much of the fall of POz in periphera l tissues occurs in the immediate vicin ity of th e capillary wall and that the POz in muscle cells, for example, is very low (1 to 3 rom Hg) and nearly un iform . This pat tern can be explain ed by th e presence of myoglobin in the cell that acts as a reservoir for O 2 and enhances its d iffusion with in th e cell. How low can the tissue POz fall before O 2 utilization ceases? In measurement s on suspensions of liver mitochondria in virro, O 2 consumpt ion continues at the same rate until the Po z falls to th e region of 3 mm Hg. T hus, it appears tha t the purpose of the much higher POl in capillary blood is to en sure an adequat e pres ~ sure for diffusion of Oj to the mitochondria and that at th e sites of O 2 utili zati on th e Po, may be very low. Cap Tissue Cap

J l ~luru A

B

c

Figure 6-9. Sche me showing th e f all of P02 betw een adj acent ope n cap illa ries. In A, o xy gen delivery is ad equate; in B, criti cal; and in C, inadequ ate for aero bic m eta bo lism in the cent ral co re of tissue.

A n abnormall y low P O l in ti ssues is ca lled t issue hyp ox ia. T h is is freq uen tly caused by low Oz delivery, which can be expressed as the cardiac outpu t multiplied by the arterial Oa con cen trat ion, or QX Caoz. The factors th at det ermine C ao , were discussed on page 65. Tissue hypoxia ca n be du e to (l) a low P Ol in arrerial blood caused, for examp le, by pulmonar y disease ("hypoxic hypox ia"); (2) a reduced ab ility of blood to carry O 2 as in an em ia or carbon mo noxide poiso ning ("anemic h ypoxia") ; or (3) a reduct ion in t issue blood flow, either generalized, as in sh ock, or because of local obstru ction ("circulatory hypoxia"). A fourth cause is some to xic substa nce tha t in terferes with the ability of the ti ssues to utilize available O 2 ("h isto toxic hy pox ia"). A n example is cyanide, wh ich prev en ts the use of O 2 by cytochrome ox idase. In thi s case, th e O 2 conce ntr at ion of venous blood is high , an d the O 2 consumption of the ti ssue extremely low because these are related by the Fick princi ple as app lied to perip heral O 2 consu mpt ion. Table 6 ~ 1 summar izes some of th e features of th e differen t types of hypoxemia and ti s, sue h ypox ia.

Table G . Features of Different Types of Hypoxemia or Tissue Hypoxia " a1

PA02

Lungs Hypoventilation Diffu sion impairment Shunt 'it,,;o inequality

PAco2

Pao2

Paco2

I

1

1

0 0 Varies

0 0 l or 0

0 0 l or 0

Blood Anemia CO poisoning

0 0

0 0

0 0

0 0

Tissue Cyanide poisoning

0

0

0

0

"'0, normal; l lncreasect l dec reased . "Of some (but lim ited) value because of increased disso lved oxyge n "lt 0 2 saturat ion is calculated for hemoglobin not bound to CO.

Caoz

5 a02

PV02

C'il° 2

O2 Admin istrati on Help ful 7

Yes Yes YesYes

YesYes-

0 0"

0

0

1

No

QUESTIONS For each quest ion, choose t he one bes t answe r.

1. The p resence of hem oglobin in normal arterial bloo d increases its oxygen conc entration approximately how many t imes?

A. 10 B. 30 C. 50 D. 70 E. 90 2. An incre ase in w hic h of th e f ollow ing increase s t he 0, affi nity of hem o glo b in ? A. Tem perature .

B.

PCO, .

C.

H + con cent rat ion . .l

D. 2,3 DPG. 3.

E. Carbo n m onoxide added to t he blo od . A patient w it h carbon monox ide po isonin g is tre ated w it h hyperbar ic oxyg en that inc reases t he arterial Po, to 2,000 m m Hg . The amount of oxygen dissolved in the arter ial blood (in m l . 100 rnt" ) is: A. 2

B. C. D. E. 4.

5.

6.

3 4 5 6

A pat ient with sever e anemia has normal lungs. Wh ich of t he fo llowing is mo st likel y to be FALSE ? A. Normal arterial Po 2 .

B.

Normal arterial O2 saturation.

C.

Low arte rial O2 conce ntration.

D. E.

Low oxygen concentration of mixed venous blood. Normal tissue Po2 .

Al l of the follow ing sta tements are t rue about acut e carbo n monoxide poiso ning EXCEPT: A. Reduced arterial Po, . B. Red uced oxygen concen trat ion of arterial blood. C. Redu ced oxy gen conce ntration of m ixed venous blood. D. 0 , di ssociation curve is shifted to the left. E. Carbo n mono xide is colorless and odor less . The laboratory repo rt s th e f ollowing arterial blood gas value s in a pat ient w it h severe lun g disease w ho is breath ing air: Po, 60 mm Hg, Peo, 110 mm Hg, pH 7.20 . All of t he f ollowi ng sta tement s are true EXCEPT: A. Pat ient has hyp o xemia. B. Patient has seve re CO 2 rete nt ion. C. There is a res piratory acido sis . D. Th e res piratory acido sis is part ially com pensate d. E. The value s for P0 2 and Peo2 are internally consist ent.

7. Most of the carbon dioxide t ransported in t he blood is in the fo rm of: A. Dissolved. B.

Bicarbonate .

C.

Attach ed to hemoglobin.

D.

As carbami no compounds .

E.

Carbonic acid.

8 . A patient w ith chronic lung disease has arterial P0 2 and Peo2 values of 50 and 60 mm Hq, respect ively, and a pH of 7.35. How is his acid-base status best described? A. Norma l. B.

Partially compensated respiratory alkalosis.

C. Partially compensated respiratory acidosis. D.

M etab olic acidosis.

E.

M etabolic alkalosis.

9 . The P0 2 (in mm Hg) inside ske leta l m uscle ce lls during exercise is closest to:

A. B. C. D. E.

3 10 20 30

40

10. A patie nt wi th chronic pulmon ary disea se unde rgoes e me rgency surgery .

Postoperatively t he arterial Po,. Pea, and pH are 50 mm Hq. 50 mm Hg and 7.20. respect ively. How would the acid-base status be best described ? A. Mixed respiratory and metabolic acidosis. B.

U ncomp en sated resp iratory acidosis.

C.

Fully compensated respiratory acidosis.

D.

Uncompensated meta bolic acidosis.

E. Fully compensated metabolic acidosis. 11. The laboratory provides th e fo llow ing report on arterial blood from a patient: Pea, 32 mm Hg, pH 7.25. HCO- 3 conce ntration 25 mmol . 1- 1 . You conclud e t hat t here is:

A. Respiratory alkalosis w ith metabolic com pensation. B.

Acute respiratory acidosis.

C.

Metabolic acidosis wi th respiratory compe nsat ion.

D.

Metabolic alkalosis w ith respiratory com pe nsation.

E.

A laboratory error.

12 . A pat ient with shortness of breath is breath ing air at sea level and an arte rial

blood sample shows Po, 90 mm Hq. Pco, 32 mm Hg, pH 7.30. Assumin g that the resp iratory ex change ratio is 0 .8 . the se data indicate:

A.

Primary respiratory alkalosis wi th m et abolic compensation.

B.

Norm al alveo lar-arter ial P0 2 diffe rence .

< 70 % .

C.

Arte rial O 2 saturat ion

D.

T he sample w as m istake nly taken from a ve in.

E.

Partially com pensated m etabolic acidosis.

....

Mechanics of Breathing How the Lung Is Supported and Moved ,. scles of Respirat ion nspiratio n Expiration

sti c Properties of the Lung

Mea surem ent of Airway Resistance Pressures during t he Breathing

Cycle

Pressure-Volume Curve

Chief Site of Airway Resistan ce

Com pliance

Factors Det ermin ing Airway Resist ance

Surfa ce Tension

ses of Regi onal Differences

Ventilation Airw ay Closu re

stic Propert ies of the Chest all ay Res ist ance Airfl ow throug h Tubes

Dynamic Comp ression of Airways

Causes of Uneven Ventilation Tissue Resistance Work of Breathing W ork Do ne on the l ung

Total Wor k of Breathin g

Ve saw in Chapter 2 that gas gets to and from the alveoli by the process of ven.etion. We now tum to the forces that move the lung and chest wall, and the resistsnces thattheyovercome. Firstwe consider the muscles of respiration, both inspiration and expiration. Then we look at the factors determining the e astic properties of the lung including the tissueelements and the air-liquid surface tension. Next we examine the mechanism of regionaldifferences in entiletion andalso the closure of small airways. Just as the lung is elastic sois -'e chest wall and we look at the interaction between the two. The physical

principles of airway resistance are then considered along with its measurement, chief site in the lung, and physiological factors that affect it. Dynamic compression of the airways during a forced expiration is analyzed. Finallythe work required to move the lung and chest wall is considered.

Muscles of Respiration Inspiration

.1

~; ,.Ii

T he most important muscle of inspiration is th e diaphragm . This consists of a th t do me-shaped sheet of muscle th at is insert ed int o the lower ribs. It is suppli ed the ph renic ne rves from cerv ical segments 3, 4, and 5. W hen it cont racts, the a' dom ina I cont en ts arc forced down ward and forward . and the vert ical dimensi of th e ch est cavity is increased. In addit ion , th e rib margins are lifted and m o v out, causing an increase in the transverse diamet er of th e tho rax (Figure 7 ~ 1). In normal tidal breath ing, the level of the d iaphragm moves about 1 em or ~ hut on forced inspiration and expiration , a tota l excursion of up to 10 cm may Cuf. W hen the d iaphra gm is paralyzed, it moves up rather than down with in-p ration because th e in trath oracic pressure falls. T h is is kn own as parado.\ical mot ment an d can be de monstrated a t fluoroscopy when th e subject sn iffs. The external imercostal muscles connect adjacent ribs and slope downward a forward (Figure 7-2) . When th ey contract, th e rihs are pulled upward and forwar causing an increase in both the lateral and ante roposte rior diameters of th e rh rax, T he lateral d imension increases because of th e "bucker-hand le" movemen of the ribs. The in tercostal muscles are supplied by in tercostal nerves th at co off the spinal cord at the same level. Paralysis of th e in tercostal muscles alon does not seriously affect breath ing because th e diaphragm is so effective.

r-

+1 .: ...,

Diaphragm

Inspiration

EXP~~ -~ Abdominal muscles ~ Active

- - - - .... Passive Figur e 7-1. On insp ir ati on , t he dom e-shaped diaph ragm co ntracts . the abdomina

conte nts are fo rced down and forward, and t he rib cage is wid ened . Bot h increase th e vo lume of t he tho rax. On forced expi ration, the abdomi nal m uscles con tract: and pu sh the dia phr agm up.

Intercostal muscles Spine

Axis of rotation Figu re 7 -2. Wh en th e ext ernal intercostal mu scles co ntract. th e rib s are pulled upw ard and forwa rd, and they rot ate o n an ax is j oining the tubercle and head of rib. As a result , bot h th e lateral an d ante ro po ster ior diam eters of the tho rax increase. The in te rn al int ercostals have the opposite actio n.

T he accessory muscles of inspiration includ e the scalene muscles whic h elevat e the first two ribs, and the srcm ornastoids whic h raise th e sternum. T here is lit tle, if any, act ivity in the se muscles d uring quiet breathing, but during exercise they may contract vigoro usly. O ther muscles that play a minor role include th e alae nasi, which cause flarin g of th e nostrils, and small muscles in the neck and head.

Expirat io n Th is is passive during quiet breathing. The lung and chest wall are elastic and tend to return to their equilibrium posit ions after being actively expanded Ju ring inspiration . During exercise an d volunta ry h yperventilat ion , expiration becomes active. The most important muscles of expirat ion are th ose of the abdominal wall, including the rect us abdomi nis, internal and externa l ob liq ue muscles, and transversus abdom inis. When these muscles contract, intra-abdominal pressure is raised, and the diaphra gm is pushed upward. These muscles also con tract forcefully Juring coughing, vomiting, and defecation. The internal intercostalmuscles assist active expiration by pulling the ribs downward and inward (opposite to the action of th e externa l int ercostal muscles), th us decreasing th e tho racic volume. In addition , they stiffen th e inte rcostal spaces to preven t th em from bulging outward during st rain ing. Experimental studies show tha t the actions of the respiratory muscles, especially the intercostals, are more complicated tha n th is brief account suggests.

Respirat o ry Muscles • Inspiration is active; expiration is passive during rest • Diaphragm is the most importa nt muscle of inspiration; it is supplied by phrenic nerves wh ich originate high in the cervical region • Other muscles include the int ercostals. abdomina! muscles, and accessory muscles

Elastic Properties of the Lung Pressure-Volume Curve Suppose we take an exc ised animal lung, cannulat e the tra chea, and place it inside a jar (Figure 7-3 ). When rhe pressure with in the jar is reduced below atmospheric pressure, th e lung expands and its cha nge in volume can be measured with a spirometer. T he pressure is hel d at each level, as indicated by the points, for a few seconds to allow the lung to come to rest. In thi s way, th e pressure-volume curve of the lung can be plotted. In Figure 7-3 , th e exp and ing pressure around the lung is generated by a pump, but in hum ans it is developed by an increase in volume of th e chest cage. T he fact that the intrapleural space between the lung and chest wall is much smaller than the space between the lung and the bottle in Figure 7 ~3 makes no essential difference. The intrapleural space contains only a few millili ters of fluid. Figure 7-3 shows that the curves which th e lung follows during inflation and deflation are d ifferen t. This behav ior is known as!ysteresis. No te th at th e lung IS: volume at any given pressure during deflat ion is larger tha n during inflation. Note (i; also that the lung without an y expanding pressure has some air inside it. In fact , even if the pressure around th e lung is raised above at mosphe ric pressure, little further air is lost because small airways close, tr apping gas in (he alveoli (compare Figure 7-9). This airu.!ay closure occ urs at higher lung volum es with increasing age and also in some types of lung disease. In Figure 7 ~3 the pressure inside the airways and alveoli of the lung is the same as atmospheric pressure, which is zero on th e horizontal axis. Thus, this axis also measures the differenc e in pressure between the inside and outside of the lung. This is kno wn as transpulmonary pressure and is numerically equal to the pressure

Volume (I) 1.0

Volume

Pump --+

Pressure

o

- 10

- 20

- 30

Pressure around lung (cm water) Figure 7-3. Measu reme nt of the pr essur e-vo lume curve of exci sed lung. The lung is held at each pressure fo r a few seconds w hile it s vo lume is mea su red . The curve is nonl inear an d becomes flatter at high ex pa nd ing pr essur es. Note that th e inflation and deflatio n curves are no t the same; thi s is called hy ster esis.

around th e lung when the alveolar pressure is atmospheric. It is also possible to measure the pressure-volume relationship of the lung shown in Figure 7-3 hy int1ating it with positive pressure and leaving the pleural surface exposed to the atmosphe re. In th is case, the horizon tal axis could be labeled "airway pressure," and the values would be positive. The curves would he identical to th ose shown in

Figure 7-3.

Com pliance The slope of the pressure-vo lume curve, or the volume change per unit pressure change, is known as th e compliance. In the nor mal range (expanding pressure of about - 5 to - 10 em water) the lung is rernarka hlv distensible or very complian t. The complian ce of.the h uman lung is abou t 200 mi · em water-i . However, at high expa ndi ng pressures, the lung is stiffer, and its compliance is smaller, as shown by the flatter slope of th e curve. A reduced compli ance is caused byan inc rease of fibrous tissue in th e lung (pul monary fibrosis). In addition, complianc e is reduced by alveolar edema \v-hich prevents the inflation of some alveoli. Compliance also falls if the lung remains unven tilated for a long period, especia lly if its volume is low. This may be partly caused by atelec tasis (collapse) of some un its, but increases in surface tension also occur (see below ). Compliance is also reduced somewha t if the pulmonary venous pressure is incr eased and the lung becomes engorged with blood . A n increased compliance occurs in pulmonar y emphysema and in the normal aging lung. In bot h instances, an alteratio n in the clastic tissue in the lung is probably responsible. Increased complian ce also occurs dur ing an asthma attack, hut th e reason is unclear. The compliance of lung depends on its size. C learly, the change in volume per unit cha nge of pressure will be larger for a human lung than, sayt a mouse lung. For thi s reason , th e complia nce per unit volume ofl ung, or specific compliance, is sometimes measured if we wish to draw conclusions about the in trinsic elastic properties of th e lun g tissue. The pressure surrounding th e lung is less tha n at mospheric in Figure 7;3 (and in the living chest) because of th e elastic recoil of the lung. W hat is responsible for the lung's elastic behavior, that is, its tendency to return to its resting volume an er distension ?One factor is the elastic tissue whic h is visible in histological sections. Fibers of elastin and collagen ca n be seen in th e alveolar walls and around vessels and bronch i. Probably th e clastic behav ior of th e lung has less to do with simple elongation of th ese fibers th an it does with th eir geometr ical arrangemen t. An ana logy is a nylon stoc king which is very distensible becau se of its knitted make-up, although the indi vidual nylon fibers arc very difficult to stretch . The changes in elastic recoil th at occ ur in the lung with age and in emphysema are presumably caused by cha nges in this clastic tissue.

Surf ace Tension Another importan t factor in the pressure-vo lume behavior of lung is the surface tension of the liquid film lin ing the alveoli. Surface tension is th e force (in dynes, c r example) acting across an imaginary line I -ern long in rhe surface of the liq-

Pressure-Volume Curve of the Lung • • • •

.-"

Nonlinear with the lung becomin g stiffer at high volum es Shows hysteresis betw een inflation and defl ation Complia nce is t he slop e J.V/J.P Behavior depends on both structural proteins (collagen, elastin) and surface tension

uid (Figure 7~4A ) . It ari ses be cause the att rac tive forces bet ween adja ce n t molecules of the liqu id are much stronger th an th ose between the liquid and gas, with the result th at the liquid surface area becomes as small as possible. This behavior is seen clearly in a soap bubble blown on the end of a tube (Ftgure 7-4B). The surfaces of the bubble con trac t as much as th ey can, forming a sphere (smallest surface area for a given volume ) and generating a pressure th at can be pred icted from Laplace's law: pressure = (4 X surface tension )/radius. Whe n onl y one surface is involved in a liquid-lined spherical alveolus, the n umerato r has th e numb er 2 rather than 4. The first evidence th at surface tension might contribute to the pressurevolume beh avior of the lun g was obta ined by ea rly ph ysiologists when they showed th at lungs inflat ed with saline h ave a much larger complianc e (are easier to distend) than air-filled lungs (Figure 7-5). Because th e saline abolished th e surface ten sion forces but presumably did not affect th e tissue forces of th e lung, this observation meant th at surface tension contributed a large part of th e static recoil force of the lung. Some time later, workers studying edema foam co ming from the lungs of an imals exposed to noxious gases not iced that th e tiny air bubbles of the foam were extremely sta ble. T hey recogni zed th at thi s ind icated a very 10\'L surface tension , an observation whic h led to th e remarkable discovery of pulmonary surfactant.

1 em

->-,,

,+, ,,

, • ,

i/ /:/ III

7,

T );: ,

~_. ~

--J,

.....t.: ?\

~

Soap bubble

A

B

C

Figure 7-4. A. Su rface t ension is th e fo rce (in dynes, f o r exa m ple) act ing acros s an imag in ary line 1 em lon g in a li quid surface . B. Surface fo rces in a soap bubble

tend to reduce the area of th e surface and gene rate a pres sure w ithin the bu bbl e. C. Because the sm all er bu bbl e ge nerates a larger pressu re, it bl ows up the larger bu bb le.

Saline inflation 200

150

'[ E '" .2

100

0

> 50

0 0 Pressure (em water)

Figure 7-5. Compa rison of press ure-vo lu me curves of air-filled and safine-fllled lungs (cat) . Op en ci rcles, inf lation; closed circles, def lation . Note that the salinefilled lung has a higher compliance and also much less hy steresis than the air filled lung.

It is now known th at some of th e cells lin ing the alveoli secrete a materi al that profound ly lowers th e surface tension of th e alveolar lining fluid. Surfactant is a phospholipid, and dipa lmitoyl phosphat idylcholin e (OPPC ) is an important constituent. A lveolar epit he lial cells are of two types. T ype I cells have th e shape of a fried egg with long cytoplasmic extensions spreading out thinly over th e alveolar walls (Figure 1-1). T ype II cells are more compact (Figure 7-6), and electron microscopy sho ws lamel lated bodies within them that are extruded into th e alveoli an d transform into surfactant. Some of m e surfacta nt can be washed out of an imallungs by rinsing them with saline. The phospholipid OPPC is synthesized in th e lung from fatt y acids th at at e either extract ed from the blood or are themselves synt hesized in th e lung. Synt hesis is fast, and th ere is a rapid turnover of surfact ant. If the blood flow to a region of lung is abolished as th e result of an em bolus, for example , th e surfactant there may be depleted. Surfactant is formed relati vely late in fet al life, and babies born without adequate amounts develop respiratory d istress and may die. The effects of this material on surface ten sion can be studied with a surface balance (Figure 7·7) . This consists of a tray containing saline on which a small amount of test material is placed . The area of the surface is th en alternately expanded and compressed by a movable barrier while rhe surface ten sion is measured from th e force exerted on a platinum strip. Pure saline gives a surface ten sion of about 70 dynes/em, regardless of th e area of its surface. Adding detergent reduces th e surface ten sion, but again this is independ ent of area. Wh en lung washings are placed on th e saline, the curve shown in Figure 7-7B is obtained. No te th at the surface ten sion changes greatl y with th e surface area and m at ther e

Figure 7-6. Electron micrograph of ty pe \I epit helial cell (x 10,OOO). Note th e lam ellated bodies (LB), large nu cl eus, and mi crovilli (arrows). The in set at top right is a scanni ng electro n m icro grap h showing the surf ace view of a typ e II cell wi th its characteristic dist rib utio n of mi crovi lli (x3400).

is hysteresis (compa re Figure 7~3 ) . Note also th at the surface ten sion falls to ex, tremclv low values whe n th e area is small. How does surfactant reduce the surface te nsion so much ? A pparen tly the molecules of DPPC are h ydrophobic at one end and h ydroph ilic at the ot her, and th ey align themselves in the surface. W he n thi s occurs, the ir in ter molecular re, pulsive forces oppose the normal attracting forces between th e liquid surface molecules that are responsible for surface tension . The reduct ion in surface ten , sion is grea ter whe n the film is compressed because the molecules of DPPC are the n crowded closer together and repel each ot her more. What arc the physiolog ical advan tages of surfacta n t? First, a low surface ten, sion in th e alveoli increases the compliance of the lung and reduces the work of expa nding it with each breath. Next, stability of the alveoli is pro mote d. TIle 300 million alveoli appear to be inh erentl y unsta ble beca use areas of atelectasis (co llapse) often form in the presen ce of d isease. This is a comp lex subject, but one wav of looking at the lun g is to regard it as a collection of millions of tiny bubbles (alt ho ugh th is is clear ly an oversimplification) . In such an arrangement , the re is

Force transducer

100

-

''""

.IT

i"

'"

.z '"

'I

50

Water 11

II

I'i

t~

1;j

m

?if

I

i

11 Detergent

a:

a

25

50

75

Surface tension (dynes/ em)

A

B

Figure 7-7. A. Surface ba lan ce. The ar ea of th e surf ace is alter ed, and the surface te nsion is measu red from th e f or ce exe rte d on a plat inum strip dip ped into th e surf ace. B. Plots of surface t ensio n and area obtained with a surfa ce balance. Note that lu ng wash ing s show a change in surface tens ion w ith area and t hat th e minim al ten sion is ve ry smal l. The axe s are chosen t o allow a com paris on w ith the pressure-volu me cur ve of th e lung (Fig ures 7 ~ 3 and 7-5).

a ten dency for small bubb les to collapse and blow up large ones. Figure 7-4C shows th at the pressure generated by the surface forces in a bubble is in versely proportional to its radius, with the result that if the surface tensions arc the same, the pressure inside a small bubble exceeds th at in a large bubble. However, Figure 7 ~ 7 sho ws that whe n lun g washings are present, a small surface area is associated with a small surface tension. Thus, the ten dency for small alveoli to empty into large alveoli is apparentl y reduced . ">, ; A thi rd role of surfac tant is to help to keep th e alveoli dry. Just as th e surface ten sion forces tend to co llapse alveo li, th ey also ten d tiJsu~k fluid into the alveo lar spaces from the cap illaries. In effect , th e surface tension of th e curved alveo lar surface reduces th e h ydrostatic pressure in thc t issue outside th e capillari es. By reduc ing th ese surface forces, surfactan t prevents the tr an sudation of fluid . W ha t are the consequen ces of loss of surfactant? On the basis of its func tions discussed above , we would expect these to be stiff lungs (low compliance), areas of ate lectasis, and alveoli filled with transudat e. Indeed, these are the pat hophysiological feat ures of th e "infant respiratory distress syndrome,' and thi s disease is caused by an absence of th is cruci al material. It is now possible to treat the se tnfants by instilling syn thes ized surfactant int o th e lung. Pulmo nary Surfactant • • • •

Reduces the surface tension of the alveolar lining layer Produced by type II alveolar epithelial cells Contains dipalmitoyl phosphatidylcholine Absence results in reduced lung compliance, alveolar atelectasis, and tendency to pulmonary edema

There is another mechan ism tha t apparen tly con tributes to the stab ility of the alveoli in th e lung. Figures 1-2, 1-7, an d 4-3 remind us that all the alveoli (excep t those immed iately adjacent to th e pleural surface) are surrounded by other alveoli and are the refore supported by each other. In a structure such as this with many connecting links, any tend ency for one group of un its to reduce or increase its volume relat ive [0 the rest of th e structure is opposed. For example, if a group of alveoli has a tendency to collapse, large expanding forces will be developed on them beca use the surroundi ng parenchyma is expanded. This support offered to lung uni ts by those surroundi ng them is ter med "inte rdependence." The same factors explain the developmen t of low pressures around large blood vessels and airways as the lung expands (Figure 4-2) .

Cause of Regional Differences in Ventilat io n \Y,fe saw in Figure 2-7 th at the lower regions of the lung ventilate more tha n do the upper zones, and this is a convenient place to discuss th e cause of these topographical differences. It has been sho wn that the in trapleural pressure is less negative at the bottom rhan th e top of the lung (Figure 7-8). The reason for thi s is the weight of th e lung. A n yth ing th at is supported requ ires a larger pressure below it th an above it to balance the down ward-acti ng weigh t forces, and the lung, which is partly supported by the rib cage and d iaph ragm, is no exception. T h us, th e pressure near th e base is higher (less negative) th an at the apex.

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Intrapleural pressure (ern H20) Figure 7-8. Exp lanatio n of the regio nal di fferences of ve nt ilat io n down t he lu ng . Becau se of t he w eight of t he lung, t he intr apl eu ral pressu re is less nega t ive at t he base t han at the apex. A s a co nseq uence , t he basal lun g is relativ ely co mpressed in its rest in g st ate b ut exp and s m or e o n in sp ir ation t ha n t he ap ex.

Figure 7~8 sho ws th e way in which th e volume of a portion of lung (for example, a lobe ) expands as th e pressure around it is dec reased (compare Figure 7-1) . The pressure inside th e lung is th e same as atmospheric pressure. Not e th at the lun g is easier to inflate at low volumes than at h igh volumes, where it beco mes stiffer. Because the expanding pressure at th e base of th e lung is small, this region has a small resting volume. However, because it is situated on a stee p part of the pressurevolume curve, it expands well on inspirat ion . By con trast, the apex of th e lung has a large expanding pressure, a big resting volume, and small cha nge in volu me in inspirat ion . * No w when we talk of regional differenc es in ven tilation , we mea n the change in volume per unit resti ng volume. It is cle ar from Figure 7-8 tha t the base of the lung h as bot h a larger ch ange in volume and smaller rest ing volume th an the apex. Thus, its ven t ilat ion is grea ter. N ot e the paradox that , alth ough the base of the lung is relati vel y poorly expa nde d compared with the ape x, it is better ve nt ilated . The same explan ati on ca n be given for thc large ventila tion of depend ent lung in both the supine an d latera l positions. A remarkable change in the distribution of ventilation occurs at low lung volumes. Figure 7-9 is similar to Figure 7· 8 except tha t it represents the situa t ion at

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Figure 7-9 . Situa tion at ve ry lo w lu ng v o lu m es. Now i nt ra ple u ral pres sur es ar e less n eg ati v e, and t he pr essure at t h e base actu ally exceeds ai rway (at m o sph eric) pressu re. A s a co nse q u enc e, air w ay cl o su re occu rs in t his reg ion, an d n o gas en te rs w it h small i ns p irations .

* Th is ex p lana tion is an over simp lificat ion because th e pressure-v olume behavior of a portion of a structure like th e lung may not be ide ntical to th at of th e whole o rgan.

residual volume (that is, after a full expiration , see Figure 2-2). Now the intrapleural pressures arc less negat ive beca use th e lun g is not so we ll expanded and the elastic recoil forces are smaller. However, the d ifferences bet ween apex and base are still presen t because of the weight of the lung. Note th at the intrapleural pressure at the base now ac tua lly exceeds airway (at mospheric) pressure. U nder these conditions, the lung at the base is not being expanded but compressed , and vent ilation is impossible until the local intrapleural pressure falls below atm osphe ric pressure. By contrast, the apex of the lung is on a favorable part of the pressure-volume curve and ventilates well. Thus, the normal distr ibut ion of ventilation is inverted , the upper regions ven tilating better than th e lower zones.

Airway Closure The compressed region of lung at the base does not ha ve all its gas squeezed out. In practic e, small airways, probably in the region of respiratory bronc h ioles (Figure 1~4 ), close first, thus trapping gas in the distal alveoli. This airway closure occurs only at very low lung volumes in young normal subjects. However, in elderly apparen tly normal people, airway closure in the lowermost regions of th e lung oc curs at h igher volumes and may be presen t at functiona l residual capacity (Figure 2 ~ 2) . The reason for th is is that the aging lung loses some of its elastic recoil, and int rapleural pressures therefore become less negative, th us approach ing the situation sho wn in Figure 7~9 . In these circumstances, dependent (rhar is, lowermost) regions of the lung may be only in termittently ven tilated, and this leads to defect ive gas exchange (C ha pte r 5 ). A similar situation frequently develops in patien ts with so me types of ch ronic lung d isease.

Elastic Properties of the Chest Wall Just as th e lung is elastic, so is the thoracic cage. This can be illustrated by putt ing air into the int rapleural space (pne umot ho rax) . Figure 7~ 10 sho ws that the nor mal pressure outside th e lung is subatmosphe ric just as it is in th e jar of Figure 7~3. When air is introduced into th e int rapleural space, raising the pressure to at mospheric. the lung collapses inward, and the chest wall springs outward. T his

P=- 5

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Figure 7-10. The te nde ncy of th e lung t o recoil to its d efl ated v olu m e is balanc ed by th e t endency of the chest cag e to bo w out . As a resul t, the int rapleural p ressure is subatmosph eric . Pneum ot ho rax allows t he lun g to co ll apse and t he t horax to spring o ut .

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Figure 7-11. Relaxat io n pressure-vo lume cu rve o f the lu ng and che st w all. The subj ect inspir es (or ex pi res) to a cert ain vo lu me f rom t he spirometer, t he tap is clo sed, and th e subject t hen relaxes h is re spiratory mu scles. The curve f or lung + chest w all can be ex plained by the ad d it io n of t he in d iv id ual lun g and chest w all cu rv es.

shows th at under eq uilib rium co ndi t ions, the chest wall is pulled in ward while th e

lung is pulled Durward, the rwo pulls balanc ing each other. These in teractions can be seen more cl ea rly if we plot a pressure-volume curve

for th e lung and chest wall (Figure 7-11) . For this, th e subject inspires or expires from a spiromete r and then relaxes th e respira tory muscles while the airway pres, sure is measured ("relaxation pr essure"). Inc iden tally, th is is difficult fo r an urt-

rrained subject. Figure 7-11 sho ws that at functiona l residual capacity (FRC) , the relaxation pressure of the lung and chest wall is atmosphe ric. Indeed, FRC is the equilibrium volume whe n the clastic recoil of th e lung is balanced by the norma] rendenc vfqr th echest wall [Q spring o ut. At volumes above thi s, the pressure is posit ive, and at sma ller volumes, the pressure is subatmospheric. Figure 7-11 also shows the curve for th e lung alone. This is similar to that

shown in Figure 7,3 , except that for clarity no hysteresis is indicat ed and the pressures are positive instead of negative. They arc the pressures that would be found from the experimen t of Figure 7~3 if, afte r th e lung had reach ed a certain volume,

th e line to the spiromete r were clamped, the jar opened to the at mosphe re (so that th e lung relaxed against the closed airway), and the airway pressure measured. Note tha t at zero pressure the lung is at its minimal volume, which is below residual volume (RV) . The th ird curve is for th e che st wall only. We can imagine this being measured on a subject with a normal chest wall and no lung! Note that at FRe th e relaxation pressure is negative. In other words, at thi s volume the chest cage is ten ding to spring out. It is not un til the volume is increased to abo ut 75% of th e vital capa city that th e relaxat ion pressure is atmospheric, th at is, th at th e che st wall has found its equilibrium position. A t every volume, the relaxation pressure of the lung plus ches r wall is the sumof the pressures forthe lung and the chest wall measured separately. Because th e pressure (at a given volume) is inve rsely propor tion al to compliance, thi s implies that th e total compliance of th e lung and chest wall is the sum of the reciprocals of th e lung and chest wall compliances measured separa tely, or IICT = IICL + IIC c w .

Relaxation Pressure-Volum e Curve

j "

• Elastic properties of both the lung and chest wall dete rmine thei r combined volume • At FRC, the inward pull of the lung is balanced by the outwa rd spring of the chest wall • Lung retracts at all volumes above min imal volume • Chest w all tends to expand at volumes up to about 75% of vital capacity

Airway Resistance Airflow Through Tubes If air flows th rough a tube (Figure 7 ~ 12), a d ifferen ce of pressure ex ists between th e end s. The pressure difference depends on the rate and pattern of flo"..·. At low flow rates, rhe strea m lines are parallel to the sides of th e rube (A). This is known as laminar £10\\-' . As th e flow rate is increased, unstead iness deve lops. especially at branc hes. Here, separation of the strea m lines from th e wall may occu r with th e formation of local eddies (8). Ar srill higher flow rates, complete disorganization of th e stream lines is seen ; thi s is turb ulen ce (C). The pressure-flow characteristics for laminar flow were first described by the French ph ysician Poiseuille. In straigh t circular rubes, th e volume flow rate is given by

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Fig ure 7-12. Patterns of airflow in tubes. In A, th e flow is lami nar; in S, tra nsitio nal wit h eddy fo rma t ion at b ran ches; and in C, tu rbu le nt. Resistance is (Pl - P2)1f low .

Because flow resistan ce R is driving pressure div ided by flow (compare p. 32), we have

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Note th e critical importance of tube radius; if the radius is halved, th e resistance increases 1 6~fold! , Howevcr, doubling the length on ly doubles resistance. Note also ~ that th~scosi~)cof th e gas, but ,n...9-.l1ts density, affects the pressure-flow relation~/ sh ip. Another feature of laminar flow whe n it is fully devel oped is that th e gas in the cen te r of the tube moves twice as fast as the average veloc ity. Thus, a spike of rapidly moving gas travels down the ax is of the tube (Figure 7-12A) . This chan ging velocity across the diameter of the tube is known as th e velocit), profile. Turbulent flcxv has different properti es. Here pressure is not proport ional to flow rate but , appro ximately, to its square: P = KV2 • In addition, the viscosity of the gas becomes relat tvelv u nunpcr tantbut an increase in gas den sity increases___ the pressure drop for a given flow. Turbulen t flow does not have the high ax ial---\ flow velocity that is characteristic of laminar flow. ~ Whether flow will be laminar or turbulen t depends to a large exten t on the Reynolds number, Re. This is given by 2rvd

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(y

where d is density, v average velocity, r radius, and n viscosity. Because density and veloc ity are in the nume rator, and viscosity is in th e den ominator, the ex-

pression gives the rati o of inertial to viscous force s. In stra ight, smooth tubes, tu r-

bulence is probab le when th e Reynolds number exceeds 2000. The expression shows that turbu lence is most likely to occ ur when the velocity of flow is high and th e rube diameter is large (for a given velocity). Note also th at a low-density gas like helium tends to produce less tu rbulence. In such a complicated system of tubes as the bronc h ial tree with its man y branches, chan ges in caliber, and irregular wall surfaces, the applica tion of the above princ iples is difficult. In practice, for laminar flow to occu r, th e entrance conditions of the tube are critica l. If eddy format ion occurs upstream at a branch po in t, thi s disturbance is carried downstream some distance before it disappears. Thus, in a rapidly branching syste m like the lung, fully develo ped lamina r flow (Figure 7-12A ) probab ly only occurs in th e very small airways where the Reyn olds numbers are very low (approxi mate ly 1 in termina l bronchioles). In most of the bronchial tree, flow is transitional (B), while true turbulen ce may occur in the trachea, especiall y o n exercise wh en flo w velocities are high. In general, driving

pressure is determined by both the flow rate and its square: P

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Laminar and Turbulent Flow

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J

Measurement of Airway Resistance Airw ay resistance is th e pressure differen ce between th e alveoli and th e mouth d ivided by a flow rate (Figure 7-12). Mouth pressure is easily measured with a man ometer. Alveolar pressure can be deduced from measurements made in a bodv plethysmograph . More information on thi s techn ique is given on p. 152.

Pressures During the Breathing Cycle Suppose we measure th e pressures in t he in trapleura l and alveolar spaces during norm al breath ing." Figure 7 ~1J sho ws that before inspirat ion begins, the intrapl eural pressure is - 5 cm wate r because of the elastic recoil of th e lung (cornpare Figures 7 ~3 and 7 ~ 10). A lveolar pressure is zero (a tmosphe ric) because with no airflow, there is no pressure dro p along the airways. However , for inspiratory flow to occur, the alveolar pressure falls, thus establish ing the dri ving pressure (Figure 7- 12) . Indeed , the exten t of the fall depends on the flow rate and the resistance of th e airways. In norm al subjects, th e cha nge in alveo lar pressure is only I -cm wat er or so, but in pati en ts with airway obstruct ion , it may be man y times that. In trapleural pressure falls during inspiration for two reasons. First, as the lung expands, its elast ic recoil increases (Figure 7 ~3 ) . T his alone would cause the in-

Expiration

Figure 7-13. Pressures du rin g th e bre athi ng cycle . If there we re no _ainYay resistance, alveolar pressu re w ould rema in at zero, and intrapleu ral pressure w ould follow th e brokentine ABC. wh ich is det er min ed by the elastic recoi l of the lung . Airway (and tissue) resist ance contributes th e hatched portion of int rap leural - pres sur e (see t ext ).

trapleural pressure to move along th e broken line ABC. In addition , however, th e pressure drop along th e airway is associated with a further fall in intra pleural pres, sure,' represenred by the hatched area, so that the actual path is AB'C. T h us, th e vertica l distance between lines A BC and A B'e reflects the alveolar pressure at an y instant. As an equation of pressures, (mouth - intrap leural) = (mouth alveolar} + (alveolar - intrapleural) . O n expiration, similar cha nges occur. Now int rapleural pressure is less negative than it would be in the absence of airway resistance because alveolar pressure is positive. Indeed, with a forced expira tion, intrapl eural pressure goes above zero. No te tha t th e sha pe of th e alveolar pressure tracing is similar to th at of flow. Indeed, they would be ident ical if th e airway resistance remained constan t during the cycle. Also, the intrapleural pressure curve A BC would have the same shape as th e volume tracing if the lung compli ance remained constant.

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T here is also a co n tri bution made by t issue resistan ce, wh ich is cons ide red later in th is chapter.

Chief Site of Airway Resistance

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A s the a irways penetrat e toward th e periphe ry of th e lung, th ey become more n umerous but much narrower (see Figures 1 ~3 and 1 ~ 5 ) . Based on Po iseu illc's equation with its (radius)" term, it would be nat ural to think that the major part of the resistanc e lies in th e very na rrow airways. Indeed, thi s was th ought to be the case for man y yea rs. H ow ever , it has now been shown by d irect measure men ts of the pressure d rop along th e bron chial tree that the ma jo r site of resistance is the med ium -sized bron chi and that th e very small bronchi oles con tr ibute relat ivel y littl e resistan ce. Figure 7· 14 shows that most of th e pressure d rop occurs in the a irways up to the seven th gene rat io n. Less than 20 % can be attributed to ai rways less th an 2 mm in diameter (ab o ut gen erat ion 8 ). T he rea son for th is ap paren t paradox is the prod igiou s number of sma ll a irways. The fact th at th e pe ripheral a irways con tribute so lit tle resista nce is impo rtan t in the de tec tion of ea rly airway d isease. Because they co nsti tute a "silen t zone ," it is probable that considerable small a irway disease can be presen t before the usua l measurem ents of airway resistance can detect an abnormali ty. Th is issue is considered in more det ail in C h apter 10.

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Figure 7-15. Variatio n of airway resist ance (AWR) w ith lun g vol ume. If th e reci proca l of airway resistance (co nd uct an ce ) is plotted, t he g ra ph is a st ra ig ht li ne .

Fact ors Determining Airway Resistance Lung volume has an important effect on airway resistance. Like the extra-alveolar blood vessels ( Figure 4-2), th e bronchi are suppo rte d by th e rad ial tracti on of th e surro unding lun g tissue, and th eir calibe r is increased as the lung expand s (compare Figure 4,6). Figure 7-15 shows tha t as lung volum e is red uced , airway resislance rises rapi dly. If th e reci procal of resistanc e {conductanc e} is plotted against lung volum e. an approx ima tel y linear rel at ion sh ip is obtained. A t very 10\\·- lung volumes, th e small airways may close comp let ely, especially at th e bo ttom of the lung, wh ere the lun g is less well expanded (F igure 7-9) . Patien ts wh o have increased airway resistance often breat he at high lung volurnes; thi s helps to reduce th eir airway resistan ce. Con tract ion of bronchial smooth muscle narrows the air ways and increases air, way resistance. This may occur reflexly through the stimulation of receptors in th e trachea an d large bronch i by irritants such as cigaret te smoke. Motor inner' vation is by the vagus nerve. The tone of the smooth muscle is under the con trol of the autonomi c nervous system. S timulation of adrenergic recept ors causes bronchod tlaration as do epinep hrine and isoproterenol. J1,Adren ergic receptors are of two types: ~ l receptors occur princi pally in the heart, while 132 receptors relax smooth muscle in th e bronchi, blood vessels, and ute rus. Select ive 132,adren ergic ago n isrs are now extensively used in th e treat, ments of asthma. Parasympat hetic activity causes bronchoconstr icrion , as does acety lcholine . A fall of r eo z in alveolar gas causes an increase in airway resistance, apparen tly as a result of a di rect ac tion on bronch iolar smoo th muscle. The injecti on of his,

Airway Resistance • Highest in the medium-sized bronchi; low in very small airways • Decreases as lung volume rises because the airway s are then pulled open • Bronchial smooth muscle is controlled by the autonomic nervous system; stimula tion of J!-adrenergic receptors causes bronchodilatation • Breathing a dense gas as in diving increases resistance

tamine in to the pulmonary artery causes constriction of smooth muscle located in th e alveolar ducts. TIle density and viscosity of the inspired gas affect the resistance offered to flow. The resistance is increased duri ng a deep dive because th e increased pressure raises gas de nsit y, but it is red uced when a helium-O j mixture is breathed. The fact th at changes in density rather than viscosity have such an influence on resistanc e is ev idence that flow is not purely lam inar in th e medi um-sue d airways, where the main site of resistance lies (Figure 7-14).

( Dynam ic Compression of Airways' . Suppose a subject inspires to tota l lung capacity and then exhales as hard as possible to residual volume. \X'e can record a fiow~t'olume curve like A in Figure 7 ~ 16, which shows that flow rises very rapid ly to a high value but th en declines over most of expiration. A remarkable feat ure of th is flow-volume en velope is that it is virtually impossible to pen etrate it. For example , no matter whether we start exha ling slowly and th en accelerate. as in B. or make a less forceful expira tion, as in C . the descend ing port ion of the flow-volume curve takes virtually the same pat h .

Flow

Volume Figure 7-16. Flow -vo lume curves. In A, a maximal inspira tio n w as f ollowed by a fo rced expir ation. In 8, expiration w as initially slow and then fo rced. In C, ex pirato ry effort was subm ax im al. ln all th ree, t he descending porti o ns of th e curve s are alm ost supe rimposed.

Expiratory flow (ilsee)

B

High lung volume

Mid volume

Low volume

2

5 10 15 20 25 Intrapleural pressure (em H20 )

4

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6

Figure 7-17. lsovolu m e pr essur e-flow cur ves d raw n fo r three lu ng vo lu m es. Each of t hese w as o btai ned f ro m a series of forced ex pir at ions and ins pi rat ions (see text) . Note t hat at t he high lung volume, a rise in intrapleural pressu re (o bt ai ned by increasi ng ex pi rato ry effo rt) resu lts in a gr eat er expir at o ry f low . How ever , at m id and lo w vo lu m es, fl ow beco me s independ ent of effort aft e r a cer ta in in t raple ural pre ssure has been exceeded.

Thus, something powerful is limiting expiratory flow, and over most of th e lung volume , flow rate is independen t of effort. W e can get more information about this curious stat e of affairs by plotting the dat a in anothe r way, as sho wn in Figure 7-17. For thi s, the subject takes a series of maximal inspirations (or expirations) and then exha les (or inhales) fully with varying degrees of effort. If the flow rates and intr apleural pressures are plotted at the same lung volume for each expiration and inspiration, so-called isovolume pressure~jl.ow curves can be obtained. It can be seen tha t at h igh lung volumes, the exp iratory flow rat e con tinues to incr ease with effort, as might be expected. However, at mid or low volumes, the flow rat e reach es a plat eau and canno t be increased with further increase in intrapl eural pressure. Unde r these conditions, flow is th erefore effort indet)endent. The reason for th is remarkable behavior is compression oi the airways by int rathoracic pressure. Figure 7 ~1 8 sho ws schematically the forces acting across an airway within the lun g. T he pressure out side the airway is shown as int rapleural, although this is an oversimplification . In A , before inspiration has begun, airway pressure is everywhe re zero (no flow), and beca use intrap leural pressure is - 5 ern wate r, there is a pressure of 5 cm water holding the airway open. As inspirat ion

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starts ( B), bot h intrapleural an d alveolar pressure fan by 2 ern wat er (same lung volume as A and tissue resistan ce is neg lected), and flow begins. Because of the pressure drop along the airway, the pressure inside is - 1 em water, and there is a pressure of 6 ern water hold ing the airway ope n. A t end -inspiration (C ), again flow is zero, an d there is an airway tran smural pressure of 8 em water. Fina lly, at the onset of forced expi rat ion (D), both int rapleural pressure and alveolar pressure increa se by 38 em water (same lung volume as C ). Because of th e pressure drop along the airway as flow begins, th ere is now a pressure of 11 em water, tendin g to close th e airway. Airway compression occurs, an d th e downstream pressure lirrunng flow becomes the pressure outside the airway, or in trapleural pressure. Thus, th e effective driving pressure becom es alveolar minus intra pleural pressure. This is the same Sta rling resistor mechani sm that limits the blood flow in zone 2 of the lung, whe re venous pressure becomes un importan t just as mouth pressure does here (Figures 4~ 8 and 4~ 9 ) . No te that if intrapleural pressure is raised furthe r by incr eased muscular effort in an attempt to expel gas, the effective dri ving pressure is una lte red. T hus, flow is independent of effort. Maximal flow decreases with lung volume (Figure 7-16) because the difference between alveolar and imrap leural pressure dec reases and the airways become narrower. Note also that flow is inde pendent of the resistance of the air, ways downstream of the point of collapse, called the equal pressure point. As exp iration progresses, th e equal pressure point moves dista lly, deeper into the lung. Th is occurs becau se th e resistance of the airways rises as lun g volume falls,

Dynamic Compression of Airways • Limits air flow in norma l subjects during a forced exp iration • May occur in diseased lungs at relatively low expiratory flow rates thus reducing exercise ability • During dynamic com pression flow is determined by alveolar pressur e minus pleural pressure (not mouth pressure) • Is exaggerated in some lung diseases by reduced lung elast ic recoil and loss of radial traction on airways

and th erefore the pressure withi n the airways falls mor e rapid ly with distance from the alveoli . Severa l factors exaggerate this flow-limiting mechanism. One is any inc rease in resistance of the pe ripheral airways because that magnifies the pressure drop along th em and thus dec reases th e intrabronchial pressu re during expiration (19 cm wat er in D). A nother is a low lung vol ume because that red uce s the driving'-pressure (alveolar-intrapleura l) . Th is dr iving pressure is also reduced if recoil ( pressure is reduced, as in emp hysema. A lso in th is disease, radial tr act ion on th e airways is reduced and they are compressed more readily. Indeed, wh ile this type \ of flow lim itat ion is on ly seen during forced expirat ion in normal subj ects, it may ( occur duri ng th e exp iratio ns of normal breath ing in pati ents with seve re lung disease. ----In th e pulmonary function labora tory, the flow rat e during a maximal expi ratio n is often dete rm in ed from th e forced expirator)' volume o r FEY 1.0 which is th e vo lume of gas th at ca n be exhaled in 1 seco nd afte r a maximal inspirati on. A nothe r popu lar measuremen t is the forced expiratory flow o r FEFz'5_ 7'5'){> which is the average flow rate measured over the middle half (by vo lume) of the expirat ion . More in format ion about these tests can be found in Chapter 10.

Causes of Uneven Ventilation T h e ca use of the region al differences in vent ilat ion in th e lung was discussed on p. 103 . Apart from these topographical d ifferences, th ere is some additional in equality of venti lat ion at an y given vertical level in the n ormal lun g, and this is exaggerat ed in many diseases. O ne mech ani sm of un even ven t ilat ion is shown in Figure 7 ~ 19. If we rega rd a lun g unit (Figure 2~ 1) as an elastic chamber connected to the at mosphe re by a rube , the amo un t of ventilation depen ds on the co mpli ance of the chamber and the resista n ce of the t ube. In Figure 7~ 19, uni t A h as a n ormal diste nsibility an d airway resistance. It can be seen th at its volume change o n insp irat ion is large an d rapid so that it is comp lete before expiratio n for the whole lung begins (broken line) . By co ntras t , unit B h as a lo w complian ce, and its ch ange in volu me is rapid but small. Fin ally, uni t C has a large airway resistan ce so that inspiration is slow and not co mp lete before the lun g has begun to exhale . N ote that the shorte r the time ava ilable fo r in spiration (fast breathing rate ), the smaller the inspired vo lume. Such a un it is said to h ave a long time constant, the

A

Volume

-----------l----' l Inspiration

Expiration

Time - . . . Figure 7-19. Effects of decreased co m pliance (8) and in creased airw ay resistance (Cl an ve nt ilat io n of lun g unit s co mpare d w it h no rm al (A ). In bot h insta nces, the inspired vo lume is abno rm ally low .

value of which is given by the product of th e compliance and resistance. Thus. inequality of ventilat ion can result from alte rations in either local diste nsibility or airway resista nce , and the pattern of inequalit y will depend on t he frequency of breath ing. A no th er po ssible mech an ism of un even ven t ilat ion is incomplete diffusion with in th e airways of rhe respira tory zone (Figure 1 ~ 4 ) . W e saw in C hapter 1 tha t th e dominan t mecha n ism of vent ilation of th e lung beyond th e term inal bronchioles is diffusion . N orm ally th is occ urs so rapidly th at differences in gas concentration in the acin us are virt ually abolish ed with in a fraction of a second. H owever, if th ere is dila tion of the airways in the region of the respirato ry bron chioles, as in some diseases, the dista nce to be covered by diffusion may be enormously increased. In these circumstances, inspired gas is not d istr ibuted un iformly within the respiratory zone because of un even ven tilat ion along the lung un its.

Tissue Resistance W hen the lung and chest wall are moved , some pressure is requ ired to overcome the viscous forces with in the tissues as t hey slide over each other. Thus, part of the h atched portion of Figure 7- 13 should be attri buted to th ese tissue forces. However th is tissue resistan ce is only about 20% of the total (t issue + airway) resistance in young n ormal subjects, although it may increase in some diseases. This total resistance is sometimes ca lled pulmonaryresistance to d istinguish it from airway resista nce. I

Work of Breathing \Vork is required to move the lung and chest wall. In th is co ntext, it is most con ven ien t to measur e work as pressure X vo lume.

Work Done on the Lung This can be illustrated on a pressure-volume curve (Figure 7~20). Dur ing inspirat ion , the intrap leura l pressure fo llows the curve A BC, and th e work done on th e lun g is given by the area OABCDO. Of th is, the tra pezoid OAECDO represents th e work required to overco me the elastic forces, and th e hat ched area ABCEA rep resents the work overcoming viscous (a irway and tissue) resistan ce (compare Figure 7-13). The hi gher the a irway resistance or the insp iratory flow rate , the more negative (rightward) would be the in trap leural pressure exc ursion between A and C and th e larger th e area. O n expirat ion , the area AECFA is work required to overcome airway ( + tis, sue ) resistance . Nor mally, thi s falls withi n th e t rape zoid OA ECDO, and thu s th is work can be accomp lished by th e en ergy stor ed in th e expanded elastic structures a nd rele ased duri ng a passive' exp iration. The d iffe rence between the areas AECFA and OA ECDO represents the work dissipated as he ar. The h igh er the breath ing rate, th e faster th e flow rates and the larger the visco us work area A BCEA. O n the other hand , th e larger the t idal volume, the larger th e elast ic work area OAECDO. It is of interest th at patient s who have a reduc ed co mplian ce (st iff lungs) tend to take small rapid breaths, while pat ients with severe airway obst ruc tion somet imes breathe slowly. These pattern s tend to red uce th e work done on the lungs.

o

1.0

c

o c: u,

~ '" E g"

0.5


A

o

-5

- 10

Intrapleural pressure (cm H20 ) Figure 7-20. Pressu re-v olume curv e of t he lung showing t he inspiratory w o rk do ne ov erco ming elastic f or ces (a rea OAECDO) and visco us forces (ha tched area A BCEA ).

Total Work of Breathing The tot al work done moving the lung and chest wall is difficult to measure, although es timates have been o btained by artificia lly ventilating paralyzed pati en ts (or "completel y relaxed" vo luntee rs) in an iron lung type of ventilator. Alrernarlvelv, the to tal work can he calculated by measuring the O 2 cos t of breat hing and assum ing a figure for the efficienc y as given by U seful work Efficiency % =

".l"

T ot al energy expended (or

0, cost)

X 100

The effic ien cy is believed to be about 5 to 10%. Th e O 2 cost of quiet breath ing is extremely small, being less than 5% of the total resting O 2 co nsumption . W ith vo luntary hyperventilation it is possible to increase this to 30%. In patient s with obstructive lung disease, the O 2 cost of breathing may limit the ir exe rcise ability.

QUESTIONS For each question, choose the one best answer. 1.

., ,J

All of the fo llowin g statement s are tru e about contraction of t he diaphragm EXCEPT: A. The nerves that are responsible originate high in the neck. B. It flattens the diaphragm.

C. It reduces the lateral distance between the low er rib margins. D. It cause s the anterior abdominal wall to move out. E. It increases lung volume . 2. Which of the follow ing statements about the pressure-volume behavior of the lung is FALSE? A. Compliance increases w ith age. B. Filling an animal lung with saline increases compliance. C. Removing a lobe reduces total pulmonary compliance. D. Absence of surfactant reduces compliance . E. In the upright lung at FRC, for a given change in intrapleural pressure, the alveoli near the base of the lung expand less than those near the apex. 3. Tw o bubbles have the same surface tensio n but bubble X has 3 time s the diamete r of bubble Y. The ratio of the pressure in bubble X to th at in bubble V is: A. 0.3 : 1 B. 0.9 : 1 C. 1 : 1 D. 3 : 1 E. 9 : 1 4. Pulmonary surfactant is produced by: A. Alveolar macrophages. B. Goblet cells. C. Leukocyte s. D. Type I alveolar cells. E. Type II alveo lar cells.

5 . The basal regions of the upright huma n lung are normally bette r ve ntilated than the uppe r regions because: A.

Airway resistance to the upper regions is higher than to the lower regions.

B.

There is less surfactant in the upper regions.

C. The blood flow to the lower regions is higher. O.

The low e r regions have a small resting volume and a relatively large increase in volume.

E. The Pco, of the lower regions is relatively high. 6. Wh ich of t he follow ing statements is FALSE? Pulmonary surfactant: A. Reduces the surface tension of the alveolar lining liquid. B. Is secreted by type II alveolar epithelial cells. C. Contains dipalmitoyl phosphatidvlcholine . D.

Increases the work required to expand the lung.

E.

Helps to prevent transudation of fluid f rom the capillaries into the

alveolar spaces. 7 . All of the followi ng state ments about normal expiration during resting condi-

t ions are true EXCEPT: A. B.

Expiration is generated by the elastic forces. Alveolar pressure is greater than atmo spheric pressure.

C.

Intrapleural pressure gradually falls (becom es more negative) during the

D.

expiration. Flow velocity of the gas (in em . sec") in the large airways exceeds that in the te rminal bronchioles.

E. Diaphragm moves headw ard as expiration proceeds. 8. An anesthetized patient w ith paralyzed respiratory muscles and normal lungs is ventilated by positive pressure . If the anesthesiologist increases the lung

volume 2 liters above FRC and holds the lung at that volum e for 5 seconds. th e most likely combinat ion of pressures (in cmH, OI is likely to be: M outh Alveolar Int rapleural

A B. C. D. E.

0 0 +10 +10 +10

0 +10 + 10 + 10 0

- 5 -5 -10 0 - 10

9. Wh en a normal subject develops a spontaneous pneumoth orax of his right

lung all of the following occur EXCEPT: A Right lung collapses. B. Chest wall on the right becomes smaller. C.

Diaphragm moves down .

D. Mediast inum may move to the left . E. Blood flow to the right lung is reduced. 10. According to Poiseuille's Law reducing the radius of an airway to 1/3 w ill increase its resistance how many fold?

A 1/3 B. 3

D. 27 E. 81 11. Concerning airflow in the lung : A. Flow is rnore likely to be turbulent in srnall airw ays t han in the t rachea. B. The lower the viscosity, the less likely is turbul ence to occu r. C.

In pure laminar flow , halving the radius of t he airw ay increases its

resistance 8-fold. D.

For inspiration to occur, m outh pres sure mu st be less than alveo lar

pressure. E. Airway resistance increases during SCUBA diving . 12. The most important factor limiting flow rate during most of a forced expiration from total lung capacity is: A. Rate of contraction of expiratory muscles. B. Action of diaphragrn . C.

Constriction of bronchial smooth muscle .

D. Elast icity of chest wall. E. Comp ression of airways. 13 . All of th e followi ng fact ors increase the resist ance of the airw ays EXCEPT: A. Reducing lung vol urne below FRC. B.

Increased sym pathetic stimul ation of airw ay smooth mu scle .

C. Divi ng to a great depth. D. Inhaling cigarette smoke. E. Breathing a rnixt ure of 21% 0 , and 79 % sulfur hexafluoride (mol ecular w eight 146 ). 14. A normal subject makes an inspiratory effort against a closed airway. All of the following staternents are true EXCEPT: A. Tension in the diaphragm increases. B.

The external intercostal muscles become active.

C.

Intrapleural pressure falls.

D.

Alveolar pressure falls mo re than intrapleural pressure.

E.

Pressure inside the pulrn onary capillarie s falls.

'?xpira-

Control of Ventilation How 605 Exchange 15 Regulated EXCEPT:

Central Controlle r ....,olecular

cy. All of

Integrated Responses

Brainstem

Response to Carbon Dioxide

Cortex Other Parts of the Brain

Response to Oxyge n Response to pH Respo nse to Exercise

Effectors Sensors Central Chemoreceptors Peripheral Chemorecepto rs

Abnormal Patterns of Breathing

Lung Receptors

Other Recepto rs

Wehave seen that the chief function of the lung is to exchange O2 and CO2 between blood and gas and thus maintain normal levels of P02 and PC02 in the anerial blood. In this chapter we shall see that in spite of widely differing demands for O2 uptake and CO2 output madeby the body, the eneriet P02 and Pe02 are normallykept within close limits. This remarkable regulation of gas exchange is madepossible becausethe level of ventilation is so carefully controlled. First we look at the central controller, and then the various chemoreceptors and other receptors that provide it with information. The integrated responses to carbon dioxide, hypoxia and pH are then described.

j •I

Cent ral co ntroll er Inout / /

Sen so rs

Pons, medulla , other parts at brain

1 ..

~~t OutDl;

--hhhhu-nn-n-nn---1

Chemcreceptors . tung and other receptors

Eff ectors

I

Respiratory muscles

Fig u re 8-1. Basic elem ents of t he res pi rat ory control sy ste m . Info r m at io n fro m vario us se nsors is fed to the ce ntra l co ntro ll er, the ou t put of w hic h go es t o t he res piratory m uscl es. By cha ngi ng ve nt il atio n, t he respi rato ry m u scle s reduce perturbatio ns of t he se nsors (nega tive feed back).

--

.' "

The thr ee basic elements of th e respiratory con trol system (Figure 8, 1) are:

1. Sensors which gathe r informationilnJ feed it to th e 2. Central controller in th e brain which coordina tes th e infor mation and, in tum , sends impulses to the 3. Effecwrs (respiratory muscles) which cause ventilation . W e shall see that increased activity of th e effecto rs generally ultimately decreases the sensory input [0 the brain, for example, by decreasing the arterial Pc o z. This is an example of negative feedback.

Central Controller The normal automatic process of hreath ing originates in impulses th at come from the brainsrcm. TIle cortex can override these centers jfvoluntary control is desired. Additiona l input from other parts of the brain occurs under certa in conditions.

Brainstem T he periodic nature of inspira tion and exp irat ion is con trolled by neurons locat ed in the pon s and medulla. These have been designat ed respirator)' centers. How, ever, th ese sho uld not be th ought of as discrete nucl ei but rather as somewhat poorl y defined collections of neurons with various components. T hre e main groups of neurons are recognized. 1. l\.1edullary resprmrory center in the reticular format ion of the medulla be, neath th e floor of th e fourth ven tricl e. T his comprises two iden tifiable areas. O ne group of cells in the dorsal region of the medulla (dorsa l respirato ry group) is chiefly associat ed with inspiration; the ot he r in the ventral area (ventral respiratory group) is mainly for expiration. O ne popular (rbough not un iversally ac-

cepted) view is tha t the cells of the ins/JirawT)' area have th e property of in trins ic periodic firin g, and they a re responsible for the basic rh ythm of ven t ilat ion, W he n all known afferent stimuli hav e been abolished, these inspirarory cells generate repeti tive bursts of act ion pot entials th at result in nervous impulses going to th e dia phragm and other inspiratorv muscle s, T he intrinsic rh ythm pattern of the inspiratory area start s with a latent period of se veral seco nds during whi ch there is no activity. A cti on pot entials th en begin to appea r, incre asing in a crescendo over th e next few seco nds, During this time, inspirator y muscle act ivity becomes stro nger in a "rarnp'l-tvpe pattern . Finally, the inspiratory act ion pot entials cease, and inspiratory muscle tone falls to its prctnspirarorv level. The inspiratory ramp can be "turned off " premat urely by in h ib it ing impul ses from the pneumotaxic center (see below) . In this way, in spira t ion is sho rten ed and , as a consequenc e, the brca th inu rate increases. The output of the inspira ror y ce lls is further modu lated by impul ses from th e vagal an d glossopharyn geal nerves. In de ed, th ese ter min ate in the tra ctus solirarius, which is situated close to the in spirarory area . The expiraw'!)' area is quiescent J uring normal qu iet breat h ing because ven t ilat ion is the n ach ieved by acti ve co ntrac t ion of inspirat ory muscles (chiefly the diaphragm ), followed by passive relaxation of th e chest wall to its equ ilibrium po sit ion (C hapte r 7). However, in more forceful breathing, for example, on exe rc ise, expirat ion becomes acti ve as a result of th e ac tivity of the expiratory cells. Nore that there is st ill not uni versal agreeme n t on how the intrinsic rhyt hmic ity of respirati on is brou gh t abo ut by the medu llar y cen ters. 2. A pneustic center in the lower pons. This area is so na med beca use if the brain of an ex perimen tal anima l is sec tioned just ab ove this site, pro longed inspiratory gasps (apn euses) in terrupt ed by transient ex pirato ry efforts are seen. Apparent ly, th e impul ses from the center have an exci tato ry effec t on th e inspirat ory area of th e medu lla , tending to prolong the ramp actio n poten t ials. Whether th is apneu stic center plays a role in normal h uman respiration is not kn own , although in some types of severe brain injur y, thi s type of abnormal breat hing is seen, 3, Pneumomnc center in th e upper pons. A s ind icated above, this are a appears to "switch off " or inh ibit inspiration and thus regulate inspiration volume and, secondarily, respirato ry rate. T hi s has been deruonsrrated experimen tally in an imals hy direct electrical st imulat ion of the pn eumotax ic cen ter. Some investt gators believe that the role of th is cent er is "fine tuning" of respi ratory rhythm because a normal rh ythm can exist in the absence of this cent er.

Cortex Breathing is und er voluntary con trol to a co nsiderable extent, an d th e cortex can ove rr ide th e function of the brainstem with in limits, It is not difficu lt to halve the arter ial Peo , by h ypervent ilat ion, although the conseq uen t alkalosis ma y cau se tetany with con tract ion of the mu scles of th e ha nd and foot (carp opeda l spasm ), Halving th e PCO , increases rhe arterial pH by about 0.2 un ir (Figure 6-8). Vo lun tary hypoventt lan on is more d ifficu lt. The dura t ion of breath-h olding is [uni ted by several factors, incl uding the arterial P O ) l and Po z- A pre liminary

",

Respiratory Centers • Responsible for generating the rhythmic pattern of inspiration and expiration • Located in the medulla and pons of the brain stem • Receive input from chemoreceptors. lung and other receptors. and the cortex • Major output is to the phrenic nerves

.'

pe riod of h yper ventilat ion increases breath -holding t ime, espec ially if oxygen is breathed. However, factors othe r th an chemical are involved. T his is shown by the ob servation that if at the breaking point of breath-h old ing, a gas m ixt ure is inh aled that raises th e arterial Peo z and lowers the POl' a further period of breathholding is possible.

Other Parts of the Brain O the r parts of th e brain, such as the limbic system an d hypoth alamus. can alter th e pattern of brea thing, for examp le, in emotional stat es such as rage and fear.

Effectors The muscles of respira tion includ e the d iaph ragm, inte rcosta l muscles, abdo mina l muscles, and accessory muscles such as the sternomasroids. The actions of th ese were described at the heginn ing of Chapte r 7. In th e conte xt of th e control of ven tilation, it is crucially import an t th at these various muscle groups work in a coord inated manner, and this is th e respon sibility of the cen tral controller. There is evidence th at some newborn ch ildren, particularly those that are premature, have uncoordinated respiratory muscle act ivity, especially during sleep. For example, the thoracic muscles may try to inspire while the abdomina l muscles expire. This may be a facto r in the "sudden infan t death syndrome."

Sensors Central Chemoreceptors A chemorecept or is a receptor that respond s to a cha nge in the che mical composition of the blood or other fluid aroun d it. The most importan t recept ors involved in the min ute-by-m inut e control of ventilation are those situated near the vent ral surface of the medull a in th e vicinity of the exit of the 9th and l Oth nerves. In animals, local applicat ion of H + or dissolved CO 2 to th is area st tmulares breat h ing with in a few seco nds. A t one time, it was t houg h t th at the medu llary respirator y center itself was the site of action of CO2 , hut it is now accepted that the che moreceprors arc anato mically separate. Some evidence suggem th at th ey lie about 200 to 400 11m below the ven tral surface of the medu lla (Figure 8-2).

=

Brain

Ill"~

'

Figure 8·2 . Environment of the central chernoreceptors . They are bathed in brain extracellular fluid (ECFl, through w hich CO2 easily diffuses fro m blood vessels to cerebrospinal fluid (CSF). The CO2 reduces the CSF pH, thus stimulating the chemoreceptor. H'" and HC0 3 ions cannot easily cross the blood-b rain barrier.

The central che morecepto rs arc surrounded by brain extracellular fluid and respond to cha nges in its H + concentration. A n increase in H + concentratio n stimulates ven tilatio n, whereas a decrease inhibits it . The co mposition of the extracell ular fluid around the recepto rs is go ve rned by the cerebrospinal fluid

(CS F), local blood flow, and local metabolism. Of these, the CS F is apparen tly the most important . It is separated from th e blood by th e blood-brain barrier. wh ich is relat ively impermeable to H + an d HCO , ions, although molecular CO , d iffuses across it easily. W hen th e blood Peo, tises, CO, d iffuses into the CS F from the cerebral blood vessels, liberating H + ions wh ich stimulate the chemoreceprors. Thus, the CO2 level in blood regulates vent ilation ch iefly by its effect on the pH of the CSF. The resulting hyperventilation reduces the PU )z in the blood and therefore in the CSF. The cerebral vasodilation that accompa nie s an increased arterial Pc..'oz enhance s diffusion

of CO , into the CS F an d th e brain extracellular fluid. T he normal pH of rhe C SF is 7.32, an d because the CS F cont ains much less protein than blood , it has a much lower buffering capacity. As a result , the change

in CSF pH for a given change in Peo, is greate r th an in blood. If th e CS F pH is displaced o ver a prolonge d period , a com pen sato ry change in HCO )" occ urs as a result of transport across the blood-brain barrier. However, the CSF pH does no t

usually ret urn all the way ro 7.32. The cha nge in CSF pH occurs more promptl y tha n the cha nge of rhe pH of arrerial blood by renal compensation (Figure 6.8), a process that takes 2 to 3 days. Because CSF pH returns to ne ar its normal val~ e

more rapidly than does blood pH, CSF pH has a more important effect on cha nges in the level of ve nt ilation and the arterial P COl" "":,\-"'. O ne example of these changes is a patien t with chronic lung disease and CO 2 retent ion of lon g standing who may have a nearly normal CSF pH and, therefore ,

Central Chemoreceptors • Located near the vent ral surface of the medulla • Sensitive to the Peo2 but not P0 2 of blood • Respond to the change in pH of the ECF/CSF when CO2 diffuses out of cerebral capillaries

an abnormally low vent ilation for h is or her arterial PC-D r A similar situa tion is seen in normal subjects who are exposed to an atmosphe re containing 3% CO2 for some J ays.

Peripheral Chemoreceptors

'1"

These are loca ted in th e caro tid bodies at the bifurcation of the common caro tid arte ries, and in the aort ic bod ies above and below the aorti c arch. The carotid bodies are th e most importa nt in humans. T hey con ta in glomus cells of two types. T vpe I cells show an int en se fluorescent sta in ing because of th eir large content of l dop~These cells are in close apposition to end ings of th e afferen t carotid sinus ner ve (Figure 8-3 ). The carotid bod y also con tains type II cells and a rich supply of capillaries. The precise mechan ism of the caro tid bodies is still uncert ain, but man y physiologists bel ieve that the glomus cells are the sites of che moreception and that modulation of ne urotransmitter release from the glomus cells by physiological and chemical stimuli affects th e disch arge rate of th e carotid body afferen t fibers (Figure 8-3A ).

Figure 8-3. A. Diag ram of a caro tid bo dy w hic h contai ns typ e I and ty pe 1\ cells w ith ma ny capillaries (Cap). Impulses trav el to the cent ral nervous syst em (e NS) throu gh th e carotid sinus nerv e. B shows the non li near respo nse t o arte ri al P 0 2. Note that the maximum respo nse occurs be low a P0 2 of 50 mm Hg .

The peripheral che moreceptors respond to decreases in art erial P OI and pl-i, and increases in arterial PCOz. They arc un ique among tissues o[th e body in that their sensitivity to changes in arterial Paz begins around 500 ~m Hg. Figure 8-3B sho ws that the relation shi p between firing rate and art erial Po , is verv non linea r; relat ively little response occurs until the arte rial P 0 2 is reduced below (!.Q9 mm Hg. but t hen the ta te rapid ly in creases. The carotid bodies h ave a vet) high blood flow for th eir size, and th erefore in spite of th eir h igh metaboli c rate, the arterialvenous O 2 difference is small. As a result, they respond to arterial rather than to ven ous Po r The response of the se receptors can be very fast; indeed, thei r discharge rate can alter duri ng the respiratory cycle as a result of th e small cyclic changes in blood gases. The peripheral chemoreccpto rs are responsible for all th e increase of ven tilat ion that occurs in hum ans in re§lio nse-tG...at tcrial nYP.9¥ct'; !TIia'. In deed, in the absen ce of these receptors, severe h ypoxemia depresses ven tilation, presumably th rough a direct effect on the respiratory cent ers. Comp lete loss of h vpox ic ven tilato ry drive has been sho wn in patients with bilateral ca rotid body resecti ~ The response of the periphe ral che morcccptors to arterial PcUz is less import ant . th an th at of th e cent ral ch emoreccptors. For example, when a normal subject is given a CO 2 mixt ure to breathe , less than 20% of the ven tilatory response can he attributed to the peri phera l che morcccptors. H owever, th eir response ~~ore ~p iJ, and they may be useful in marchi ng ven tilati on toabr~p~ changes in PCOl' In humans, th e carotid but not t he aort ic bodies respond to a fall in "arierial pll. T h is occurs regardless of whether the cause is respiratory or metabolic. Interaction of the var ious stimuli occurs. T h us, inc reases in chemoreceptor acti vity in response to decreases in arterial P<.1z are poten tiated by incr eases in p~ and, in the carotid bodies, by decreases in pH .

lung Receptors 1. Pulmonary Stretch Receptors T hese are also known as slowly adapt ing pulmonary stretch recept ors and are believed to lie with in airway smooth muscle. They disch arge in response to disrcn sion of the lung, and th eir activity is sustain ed with lung inflation, that is, th ey sho w littl e adaptation. T he impu lses travel in th e vagus nerve via large myelin ated fibers. The main reflex effect of stimulat ing these receptors is a slowi~ROf respiratory frequency due to an inc rease in expiratory time. This is known as the Henng~er ~nf1at ion reflex. ! t can be well demonstrated in a rabbit prepara tion in

Peripheral Chemoreceptors • Locate d in the carotid and aortic bodies • Respond to decre ased arteri al POz, increased PcOz and H -'• Rapidly respond ing

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which the d iaphragm has a slip of muscle from which reco rdings can be made without int erfering with the ot he r respiratory muscles. C lassical experimen ts sho wed th at inflation of the lungs tended [Q inhi bit furthe r inspiratory muscle activity. The opposite respo nse is also seen , t hat is, deflation of the lungs tends to initiate inspiratory acti vit y (deflat ion reflex). T h us, these reflexes can provid e a self-regulatory mech anism or negative feedback. The H ering-Breuer reflexes were once though t to playa major ro le in ven tilation by determining th e rate anddeprh ofb rearhmg. This could be done by using the information from the se stretch receptor s to modu late the "switching off" mech anism in th e medull a. For example, bilateral vagotomy, which removes th e input of these receptors, causes slow, deep breathing in most animals. However, more recen t work ind icates that the reflexes are largely inactive in adu lt hu mans unless.rhe.ridal volume excceds(f~s in exerci se. Transien t bilateral blockado of the vagi by local anesthesia in awake h umans does not change either breathing rat e or volum e. There is some evidenc e th at th ese reflexes may be more important in newborn babies.

2. Irritant Receptors These are thought to lie between airway epithelial cells, and they are stimulated by noxious gases, cigarett e smoke, in haled dusts, and cold air. The impulses trave l up the ~s' inmyeh na red fibers, and the reflex effects include bronchoconsrnction andnYI"'...ilm ea. Some physiologists prefer to call these receptorst'rapidly adapting r pulmonary stretch receptors" because they show rapid adapt ation and are apparent ly involved in addit ional mechanoreceptor functions, as well as responding to noxious stimuli on the airway walls. It is possible that irritant recept ors play a role -4J in th e hronchocOJ:llli.ic;.tion of asth ma atta_cks as a result of th eir response to released .h istarnine.

3. J Receptors T hese are the endings of non myelim ited C fibers and sometimes go by t his nam e. The term "juxta -capillary," or J, is used beca use th ese receptors are be. lieved to be in th e alveolar walls close to the ca pillaries. T he evidence for thi s locati on is that th ey respond very quickly to chemicals injected in to the pulmonary circul ation . The impulses pass up the y"agus nerve in slowly conducting ~onmyelina teJ fibers and can result in rapid, shallo w brea th ing, although intense stimulation causes apnea'Vl'here is evide nce th at engorgeme nt of pul.. monarv capillaries and in"cr eases in th e in terstitial fluid volume of the alveo lar wall activate these receptors . T hey may play a role in the rapid, sha llow brea th ing and dyspnea (sensarion of difficulty in breathing) associated with left heart. ~ilu re and interstitial lun g disease.

4. Bronchial C-fibers T hese are supplied by the bronchi al circulation rather than the pulmonary circulation as is the case for J receptors described above. T hey respond qu ickly to chemicals injected into the bronchial circulation . T he reflex responses to stimulation include rapid shallow breath ing, bronchcconstriction, and mucous secretion.

Other Receptors 1. Nose and Upper Airway Receptors T he nose, nasopharyn x, laryn x, and trach ea con tain recepto rs th at respond to mechan ical and che mica l sti mulat ion . T hese arc an ex te ns ion of th e irrita nt reccprors described al~o\'e. Various ret1~x respon ses have been describ ed, including sneezing, coughing, and bronc hoconsrriction, Laryngeal spasm may occ ur if the laryn x is irritated mechanically, for example, dur ing inserti on of an endotrach eal tube with insufficien t local anesthesia .

2. Joint and Muscle Receptors Impul ses from mo ving lim bs arc bel ieved to he part of the stim ulus to vent ilation during exercise, espec ially in the earl y stages.

3. Gamma System Man y muscles, including th e intercostal muscles an d d iaphragm, cont ain muscle spindles that sense elonga tion of the muscle. T h is informacion is used to reflexly control the strength of cont ract ion . These receptors may be involved in the sensation of dyspnea that occurs when un usually large respiratory efforts are required ro move the lung and chest wall, for example, because of airway obstruc t ion.

4. Arterial Baroreceptors A n inc rease in arterial blood pressure can cause reflex hvpovenu lation or ap nea through stimulat ion of the aortic an d carot id sinus barorcceptors. Co nve rsely, a decrease in blooJ pressure may result in hyperv enti lat ion. T he pathways of th ese reflexes are large ly unkn own .

5. Pain and Temperature St imulat ion of many affere nt nerves can hring about ch anges in ventilat ion . Pain often causes a per iod of apnea followed by hyperven tilation . Heat ing of the skin may result in hyperven tila t ion.

Integrated Responses Now th at we h ave looked at the various un its that make up th e respiratory co ntrol syste m (Fib'1.lrC 8~ 1), it is useful to consider th e overall responses of th e system to ch anges in rho arteria l C O 2 , O 2 , and pH and to exercise.

Response to Carbon Dioxide T h e most important factor in the co n tro l of ven t ilation und er normal conditio ns is th e Pe o ) of th e arte rial blood. The sensit ivity of th is control is remarkable. In the co urse-of da ily act ivity with periods of rest and exe rcise, th e arter ial P C0 2 is probab ly held to with in 3 mm Hg. During sleep it may t ise a lit tle more. T he ven tila tory response to C O 2 is nor mally measured by having the subjec t in ha le CO 2 m ixtures or rcbrcarh e from a bag so that the in spired PC0 2 gradually rises. In on e technique, the subject rehrcathcs from a bag that is prcfllled with 7(X)

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CO, and 93% 0 , . As the subject rebreathcs, mcrabolic CO, is added to the

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but th e O 2 concen tra tion remains relati vely high. In such a procedure the PI of the bag gas increases at th e rate of about 4 mrn Hg/min . Figure 8~4 5hO\\'5 th e results of experiments in which the inspired mixture adjusted to yie ld a co ns tan t alveo lar p O ]' (In th is type of experime nt on no subjects. alveolar end -tidal Po , and P~ , are gene rally taken to reflect th e a ria l levels.} It ca n be seen (h a-[ with a normal Po , the ven tilation inc reases about 2- 3 liters/min for each 1 mm Hg rise in P U l l' Lowerin g the Po z prod two effects: a h igher vent ilation for a given Pe o l • and the slope of the line co mes steeper. There is conside rable var iat ion between subjec ts. An ot her way of measurin g respiratory drive is to record th e inspirat ory r sure duri ng a brief period of airway occlusion . The subject brea th es rh roug mouth piece atta ched to a valve box, an d the inspiratory port is provided wit sh urrer. This is closed duri ng an expiratio n (the subject being unaw are), so t th e first part of the next inspiration is against an occluded airway. The sh utre opened afte r about 0.5 sec. The pressure gene rated during the first 0.1 sec of tempted inspiration (known as po.d is taken as a measure of respiratory cen

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Alveolar PC02(mm Hg) Figure 84. Vent ilatory respo nse t o CO2 , Each curve of tota l v ent il ation agains alve olar PC02 is f or a different alveolar P02' In t his stud y, no difference was fou betwee n alveolar P02v alues of 110 m m Hg and 169 mm Hg, th ough some inves t igato rs hav e foun d that t he slope of th e line is slig ht ly less at t he higher P02.

o utput. T h is is largely unaffe cted by the mechan ical prop erties of the resp iratory system, although it is influenced by lung volume. This method can be used to study the respiratory sensit ivity to COl> hypoxia, and othe r variables as well . A red uction in arter ial PC:Dz is very effective in red uc ing the st imulus to vcn- 27 n lation. Fo r exam ple , if th e reader hyperventilat es vo luntarily for a few seco nds, he or she will find that there is no urge to brea the for a short period. A n anesthctizcd pat ien t will frequ en tly stop breat h ing for a min ute or so if first ovcrventilated by the anesthes iologist. The ven tilatory response to CO2 is reduced hy sleep, increasing age, and genetic, racial, and persona lity factors. T rained athletes and divers tend to have a lo_~ _~C2z-5cnsitivity . Various drugs depress th e respiratory cen ter, includ ing morphine and barb itura tes. Patien ts who have taken an overdose of one of these drugs often ha ve marked hypoven tilat ion. The vent ilatory response to CO 2 is also rcduced if th e ~'o;k of breath ing is increased. This ca n he demonstra ted by ha ving nor mal subjects bre,;th e th rough-a nar row tube. The neural outp ut of th e rcspiratory center is not reduced , but it is not so effective in producing ven tilat ion. The abnormally small ven tilatory response to COz and the CO z reten tion in some patients with lung disease can be partly explained by th e same mechan ism. In such patients, reducing the airway resistan ce wit h bronchodilarors often increases their ven tilatory response. There is also some evidence th at the sensitivity of the respirator y cen te r is reduced in th ese patient s. -------7 As we have seen, th e main stimulus to increase ven ti lation when th e arterial I'c o , rises comes from th e cen tral chc rnoreceptors, whic h respon d to the in creased H + concentrati on of th e brain ext racellular fluid ncar th e receptors. A n additiona l stimulus comes from th e peripheral che moreceptors, because of both th e rise in arterial Peo z and the fall in pH. +:

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Response to Oxygen The way in whic h a reduction of Po z in art erial blood stimulates ven tilation can be studied by having a subject brea th e hypoxic gas mix ture s. The end-tidal P Ol and Pco , are used as a measure of the arteria l values. Figure 8~ 5 shows th at when th e alve~lar Pa l z is kept at about 36 mm Hg (by alte ring th e inspired mixture),] th e alveolar po! can be reduced to th e vicin ity of 50 mm Hg before any appre~ ciablc increase in vent ilation occurs. Raising th e Peol increases the ventilat ion at any P O l (compare Figure 8-4 ). Note that when the Pcoz is increased , a reductiOll Tr=t P O l below 100 mm Hg causes some stimulation of ven tilat ion, unlike th e

Ventilatory Response to Carbon Dioxide • Arterial Pco2 is the most important stimulus to ventilat ion under most conditions and it is normally tightly controlled • Most of the stim ulus comes from the central chemoreceptors but the peripheral chemoreceptors also contribute and thei r response is faster • The response is magnified if the arterial P02 is low ered

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Figure 8-5. Hypoxi c response cu rv es. Note th at w he n t he Pco, is 35.8 m m Hg , almo st no inc rease in v ent ilat io n occu rs un t il t he P 0 2 is red uced to abou t 50 mm Hg.

situa tion in wh ich the PC0 1 is no rmal. Thus, th e combined effec ts c!lbpthsrim; uli exceed th e sumofeach ~tirnulus given ~epan1tc:ly, and thi s is referred to as ~ teraction between the hi gh CO2 and low O jstimuli. Large d ifferen ces in response occur be tween individ ual subjec ts. Beca use the POz ca n normally be reduced so far without evoking a ven tilatorv response, the role of th is h ypoxic st imulus in the dav-ro-dav contro l of ven ti la(ion is sma ll. Ho wever, on ascen t to hi gh altitud e, a large increase in ven tilation occurs in response to th e h ypoxia (see C h apte r 9). In some pat ien ts with seve re lun g d isease, th e h ypoxic dri ve to ven tilation be, comes very important. These patients have chronic CO 2 reten tion , and the pH of th eir brain extrace llular fluid has returned to near normal in spite of a raised Pco z. Thus, they have lost most of th eir increase in the stimulus to ven tilat ion from CO 2, In addition, the initial depression of blood pH has been nearly abol ished by renal compensation so that th ere is little pH stimulation of the pcr iph eral ch emorecepto rs (see below). U nder these conditions, the art erial hypoxemi a become s th e ch ief stimulus to ventilation. If such a pati ent is given a h igh 0 .: mixture to breathe to relieve the hypoxemia, ventilation may become grossly depressed. The ven tilatory state is best mon itored by measuring arterial P C"'l) , ' A s we have seen, hypoxe mia reflexly stimulate s ven tila tion by its action on th e carotid an d aor tic bod y chcmoreceprors. It has n o action on the central che morecep to rs; indeed , in the absen ce of peri pheral chemoreceptors, hypoxem ia depre sses respirat ion. However, prolon ged hypo xemia ca n cause mild ce rebral acidos is, wh ich, in rum, can stimulate ventilation.

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Ventilatory Response to Hypoxia • Only the peripheral chemoreceptors are involve d • There is negligible cont rol during norm oxic conditio ns • The control becomes important at high altitude, and in lonq-terrn hypox em ia caused by chronic lung disease

Response to pH A reduct ion in art erial blood pH stimulates ven tilation. In practice, it is often difficult to separate the ven tilatory response resulting from a fall in pH from that caused by an accompan ying rise in Pcoz' However, in experimen ta l animals in wh ich it is possible to reduce the pH at a constant Pcoz' th e stimulus to ven u lation ca n be convincingly demonstrated . Pat ient s with a partl y compensated metabolic acidosis (such as uncontrolled diabet es mellitus) who have a low pH and low Pcoz (Figure 6~8) show an increased ven tilation. Indeed, thi s is respon sible for the reduced P= ,. As we have seen, th e ch ief site of action of a reduced arte rial pH is the penpheral chc moreceprors. It is also possible th at the cen tral chemoreceptors or the res~7 piratory cente r itself can be affected by a change in blood pl-l if it is large enough. I" In this case, th e blood-brain barrier becomes partl y permeable to H + ions. .-J

Response to Exercise O n exercise, ven tilation inc reases promptly and du ring stren uous exertion may reach very high levels. Fit young peop le who att ain a maximum O 2 consumption of 4 liters/min may have a total vent ilat ion of 120 liters/m in, that is. about 15 _ times their resting level. This increase in ventilation Closely ma-tches th e increase . ~ O 2 uptake and CO 2 output. It is remarkable th at the cause of the increased ven tilation on exercise remains largely unknown. The arterial PC02- doe{~lncrcase during exercise; indeed, during severe ex~ise ittypicall yfalls slight lY. T he arter ial PO z usually inc reases sligh tly, although it may fall at very high work levels. The arterial pH remains nearly constan t for moderat e exercise, alt hough during heavy exercise it falls because of th e liberation of lactic acid through anaerobic glycolysis. It is clear, therefore. th at non e of the mechanisms we ha ve discussed so far can accoun t for the large increase in vent ilation observed dur ing light to moderat e exercise. ~ ~7 Other stimuli have been suggested. Passive movemen rof rhe.lnnbs stimulates ven tilation in both an esthet ized animals and awake humans. This is a reflex with receptors presumably located in joints or muscles. it may be respon sible for the abrupt increase in ven tilation ili~t _<:>ccurs duri ng theJirg fu-wseconds of exerc ise. O ne hypothe sis is th af (lli;illations in arterial P 0 2 ani Pcu :-may ~timul;reth~ pe~ ..!-ipp~ral che moreceptorsfeveri 'though th e mean level remains unaltered. These fluctuation s are ca used by th e periodic nature of vent ilation and inc rease when th e tida l volume rises, as on exercise. A nothe r th eory is that the cen tra l chemoreceptors increase vent ilation to hold th fG rterial P~O? ~onstant by some kind of

servo mechan ism, just as the th erm ostat can con tro l a furnace with littl e change in temperature. T he objection that the arterial Peol often falls exercise is ~+ countered bv the assert ion that the preferred level of Pco~ is' re~ in some way. , Prop onents ~f th is th eory believe that th e ven tilato ry response to inhaled COl may not be a reliable guide to wha t h appens on exercise. - - ..... yet anoth er hypoth esis is that vent ilat ion is linked in some way to the add it ion al COz load presented [Q the lungs in th e mixed veno us blood d uring exercise. In an ima l experimen ts, an incre ase in this load produced ei th er by infusing COl in to th e venous blood or by increasin g veno us retu rn h as been sho wn to correl ate well with ven t ilat ion. However, a problem with th is hypoth esis is th at no suitable receptor h as been foun d. Ad ditiona l factors that ha ve been suggested include the increase in bod)' temperature dur ing exe rcise, wh ich stimulates ven tilation, and impulses from the motor cortex. However , n one of th e theories proposed so far is co mplete ly satisfactory.

In

Abnormal Patterns of Breathing

, • • I

Subjects with severe h ypoxemia often ex h ib it a str ik ing pattern of per iodic breath ing kn own as Che)'ne-Swkes respiration. This is cha racterized by periods of apnea of 10 to 20 sec, separa ted by approximately eq ual periods of h yperventilat ion whe n the tidal volume gradually waxes and then wan es. T his pat tern is frequently seen at h igh altitude, especially at n igh t du rin g sleep. It is also found in some patien ts with severe h eart di sease or bra in dam age. T he pattern can be reprodu ced in experimen tal ani mals by length en in g the distanc e through wh ich blood travels on its way to the brain from th e lung. Under th ese co ndit ions, the re is a lon g delay before t he cen tral ch emoreceprors sense th e alterat ion in Pe o z cau sed by a change in ven tilat ion. As a result , th e resp iratory cen ter hunts for th e equ ilibrium co nd ition, always ove rshoot ing it. However, not all instances of C h eyne -Stokes respira tion can he explained on th is basis. O ther abnormal patte rn s of breathin g can also occur in disease.

QUESTIONS For each quest ion, choose the one best answer. 1.

Whi ch of the fo llowing statements about the respiratory cente rs is FALSE ? A. The norm al rhythm ic patt ern of breathing originates from neurons in the pons and me dulla. B. Inspiratory act ivity originates in th e dorsal respiratory group of cells in the med ulla. C. Impul ses from the pneumotaxic cente r can switch off inspiratory activity. D. The cortex of the brain can override the function of the respiratory centers. E. The only output from the respiratory centers is via th e phrenic nerves.

2.

All of the following stat em ents about the central chemoreceptors are true EXCEPT: A They are located near th e ventral surface of the med ulla. B. They respond to both the Pea, and the Po, of th e blood . C. They are activated by changes in t he pH of th e surrounding extrac ellular fluid . D. For a given rise in Peo2 the pH of cerebrospinal fluid falls more th an that of blood. E. If the Peo, of the blood is increased for a long time. the pH of the CSF is returned to near normal by moveme nt of bicarbonate into it . 3. W hich of th e follow ing statem ent s about the peripheral chemoreceptors IS FALSE? A. They respond to changes in arterial Po-. Peo, and pH. 8 . Under norrnoxic condit ions the response to changes in P0 2 is very sm all. C. The response to changes in Peo2 is faste r th an for central cnernoreceptors . D. They are the most important recep tors causing an increased ventilation in response to a rise in PC02. E. They have a high blood flow per gram of tissu e. 4. All of the following state ment s about the vent ilatory response to carbon dioxide are true EXCEPT: A. It is increased if the alveolar P0 2 is raised . B. It depends on both the peripheral and central chemo receptors. C. It is reduced during sleep. D. It is reduced if the w ork of breathing is increased. E. It is a major factor controlling the normal level of ventilation. 5. All of the follow ing statements about the ven tilatory respons e to hypoxi a are true EXCEPT: A. It is t he major stimu lus to ventilation at high altitud e. B. Ventilation is inhibited if 100% oxyg en is breat hed. C. It increases if the PC02 is raised. D. It may be a major stimulus to ventilation in patients w ith severe chronic lung disease. E. It does not play a role in mild carbon monoxide poisoning. 6. The most important stimu lus controlling the level of resting ven tilation is: A. P02 on peripheral chemoreceptors. B. P C0 2 on peripheral chemoreceptors. C. pH on peripheral chemorecept ors. D. pH of CSF on central chemo recept ors. E. P02 on central chem orec epto rs. 7. Exercise is one of the mo st pow erful stim ulators of ventilation. It primarily works by way of : A. Low arterial Po, . B. High arterial Pco- .

C. Low P02 in mixed venous blood.

8.

D. Low arterial pH. E. None of the above. All of the followin g statem ents about the Hering-Breur inflation reflex are true EXCEPT: A. The impulses travel to the brain via the vagus nerve. B. It results in further inspiratory efforts if the lung is maintained inflated. C. It is only seen in adults at high tidal volumes. D. It may help to inflate the newborn lung. E. Abolishing the reflex in many animals causes slow deep breathing.

r Respiratory System Under Stress HowGas Exchange Is Accomplished During Exercise. at low and High Pressures, and at Birth Exercise High Altitude Hyperv entilatio n Pol ycyth emi a Ot he r Featu res of

Acclimatizatio n Oxygen Tox icity Absorpt ion Ate lectasis

Space Flight Increased Pressure

Inert Gas Narcosis O 2 Toxicity Hyperbaric O 2 Therapy

Polluted Atmospheres Liqu id Breathing Perinatal Respiration Place nta l Gas Exc hange The First Breat h Circulatory Changes

Decom pression Sickness

The normal lung has enormous reserves atrest, andthese enable it tomeetthe greatly increased demands for gas exchange during exercise. In addition, the lung serves as our principal physiological link with theenvironmentthatwe live in;its surface area is some30times thatof the skin. The human urge to climb higher anddive deeper putstherespiratory system under great stress, although these situations areminor insults compared with the process of being born!

Exercise

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T h e gas excha nge de ma nds of the lung are enormou sly inc reased by exercise. Typ~ ically, th e resti ng oxyge n consum ptions of 300 ml/min ca n rise to about 3000 ml/min in a moderately fit subject (an d as hi gh as 6000 ml/min in an elite ath lete). Similarly, the rest ing CO2 output of, say, 240 ml/min increases to about 3000 ml/min . T ypically, th e respiratory exchange rati o (R) rises from about 0.8 at rest (0 1.0 o n exercise. This increase reflects a greater relianc e on carbohydr are rathe r than fat to prod uce the required en ergy. Inde ed, R ofte n reach es even hi gher levels dur ing the unsteady state of severe exercise when lactic acid is produced by anaerob ic glycolysis and addit iona l CO 2 is the refore eliminated from bicarbonate. In addi tion, there is increased C O 2 e liminat ion because the increased H + can , ce n rratio n st imula tes the peripheral chemoreceptors th us increasing venti lation. Exercise is convenien tly studied on a treadmi ll or stationary bicycle . As work rare (or power) is increased, oxygen uptake increases lin early (Figure 9~ lA) . H owever, above a certa in work rate, VOz becomes co nsta nt; thi s is known as th e Vo zmax. An increase in work rate above this level can occ ur o nly th rough anaerobic glycolysis. Vent ilat ion also increases linearly ini tia lly whe n plotted aga inst work rate or V0 2' but at h igh V0 2 va lues, it increases more rap idly bec ause lact ic acid is libel" ated, and th is increases the ve nt ilatory st imulus (Figure 9,I B). So me t imes th ere is a clear break in the slope, and thi s has been ca lled anaerobic rhreshold, altho ugh the term is somewhat con trov ersial. U nfit subjec ts produce lactate at relat ively 10\\1 work level s, whereas well-trai ned subjects can reach fairly h igh work levels before substan tial anaerob ic glyco lysis occ urs. Man y fun ctions of th e respirato ry syste m cha nge in response to exe rcise. The diffusing ca pacit y of th e lung increases bec ause of increases in both the diftus'2

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ilo, (Il min)

Figure 9·1 . A . O 2 co nsum pt io n (Vo ) increas es nearl y lin early w ith work rat e until t he Vo 2max is reached. B. Vent ilat ion in iti al ly increases lin earl y w it h O 2 consu m ption but rises more rapidl y w hen substant ia l am o u nt s of b loo d lact ate are for med. If th ere is a clear break, this is so met imes called the an ae rob ic th res ho ld (ATI. Cardi ac o utp ut increase s mo re slow ly th a n ve ntilat io n.

ing capa city of the memb rane, D~vj, and the volume of blood in the pulmon ary capillaries, Ye. These changes arc brought abou t by recruitment and distension of pu lmonary capillaries, particularly in the uppe r parts of the lung. Typically, the diffusing capac ity increases at least th reefold. Never the less, some eli te athletcs at extremely high work levels show a fall in arterial Po , caused hy diffusion (imitat ion. .. Ca rdiac ou tput increases approximately lin early with work level as a result of increases in bo th heart rate and stroke volume. However, the cha nge in ca rd iac output is only about a quarter of the increase in vent ilation (in l/min ). This makes sense because it is much easier to move air than to move blood. If we look at the Fick equation, V O l = Q(CU("1z - Cvo z), th e increase in V0 2 is brough t abou t by both an increase in cardiac output and a rise in arte rial-veno us O 2 differen ce because of th e fall in th e oxygen conc en tration of mixed venous blood. By con trast, if we look at th e analogous equatio n for ventilation, Voz = \'E (Flo z FF.QZ), the difference between inspired and expired O 2 concen trations docs no t cha nge . Th is is consisten t with th e much larger inc rease in vent ilation tha n blood flow. T he increase in cardiac output is associated with elevations of both the pulmona ry artery and pulmonary veno us pressures, which acco un t for the recruitmen t and d istension of pulmon ary cap illaries. Pulmonary vascular resistance falls. In norma l subjects, the amoun t of vcn tilano n-perfusion inequality decre ases durin g moderate exercise because of the more uniform topographical d istribution of blood flow. However, because the degree of ven rilarion-pcrfusion inequa lity in normal subjects is tr ivial, th is is of little conseq uence . There is some ev idence that in elite athletes at very high work levels, some ven tilat ton-perfusion inequa lity develops, possibly because of mild degre es of in terst iti al pulmona ry edema. Ce rtainly, fluid must move out of pulmonary capillaries heca use of the increased pressure with in them . The oxygen dissoc iation curve moves to the right in exercising muscles because of the increase in P C0 2' H + concen tra tion, and temperature. This assists the unloading of oxygen to the muscles. W hen th e blood retu rns to the lung, the temperature of the blood falls and th e curve sh ifts leftward somewhat. In some animals such as horses and J ogs, the hematocrit increases on exercise because red cells arc eject ed from t he spleen, but this docs not occur in hum ans. In periphera l tissues, add itio na l capillaries open up, th us reducing th e diffusion pat h length to th e mitochondria. Periph eral vascular resistance falls because the large increase in card iac output is not associated with much of an increase in mean arte rial pressure, at least during dynam ic exercise such as run ning. During static exercise such as weigh tlifting, large increases in systemic arte rial pressure ofte n occur. Exercise train ing incre ases the nu mber of capillaries and rnitochondria in skeletal muscle. As we saw in C hapte r 8, th e very large increase in ven tilation that occurs during exercise is largely unexp laine d. However, th e net result is that th e arterial Po" P= " and pH are little affected by moderate exercise. A t very high work levels, P= , often falls, Po, rises, and pH falls because of lactic acidosis.

Altitude (ff)

a

10000

20000

800 Sea level

150

0; I

E

.s

0; I

600

100 E

.s

l' ~

"'"'

l'

a

400

a.

D-

50

0

·C

1D E

e

"C

l'

.5.

200

Mt. Everes t

'" m

"'

E

a a

a

2000

4000

6000

8000

Altit ude (m)

:

Figure 9-2. Rel ati on ship betw een altitud e and baromet ric p ressu re. No te t hat at 1520 m (5000 tt l (Denver, CO), the P 0 2 of moist inspired ga s is abo ut 130 m m Hg, but is o nly 43 m m Hg o n th e su m mit of M ount Ever est .

High Altitude The barom etri c pressure decreases with distance above the eart h' s surface in an approximately expone n tial manner (Figure 9-2). The pressure at 5800 m (19,000 fr) is on ly one-ha lf the no rmal 760 mm Hg, so the POz of moist inspired gas is (380 - 47 ) X 0.2093 = 70 mm Hg (47 mm Hg is the parti al presslire of water vapor at body temperature). At th e summit of Mount Everest (a ltitude 8848 m or 29,028 fr), the inspired Po , is on ly 43 mm Hg. A t 19,200 m (63 ,000 fr), the barometric pressure is 47 mm H g so that the inspired POz is zero . In spite of the hypoxia associated with h igh altitude, some 140 million people live at elevat ions over 2500 m (8000 ft ), and permanen t residen ts live higher than 4900 m (16,000 fr) in the A ndes. A remarkable degree of acclimatization occurs when h umans ascend to these altitudes; indeed , climbe rs h ave lived for SC \, I era] days at altitudes th at would cause unconsciousness with in a few seconds in the absen ce of acclimat izat ion.

Hyperventilation The most impo rtan t feature of accl imatization to h igh altitude is hvpervenril ation . Its ph ysiological value ca n be seen by consider ing the alveolar gas equation for a climber on the summit of Mou nt Everest. If the cl imber's alveolar Pea l were 40 and respirato ry excha nge ratio 1, th e clim ber's alveo lar Po , would be 43 - (40/ 1)* = 3 mm Hg: However, by in creasing th e climber's ven tilation five'

fo ld, and thus redu cing the climber's Pco , to 8 mm Hg (see p. 18), rhe cl imber can raise h is or her alveolar POz to 43 - 8 = 35 mm Hg. T ypically, the arterial Peo, in permanent residents at 4600 m ( 15,000 fr) is abou t 33 mm Hg. The mechan ism of the hyperventilarion is h ypoxic srimulation of the peripheral chemorecepto rs. The result ing low art erial P C'02 and alkalosis tend to inhibit th is inc rease in ven tilation , but after a day or so, the cerebrospina l fluid (CSF) pH is brough t part ly back by movement of bica rbona re out of th e CSF, and after 2 or 3 days, th e pH of the arterial blood is returned to nea r normal by renal excretion of bicarbonate. These brakes on ventilation are th en red uced , and it increases further. In addit ion , th ere is now evidence th at th e sensitivity of the carotid bodies to hypoxia increases dur ing accl imatization . In terestingly, people who are bor n at h igh alt itude have a diminished ven tilatory response to h ypoxia that is on ly slowly corrected by subsequent residence at sea level. Conversely, those born at sea level who move to h igh altit udes retain their hypoxic response in tact for a lon g time. A pparcntly, th erefore, this ventilatory rcsponse is determin ed very early in life.

Polycythemia Another apparen tly valuab le feature of accl imat izat ion to h igh alti tude is an in crease in the red blood cell concen trat ion of th e blood. The result ing rise in h emoglob in con cen tration, an d the refore Oz~carry ing capacity, means that alth ough the arter ial Poz and O 2 satu rat ion arc dim ini shed, th e O, con cen trat ion of th e arterial blood may be nor mal or even above normal. For ex amp le, in perman ent residen ts at 4600 m (15, 000 ft) in th e Peruvian Andes, th e arteria l PO, is on ly 45 mm Hg. and the correspon ding arteri al O 2 saturat ion is on ly 8 1%. Ord inarily, th is would co nsiderab ly decrease the arterial O 2 co ncen trat ion , but because of the po lycyth emia , th e h emo glob in co ncen tra t ion is increased from 15 to 19.8 gm/ IOOml, giving an arterial 0, concentratio n of 22.4 ml/l OOml, wh ich is act ually high er than the nor mal sea level valu e. The po lycythemia also tends to maintai n th e PO z of m ixed venous b lood, and typ ica lly in Andean na t ives ltving at 4600 m (15,000 fr), thi s Po , is on ly 7 mm Hg below normal (Figure 9-3 ). The st imu lus for the increased producti on of red blood cells is hypoxe m ia, wh ich releases erythropoie t in from the kidney, wh ich in turn stimulat es th e bone marrow. Polycythe mia is a lso seen in man y patients with chronic hypoxemia cau sed by lung or h eart d isease. A lthough the polycythe mia of hi gh alt itude increases th e O s-carrving capacity of the blo od , it also raises th e blood viscosity. This can be del eterious, and some ph ysiologists believe that the marked po lycythe mia th at is someti mes seen is an inappropriate response.

Other Features of Acclimatization There is a rightward sh ift of the O 2 dissociation curve at moderate altitudes th at results in a better un load ing of O 2 in venous blood at a given PO z . T he cause of the shift is an increase in concentration of 2,3-dip hosphog lycera te, wh ich deve lops primarily beca use of the respirato ry alkalosis. At h ighe r altitudes th ere is a leftward shift in the dissoc iati on curve ca used by the respirato ry alkalosis, and th is assists in the load ing of 0, in the pu lmonary capillaries. T h e number of capillaries

Inspired gas

Alveolar gas

Arterial blood

Mixed venous blood

150

Figure 9-3. POz values fr om inspi red air t o m ixed v eno us bloo d at sea level and in resid ent s at an alt it ud e of 4600 m (15,000 ttl. Note that in spi te of the m uch lower inspired POz at alt itude , the POz of the mi xed ve nous blood is on ly 7 m m Hg low er.

per unit volume in perip heral tissues incr eases, and cha nges occur in the oxidatit'e enzymes inside th e cells. The maximum breathing capad t)1inc reases beca use the air is less dense, and this assists th e very high ven tilations (up to 200 liters · min - 1) that occur on exercise. However, th e maximu m O 2 uptake declines rapidl y abov e 4600 m (15,000 ft) . This is co rrected to a large exte nt (though not com pletely) if 100% 0 , is breathed. Pulmonary vasoconstriction occurs in response to alveolar h ypoxia. This increases th e pulmonary arte rial pressure and the work don e by the right heart. T he hypertension is exaggerated by the pol ycyth emia which raises th e viscosity of the blood. H ypertrophyof the right heart is seen with characte ristic cha nges in th e electrocardiogram. There seems to be no physiological advamage in thi s response, ex-

Acclimatization to High Altitude • Most important feature is hyperventilation • Polycythemia is slow to develop and of mi nor value • Other features include increases in cellular oxidative enzymes and the concentration of capillaries in some tissues • Hypoxic pulmon ary vasoconstriction is not beneficial

cept that the topograph ical distribution of blood flow becomes more uniform. The pulmonary h ypertension is somet imes associated with pulmona ry edema, alth ough the pulmonary venous pressure is normal. The mechanism for this is uncertain, but one h ypothesis is that th e arteriolar vasoconstrict ion is uneven , and leakage occurs in unprotected, damaged cap illaries. The edema fluid has a high protein concentration, indicat ing th at the permeability of th e cap illaries is increased . Newc omers to high altitude frequently complain of headache, fatigue, d iaainess, palpita tions, insomnia, loss of appetite, and nausea. This is known as acute mountain sickness and is at tributable to the hypoxem ia and alkalosis. Long-term residen ts somet imes develop an Ill-defined syndrome chara cterized by marked po lycyth emia, fatigue, reduced exercise toleran ce, and severe hypoxemia. This is called chronic mountain sickness.

O 2 Toxicity The usual problem is gett ing enough O 2 into th e body. but it is possible to have too much . W he n high concen tra tions of O 2 are breat hed for man y hours, damage to th e lung may occu r. [f guinea pigs are placed in 100% O 2 at atmospheric pressure for 48 hours, they develop pulmon ary edema. The first pathological changes are seen in the endothelial cells of th e pulmonary capi llaries (see Figure 1-1). Ir is (perhap s fortunately) d ifficult to administer very high concen trations of O 2 to pat ient s, but evidence of impaired gas exchange ha s been demonstra ted afte r 30 hours of inhalation of 100% 0 ,. Normal volunt eers who breath e 100% 0, at at mosphe ric pressure for 24 hours complain of substern al distress that is aggravated by deep breath ing, and they develop a dimi nut ion of vita l capacity of 500 to 800 ml. T his is probably caused by absorpt ion atelectasis (see below ). A no the r hazard of breathin g 100% O 2 is seen in premature infan ts who develo p blindne ss because of retrolen tal fibrop lasia, t ha t is, fibrous tissue formation beh ind th e len s. Here the mecha nism is local vasoconstriction caused by th e h igh P 0 2 in t he incubator, and it can be avo ided if the arterial PO l is kept below 140 mm Hg.

Absorption Atelectasis This is ano the r da nger of breat hing 100% O 2 , Suppose that an airway is obstructed by mucus (Figure 9-4) . The tota l pressure in th e trapped gas is close to 760 mm Hg (it may be a few mm Hg less as it is absorbed because of elastic forces in the lung). But th e sum of th e part ial pressures in the veno us blood is far less th an 760 mm Hg. T hi s is because th e Po, of th e venous blood remain s relatively low, even when O 2 is breathe d. In fact, th e rise in O 2 concentration of arterial and venous blood when O 2 is breathe d will be the same if cardiac output remains unchanged, but because of th e shape of the O 2 dissociation curve (see Figure 6-1), th e increase in venous n .) z is only about 10 to 15 mm Hg. Thus, because th e sum of th e part ial pressures in th e alveolar gas green ly exceeds th at in the vcnous blood. gas diffuses into th e blood , and rapid collapse of the alveoli occurs. Reope ning such an atelectatic area may be difficult because of surface ten sion effects in such small units.

)( 0,(100)

0,668 CO, 45

CO, (40) N, 573 H, O -.£..

H20 --iZ. Total 760

O2

CO 2

.'.,

55 45

O2 CO2

N,

40 45 573

H2 0 47 Total 147

H 20 47 Total 705

A

B

Total

760

Figure 9-4. Reason s for atelectasis of alveol i beyond bloc ked airways w he n O2 (A) and w hen air (B) is breath ed. Note that in both cases, the sum of the gas partial pre ssures in th e mixed veno us blood is less than in the alveolL ln B, th e P02 and Pee , are shown in parentheses because th ese va lues change w ith ti me. How ever , the t ot al alveo lar pressure rema ins w it hin a few mm Hg of 760.

A bso rpt io n co lla pse al so occurs in a blocked regio n e ven when ai r is brea the d, alrhough here rh e process is slower. Figure 9-4B shows rhat again the sum of the partial pressures in ven ous blood is less than 760 mm Hg because the fall in P0 2 from arterial to venous blood is much greater th an the rise in pco! (thi s is a reflect ion of the steeper slope of the CO 2 compared with the Oz dissociation curve-see Figure 6-7) . Because the tota l gas pressure in th e alv eoli is near 760 mm Hg, absorpt ion is inevit able. Actually, the cha nges in the alveolar parti al pressures du ring absorption are somewhat complicated, but it can be shown that the rate of collapse is limited by the rate of absorption ofN z. Because this gas has a low solubilit y, its presence acts as a "splint" that, as it were, supports the alveoli and dela ys collapse. Even relati vel y small concen tratio ns of N z in alveolar gas ha ve a useful splin ting effect. Neverthe less, postoperati ve atelectasis is a common prob lem in patient s who are tre at ed with hi gh O 2 mixtures. Collapse is particulady likely to occur at th e bottom of the lung, where the parench yma is least well expanded (see Figure 7-8) or the small airways are act ually closed (see Figure 79). This same basic mech an ism of absorption is respon sible for the gradu al d isappearanee of a pneumothorax, or a gas pocket int roduced under the skin.

Space Flight The absenc e of gravity causes a number of ph ysiological changes, and some of these affect th e lung. The distr ibuti on of ven tilation and blood flow become more

un ifor m, with a small corresponding improvement in gas exc hange (see Figures 5 ~ 5~ 10), th ough some inequality remains because of no ngravirat.iona ] facto rs. The deposition of inhaled aerosol is altered because of the absenc e of sed irnentario n . In addition, th orac ic blood volume in itially inc reases because blood does not pool in th e legs and th is raises pu lmon ary capillary blood volume and diffusing capacity. Postural h ypote nsion occurs on retu rn to earth; th is is kn own as cardiovascular deconditioning. Decalcificat ion of bon e and muscle atrop h y may occur, presumably th rough d isuse. T here is also a small reduction in red cell mass. Space sickne ss d uring th e first few days of flight can be a serious operational problem .

8 and

Increased Pressure During J iving, th e pressure increases by 1 at mosphe re for every 10 m (33 fr) of desce nt . Pressure by itself is relatively innocuous, as lon g as it is balanc ed.t Ho wever, if a gas cav ity such as th e lun g, midd le ear, or intracrani al sin us fails to commun icat e with th e outside , the pressure difference may cause compression on descent or overexpansion on ascen t. For example, it is very important for scuba dive rs to exhale as they ascend to prevent ovcrinflation and possible rupt ure of th e lungs. T h e increased den sity of the gas at depth increases the work of breat h ing. T his may result in COl reten tion, espec ially on exercise.

Decompression Sickness During diving, th e high part ial pressure of N, forces this poorly soluble gas into solution in body tissues. This part icularly occurs in fat, \',rh ich has a relatively h igh N 2 solub ility. However, th e blood supply of adipose tissue is meager, and the blood can carry little N 2• In addition, the gas diffuses slowly because of its low solubility. As a result , equilibration ofN 2 between the tissues and the env ironmen t takes h ours. During ascent, N 2 is slowly removed from th e tissues . If decompression is un dul y rapid, bubbles of gaseous N 2 form, just as CO 2 is released when a bottle of champagne is opened. So me bub bles can occ ur wit hout ph ysiological d isturbanc es, but large n umbers of bubbles cause pain, especially in the region of joints ("be nds"). In severe cases, the re may be neurological disturban ces such CIS deafness, impaired vision, and even paralysis caused by bubb les in the centra l n ervous system (eNS) [h at obstruct blood flow. The treat ment of decompression sickness is by recompression. This reduces th e volume of th e bubbles and forces the m bac k into solution, and often results in a dramat ic reduction of symptoms. Preven tion is by careful decompression in a se ries of regulated steps. There are schedules th at arc based partl y on theory and partly on expe rience and sho w how rapidly a di ver can come up with little risk of developing bends. A short but very deep d ive may req uire hours of gradual decompression. It is n ow known th at bubble formation during ascen t is very cornmo n oTherefore, th e aim of the decom pression schedules is to preven t th e bubbles from growing t oo large.

t

At pressures of hundreds of atmospheres, chemical reactions arc affected. For example, the Oz dissociation curve is displaced.

.

~

Ie. o'

j

The risk of decompression sickness following very deep Jives can he reduced if a he lium-O r mixture is breath ed during th e J ive. Helium is about orre-hal f as sol; uble as N z so th at less is dissolved in tissues. In addition, it has one-sevent h of th e molecul ar weight ofN z an d therefore diffuses more rapidly th rough tissue (Figure 3- 1). Bot h these factors reduce th e risk of bend s. A nother advant age of a hel iumO z mixture for d ivers is its low density, which reduces the work of breath ing. Pure O 2 or en riched O 2 mixtures can not be used at depth because of the dan gers of 0 1 toxicity (see below). Commercial divers who arc working at great depths, for example on pipelines, sometimes use saturari<m diq,,·ing. W hen they are not in the water, th ey live in a h igh pressure chamber on the supply ship for several days, which mean s th at th ey do not retu rn to normal atmospheric pressure during this time. In this way they avo id decompression sickness. However at the end of the period at high pressure, th ey may take man y hours to decompress safely.

Inert Gas Narcosis Althou gh we usually think of N j as a ph ysiological inert gas, at high part ial pres; sures it affects the e NS. A t a depth of about 50 m ( 160 fr) there is a feeling of euphor ia (no t unlike that following a mart ini or two ), and di vers ha ve been known to offer the ir mouthpi eces to fish ! At higher partial pressures, loss of coordination and eventually coma may develop . The mech ani sm of action is not understood but may be related to the high fat.water solubilirv of N z, which is a general property of anesthe tic agent s. Othe r gases, such as hel ium and hydrogen , can be used at much greater depths witho ut narcotic effects.

O2 Toxicity W e saw earlier th at inhalation of 100% Oz at 1 atmosphe re can damage the lung. Another form of O 2 toxicity is stimulat ion of the e NS, leading to conv ulsions, when th e Po z cons iderably exceeds 760 mm Hg. The convulsions may be preceded by premoni tory symptoms such as nausea, ringing in the ears, and twitch.. ing of the face. The likeliho od of convul sions depends on the inspired P O I and the J uration of exposure, and it is increased if the subject is exercising. At a Po z of 4 at1110; spheres. convulsions frequent ly occur wit hin 30 min utes. For increasingly deep d ives, the O z conc entration is progressively reduced to avoid toxic effect.s and may even tually be less than 1% for a normal inspired R1z! The amateur scuba diver should never fill his or her tanks with 0 1 because of th e danger of a con vulDecompression Sickness • • • • •

Caused by the formation of N2 bubble s during ascent f rom a deep dive May result in pain (vbenos"! and neurolog ical disturb ances Can be prevented by a slow, staged asce nt Treated by recompression in a chamber Incidence is reduced by breathi ng a helium-oxygen m ixture

sion underwat er . H owever , pur e O 2 is somet imes used by th e military for sh allow Jives because a closed brea th ing circuit with a CO2 absor ber leave s no tell tal e bubbles. T he bioche mical basis for the deleterious effects of a high Po , on the CNS is no t fully understood but is probabl y the inact ivation of certain enzymes, especially deh vdropenascs co nta in ing sulfhyd ryl groups.

Hyperbaric O2 Therapy Increasing the arter ial PO I to a very h igh level is useful in some clinical situ at ions. O ne is severe CO poison ing in whi ch most of the hemoglo bin is bou nd to C O and is th erefore una vailable to ca rry Oz. By raising the inspired PO I to 3 atmosphe res in special chambers, th e amo unt of dissolv ed O 2 in art erial blood ca n be inc reased to abo ut 6 ml/l OO ml (see Figure 6-1), and thu s th e needs of the tissues can he me t without fun ct ioning hem oglobin . Occas iona lly, an an emic crisis is managed in th is way. H yperbaric Oz is also useful for tre at ing gas gangrene because the or gan ism cannot live in a h igh PO I enviro nme nt. A hyperbar ic cha mber is also useful for treat in g decompression sickness. Fire and explosions are serious hazard s of a 100% Oz atmosphe re, especially at increased pressure. For thi s reason , O 2 in a pressure chamber isgiven by mask, and th e cha mber itself is filled with air.

Polluted Atmospheres' Atmosph eric pollut ion is an inc reasin g problem in ma ny co unt ries as the number of motor veh icles and indu str ies increas es. T he chief pollut ants arc va rious ox ides of nitrogen and sulfur, ozone, carho n monoxide , various h ydrocarbons, and partic ulare matter. Of th ese , nitrogen ox ides, h ydroc arbons, and CO arc prod uced in large quantities by the in tern al co mbu stion eng ine, th e sulfur ox ides mainl y come from fossil fuel pow er sta t ions, and ozone is ch iefly formed in the at mosphere by the ac t ion of sun ligh t on nitrogen ox ide s and h ydrocarbons. The co ncentra t ion of at mosph eric poll utants is gre atl y increased by a temperature inversion whi ch preven ts th e norma l escape of the warm surface air to the Lipper atmosphere. Nitrogen ox ides cause infl ammation of the upp er resp iratory trac t and eye irrita tio n , and they arc respo nsible for th e yellow haze of smog. Sulfur oxi de s an d ozone also cause bronchi al in flammat io n , and ozone in high co nc ent ratio ns can prod uc e pu lm onary ed ema. T h e dan ger of C O is its propensity to t ie up hem oglo hin (see p. 80) , and cycl ic h ydrocar bons are potent ially ca rc ino genic. Both th ese po lluta nts exis t in tobacco smoke, wh ich is inh aled in far hi gh er concen trati ons th an an y other at mosp heric pollutant. There is evidence that some pollu tants act syn ergist ica lly, that is, t he ir co mbine d act ion s exceed the sum of the ir individ ual ac t ions, hut more work is req uired in this area. Many poll utants exist as aerosoL~, that is, very small part icles that rem ain suspend ed in th e air. W hen an ae roso l is inh aled, its fate depends o n th e size of th e pan icles. Large parti cles are removed by impaction in the nose and ph aryn x. This

:j:

For a more detailed account, Sl'C JB \Ve st: Pulmonar)' PathoJ)hysiology- The Essenuais, ed 6. Baltimore, Lippin cot t W illiams & Wilkins, 2003.

mea ns that the particl es are una ble to tur n the co rners rap idly be cause of th eir in ert ia, and th ey impi nge on the wet mucosa and are trapped. Med ium- sired r ani, des deposit in small airways and elsewhere because of th eir weight. T his is called sedimen tation and occurs especiall y wh ere the flow veloc ity is sudden ly red uced becau se of th e enor mo us increase in co mbine d a irway cross sect ion (Figure 1, 5). For this reason, deposition is heavy in the termina l and respiratory bronch ioles. and th is region of a coa l miner's lung shows a large d ust conce n trat ion. The smallest part icl es (less than 0. 1 micron in d iameter) reach the alveoli, where some deposition occurs through diffusion to the walls. ~1any small part icles are no t de posited at all hut are exh aled with th e ne xt breath . O nce dep osited , most of the part icles are removed by various clearance mech an isms. Parti cles that dep osit on bronch ial walls are swept up the mov ing stair, case of mucus whi ch is prop e lled by c ilia, and th ey are either swallowed or ex, pectorated . However, rh e ci liary ac tion can be paralyzed by inh aled irritants . Part icles deposited in th e al veoli are ch iefly engulfed hy mncrophagcs that leave via the blood or lymph atics.

Liquid Breathing

•

It is possible for mam mals to survive for some hours breathing liquid inst ead of air. T hi s was first shown with mice in sa line in wh ich th e O 2 concent ration was in creased by exposure to 100% O 2 at 8 a tmosp heres pressure. Subsequen tly, mice. Ta ts, and dogs have survived a period of breath ing fluorocarbon exposed to pure O 2 at I atmosphe re. This liquid has a high solubility for bot h 0 , and CO2 , T he an ima ls succe ssfully returned to air breath ing. Because liquids h ave a much hi gher de nsit y and viscosity than a ir, the work of breath ing is eno rmo usly increased . However, adequate ox ygenation of the urterial blood can be obtained if th e in spired co nc ent rat ion is raised sufficiently. In , terestinglv, a serious pro blem is eliminat ing C O 2 • \Ve Sa\V earlier th at d iffusion with in the a irways is ch iefly responsihle for the gas exchange tha t oc curs bet ween the alveoli and th e termin al or respirat or y bronch ioles, wh ere bulk or convective flow takes over. Because th e diffusion rates of gases in liqu id are many orde rs of magn itude slower than in th e gas ph ase, th is means that a large partial pressure differenc e for CO2 between alveoli and te rmin al bronchioles m u st be ma intained. A n imals breath ing liquid, th erefore, commonly develop C O 2 reten tion and acidosis. No te th at th e diffusion pressure of O 2 can always be raised by increasing the inspired P O I ' hut thi s opt ion is not ava ilable to h elp elim ina te CO 2 , Liquid brea th ing has been proposed as a possible way of ve ntilat ing infan ts with t he respiratorv d istress syndro me caused by lack of surfactan t. The a im is to tide th em over th e danger per iod un t il th e surfactant system matures.

Perinatal Respiration Placental Gas Exchange During fetal life, gas exch ange takes place th rough th e placenta. Its ci rculation is in parallel with that of th e peripheral tissues of th e fetus (Figure 9-5) un like the

149

Respiratory System Under Stres s

situation in the adult in wh ich the pulmonary circulation is in series with th e svstemi c circulation . Maternal blood ente rs the placen ta from th e uterine arte ries and surges into small spaces called intervillous sinusoids wh ich function like th e alveoli in the adult. Fetal blood from the aorta is supplied to capill ary loops th at protrude into the intervillous spaces. G as exchange occurs across the blood, blood barrier, approximately 3.5 u rn thick. This arrangemen t is much less efficien t for gas exchange th an in th e adult lung. Ma tern al blood apparen tly swirls around the sinusoids somewha t haph azardly, and th ere are probably large d ifferences of Po , within these blood spaces. Contrast this situation with th e air-filled alveoli in whic h rapid gaseous diffusion stirs up the alveolar contents. The result is that the P0 2 of th e fetal blood leaving the placen ta is only about 30 mm Hg (Figure 9-5) . This blood mixes with venous blood draining from th e feta l tissues an d reaches the right atr ium (RA) via the inferior vena cava (l v e ). Because of streaming with in the right atr ium, most of this blood th en flows directl y into th e left atrium

FO

ivc

RV

i

LV

22

1 14

30

[

Tissues

Placenta

J

Figure 9-5. Blood circ ulation in the human fetus . The nu mbers sho w th e app rox im ate P02 of th e blood in mm Hg. See text f or details.

(LA) through th e ope n foramen ovale (FO) and rhus is d istributed via th e ascend ing aort a to th e brain and he art. Less well oxygena ted blood retu rn ing to the right atrium via th e superio r vena cava (S VC) finds its way to the right ven tricle (RY ), hut on ly a small portion reach es th e lun gs. Most is shun ted to the aorta (Au) thro ugh th e ductu s arteriosus (DA). T h e net result of thi s complex arrangc men r is that the hest oxygen ated blood reaches th e brai n a nd h eart, and the non -gas-exchan ging lungs receive on ly about 15% of the card iac output. No te that the arte rial Po z in th e descending aor ta is onl y about 22 mm Hg. T o summarize th e th ree most important difference s betw een the feta l and adult circu lati o ns: 1. Th e pl acen ta is in parallel with the circulation to the t issues whereas th e

.., ,

'", .'

lung is in series in th e adult. 2. T h e ductus arteriosus sh unts most of th e blood from the pulmon ary artery to th e descending aorta. 3 . Str eaming within the right atr ium mean s th at the oxygenated blood from the placen ta is preferen tially delivered to th e left at rium through the foramen ova le and therefore via th e aorta to the brain.

The First Breath The emergence of a baby int o th e outside world is perhaps the most cataclysmic event of h is or h er life. T he baby is sudden ly bombarded with a variety of external stimuli. In add ition, th e process of birth int er feres with placen ta l gas exch ange with resultin g hypo xem ia and h ypercapnia. Finally, the sensitivity of the che rnorecepto rs apparen tly increases drama tic ally at birt h, altho ugh the mechanism is un known . As a consequence of all these ch anges, the bab y makes the first gasp. The feral lung is nor collapsed bur is inflated with liquid ro about 40% of total lung capacity. This fluid is conti nu ously secreted by alveolar cells during feta l life and h as a low pH. Some of it is squeezed ou t as the infant moves th rough th e birt h can al, bur the remaind er h as an import ant role in th e subsequen t in flation of the lung. A s air en ters th e lun g, large surface tension forces have to be overcome. Because th e larger the radius of curvature , th e lower the pressures (see Figure 7 ~4 ) , th is preinflation red uces the pressures requi red. Ne verth eless, the intrapleural pres.sure during the first breath may fall to - 40 cm water before any air enters th e tung, and peak pressures as low as - 100 em water during the first few breaths have been recorded. These very large tran sien t pressures are partly caused by the high viscosit y of th e lung liquid compa red with air. The fetus makes very small, rapid breathi ng movements in the uterus over a considerable per iod before bi rth . Expan sion of the lung is very une ven at first. However, pulmo nary surfactant, wh ich is formed rela tively late in fetal life, is ava ilable to stabilize open alveoli, and th e lun g liquid is removed by th e lvmpha tics and capillar ies. Wir h in a few moments, th e functiona l residual cap acit y ha s almost reached its norma l value and an adequate gas excha nging surface h as been esta blishe d. However, it is several days before un iform ven tilation is ach ieved .

Changes at or Shortly After Birth • • • •

Baby makes strong inspiratory efforts and takes its first breath Large fall in pulmonary vascular res istance Ductus arteriosus closes, as does the foramen ovate Lung liquid is removed by lymphatics and capillaries

Circulat ory Changes A drama tic fall in pulmo nary vasc ular resistance foll ows th e first few breaths. In the fetus, the pulmonary art eries are exposed to th e full syste mic blood pressure via the ductus art eriosus, and th eir wall s are very muscular. As a result, the resistanee of the pu lmo nary c irculation is exquis itely sensitive to such vasoconstrictor agents as hypoxe mia, ac idos is, an d sero tonin an d to such vasodilators as acetylcholine. Several factors account for th e fall in pul mo nary vasc ular resis ta nc e at birth , including the abrupt rise in alveola r P O l th at abolishes the h ypoxic vasoconstriction an d the increased volume of th e lung tha t widens the ca liber of the extra-alveo lar vessels (see Figure 4~2 ) . W ith the resulting increase in pulmonary blood flow, left atrial pressure rises and the flap-l ike foram en ov ale quickly closes. A rise in aortic pressure result ing from the loss of the para llel umbilical circulation also incre ases left atr ial pressure . In addition, right atrial pressure falls as the um bil ical flow ceases. The d uctus arte riosus constricts a few minutes later in response to the direct action of th e increased P0 2 on its smoo th muscl e. In addi t ion, this cons tric tion is aided by alterat ion s in the levels of local and circulat ing pro staglandin s. Flow through the duetus arte riosus soon reverses as the resistance of the pul monary c irculat ion falls.

QUESTIONS For each question, choose the one best answer. 1.

2.

All of t he fol low ing st atements about exe rcise are true EXCEPT: A. It can increase the oxyg en consumption more than te nfold co mpared with rest. B. The measu red respiratory exchange ratio may exceed 1.0. C. Vent ilation Increases much m ore than cardiac outpu t. D. At high levels of exe rcise blood lactate concentrations may rapidly Increase . E. The change in vent ilatio n on exe rcise can be exp lained by the fall in arte-

rial pH. Features of acclimat ization to high altitude include all of t he fo llow ing EXCEPT: A. Hyperventilation. B. Polycythemia. C. Rightwa rd shift of the O2 dissociation curve at extreme altitudes . D. Increase in t he number of capillaries per unit volume in skeleta l muscle . E. Changes in oxidative enzymes inside m uscle cells .

3.

If a small airway in a lung is blocked by mu cus. t he lung distal to this may become atelect atic. W hich of the fo llowing statem ent s is FALSE ? A. Atel ect asis occurs faster if the person is breathing oxygen rather than air. B. The sum of the gas part ial pressures in mixed venous blood is less than in arterial blood. c. The blood flow to th e ate lectatic region w ill fall. D. The sam e m echanism explains the absorption of a spontaneous pneu-

mothorax. 4.

5.

6.

7.

E. The elastic properties of the lung st rongly res ist atelectas is. Helium-o xygen mi xtu res rat her than nitrogen-oxygen m ixtures (with the same oxyg en conce nt ratio n) are preferable for very deep diving because all of the following are reduced EXCEPT: A. Risk of decompression sickness. B. Work of breathing . C. Airway resistance. D. Risk of O 2 toxicity . E. Risk of inert gas narcosi s. The absence of gravity du ring spacef light alte rs all of the follow ing EXCEPT: A Distr ibution of pulm onary blood flow . B. Distribution of ventilation. C. Deposit ion of inhaled aerosol part icles. D. Thoracic blood volume . E. Wo rk of breat hing. Which of the fo llow ing increases by th e largest percentage at max ima l exe rcise com pared w ith rest ? A Heart rate . B. Alveolar ventila tio n. C. Pcoz of mix ed venou s blood. D. Cardiac output. E. Tidal vo lum e. The t ransition fro m placental t o pulmonary gas exchange is accompanied by all of t he following EXCEPT: A. Increased arterial POz' B. Fall of pulmonary vascular resistance . C. Closure of the ductus arte riosus . D. Reversal of blood flow through th e foramen ovale. E. Stro ng respiratory efforts.

Tests of Pulmonary Function How Respiratory Physiology Is Applied to Measure Lung Function'

Ve nt ilat io n Forced Expi ration

Blood Gases and pH Mechanics of Breathing

Lun g Volum es

Lung Com plianc e

Diffusion Blood Flow Ve nt ilation-Perfusion Relationships

Airway Resistance

Top ograph ical Distribution of V entilation and Perfusion

Closing Volume

Control of Ventilation Exercise Perspective on Tests of Pulmonary Function

Ineq uality of Ven tilat ion Ineq uality of Venti lation Perfusion Ratios

This final chapter deals with pulmonaryfunction testing which is an important practical application of respiratory physiologyin the clinic. First we look at the forced expiration. a very simple but nevertheless very useful test. Then there are sections on ventilation-perfusion relationships. blood gases, lung mechanics, control of ventilation and the role of exercise. The chapter concludes by emphasizing that it is more important to understandthe principles of respiratory physiology contained in Chapters 1-9 than to concentrate on the details of pulmonaryfunction tests.

* This cha pter is o nly a brief introducti on to pulmon ary functi on tests. A more derailed descriptio n can he fo und in ]B We st: Pulmonary Pathophysiology-The Essentials , cd 6. Balt imore , Lippincott, W illiams & Wi lkins, 2003 .

"

An importan t p ractical app lication of respira tor y phys iology is th e test ing of pulmonary funct ion. These te sts are useful in a va riety of settings. T h e most importan t is the hospital pulmon ary func tion laborato ry Of, on a sma ll sca le, th e physician 's office, wh er e these tests h elp in th e d iagn osis and the ma nagement of pat ien ts with pulmonary or card iac di seases. In ad d ition, they may be valuable in deciding whe ther a pat ien t is fit enough for surgery_ A no ther use is the eva lua tion of d isability fo r t he purp oses of in surance and wor ker's co mpe nsat ion. Again, some of th e simpler tests are emp loyed in epidemiological surv eys to assess ind ustr ial h azard s or to document th e prevalence of disease in th e commun ity. The rol e of pulmon ary funct ion te sts should be kept in perspect ive . They are rarely a key factor in ma kin g a defin itive di agn osis in a pat ient with lung d isease . Rat h er, th e various pa tterns of impaired funct io n overlap d isease entities. W h ile the te sts are often val ua ble for following the progress of a patient with chron ic pu lmo na ry d isease and assessing the results of treatment, it is genera lly far more importan t for the me dical stu dent (o r physician ) to understa nd the pr inciples of h ow th e lun g wor ks (Chapters 1 through 9 ) than to concentrate only on lung func t ion tests.

::

Ventilation

.>

:~ 1

Forced Expiration A very useful and sim ple test of pu lm onary func t ion is th e measur em ent of a single forced expiration, Figur e 1O~ 1 shows t he spiro meter record obtai n ed wh en a subject inspires m ax imally and then exhales as h ard and as completely as he or she can , The vo lume exhaled in the first seco nd is called the forced expirato ry vo lume, or FEY 1.0, an d the tot al vol ume exh aled is the fo rced vita l capacity, or FVC (th is is often sligh tly less than th e v ital ca pacity measu red on a slow exha-

lation as in Figure 2-2). Normally, the FEVl.o is abou t 80% of th e FVC.

A.

B. Obstructive

Normal

n 1 ~

FEV= 4.0 FVC= 5.0 % =80

FVC

C. Restrictive

~ \E; FVC

I

..

11 sec ]

FEV=1 .3 FVC = 3.1 %=42

FEV FVC

I

j.

11 sec ]

FEV = 2.8 FVC = 3.1 % =90

Figur e 10-1. M eas ure m ent of f or ced exp irat o ry vo lu me (FEV1.Q) and forced v it al capacity (FVC).

B

A ( Airway collapse

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8 ",

6 4

Effort inde penden t " ~, ~ortion

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g

u,

2 6

5

4

3

2

Lung volume (I)

o

98

765432

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Lung volume (I)

Figure 10-2. Flo w vo lu me curve o bta ined by recor din g flow rate ag ai nst v o lu m e during a fo rced expiration fro m maximum inspi ration. The fig ure shows absolute lu ng vo lumes, althoug h these cannot be m easured f ro m single expiratio ns.

In disease, ( \\-'0 genera l pattern s can be d ist inguishe d. In restrictive diseases such as pulmonary fibrosis, bo th FEY an d FYC ate red uced , but cha racte rist ically the FEYl.o/FVC% is nor mal or increased. In obstructive d iseases such as hronc h ial asthma, th e FEV 1.0 is redu ced m uch more than the FVC, giving a low FEVjFVC % . Frequently, mixed restr icti ve an d o bstr uc tive pattern s are seen. A related measurement is the farced expiratoryflow rate, or FEFZS_ 75'X> ' wh ich is the ave rage flow rate measured over the m iddle half of the expirat ion. Ge nerally, th is is closel y related to the FEY1.0 , alth ough occasionally it is reduced when the FEV LO is norm al. So met imes other indices are also measured from the forced expirati on curve. A useful way of look ing at forced exp irat ions is with j1ow-volume curves (see Figure 7 ~ 16 ). Figure 1 0~2 reminds us th at after a relati vely small amoun t of gas ha s bee n exha led, flow is limi ted by airway compression and is dete nn ined by the elastic recoil force of the lung and the resistance of the airways upstream of th e co llapse poi n t. In restrictive diseases, th e maximum flow rate is red uced , as is th e tota l volume exh aled. However , if flow is related to th e abso lute lung volume (that is, including th e residual volum e which cannot be measured from a sing le expiration ), th e flow rat e is often abnor mally hi gh during the latt er part of expirat ion because of th e increased lun g reco il (Figure 10-213). By contra st, in obstructive diseases the flow rate is ve ry low in relat ion to lun g volume, and a scooped-out appearance is often seen following th e po int of maximu m flow. What is the sign ificance of th ese measurem ents of forced expirat ions ? The FYe may be reduced at its top or bottom end (see Figure 1 0 ~ 2 ) . In re5tTictit'e

Forced Expiration Test • Measures the FEV and the FVC • Simple to do and often informative • Distinguishes between obstructive and restrict ive disease

diseases, inspiration is limited by the reduced compliance of the lung or chest wall, or weakn ess of th e inspiration muscles. In obstrucrit!e disease, th e rotal lung capacity is typically abnormally large, but expiration ends prematurely. T he reason for this is early airway closure brought about by increased smooth muscle tone of the bron ch i, as in ast h ma, or loss of rad ial tracti on from surro und ing parenchyma, as in emphysema. O the r causes include ede ma of th e bronch ial walls, or secretions within the airways. The FEYl.o (or FEF Z5 _75%) is reduced by an increase in airway resistanc e or a reduction in elastic recoil of the lung. It is remarkably independent of expiratory effort. T he reason for th is is the dynamic compression of airways, wh ich was d iscussed earlier (see Figure 7 ~ 18). This mechan ism explains why th e flow rate is independent of th e resistan ce of the airways down stream of th e collapse poin t but is determ ined by th e elastic recoil pressure of the lung and the resistan ce of the airways upstream of th e collapse poin t. The location of th e collapse point is in the large airways, at least initially. T hus, both th e increase in airway resistance and the reduct ion of lung elastic recoil pressure can he importa n t factors in the reduct ion of th e FEY LO, as, for example, in pulmonary emphysema.

Lung Volumes T he determination of lung volumes by spirometry and the measurement of functiona l residual capac ity (FRC ) by helium diluti on and body plethysmography were discussed earlier (see Figures 2-2 th rough 2-4). The FRC can also be found hy ha ving the subject breathe 100% 0 , for several minutes and washin g all the Nz out of the subject's lung. Suppose th at the lung volume is V I and that the total volume of gas exha leJ ove r 7 min utes is Vz and th at its conce ntration of N 2 is C z- We know that th e con cen tration ofN z in the lung before washout was 80%, and we can measure th e conc entra tion left in th e lung by sampling end-expired gas with an N z meter at the lips. Call this conce n tration C '}. Then , assuming no net cha nge in th e amount "fN " we can write V I X 80 = (VI X e ,l + (V , X C,l. Thus, VI can he derived . A disadva ntage of thi s method is th at th e conce ntration of nitrogen in the gas collected over 7 minutes is very low, and a small error in its measurement leads to a larger error in calculated lung volume. In add ition, some of the N z that is washed out comes from body tissues, and this sho uld he allowed for. T his method, like the helium dilu tion techniq ue, measures on ly ve n t ilated lung vo lume, whereas, as we saw on p. 16, th e bod y plethysmograph method includes gas trapped behind closed airways, The measurement of anatomic dead space by Fowler's method was described earlier (see Figure 2-6 ).

Diffusion The princ iples of the measurement of the diffusing capacity for carbon monox ide hy the single breath method were d iscussed on p. 3 1. The diffusing capacity for O 2 is very difficult to measure, and it is only done as a research procedure.

Blood Flow The measurement of to tal pulmonary blood flow by the Fick pri nci ple an d by th e indicator dilution meth od was alluded to on p. 4 2.

Ventilation-Perfusion Relationships Topographical Distribution of Ventilation and Perfusion Regional d ifferen ces of ven t ilat ion and blood flo w ca n be measured usin g rad ioactive xeno n, as briefly described earl ier (see Figures 2-7 and 4-7).

Inequality of Ventilation This can he measured by single breath and multiple breath methods. The single breath method is very sim ilar to that described by Fowler for measur ing ana to mic dead space (Figure 2-6) . There we saw tha t if the N z concen tration at the lips is measured following a single breath of O a. the N 1 conce nt ration of th e expired alveolar gas is almost uniform, giving a nearly flat "alveolar plateau." This reflects th e approxima tely uni form d ilut ion of th e alveolar gas by th e inspired O z. By cont rust, in pat ients with lung disease, the alveolar N z concen trat ion continues to rise during expiration. T h is is caused by the uneven d iluti on of the alveolar N z by inspired O 2 , T he reason why the concen tration rises is that the poorly ven tilated alveoli (those in wh ich the N, has been d iluted least) always empt y last, presumably because th ey have lon g time constants (Figures 7~ 19 an d 1 0~ 5 ) . In practice, the cha nge in N z percentage concent ration betwe en 750 and 1250 ml of expired volume is often used as an index of uneven vent ilation . This is a simple, qu ick, and useful test. T he multiple breath meth od is based on the rate of washout of N z as shown in Figure 1 0~3 . The subject is connec ted to a source of 100% Oz, and a fast-respondi ng N z meter samples gas at th e lips. If the vent ilat ion of th e lung were uni form , the N z concen tration would be reduced by the same fraction with each breath. For example , if the tid al volume (excluding dead space ) were equal to the FRC, th e N z concen tration would ha lve with each breat h. In general, the N z concent ration is FRC/lFRC + (V T - Vn )J tim es that of th e previous breath , where VT and VI)are the tidal volume and an atomic dead space, respectively. Beca use th e N z is reduced by the same fract ion with each breath, the plot of log N 2 concent ration against breath number would be a straigh t line (see Figure 1O~ 3) if the lung beha ved as a single, un iformly vent ilated compartm ent. This is very nearly the case in norma] subjec ts. In patien ts with lung disease, however, th e nonuniform vent ilat ion result s in a curved plot because different lung un its have their N z dilu ted at d ifferent rates. T hu s, fast ven tilated ahveoli cause a rapid initial fall in Na. whereas slow ven tilated spaces are responsib le for the lon g tail of th e washo ut (see Figure

10-] ).

100%02~ ~n <' 80

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Nu mber of breaths

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40

Number of breaths

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Sl ow ... space

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Figure 10-3. N 2 washou t obta ine d w he n a su bj ect bre athes 100% O2 _ Nor m al lu ngs gi v e an al m ost li near pl ot of N 2 conce ntration against number of b reat hs o n semlloqa rtthm lc pap er, but this plot is nonlinear w hen un ev en vent ilation is present.

., "

Inequality of Ventilation-Perfusion Ratios One way of assessing th e mismatch of ven tilation and blood flow with in the d iseased lung is th at in troduced by Riley. T h is is based on measuremen ts of P0 2 and pco! in arterial blood and ex pired gas (th e princi ples were briefly described in C hapt er S). In practice, expired gas and arte rial blood are co llected simulraneously from th e patient, and various indices of venti lation-perfusion inequali ty are computed . O n e useful measurement is th e alt!eolar~arterial PO l difference. W e saw in Figure S~ 11 how thi s develops becau se of regional differences ofgas exchan ge in th e nor' mal lung. Figure l OA is an 02 ~C02 diagram th at allows us to examine th is development more closely. First, suppose that there is no ve nti lat ion- perfusion inequality and th at all the lung units are rep resented by a single point (0 o n the ventilat ion -perfusio n lin e. This is known as th e "ideal" point. N ow as venulan on -perfusion inequality develops, th e lung un its begin to spread away from i toward both (low ven rilarion -perfusion rati os) and I (hig h ventilatio n-perfusion rati os) (compar e Figure 5-7) . When th is happens, th e mixed capi llary blood (a} and mixed alveolar gas (A) also diverge from i. They do so along lines i to and i to I, which represent a constan t respirator y exc hange ratio (C0 2 output/02 uptake), 3 5 th is is det ermined by th e me tabolism of th e bod y tissues." The horizo nta l dista nce between A and a represents th e (mixed ) aft'ealnr, arterial O 2 difference. In practice, th is can on ly be measured easily if ventilation i.. . essentially un iform but blood flow is un even, because on ly th en ca n a reprcsen -

v

v

t

In this necessaril y simplified descripti on , some det ails are om itted. For exa mp le, the mixed veno us poin t alters wh en ventilarion -pertusion inequ alit y de velops.

60

v , 0>

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40

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Low

VA/a

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Blood A line

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0..

20

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0 40

60

80

100

120

,

140

Paz mm Hg

Figure 10-4. 0 2-C0 2 di ag ra m showing the idea l poi nt (i), that is, th e hypoth et ical com pos ition of alveo lar gas and end-ca pilla ry blood whe n no ventilation-perfusion inequality is present . As inequa lity develops. th e art erial (a) and alveo lar (Al poi nts diverge alo ng t heir respect ive R (respira tory exc hange ratio) lines. The mi xed alv eol ar-a rt eria l P02 differen ce is th e horizo nt al d ist ance betwee n t he

points.

rat tvc sample of mixed alveo lar gas be obta ined . This is sometimes the case in pulmonary embolism. More frequ ently, th e POl d ifference between ideal alveo lar gas and arte rial blood is calculated-the (ideal) al"eolar-arterial 0 1 difference. T he ideal alveolar Po z can be calc ulated from th e alveolar ~as equation wh ich relates th e Po z of an y lung un it to the compositio n of th e inspired gas, the respirato ry exchange ratio, and th e Pa Jz of th e uni t. In the case of ideal alveoli , th e rCX)z is taken to be the same as art er ial blood because the line alon g wh ich poin t i moves is so nearly h orizon tal. Note th at thi s alveolar-arte rial PO l d ifference is caused by uni ts between i and Y, that is, those with low ventilati on -perfusion ratios. Two more indices of ven tilation-perfusion inequality are frequently der ived. O ne is /)hysiologic shunt (also called venousadmixture). For thi s we pretend tha t all of th e leftward movement of th e arte rial point (a ) away from th e ideal poin t (i) (th at is, the h ypoxem ia) is caused by th e additio n of mixed veno us b100d m to ideal blood (0. T h is is not so fancifu l as it first seems, because un its with very low vent ilation-perfusion rati os put out blood th at ha s essentia lly th e same co mposition as mixed venous blood (see Figures 5-6 and 5-7) . In pract ice, the sh un t equation (see Figure 5-3) is used in the following form :

Cio, - Cao , Cio z - evoz where Q rs/Qr refers to th e ratio of the ph ysiologic sh unt to to tal flow. The 0, concen tration of ideal blood is calculated from th e ideal Pa z and O 2 dissociation curve.

160

Chapter 10

T he othe r index is alveolar dead spece. Here we pretend that all of the movement of th e alveolar point (A ) away from the ideal point (i ) is caused by the addi tion of inspired gas ill to ideal gas. Aga in , thi s is no t such an o utrageous notion as it may first appea r because un its with very hig h vent ilatio n-perfusio n rat ios behave very much like poin t I. After all, a un it with an infinitely high ven tilation-perfusion ratio contai ns gas that has the same composition as inspired air (see Figures 5.6 and 5.7) . The Boh r equation for dead space (see p. 19) is used in th e following form: Pico! - PAa )!

Piex)z

where A refers to expired alveo lar gas. The result is called all'eolar dead space to d istin guish it from the anatomic dead space, that is, th e vo lume of th e cond ucting airways. Because expired alveolar gas is often difficult to collect witho ut con tamina tio n by th e ana tomic dead space, the mixed expired CO 2 is often measured . The result is called the physiologic dead space , wh ich includes components from th e alveolar dead space and anatomic dead space. Because th e Peo l of ideal gas is very close to th at of arterial blood (see Figure 10-4) , th e equation for physiologic dead space is

P"co, - PEco, Pac o l The normal value for physiologic dead space is about 30% of th e tidal vo lume at rest and less on exercise, and it consists almost completely of anatomic dead space. In lung disease it may increase to 50% or more due to th e presence of vennl an on-perfuston ineq ualit y.

Blood Gases and pH POl' Pc o ., and pH are easily measured in blood samples with blood gas elect rodes. A glass electrode is used to measure the plI of who le blood. The PCX), elect rode is, in effect, a tiny pH meter in whic h a bicarbonate buffer solut ion is separated from the blood sample by a thin membrane. When carbon dioxide diffuses across the membrane from th e blood , th e pH of th e buffer changes in accordance with th e Henderson-Hasselbalch relat ionsh ip. The pH met er then reads out th e Peo l" T h e 0 , electrode is a polarograph , that is, a device which , when supplied with a suitable voltage, gives a min ute current th at is proport iona l to the amount of dissolved O 2. In practi ce, all thr ee electrodes are arranged to give their outputs on th e same met er by appropriate switch ing, and a co mplete ana lysis on a blood sampie ca n be do ne in a few minut es. W e saw in Chapter 5 that there are four causes of low arterial Po z or hypoxemia: (I ) h ypoventilati on , (2) d iffusion impairment, (3 ) sh unt, and (4) ven tilationperfusion inequality. In distin guishin g betw een these causes keep in mind th at hvpoven tilation is always associated with a raised arte rial PCOl and tha t on ly when a sh unt is presen t does t he arterial POz fail to rise to the expected level when 100% O 2 is udminis-

tcred. In diseased lungs. imp air ed diffu sion is always accompanied by ve nt ilatio nperfu sion inequality, and, ind eed, it is usuall y impossible to det erm ine how much of th e h ypoxemia is att ribu table to defective d iffusion . There are two causes of an inc reased art erial Peo l: (1) hvpovennlan on . and (2) vent ilat ion- perfusion ine qua lity. The latter does not always cause CO 2 rep rent ion because an y tende ncy for the arte rial PeX)l to rise signals th e respiratory

center via the che moreceptors to increase ven tilation and th us hold the PCOl down . However, in the absence of th is increased ventilat ion, the Peo l must rise. Cha nges in the blood gases in different types of hypoxemi a are summarized in T ahle 6.1. The assessmen t of the acid-ba se status of the blood was d iscus sed o n pp. e[O

86-87.

Mechanics of Breathing Lung Compliance

e at

dead

nodes.

IectroJe parared

Com plianc e is de fin ed as the vo lume cha nge per uni t of pre ssure cha nge across th e lung. T o obta in th is, we need to kn ow intrapleural pressur e. In practi ce, esop hageal pressure is measured by having the subject swa llow a sma ll ba lloon on th e end of a cathet er. Esophagea l pressure is not identical to intrap leura l pre ssure but reflects its pressure changes fairly well. The measurem ent is not reliable in supin e subjects beca use of in te rference by th e weigh t of the med iastinal struc tu res. A simple way of measuring complian ce is to h ave the subjec t breathe out from total lun g capacity into a spirometer in ste ps of, say, 500 ml and measure his or h er esoph ageal pressure sim ulta n eo usly. The glott is should be open , and the lung sho uld be allo wed to stabilize for a few sec onds after eac h step. In this way, a pressure -vo lum e curve similar to the upper line in Figure 7 ~3 is obtained. The whol e curv e is the mo st inform ative way of rep orting the elast ic be havior of the lung . Ind ices of the share of the cur ve ca n be derived. Not ice th at the co mpiiancc, which is the slope of the cu rve, will var y depe nd in g on what lung vol ume is used . It is co n ven t iona l to report th e slope over the lit er above FRC measured du ring deflat ion . Even so, the measur ement is not ve ry repeat able. Lung co mpliance can also be measured d ur in g resting breathin g, as shown in Figure 7~ 13. H ere we make use of the fact that at no-flow po in ts (end of inspi rati on or ex pira t ion ), the intrap leural pre ssure reflec ts o nly th e ela sti c recoi l forc es and not those assoc iate d with a irflow. Thus, the vo lume d ifference di vided by the pressure difference at these points is the co mplianc e. Th is method is not valid in pa tie nts with airway di sease be cause the variati on in time co ns tan ts th ro ugh out the lung mean s that flow st ill ex ists with in th e lu ng when it ha s ceased at the mouth. Figure 1 0~ 5 shows th at if we conside r a lung region tha t has a partia lly ob structed ai rwa y, it will always lag be hi nd the

rest of rhe lung (compare Figure 7-19) . In fact, it may con tin ue to fill whe n the rest of the lung h as begun to e mp ty, with the result th at gas moves into it fro m

ml arion is - i~ r resen t 1j admin ls-

adjoining lon g un its-so called pendelluft (swinging air). As the breathi ng freque n cy is in creased, th e prop o rtion of the t ida l vo lume th at goe s to th is pa r-

t ially obstructed region beco mes smaller and smaller. Thus, less and less of t he

A

B

c

o

c:., 2

Figure 10-5. Effe ct s of un eve n tim e constants o n v entil at io n. Co m partment 2 has a partia ll y o bst ruct ed air wa y and, t herefo re, a long ti m e co nstant (co m pare Figure 7-19 ). Duri ng inspirati on (A ), ga s is slow to ent er it, and it t he refo re co nt inues t o f ill after t he rest of t he lu ng (1) has sto ppe d moving (6 ). Ind eed at t he begi nning of t he exp ir atio n Ie). t he ab normal re g io n (2) m ay st ill be in haling w hile th e rest of the lun g has beg un to exha le. In D, bo th re g io ns are exhaling but co m partme nt 2 lags behind co m partme nt 1. At hig her fr equen cies , th e tida l vo lu m e to th e abnormal regio n becomes prog ress ively smaller.

lung is partici pating in the tid al volume ch anges, and therefore th e lun g appears to become less co mplian t.

Airway Resistance This is the pressure differenc e between the alveo li and th e mouth per unit of air' flow (Figure 7-12). It can be measured in a body plethysmograph (Figure 10-6) . Before inspiration (A) , the box pressure is atmosphe ric. A t th e onse t of inspiration, th e pressure in the alveoli falls as th e alveolar gas expands by a volume ~ V. This compresses the gas in th e box and from its ch ange in pressure av can be calculate d (com pare Figure 2-4). If lung volume is known, f!,. V can be convert ed into alveolar pressure using Boyle's law. Flow is measured simultaneously, and thu s airway resistan ce is obtained. T he measurem ent is made during expiration in th e same way. Lung volume is determined as described in Figure 2-4. Airw ay resistance can also be measured during norm al breath ing from an in, rrapleural pressure record as obtai ned with an esophageal balloon (see Figure 7,13). However, in th is case, tissue viscous resistance is included as well (see p. 116). In trapleural pressure reflects two sets of forces, th ose opposing the elastic

163

Tests of Pulmonary Function

reco il of th e lung an d th ose overcoming resistance to air and t issue flow. It is pos~ sible to subtract the pressure caused by th e recoil fo rces during qu iet breath ing because th is is proportional to lung vo lum e (if comp lian ce is consta n t ). T he subtraction is done with an ele ctrical c ircuit. W e are th en left with a plo t of pressure against flow whi ch gives (a irway + t issue ) resistance . This me thod is not sati sfact ory in lungs with seve re airway disease because the uneve n time constan ts Preven t all regions from moving toge ther (see Figure 1 0~ 5 ) .

Closing Vo lume Earl y disease in small a irways ca n be sought by using the sing le brea th N z washout (see Figure 2~6 ) and thus exploiting th e topographical differen ces of ventilati on (see Figures 7-8 and 7-9). Suppose a subject takes a vita l capacity breath of 100% Oz an d during th e subsequent exh alat ion the N z concentrat ion at t he lips is mea, sured (Figure l O~ 7 ) . Four phases can be recogn ized. First, pure dead space is exha led ( I ) followed by a mixture of dead space and alve olar gas (2), and th en pur e a lve olar gas (3). T o ward the end of expiratio n , an abru pt inc rease in N z con cen trat io n is seen (4 ). T hi s signa ls closure of ai rways at the base of the lun g (see Figur e 7 ~9 ) , and is ca used hy prefer en tial emp ~ ty ing of the ap ex, wh ich h as a re latively h igh con cen tration of N z. The rea son for the h igh er N z at th e ape x is th at during a vital cap aci ty breat h of O z, th is region expands less (see Figure 7 ~9) , and, th erefor e, the N z there is less dil uted with Oz . T hus, th e vo lume of the lun g at wh ich dependent a irways begin to clo se ca n be read off th e tr ac ing. In young no rm al subjects, the closing vo lume is about 10% of th e vital capa city (Ve). It increases steadily with age and is equal to about 40% of the ve, that is the FRe , at about th e age of 65 years . Relat ively sma ll amoun ts of disease in the sma ll airways appare ntly increase the closin g vo lume. So me t imes the closing czpacity is repor ted . T h is is th e closin g vo lum e plus the residual volume .

Preinspiration

During inspiration

During expiration

(I) !N

A

B

C

Figure 10-6. Me asu rem ent of airw ay resist ance w it h t he bo dy p leth ysm o gr aph. Du rin g insp ir ati o n, th e alveo lar gas is expanded, and box pressu re t he ref o re rises. From t hi s, alveo lar pressure can be calcula ted. The d iff erence between alveol a r and m o ut h p ress u re, di vided by fl ow , g iv es airw ay resista nce (see te xt ).

·:'1

'"

r "

RV

TLC

50

~_.

-

-

VC -------+ l~

-

2

4

3

40

0"c 0

~c

"c

30

0

0

o

20

r

N

Closing I volume :

Z

10 0

,, ,,

6

5

4

3

2

0

Lung volume (I)

Figur e 10-7. M easu rem ent of t he clo sing vo lume. If a v it al capacity inspi ration of 100% O2 is follo w ed by a f ull expirat io n, fo ur p ha ses in t he N 2 co nce nt rati o n measu red at t he lips can be recognized (see text). Th e last is caused by pre fer ent ial em ptyi ng of th e apex of t he lung aft er t he low er zo ne airw ay s hav e cl osed .

Control of Ventilation The responsiveness of the c he mo rece ptors and respirato ry cen t er to C O 2 can be measured by having the subject rebrearhe in to a rubber bag, as d iscussed on p. 129. We saw tha t the alveo lar POz also affects ventilat ion so that if th e rcsponsc to CO2 alone is requi red . th e inspired P O l should be kept above 200 mm Hg to avo id any h ypoxic d rive. The vent ilatory response to h ypoxia can be measured in a similar way if th e subject rebreathes from a bag with u low P O l but consta n t P COl '

Exercise Additiona l information about pulmonary function can ofte n be obtained if tests are made whe n the subject exercises. As discussed at th e beginning of Cha pter 9, th e resting lung has enormous reserves; its ventilat ion , blood flow, O 2 and CO 2 transfer. and diffusing capacity can be increased severalfold on exercise. Prequently, patients with early disease have pulmonary function tests that are with in normal limits at rest, but abn ormaliti es are revealed when the respirato ry system is stressed by exercise. Met hods of providin g con trolled exercise inclu de the treadmill and bicycle er.. gometer. Measurements most often made on exercise include total ven tilation, pulse rate, O 2 uptake, CO 2 outpu t, respirato ry exchange rat io, arte rial blood gases, and the diffusing capacity of th e lung for carbon monoxide.

Perspective on Tests of Pulmonary Function In th is chapte r, we have touched on some of the lung func tion tests th at are present ly ava ilable. In conclusion, it should be emphasized th at not all th ese tests are co mmo n ly used in a hospita l pulmonary funct ion labo ra tory. O n ly a few can

he used in a doctor's office or on an epidemiological survey. The most useful and simple test in the clinical sett ing is th e forced expiration. I t does not matter much wh ich ind ices are de rived from this test , but the FEY 1.0 to measure arterial blood gases is essent ial if pat ients wit h respira tory fa ilure are man aged and is valuab le in

and FVC are very frequen tly reported. Ne xt, the ability

any case . After th ese, the relati ve impo rt anc e of tests becom es more a matt er of

persona l preference, but a well-equ ipped pulmonary fun ction laboratory would be able to measure lung volumes, inequality of ven tilation , alveolar-art erial Po z d ifference, physiologic dead space and sh un t, diffusing capaci ty for carbon monoxide, airway resistance, lung complianc e, ven tilatory response to CO 2 and. h ypoxia, and the patie nt 's response to exercise. In large laborator ies, more specialized measuremen ts such as the topographi cal distribution of ven tilation and blood flow would be available.

QUESTIONS For each question, choose the one best answ er. 1. W hich of the following statem ents about the 1 second forced expiratory volume is FALSE? A. It can be used to assess the eff icacy of bronchooilators. B. It is reduced by dynamic com pression of the airw ays. C. It is reduced in pat ients w ith chronic obstructive pulmonary disease but not pulmonary fibrosis. D. It is reduced in patients wi th asthma. E. The test is easy to perform . 2. All of the followi ng may reduce the FEV1 in a pat ient with chronic obstr uctive pulmonary disease EXCEPT: A. Hypertrophy of the diaphragm. B. Excessive secretions in the airways. C. Reduction in th e number of small airw ays. D. Loss of radial traction on th e airw ays. E. Loss of elastic recoil of the lung. 3. All of the follow ing statements are true of the Single breath nitrog en test for uneven ventilation EXCEPT: A. The slope of the alveolar plateau is increased in chronic bronchit is. B. The slope occurs because poorly ventil ated units empty later in expirat ion than w ell-ventilate d units. C. The last exhaled gas comes fro m the apex of the lung. D. A similar procedure can be used to measure the anatomic dead space. E. The test is very time consuming.

4.

..

(,

In the assessment of ventilation-perfusion inequality based on measurements of P02 and P C02 10 arte rial blood and expired gas, all of th e fo llowin g stat ements are true EXCEPT: A. The ideal alveolar P02 is calculated using the arterial Peo2' B. The alveolar P 0 2 is then calculated from the alveolar gas equation. C. VA/O inequality increases the alveolar-arterial P0 2 difference. D. VA/a. inequality increases the physiologic shunt. E. VA/a.inequality reduces the physiologic dead space. 5. A seated normal subject exhales to residual volume (RV). A. The volume of gas remaining in the lung is more than half of the vital capacity. B. The PC0 2 of the expired gas falls just before the end of expirati on. C. If th e mouthp iece is closed at RV and the subject completely relaxes, the pressure in the airways is greater than atmospheric pressure. D. Intrapleural pressure exceeds alveolar pressure at RV. E. All small airways in the lung are closed at RV.

Symbols, Units, and Equations Symbols Primary Symbols

C F P Q

Q R S V

V

Co ncen tra tio n of gas in blood Frac t ional co nc en tra tion in dry gas Pressure or parti al pressure Vo lume of blood Vo lume of blood per un it tim e Respiratory exch ange rat io Sat urat ion of h emoglo bin with O 2 Volume of gas Volume of gas per un it rime

',: ••

,,' '-J' J.,I

,I: '

Secondary Symbols for Gas Phase A B D E I

A lveolar Baro me tric Dead space Expired Inspired

L

Lung

T

T idal

Secondary Symbols for Blood Phase a c c' v

v

ar te rial capillary end-capillary ideal veno us mixed venous

Examples

O 2 concen tration in arterial blood Cao , Frac tional conc en trat ion of N z in expired gas FE\';2 Parti al pressure of O 2 in mixed venous blood Pvoz

167

Units T raditional metric units have been used in th is book. Pressures are given in mm Hg. th e W IT is an almost iden tical uni t. In Europ e. 51 (Svsteme In tern ati onal) units arc common ly used. Most of th ese are familiar, but th e kilopascal, th e un it of pressure , is confusing at first. O ne kilopascal = 7.5 mrn Hg (app rox imatel y).

Equations Gas Laws

General gas law: PV = RT

(

where T is temperatu re and R is a constant. This equation is used to correct gas volumes for changes of water vapor pressure and temperature. For example, ven tilation is conve nt ionally reported at BTPS, th at is, body temperature (3r C ), ambient pressure, and satu rated with water vapor because it th en corresponds to th e volume changes of the lun g. By con trast, gas volumes in blood are expressed as ST PD, th at is, standard temperature (O°C or 273°K) and pressure (760 mm Hg) and dry, as is usual in chemistry. T o con vert a gas volume at BTPS to one at ST I'D, mult iply by

273

PB

-

47

-31-0 X --;:7"'60~ whe re 47 mm Hg is th e wate r vapor pressure at 3

Boyle's law and Charles' law

P IV I =

re.

PzV1 (te mpera ture constan t )

T,

= -

T,

(pressure constant]

are special cases of the gen eral gas law. A vogadro's law states th at equal volumes of differen t gases at th e same rernperut ure and pressure con tain th e same n umber of molecules. A gram molecule, for example, 32 gill of 0 " occupies 22.4 liters at ST PD. Dalton's law stat es th at th e partia l pressure of a gas [x] in a gas mixtur e is th e pressure that this gas would exert if it occupied th e to tal volume of th e mixt ure in the absence of th e oth er compon ents. Thus, P, = p . Fx , wh ere P is th e to ta l dry gas pressure, sinc e F, refers to dry gas. In gas with a water vapor pressure of 47 mm Hg

A lso, in th e alveoli, Po, + Pco, + PN , + PHzO = PB· The partial pressure of a gas in solution is its part ial pressure in a gas mixtu re th at is in equilibrium with the solution. Henry's law states th at th e conc en tration of gas dissolved in a liquid is proportion al to its part ial pressure. Thus, ex= K . Px -

VT = VD + VA where

VA here refers to the vo lume of alveo lar gas in the tidal vo lume VA = VE

-

VD

Va>, = VA . FAco, (bot h V measured at BTPS )

.

Ve 0 2

VA = PAco

X K (alveo lar ventilation equation)

z

If VA is BT PS and Va>, is ST PD, K = 0.863. In normal subjec ts, PA= , is nea rly identical to P"=z'

Bohr equntion

VD V

PA= , - PEe o , =

T

PA<X),

Or, using arterial pcoz.

VD VT

-

=

P"=, - PE=,

P-=,

This gives physiologic dead space.

Diffusion In the gas phase, Graham's law sta tes that th e rat e of d iffusion of a gas is inve rsely proportional to the square root of its molecular weig ht . In liquid or a tissue slice, Fick's law * states that the vo lume of gas per un it time whic h diffuses across a tissue sheet is given by

.

V,,,

A

= T .0

. (P, - P, )

wh ere A and T are the area and th ickn ess of th e sheet, P, an d Pz are the partial pressure o f the gas on the two sides, and D is a diffusion constant sometimes called the permeability coe fficie nt of the tissue fo r that gas.

This diffusion constant is related to the solubility (Sol) and the mol ecular weight (MW) of the gas So l On ~MW When the diffusing ca pacity of th e lun g (Dc> is measured with carbon mon oxide and the cap illary l'co is taken at zero,

Veo PAeo

0 - L -

* Pick's law was originally expressed in terms of concent rations, but partial pressures are more co nve nie nt for us.

DL is made up of two com ponents. O n e is the diffusing capacity of th e alveolar membrane (D M), and th e othe r depends on th e volume of capillary blood (Vel and th e rate of reaction of CO with hem oglob in e

I

I

1

- = - + -DL DM O·V, Blood Flow Fick principle

Pulmonary q,uscular resistance

PVR =

P art -

P \ T Il

wh ere P arr and P wn are the mean pulmona ry arterial and venous pressures, respect ively. StarhnK' 5 law of fluid exc hange across the cap illaries N et flow out = K[(P, - Pi) -
Ventilation -Perfusion Relationships A lveolargas equation

l-R]

PAco, [ PAo, = Pia , - - R- + PA"o,· Flo, · - -R -

This is only valid if th ere is no CO 2 in inspired gas. T he term in squa re brackets is a relatively sma ll correction facto r when air is breat hed (2 mm lIg whe n Peo = 40, Flo, = 0. 21, and R = 0.8). Thus, a useful approxima t ion is -

Respiratory exchange ratio If no CO 2 is presen t in th e inspired gas

PEco, (l - Flo, ) Pia , - PEo, - (PEc0 1 • Flo, )

171

Append ix A

Venous to arterial shun!

Qs

CCo z - Cao z

Or

Cc'o, -

eva,

where c ' means end-capillary. Ventilation~perfusion ratio equation

8.63 R(Cao , - CVo,)

VA

Q

PAco,

=

where blood gas concentrations are in mI· 100 mt-

I.

Physiologic shunt

Cia , - Cao , Cio, - CVo,

:,

Alwolar dead space

Picx12

-

I, ,, lof!

PAC02

j'

Pico 2 T he equation for physiologic dead space is on p. 160. Blood Gases and pH

a, dissolved in blood Co , = Sol · Po, where Sol is 0.003 ml O j . 100 ml b1o<xl- 1 . mm Hg-

I

lienderson,Hassdbalch equation

pl-l

= pKA + log

(HCO j) (CO, )

The pKA for thi s system is normally 6.1. If HCO "l and CO 2 co nc entratio ns are in

millimoles per liter, CO, can be replaced by Pco , (rnrn Hg) X 0.030. Mechanics of Breathing

Complinnce = !:N /i1P Specific compliance = i1V/( V . i1P) Laplace equation for pressure caused oy surface tension of a sphere

2T

P= -

r

where r is the radius. Note that for a soap bubble, P = 4T/r, because there arc two surfaces .

where n is the coefficien t of viscosity" and P is the pressure difference across th e len gth l. Reynolds numbeT

2rvd

Re = - n

where v is average linear veloc ity oft he gas, d is its den sity, and n is its viscosity. Pressure drop for laminar flow, P« V, but for turbulent flow, Pc y2 (approximately). A irway resistance P al\' -

P mo uth

v where P~ll\' and

P mo uth

refer to alveo lar and mouth pressures, respectivel y.

Answers Chapter 1 1.

2. 3. 4. 5. 6.

E 8 8 D

8 A

Chapter 2

8 2. E 3. e 4. D 5. 8 6. 8 1.

Chapter 3 1.

e

2. 3. 4. 5. 6.

E E A A D

Chapter 5

1. 2. 3. 4. 5 6.

D

9.

D

8 A 8 8 E 7. A 8. E

Chapter 6 1.

D

2. 3. 4. 5. 6.

E E E A E 7. 8 8. e 9. A 10. A 11. E 12. E

Chapter 4 1.

D

2. e 3. E 4. E 5. e 6. E 7. D 8. A 9. A 10 . E

Chapter 7 1.

e

2. 3 4. 5. 6.

E A E D D

7. e 8. D 9. 8

10. E 11. 12. 13. 14.

E E B D

Chapter8 1. E 2. B 3. D 4. A 5. B 6. D 7. E R R

Chapter 9 1. E 2. C 3. E 4. D 5. E 6. B 7. D

Chapter 10 1.

2. 3. 4. 5.

C A E E B