Chapter 1. Physiology of ventilation and gas exchange. Functional anatomy of the lung HUGH MONTGOMERY. The airways

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1 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie Physiology of ventiltion nd gs exhnge HUGH MONTGOMERY Chpter 1 Among its mny funtions, the lung hs two mjor ones: it must hrvest oxygen to fuel eroi respirtion nd it must vent id-forming ron dioxide. This hpter will offer rief overview of how the lung fulfills these funtions. It will lso disuss some of the mehnisms through whih dequte oxygention n fil. A seure understnding of these priniples llows n insight into the wy in whih mehnil ventiltion strtegies n e ltered in order to enhne oxygention nd ron dioxide lerne. Funtionl ntomy of the lung The irwys During inspirtion, ir is drwn into the orophrynx through either the mouth or the nsl irwy. Nsl rething is preferred, s it is ssoited with enhned prtile removl (y nsl hirs nd muus-lden turintes) nd humidifition. However, this route is ssoited with fll in phryngel pressure. Just s Ohm s lw dittes tht voltge is the produt of urrent nd resistne, so phryngel pressure is the produt of gs flow nd phryngel resistne. A ft pron round the phrynx euse of oesity my led to inresed phryngel ompline, nd thus inrese the risk of dynmi phryngel ollpse in suh ptients. In dults, when phryngel flows exeed 30 to 40 litres per minute, the work of rething eomes high nd the fll in phryngel pressure too gret for the dequte intke of ir: the mouth then eomes the preferred route for rething. The lrynx remins protetor of the irwy, with ryepiglotti nd rytenoid musles le to drw the lryngel entrne losed like purse-string nd the epiglottis pulled down from ove like trp door. In ddition, the rytenoid rtilges n swing inwrds to ppose the vol ords themselves, thus offering n effetive sel to the entry of prtiles or gses to the irwy eneth. Menwhile, tight olusion n e hieved during swllowing or to fix the thorx during hevy lifting, llowing the lrynx to resist internl pressures of some 120 m H 2 O. Lryngel sensitivity to irrittion, using ough, mkes the lrynx effetive t limiting entry of noxious gses or lrger prtiles, while more intense hemoreeptor stimultion n use severe lryngel spsm, preventing ny meningful gs flow. In the nestheti room, this n e life-thretening. When ir enters the trhe, it is supported y nterior horse-shoes of rtilge (Figure 1.1). However, these re omplint, nd trhel ollpse ours with extrinsi pressures of only 40 m H 2 O. Cilited olumnr epithelium yields n upwrd-moving muus esltor. The trhe then divides into the right nd left min ronhi (genertion 1 irwys), nd then into lor nd Core Topis in Mehnil Ventiltion, ed. Iin Mkenzie. Pulished y Cmridge University Press. C Cmridge University Press Cmridge University Press

2 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie Nsophrynx Orophrynx Epiglottis Lryngophrynx Vol ords Trhe i iii iv ii v vi vii viii x d ix Cmridge University Press

3 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge segmentl ronhi (genertions 2 4). The right min ronhus is wider nd more vertil thn the left, nd is thus the preferred pth for inhled foreign odies. Crtilginous horse-shoe supports in the upper irwys give wy to pltes of rtilge lower down, ut ll will ollpse when exposed to intrthori pressures of >50 m H 2 O (or less in situtions in whih the wlls re disesed, suh s in hroni ostrutive pulmonry disese or ronhomli). Suessive division of ronhi (genertions 5 11) yield ever-smller irwys (to out 1 mm dimeter), ll of whih re surrounded y lymphti nd pulmonry rteril rnh vessels. They re supported y their rtilginous pltes nd rrely ollpse euse intr-ronhil pressure is nerly lwys positive. So long s there is pteny etween lveoli nd ronhi, even fored expirtion llows suffiient gs flow to mintin intr-ronhil pressures to level ove intrthori pressures. Bronhioles (genertions 12 16) lk rtilginous support, ut re held open y the elsti reoil of the tthed lung prenhym, mking irwy ollpse more likely t lower lung volumes. The ross-setionl re of these very smll distl irwys, nd their very thin wlls, mkes irwy resistne t this level lmost nil in the sene of ontrtion (ronhoonstrition) of the wll s smooth musle ells. Susequent respirtory ronhioles (genertions 17 19) hve inresing numers of gs-exhnging lveolr ss in their wlls; these ronhioles re nhored open under tension from surrounding prenhym. Eh of or so primry loules represents the distl irwy sutended y respirtory ronhiole. Distlly (genertion 20 22), lveolr dut wlls give rise to some Figure 1.1 Gross nd mirosopi ntomy of the respirtory trt. Inset i: Conventionl mirosopy view of the surfe of the ilited epithelium of the trhe showing ells ering ili djent to ells whih pper flt, ut whih in ft er mirovilli. Photomirogrph ourtesy of the Ernest Orlndo Lwrene Berkeley Ntionl Lortory, Cliforni. Inset ii: Trnsmission eletron mirosope imge of thin setion ut through the ronhiolr epithelium of the lung showing ilited olumnr ells () interspersed y non-ilited muous-sereting (golet) ells (). Slide ourtesy of Dr Susn Wilson, Histohemistry Reserh Unit, University of Southmpton. Inset iii: Setion of ronhus lined with pseudo-strtified olumnr epithelium (), nd surrounded y ring of hyline rtilge (). The presene of sero-muous glnds () differentites this from ronhiole. This setion lso ontins n rteriole (d). Br = 250 mirons. Slide reprodued with permission. Copyright C Deprtment of Antomy nd Cell Biology, University of Knss. Inset iv: Tiny islnds of hyline rtilge () onfirm tht this is ronhus rther thn ronhiole, nd djent is pulmonry vein (). Br = 250 mirons. Slide reprodued with permission. Copyright C Deprtment of Antomy nd Cell Biology, University of Knss. Inset v: The sene of rtilge nd sero-muous glnds mens tht this is ronhiole, with surrounding uff of smooth musle (). Br = 25 mirons. Slide ourtesy of Dr Susn Wilson, Histohemistry Reserh Unit, University of Southmpton. Inset vi: A smll ronhiole () surrounded y smooth musle (). Br = 25 mirons. Slide ourtesy of Dr Susn Wilson, Histohemistry Reserh Unit, University of Southmpton. Inset vii: An lveolus lined y thin flt type I pneumoytes () nd uoidl, surftnt-sereting type II pneumoytes (), with n integrl network of fine pillries () emedded within the lveolr wlls. The lumen of the lveolus ontins lrge lveolr mrophge (d). Br = 25 mirons. Slide ourtesy of Dr Susn Wilson, Histohemistry Reserh Unit, University of Southmpton. Inset viii: Snning eletron mirosope imge of the lveolr honeyom. Photomirogrph ourtesy of the Ernest Orlndo Lwrene Berkeley Ntionl Lortory, Cliforni. Inset ix: This photomirogrph shows the fine network of pillries tht enmesh the lveoli. Inset x: Trnsmission eletron mirosopi imge of lveolr ells, showing lrge uoidl type II pneumoytes () pked with vesiles ontining surftnt (). Nery lveolr pillries ontining red lood ells n e seen (). Photomirogrph ourtesy of the Rippel Eletron Mirosope Fility, Drtmouth College, New Hmpshire. 3 Cmridge University Press

4 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge 20 lveolr ss, ontining one third of ll lveolr gs. The terminl lveolr ss (genertion 23) re lind-ending. The Alveoli nd Their Blood Supply Eh lung my ontin up to hlf illion lveoli, whih re ompressed y the weight of overlying lung nd re thus progressively smller in vertil grdient. Alveolr gs n pss etween djent lveoli through smll holes lled the pores of Kohn. The pulmonry pillries form rih network enveloping the lveoli, with the lveolr epithelium losely pposed to the pillry endothelium. The other surfe of the pillry is emedded in the septl mtrix. Blood delivered into the pulmonry rteries from the right ventrile flows t pressure less thn 20% of tht of the systemi irultion. With ner identil lood flows, one n infer tht pulmonry vsulr resistne is orrespondingly five- to sixfold lower thn systemi. Working t lower pressure, the pulmonry rteril wll is orrespondingly thinner, while the pulmonry rteriolr wll ontins virtully no smooth musle ells t ll. Cpillries in dependent res of the lung tend to e etter filled thn res higher up (due gin to grvittionl effets), while lung infltion ompresses the pillry ed nd inreses effetive resistne to lood flow. Blood flows ross severl lveolr units efore pssing into pulmonry venules nd thene to the pulmonry veins. Pulmonry mehnis Air enters the lung in response to the genertion of negtive 1 intrthori pressure (in norml ventiltion, or in negtive pressure nd uirss mehnil ventiltion), or to the pplition of positive irwy pressure (in positive pressure ventiltion modes). Work is thus performed in overoming oth resistne to gs flow nd elsti tension in the 1 Also referred to s sutmospheri. lung tissue during the thori expnsion of inspirtion. A smll quntity of energy is lso dissipted in overoming lung inerti nd y the frition of lung deformtion. Elstiity nd the lung The lung s elstiity derives from elstin fires of the lung prenhym, whih ounts for perhps one third of elsti reoil, nd from the surfe tension of the fluid film lining the lveoli. When fully ollpsed, 2 the resting volume of the lung is onsiderly smller thn the volume it oupies when fully expnded in the hest vity. Fully expnded, the elstiity of the lungs genertes sutmospheri pressure in the pleurl spe of out 5.5 m H 2 O (Figure 1.2). At pek inspirtion, when the thori ge is mximlly expnded, this pressure my fll to nerly 30 m H 2 O. It is worth giving some thought to the issue of surfe tension fores within the lung. The pressure within truly spheril lveolus (P) would normlly e lulted s twie the surfe tension (T s ) divided y the lveolr rdius (r): P A = 2 T s. (1.1) r This eqution tells us tht if surfe tension were onstnt, the lveolr pressure would e inversely proportionl to the lveolr rdius. In other words, lveolr pressure would e higher in lveoli with smller rdius (Figure 1.3). If this were the se, it would men tht smller lveoli would rpidly empty their gseous ontent into lrger djent lveoli nd ollpse. Tken to its logil onlusion, ll of the lveoli in lung would empty into one huge lveolus. Fortuntely, surfe tension is not onstnt euse of the presene of mixture of phospholipids 3 nd proteins 4 tht flots on the surfe of 2 For exmple, when removed from the hest t utopsy. 3 Minly phosphtidylholine, ommonly referred to s leithin. 4 Surftnt proteins A to D, often referred to s SP-A, SP-B,et. 4 Cmridge University Press

5 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge Figure 1.2 Negtive pleurl pressure. A: The respirtory system n e ompred to ruer lloon (the lungs) pled inside glss jr (the hest vity) with the spe etween the outside of the lloon nd the inside of the jr representing the pleurl spe. B: The opening of the glss jr is seled over y the ruer lloon, seling the spe etween the outside of the lloon nd the inside of the jr from the tmosphere. C: As residul gs in this spe is evuted the pressure in the pleurl spe drops elow tmospheri nd the lloon expnds. D: One ll the gs in the pleurl spe is evuted the lung is ompletely expnded to fill the hest vity. The pressure inside the lung remins tmospheri while the pressure in the pleurl spe is sutmospheri (negtive). r A 2r Figure 1.3 Alveolr instility with onstnt surfe tension. A: With onstnt surfe tension (T s ), the lveolr pressure in the smller lveolus is 2 Ts r nd the pressure in the lrger lveolus is 2 Ts 2r, whih mens tht whtever the vlues of T s nd r, the pressure is only hlf tht in the lrger lveolus. B: Under these irumstnes, gs flows from the smller lveolus (higher pressure) to the lrger lveolus (lower pressure). the fluid lining the lveoli (the surftnt; see Figure 1.4), whih redues the surfe tension in proportion to the hnge in the surfe re: the smller the surfe re of the lveolus, the greter the redution in surfe tension. This mens tht gs in ft B tends to flow from lrger to smller lveoli, produing homogeneity of lveolr volume nd stilizing the lung. One other mjor dvntge of this effet on fluid surfe tension is tht the lung s ompline is signifintly inresed, reduing the negtive pressure generted y the lung in the pleurl spe. This onsequently redues the hydrostti pressure grdient etween the inside of the pulmonry pillries nd the pulmonry interstitium, minimizing the rte t whih intrvsulr fluid is drwn from the pillries. Lk of surftnt, for instne in intensive re ptients with ute lung injury, thus tends to use lveolr ollpse nd redue lung ompline, whih sustntilly inreses the work of rething. As the hest expnds during inspirtion, intrlveolr pressure flls to little more thn 1 m H 2 O, using the ir to flow down pressure grdient from the nose nd mouth to the lveoli. It is notle just how modest the intr-lveolr pressures hve to e to use gs to flow in nd 5 Cmridge University Press

6 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie Lipid tils (hydrophoi) A Glyerol-sed torso Phosphori id nek Hydrophili hed Air Surftnt phospholipids Surfe-ssoited phse Hypophse B Alveolr epithelium Air Surftnt phospholipids Surfe-ssoited phse Hypophse C Alveolr epithelium Figure 1.4 Surftnt. A: Surftnt phospholipids re omposed of two hydrophoi ftty id tils joined to hydrophili hed vi glyerol nd phosphori id. The most ommon phospholipid in surftnt is phosphtidylholine, while the hydrophili hed is holine. Ftty ids in whih ll the onds etween djent ron toms re single re sid to e sturted, nd re physilly flexile, llowing the moleule to pk in losely to its neighour. Ftty ids in whih one or more of the ron ron onds re doule re sid to e unsturted. These doule onds imprt n inflexile ngultion to the moleule, whih prevents it from pking losely. The most effetive phosphtidylholine moleules re ones in whih oth ftty id tils re sturted ( di-sturted ), suh s diplmitoyl-phosphtidylholine. B: The surftnt phospholipids flot on the surfe of the fluid lining the lveoli, with their hydrophili heds in ontt with the queous phse nd their hydrophoi tils stiking in the ir. C: Expirtion redues the surfe re of the lveolus, squeezing the ulkier nd less effetive phospholipids into the surfe-ssoited phse. The remining phospholipids, eing predominntly disturted, re more effetive t reduing the surfe tension nd, s their onentrtion is inresed, the surfe tension is redued further. Cmridge University Press

7 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge Pressure Proximl irwy Alveolus Interstitium Pleurl vity Atmospheri pressure Trnsmurl pressure Inspirtion Expirtion Figure 1.5 Asolute pressures long the irwy during inspirtion (lue) nd expirtion (green). During inspirtion (lue) there is pressure grdient etween the proximl irwy tht is t tmospheri pressure t the mouth nd the pleurl spe tht is reversed during expirtion. out of the lung during norml rething, ftor to e onsidered when omprison is mde with mehnil modes of ventiltion. Of ourse, muh higher pressures n e hieved. Strining ginst losed glottis, for exmple, n rise lveolr pressure to 190 m H 2 O, while mximl inspirtory effort n redue pressure to s low s 140mH 2 O. Trnsmurl pressure is defined s the differene etween the pressure in the pleurl vity nd tht in the lveolus (Figure 1.5). To remin open, lveolr pressure must e greter thn tht of the surrounding tissue. During inspirtion, intr-pleurl pressure flls to greter degree thn lveolr pressure, nd the trnsmurl pressure grdient thus inreses. Over the rnge of norml reth, the reltionship etween trnsmurl pressure grdient nd lung volume is lmost liner. This reltionship holds true for the lveoli, ut the lower down in the lung the lveoli re, the more the distending trnsmurl pressure grdient is ounterted y the weight of lung tissue ompressing the lveolus from ove. For this reson, dependent lveoli tend to hve smller rdius nd re more likely to ollpse. The expndility of the lung is known s its ompline. A high ompline mens tht the lung expnds esily. The ompline of the norml respirtory system (lungs nd thori ge) in upright humns is out 130 ml.m H 2 O 1, while tht of the lungs lone is roughly twie tht vlue, demonstrting tht hlf of the work of rething during helth simply goes into expnding the ri ge. When positive pressure is pplied to the respirtory system, suh s during positive pressure ventiltion, gs immeditely strts to flow into the lungs, whih then expnd. However, while gs is flowing, 7 Cmridge University Press

8 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge Pressure, P 0 Low ompline proximl irwys A Resistne High ompline lveoli Pressure, P 1 B Volume delivered, V Pressure, P 2 C Volume delivered, V Lungs Figure 1.6 Two-omprtment model of stti nd dynmi ompline. A: In this model the ventiltor is represented y the syringe, whih is tthed to the two-omprtment lung model tht onsists of low-ompline proximl hmer (the proximl irwys) seprted from high-ompline distl hmer (the lveoli) y fixed resistne. Prior to the onset of gs delivery (inspirtion), the whole system is t the sme pressure: P 0. B: Gs is delivered to the lung model with moderte inrese in gs pressure in the syringe (the ventiltor) nd proximl hmer (the lrge irwys) ut with only smll inrese in pressure in the distl hmer (the lveoli) s gs seeps through the resistne. Compline mesured just prior to the end of inspirtion would e given y V/P 1. C: Without the delivery of ny further gs from the ventiltor, the volume of the distl hmer ontinues to inrese until the pressure in oth hmers eomes the sme. As gs redistriutes from the high-pressure proximl hmer to the low-pressure distl hmer, the gs lso expnds slightly. At equilirium, the ompline is given y V/P 2, whih is lrger thn tht lulted in B euse P 2 < P 1. the proximl irwy pressure must e higher thn lveolr pressure, 5 nd the steepness of this pressure grdient will depend on the resistne to gs flow. Therefore, during infltion the rtio of volume hnge to inflting pressure (known s dynmi ompline) is lowered y the effet of resistne 5 Otherwise gs would not flow. to gs flow (Figure 1.6). At the end of inspirtion, the proximl irwy pressure immeditely flls s gs delivery eses (nd with it, the resistive ontriution to irwy pressure) nd then flls little further s gs is redistriuted from low-ompline proximl irwys to high-ompline lveoli. There is lso n ssoited smll inrese in totl lung volume. The perentge of totl hnge in lung volume 8 Cmridge University Press

9 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge I EIP End-inspirtory lung volume Pek inspirtory pressure, P pek Inspirtion Expirtion Pressure Initil plteu pressure, P plt-i Plteu pressure, P plt Volume (ml) Hysteresis End-expirtory lung volume Pressure (m wter) Time Figure 1.7 A pressure nd time profile during volume-trgeted onstnt flow mehnil ventiltion. For delivered tidl volume of V ml, dynmi ompline is given y V/P pek nd stti ompline is given y V/P plt. The differene etween P pek nd P plt-i is due to irwys resistne, while the differene etween P plt-i nd P plt is due to inter-lveolr gs redistriution (pendelluft) nd hysteresis. Figure 1.8 Inspirtory nd expirtory volume/pressure loop during positive pressure infltion showing the phenomenon of hysteresis. During inspirtion (lue) of the lung, oth pressure (x-xis) nd volume (y-xis) inrese, ut this is non-liner. During expirtion, the volume/pressure urve tres different pth. The re sutended y the inspirtory nd expirtory pths represents the energy onsumed y hysteresis. when held t set pressure is known s the lung s stti ompline. Put nother wy, if set volume of ir is used to inflte lung, pressure will rise ordingly, ut (with lung volume held) will then grdully fll y some 25% or so (Figure 1.7). This effet is one of the ontriuting ftors to phenomenon known s hysteresis in whih the lung tres different pth on n expirtory plot of lung pressure (x-xis) ginst volume (y-xis) thn it does during infltion (Figure 1.8). Other ontriutors to hysteresis inlude the opening of previously ollpsed lveoli during infltion, 6 displement of lung lood t higher lung volumes, stress relxtion of lung elsti fires, nd perhps most importntly, the surfe-re-dependent effet of surftnt in reduing surfe tension. In prtie, wht this mens is tht t ny given infltion pressure, lung volume will e greter during expirtion thn inspirtion euse the lungs re resistnt to epting new higher volume, nd then resistnt to giving it up gin. 6 Commonly referred to s lveolr reruitment. LUNG VOLUMES Totl lung pity (TLC) is the volume of intrpulmonry gs t the end of mximl inspirtion. Funtionl residul pity (FRC) is the volume remining in the lungs t the end of norml expirtion tht rises with ody size (s determined y height) nd on ssumption of the upright posture. In mehnilly ventilted sujets, FRC is lso known s the end-expirtory lung volume (EELV). FRC is redued when the lung is extrinsilly ompressed (from pleurl fluid or dominl distension), when lung elsti reoil is inresed, or when the lungs re firosed. Gs exhnge OXYGEN UPTAKE Oxygention is omplished through the diffusion of oxygen down its prtil pressure grdient (Box 1.1) from the lveolus, ross the lveolr epithelium, nd thene ross the losely pposed pillry endothelium to the pillry lood, distne of <0.3 µm. The pity to trnsfer oxygen from lveolus to red lood ell is determined y (1) the surfe re for diffusion nd (2) the rtio 9 Cmridge University Press

10 Cmridge University Press Core Topis in Mehnil Ventiltion Edited y Iin Mkenzie hpter 1: physiology of ventiltion nd gs exhnge Box 1.1 Diffusion nd prtil pressures PO 2 Finl Diffusion desries the pssive movement of sustne from n re of high onentrtion to one of low onentrtion. Diffusion lso pplies to gses, ut in this se the motive fore is the differentil prtil pressure of the gs. Prtil pressure simply refers to the proportion of the totl gs pressure tht is ttriutle to the gs in question. As n exmple, if you hve 1-litre flsk ontining 800 ml of helium nd 200 ml of oxygen t tmospheri pressure (101 kp), the prtil pressure of oxygen in the flsk will e = 20.2 kp etween the speed of diffusion nd the lveolr ontt time, whih is the length of time the red ell remins in ontt with the lveolus (Figure 1.9). The speed of diffusion is determined y the prtil pressure grdient of oxygen etween lveolr gs nd pillry lood, the thikness of the rrier etween lveolus nd pillry, nd the soluility of oxygen in this rrier. Beuse there re no ftors tht influene oxygen s soluility under physiologil onditions, the only soures of vrition in the speed of diffusion re the prtil pressure grdient of oxygen nd the rrier thikness. The prtil pressure of oxygen in lveolr gs is not the sme s the prtil pressure of oxygen in inspired gs euse lveolr gs ontins two other onstituents: ron dioxide nd wter vpour. Therefore, rething ir t se level, the lveolus ontins four gses: nitrogen, oxygen, ron dioxide nd wter vpour. The totl pressure of these gses must equl tmospheri pressure (101 kp): Thikness Alveolr gs PO 2 Surfe re Alveolr epithelium Cpillry endothelium Initil Cpillry lood Figure 1.9 Ftors tht determine the pity to trnsfer oxygen from lveolr gs to pillry lood. Oxygen diffusion (lue rrow) proeeds from lveolr gs (shown on the left) to pillry lood (shown on the right) ross the intervening rrier of the lveolr epithelium nd pillry endothelium, with pillry lood shown flowing wy from the oserver (red rrow). The pity to trnsfer oxygen to red lood ells depends on the surfe re for diffusion, nd the rtio etween the speed of diffusion nd the length of time tht the red ells spend in ontt with the lveolus (referred to s the ontt time ). The speed of diffusion is determined y the (1) initil prtil pressure grdient of oxygen etween lveolr gs nd pillry lood; (2) the thikness of the rrier onstituted y the lveolr epithelium, pillry endothelium nd ny other intervening tissue; nd (3) the soluility of oxygen in this rrier. The ontt time is inversely proportionl to the rdi output nd t rest is normlly 0.75 seonds. Brething ir t se level, red ells pssing the lveolus re normlly fully sturted fter only 0.25 seonds, leving reserve of 0.5 seonds. Diffusion limittion to oxygen trnsfer is therefore only seen with onditions tht redue the speed of diffusion (low lveolr prtil pressure of oxygen or inresed rrier thikness), redue the ontt time, or oth. In trined thletes t mximum exertion the ontt time flls to just over 0.25 seonds. P A N2 + P A O2 + P A CO2 + P A H2 O = 101 kp. (1.2) 10 Cmridge University Press