Search for Diffusion Limitation in Pulmonary Gas Exchange

7 Search for Diffusion Limitation in Pulmonary Gas Exchange

Johannes Piiper, M.D.

Director, Department of Physiology, Max Planck Institute for Experimen tal Medicine, Gottingen, Germany

I dedicate this chapter to the memory Estonia in the Russian Empire. With the of those who introduced me to physiology support of well-off relatives, he was able and guided and promoted me through the to complete secondary school in Tallinn years: Wolfgang Schoedel, long-time head and study biological sciences at the Uni of the Department of Physiology and my versity of St. Petersburg. He became pro predecessor; Kurt Kramer, head of the De fessor of zoology at the University of Tartu partment of Physiology at Gottingen Uni when it reopened as an Estonian univer versity (later at the University of Munich) sity in 1919, after Estonia had won its and my academic promoter, whose enthu independence from czarist Russia after siasm for physiology inspired me; and fighting both the Germans and the Red Hermann Rahn, of Buffalo, New York, Army in the years following World War I. who was unsurpassed as a questor of I was born in 1924 and grew up in a things physiological. free country during a peaceful time of economic growth and cultural develop From Estonia to Germany, ment. All this came to an end with the Through War and Peace establishment of Soviet military bases in Estonia in the fall of 1939 and the annexa My father was born in a poor family in tion of Estonia by the Soviet Union in the Tallinn, capital city of the Government of summer of 1940. After the onset of the

125 126 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

German-Soviet war in June 1941, many charged. But a fellow professor of my fa Estonians were arrested and deported to ther had come as refugee to Gottingen and northern Russia, and young Estonians searched for me by advertising in a refugee were drafted into the Red Army. Being one newspaper, which was smuggled into the year too young, I escaped the draft. camp. Finally , by the end of 1946, I was The German forces advanced quickly, discharged along with a number of Estoni but when they reached Tartu, they were ans , Latvians, and Lithuanians . The rea halted for several weeks by the river that son I went to Gottingen , where a large flowed through the city. During that time a camp for Baltic refugees was located, was large part of the city was destroyed by the that I wanted to enter the university's fires resulting from artillery shelling and medical school. This had been my par arson by Red partisans. In 1942 I gradu ents' wish, and I never hesitated to comply ated from secondary school in Tartu, after with it, although I was attracted more by which I had to join the Luftwaffe, first as biology than medicine. an auxiliary serviceman, but soon thereaf I had lost all my documents including ter as a regular soldier stationed in Esto school certificates, and it was utterly im nian territory. possible to obtain substitutes from Esto As the German army retreated from nia . All I could do was procure written the Baltic countries in September 1944, declarations from two of my former teach my unit was shipped across the Baltic to ers who had come as refugees to Germany. East Prussia. I was wounded on the out But the main reason I was accepted was skirts of Konigsberg, escaped from the en the extraordinary considerateness of circled city on horse cart, and was taken Gottingen University's counselor for for on board a hospital ship to the port of eign students, Dr. Wienert, who, after hav Sassnitz on Ri.igen Island. There the less ing heard my story, arranged my admission seriously wounded were immediately dis pending my passing an oral admission ex embarked and taken on a hospital train. amination. Because of my long absence The severely wounded stayed on board from school and my poor mastery of scien the ship, which left the port and headed to tific German , this was the most difficult the roadstead for safety, but it was hit by exam I have ever taken. My examiner in bombs dropped by Allied aircraft the fol mathematics and physics was Professor lowing night and sank with all the se Hans Loeschcke, the well-known respira verely wounded. My remarkable luck was tory physiologist. I remember one of the that, though graded as severely wounded, problems he gave me was determining the I had been helped by lightly wounded height of Egyptian pyramids using a yard German soldiers to the train, thereby es stick but without climbing the structures caping the shipwreck. During the follow (Luckily I had always been good in geome ing four days the hospital train traveled try.) across the whole of war-torn Germany, With much luck I had survived the from north to south. Finally we stopped war and was admitted to medical school, near Garmisch-Partenkirchen in Bavaria but I was alone . My parents and my sister and were put into an auxiliary hospital. remained in Estonia. I received some sup Soon after American forces occupied port from Estonian refugees, and I lodged Bavaria, my wound had healed suffi clandestinely in a Displaced Persons' ciently, and I was taken to an American camp supported by refugee organizations. prisoner -of-war camp in Garmisch-Parten I could not obtain official permission to kirchen. Being Estonian, I could not be stay there, because of my military past. released due to lack of regulations, Later I was admitted to a student home whereas Germans were continually dis- supported by a Lutheran church organiza- Diffusion Limitation • 127 tion. After finishing two and a half years of the Estonian University of Tartu). I was my preclinical studies, I applied for immi fortunate to find in Pierre Haab not only gration to the United States but was de an indispensable coworker in Buffalo, but nied because of my military involvement also a scientific companion and a friend on the wrong side. About one year later I for life . was requested to come to an emigration I learned that the alveolar-arterial P 0 ) camp for a new interview, but then I was difference (AaD0 was conventionally at~ the one who declined, intending to finish tributed to three fuechanisms: ventilation medical school in Germany. perfusion (VA/Q) inequality, shunt, and After passing the state medical exami diffusion limitation, which were not eas nation I looked for a place to work and to ily differentiated (Fig. 1). Hermann Rahn's prepare my medical doctor thesis. After idea was to demonstrate the effect of venti some unsuccessful applications, I was in lation -perfusion inequality by an experi troduced by Professor Loeschcke to Pro ment that had a simple and straight fessor Schoedel, the director of the physi forward design but could not be easily ology laboratory of the research institute performed. According to Far hi and Rahn 10

(later named the Max Planck Institute), the AaD0 due to VA/Q inequality should where I was accepted in January 1953. An be much 'reduced when N2 is eliminated important asset was that I could get a from inspired gas. This could be achieved fellowship, worth about 100 German by breathing 100% 0 2 in a hypobaric marks a month , which at that time and in chamber at a total pressure reduced to my circumstances was a good income. I such a level that alveolar and arterial P 0 never felt as rich since then. Today I am stayed normoxic, i.e ., at a total pressure of still working in that institute , and since about 197 Torr, equivalent to 10 km of 1973 I have served as director of the De altitude. The result of the exciting experi partment of Physiology. ments we carried out, with all three of us (the experimental dog, Pierre Haab, and myself) confined in the hypobaric cham Steady-State Gas Exchange: ber for many hours, was unexpected and Diffusion Limitation versus disappointing: the AaD0 in anesthetized, Ventilation!Perfusion artificially ventilated dJgs remained un Inequality and Shunt changed after elimination of N2 from in spired gas.17 We considered several possi In September 1958 I came to the ble "loopholes" such as incomplete elimi

United States to work for one year with nation of N2 , accelerated development of , Hermann Rahn in the Department of Phys atelectatic shunt in the absence of N2 and iology at the University of Buffalo , later V)Q inequality of a mainly alveolar dead called the State University of New York at space -like character (the AaD0 due to al Buffalo . The timing was awkward because veolar dead space would be little affected my wife was expecting our first child, and by elimination of N2). We also considered

I could not afford to take her to the United the possibility that the AaD0 in dogs in States. In Buffalo, I was introduced to the our experimental conditions ~as not due American way of life and to the analysis of to VA/Q inequality but to another kind of pulmonary gas exchange by Pierre Haab, maldistribution, unequal distribution of who had come to Rahn from the laboratory diffusing capacity to blood flow (D/Q ine of Alfred Fleisch at Lausanne a year ear quality) (Fig. 2). 44 lier. (An interesting coincidence is that I had developed the concept of D/Q Fleisch had invented the pneumo ratio to explain the experimentally deter tachograph as professor of physiology at mined absorption rates of inert gases of 128 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

IDEAL DIFFUSION LIMITATION

v a v a j' 7-----a 7------a r---- a l- V V - -V -V Po,

Hypoxia Normoxia Hyperoxia

) Figure 1. Models showing the mec~anisms of the alveolar-arterial PO difference (AaD0 by diffusion limitation , shunt , and V/ Q inequality . Lower panel : PO profiles in alveol1ir gas and pulmonary capillary blood. AaD is indicated by open arro'ws. 0 2

Homogeneous Inhomogeneous Shunt

o, 01 a, = a, > 02 = shunt

Decreasing gas exchange efficacy Figure 2. Models for unequal distribution of diffusing capacity (D) to blood flow (Q).D is distributed to the two compartments in such a manner that total, D = D1 + D2 , remains cori.stant. The decreasing gas exchange efficiency i_scaused by the inability of increased D/Q in one unit to compensate for the reduced D/Q in the other unit.

varied solubility and diffusivity from sub normoxia the AaD0 was mainly attribut cutaneous gas pockets in rats that Canfield able to a lung compJrtment with low D/Q. and Rahn observed prior to my arrival in In hyperoxia there would be no diffusion 50 ), Buffalo. When allowing for variance of limitation in this compartment (no AaD 0 the D/Q ratio in lungs, the dependence of and in deep hypoxia the blood flow of th1s

AaD0 on alveolar PO found in our experi compartment would be functionally close ment ' could indeea be explained. In to a complete shunt. 53 Diffusion Limitation • 129

As the CO2 electrode became avail small AaD0 to be attributable to diffusion able (after 1960), we and others showed limitation (Pig. 3). But this was a maximal that there existed an arterial-to-end effect based on the assumption that alveo expired P co difference in anesthetized lar dead space was the only effective mode dogs that explained part of the total AaD 0 of VA/Qheterogeneity. When other modes not attributable to shunt or (evenly distrib= of VA/Q inequality were assumed , the dif uted diffusion . The larger part of AaD fusion limitation component of AaD ap - 0 0 2 measured in normoxia could not , how: proached zero. ever, be explained by this factor (e.g., ref Also, measurements of Oz exchange erence 2). Yet by the elegant multiple inert in isolated, blood-perfused dog lung lobes gas elimination technique (MIGET),66,67 in hypoxia led to results that were not 46 AaD0 in man and dog has been shown to easily explained by diffusion limitation. be m~inly explainable by VA/Q variance. Following an idea of Masaji Mochizuki From my perspective today, our results (with whom I had interminable discus with elimination of N2 may have been sions as he worked with Heinz Bartels in mistaken, but they did stimulate us to look the physiology department of the Univer for other solutions and thus led to the sity of Gottingen 1953 and 1954), we per concept of D/Q and its variance. On the formed measurements with varied hemato other hand, it would be strange if the siza crit. The AaD0 was found to be indepen ble variance of pulmonary capillary transit dent of hematocrit, in agreement with time, as measured by videofluorescence Mochizuki and coworkers 40 and corre microscopy in subpleural, pulmonary ves spondingly the calculated D0 came out sels by Wiltz Wagner, 4·69,70had no effect on proportional to hematocrit. Th1s could be

0 2 exchange. Moreover, the pulsatile pul explained by a model with all resistance to monary capillary blood flow as demon Oz uptake in red blood cells (and no resis strated by Grant de Jong Lee and associ tance in the blood-gas barrier or plasma) . ates Z9 is expected to have effects analogous But the same effect would be produced by to those of local blood flow variance . a shunt beside a major compartment ex The combination of D/Q inequality hibiting no diffusion limitation. The shunt with that of VA/Q inequality in a "V/Q=D/ model could also explain the indepen 45 Q field" remained theory for a long dence of AaD0 of blood flow, which led to time. Only recently have Yamaguchi and a directly pr~portional relationship be 46 coworkers attempted to apply this con tween D0 and blood flow. cept. Combining experimental results of It followed from all the theoretical MIGET with COz, Oz, and CO exchange models and experimental results that an data obtained from pulmonary patients, AaD0 due to diffusion limitation was not Yamaguchi and coworkers 74 have been easily evaluated. Even its existence could able to estimate quantitatively both VA/Q not be convincingly demonstrated, appar and D/Q inequality. ently due to disturbing influences of func Back in Europe from Buffalo, Pierre tional inhomogeneities like ventilation Haab and I returned to the conventional perfusion and other inequalities. analysis of alveolar gas exchange in anes thetized dogs. To increase the relative dif fusion limitation effects on AaD , we Rebreathing: Attempt to 0 2 measured gas exchange variables in deep Isolate Diffusion Limitation hypoxia (Fig. 1). This time we used the recently available blood P co , electrodes The stimulus came from Paolo Cerre and mass spectrometry for cohtinuous gas telli , from the laboratory of Rodolfo Mar analysis .16 The results showed onl y a very garia in Milan (now in Gene va), with 130 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

Mean values (! SE) E' -----.----.--- i i Ai f f C,212 1.5 1.8 4.4 6.6 c'TITITTBlood R Line a fl-I"23Tocc t1~:, ::;::: Figure 3. Analysis of alveolar gas exchange in hypoxia. Left: model of lung with series dead space, alveolar dead space, and effective alveolar ventilation, capillary, and shunt

blood flow. Mean values (± SE) of PO and P co differences, obtained in 11 anesthetized, 6 paralyzed, artificially ventilated dogs are indi'cated. After Haab et al.1 • Right: P co - P 0 diagram with blood and gas R lines underlying the analysis of alveolar gas exchange according to the model at left. whom I had collaborated since 1962 on were determined by the ratio of the overall studies of 0 2 supply to stimulated isolated Oz conductance, determined by pulmo ), muscles and exercising animals. With nary diffusing capacity for Oz (D0 pul Hermann Rahn and Leon Farhi, he had monary capillary blood flow, ai71.dthe attempted to determine mixed venous P 0 slope of the blood Oz dissociation curve, in man by rebreathing, using mass spec: to the Oz capacitance, given by the total trometry. 6 Be selecting a gas mixture of gas volume of lungs and re breathing bag. 51 appropriate composition and volume, he Because an infinitely high ventilation can and his coworkers attempted to obtain not be achieved, in practice the effective mixed venous P O and P co from re ventilation and the partitioning of the total . breathing plateau v~lues of Cbz and 0 2 gas to lungs and rebreathing bag also had But in most cases this ideal condition of to be taken into account (Fig. 4). The true plateau could not be achieved. In feasibility of the method was tested in 1 stead, the mixed venous PO had to be experiments on anesthetized dogs and on extrapolated or interpolated :r;om a plot of man at rest and during exercise. 64 : rate of change of PO against PO the true The method could be improved by value was assumed where the rate of introducing a stable isotope of Oz, 18 0z, in 7 • change of PO became zero low concentration (0.07% in the re I becam2e involved when Cerretelli breathing mixture) as test gas.37 This had asked me to analyze the factors that might two important advantages. First, mixed determine the kinetics of the approach of venous partial pressure of the isotope lung gas P toward the equilibrium value, could be neglected. Second, the effective O 2 • i.e., mixed venous PO According to the blood dissociation curve of the isotopic Oz theory, in an ideal sy~tem these kinetics against its partial pressure could be re- Diffusion Limitation • 131

····-~························

Mass spectrometer

····-·Pv··-·· ···············-··

5 10 15 5 10 15 Time of rebreathing (sec)

Figure 4. Determination of diffusing capacities (D) for Oz and CO by rebreathing: model and recordings of partial pressures in rebreathing gas by mafiS spectrometry . VR, (average) vol.ume of rebreathing bag; VL, (average) lung volume; Veff, effective alveolar ventil,ation; Q, pulmonary blood flow; ~, slope of effective blood dissociation curve. For Dco, Qand ~ are not required because CO uptake may be regarded as not limited by blood flow. Time available for measurement is limited by onset of recirculation (about 12th s). garded as a straight line through the mixed that simple diffusion was the main factor venous point of the abundant isotope involved . 16 3 (0 2). From simultaneous determination Recently a group in Oxford and a of CO diffusing capacity, a stable isotope group in Bordeaux 14 have reported mea of CO, 13 CO, was used, again to be able to surements of pulmonary diffusing capac neglect CO in mixed venous blood and, ity in patients using a new test gas, nitric more important , to be able to separate CO from N2 when using continuous respira 80 ,------, tory mass spectrometry with relatively low mass resolution. D 60 1 The advantage of rebreathing is the ---+---!---+---! homogenization of lung gas by re (m;;\orr) ------Dco 40 D breathing , thus reducing or even practi ~ ~ 118 1.20 1.19 1.211 cally eliminating the effects of unequal 20 distribution of ventilation to blood flow . 50 75 100 125 Wott

Simultaneous determination of D and Rest 0 Exercise Dea in normal man showed that thJ rest 0+----.----,----,....---.----- 2 0 20 ing values were higher than usually re 1.o 02 uptake (I/mini · ported (using other methods), their in crease in exercise was moderate, a plateau Figure 5. Simultaneous determinations of the diffusing capacities for Oz and CO (D0 , Deal by value was reached, and the ratio D0 /Dea rebreathing in man at rest and during bicycle was about 1:2, i.e ., close to the ratio of ergometer exercise. Mean values ± SE obtained Krogh diffusion constants for tissue 37 (Fig. in 6 normal males , 20-33 years of age. After 5). The last finding was taken to indicate Meyer et al.37 132 • THE PULMONARY CIRCULATION AND GAS EXCHANGE oxide (N0). 36 The advantage of NO is that Hypoxia Normoxia Hyperoxia it reacts much faster with hemoglobin than does CO. But NO is a highly reactive and toxic gas , and it must be used in very low concentrations. It could be measured in gas samples using highly sensitive chemiluminescence detectors developed for monitoring atmospheric pollution . Us ing mass spectrometry, we had to go to NO CO NO CO NO CO considerably higher concentrations than used in man by the other groups (600 ppm Figure 6. Simultaneous determinations of the diffusing capacities (DJ for NO and CO by vs. 10 to 40 ppm) , and therefore we pre rebreathing in 8 anesthetized, artificially venti ferred to work on dogs. Because of the lated dogs. Mean values relative to DN0 in reactivity and instability of NO, particular normoxia. The differences between normoxia measures had to be taken for its continu and hypoxia and between normoxia and hyper DN ous recording by the mass spectrometer oxia are statistically significant for both 0 39 during rebreathing. and Dea· After Meyer et al. Simultaneous rebreathing of NO and

CO yielded average DN0 in anesthetized The problem of CO2 equilibration ki dogs about four times higher than Dco39 netics of blood in pulmonary capillaries (Fig. 6). According to literature data, the has been experimentally investigated by Krogh diffusion constant ratio NO/CO is Hyde and coworkers 24 in humans . They

/ close to 2. The higher figure for the DN0 applied a breath -holding method in which 13 Dea ratio probably is due to the slow reac the kinetics of C0 2 equilibration was tion of CO with hemoglobin. Even in hyp compared with that of acetylene. But the 13 oxia, where substantial free Hb is also equilibration limitation effect on C0 2 present in arterialized blood, the DNo/Dco uptake was too small to be measurable . ratio averaged 3.2. The inference that CO The effective diffusing capacity, Dea , was uptake is strongly reaction limited is evi estimated to be higher than 200 ml/ dently is disagreement with our conclu (min-Torr) . Using the same CO2 isotope sions from simultaneous measurements of and acetylene but applying rebreathing 13 Dco and D0 in humans (see above). Be and continuous recording of C0 2 and cause the ratio D0 /Dco was found close to acetylene during rebreathing by mass the Krogh diffusi~n constant ratio 0/CO, spectrometry, we could estimate the CO2 it was concluded that both 0 2 and CO diffusing capacity at 180 ml/(min ·Torr) at were limited by simple diffusion. The rest and at 300 ml/(min·Torr) during mod 54 high DN0 /Dco ratio would mean that true erate exercise. Dco was higher than measured and the Our main interest was comparing Dea , estimated D0 was an underestimation, with D0 both measured by rebreathing id possibly due to remaining inhomogeneity similar' experimental conditions. The effects (D/Q inhomogeneity ?). mean ratios Dea /D were 3.3 at rest and 0 2 Of particular interest was a small but 4. 7 during exercise, thus averaging 4 . But significant increase of DN in hypoxia and the Krogh diffusion constant ratio Keo IK 0 2 0 decrease in hyperoxia. 39 Because the reac is about 20- 25. Thus the capill ary: tion of Hb with NO is known to be very alveolar equilibration of CO2 was found to fast , we would like to attribute these be much slower than expected on the basis changes to real changes in D (increase in of CO2 diffusion. It is well known that the size or number of perfused pulmonary blood-gas CO2 transfer in lungs is a com capillaries) . plex process consisting of many compo - Diffusion Limitation • 133 nent processes . The bicarbonate-chloride skin , gas transfer in lungs), is a gas phase exchange between red blood cells and maintained at constant composition hav plasma , the dehydration of carbonic acid ing gas exchange with flowing blood, of a to CO2 in plasma, and the same reaction in certain effective solubility for the gas con the red cells (in spite of the presence of sidered, across a barrier constituting a re carbonic anhydrase) are known or sus sistance to diffusion. 55 The calculated par pected to be relatively slow. Thus the tial pressure profiles are shown in Figure diffusion of CO2 may lead to a rapid equili 8. They are determined by the ratio of bration of CO2 in blood with alveolar gas, diffusing capacity (D) and the product of but the subsequent slow reequilibration blood flow (Q) and the effective solubility , -, between CO2 HC0 3 and H+ in red cells (~). which is the slope of blood dissocia and plasma would lead to an elevation of tion curves in terms of concentration (con P co in arterialized blood after it has left tent) versus partial pressure (~ = dC/dP). 2 the lungs (to be eventually completed as The ratio , D/(Q~). may be termed the the blood is in a CO2 electrode) (Fig. 7). equilibration index . For the relative equil ibration deficit of arterial blood (PA- Pa)/ (PA- Pv), the following equation holds: Diffusion/Perfusion Model: Extent and Site of Diffusion PA - Pa e - -D Limitation PA- Pv - Q~ (1)

In the analysis of gas exchange, a Clearly for D/Q ~ 00 , PA- Pa~ 0, meaning basic question is to what extent gas trans absence of diffusion limitation. With de fer is limited by perfusion and by diffu creasing D/Q, PA - Pa increases, denoting sion. The simplest model, applicable to increasing diffusion limitation. The rela many situations (such as absorption from tionship of Equation (1) can be applied to tissue gas pockets, gas transfer through any gas including 0 2 •

/C0 2/HC03'H• re-equilibration L-- in blood

A------=---,.,- ~_:'-----=\

v \ I Equilibration deficit Cco2

eqA------

Capillary transit time

Figure 7. Blood-gas CO2 equilibration in lungs . Qualitative model to explain the experimental finding that the C0/0 2 ratio of diffusing capacities was much smaller than the corresponding Krogh diffusion constant ratio for tissue . The equilibration of CO2 proper is rapid and practicall y complete during the pulmonary capillary transit time, but

the equilibrium for total CO2 content is not reached. 134 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

Limitation

Figure 8. Diffusion-perfusion limitation i1,1a lveolar-capillary gas transfer. Model, partial pressure profiles for various values of D/(Q · ~), and a dissociation curve (concentration, C, as function of partial pressure , P) showing definition of the capacitance coefficient ~ = .6.C/.Afl.After Piiper and Scheid .55

Whereas in the normoxic and slightly D/Qinhomogeneity may play a role, as the hypoxic regions the assumption of a con transit times in some pulmonary capil stant ~ is problematic because of the evi laries may be reduced so much as to turn dent curvature of the Oz dissociation their flow to functional shunt flow. curve, and a procedure like Bohr integra Let us make a short excursion to lower tion should be applied, in deep hypoxia vertebrates (indeed, the comparative the Oz dissociation is sufficiently linear. physiology of gas exchange in vertebrates The effects of the curvature of blood Oz has been in the center of my research dissociation curves have been recently in interest for a long time). In amphibians, vestigated.z7,zs With the value of D0 deter cutaneous gas exchange is important, par mined in our laboratory in deep hypoxia ticularly for COz elimination, but also for and Q and ~ calculated after the values Oz uptake. Because skin must have a cer estimated by Cerretelli 5 in man in the base tain thickness to provide mechanical pro camp of Mt. Everest (altitude 5,350 m), a tection, diffusion limitation in cutaneous strong diffusion limitation results for rest gas exchange is expected to be much more ( 12 % ) and an even stronger one for maxi prominent than in lungs . Remarkably, in m um Oz uptake exercise (64%). The AaD 0 various groups of salamanders lungs have estimated therefrom (2 Torr at rest, 27 Tod been reduced so that all exchange occurs at maximum Oz uptake exercise) is in through skin (and oral and pharyngeal rough agreement with measurements per mucosa). formed by Wagner and coworkers in Randall Gatz and Eugene Crawford , normobaric or hypobaric simulated alti zoologists from Lexington, Kentucky, took tude.19,63,65,68 lungless salamanders captured in the Al There is also growing evidence for leghenies to Gottingen to study their cuta diffusion limitation of pulmonary Oz up neous gas exchange. We could measure take in very strenuous exercise in human PO and P co in blood sampled from the athletes in normoxia. 9 In these cases the siJgle ventricle and roughly estimate the Diffusion Limitation • 135 blood flow and diffusing capacity of the Forster relationship , which is based on the skin using soluble inert gases. Calcula additivity of intraerythrocyte (REC) and tions with the values thus obtained re extraerythrocyte ("membrane") transfer vealed a strong degree of diffusion limita resistances, 52 tion for both 0 2 uptake and CO2 output. Remarkably, animals are highly tolerant of 1 1 1 2 hypoxia 13 and can substantially increase DL= Dm + Ve· 0 ( ) their cutaneous 0 2 uptake during exercise. Evidently the diffusing capacity can be where DL is pulmonary D; DM, "mem adaptively increased .11 brane" D; and Ve, pulmonary capillary Estimation of the pulmonary equili blood volume. We calculated for the ratio bration deficit of CO2 in human lungs by DLIDM, equivalent to the fraction of ex introducing values of D, Q, and ~ into traerythrocyte 0 2 uptake resistance in to

Equation (1) yielded 2% for rest but 18% tal 0 2 uptake resistance, 0.88 (assuming 54 for maximum 0 2 uptake exercise. The D0 = 54 ml/(min · Torr) and Ve = 100 ml). corresponding arterial-to-alveolar P co dif Wfth a previously determined value of 0, ferences were 0.2 Torr and 7 Torr, reJpec 1.5, 20 the figure would be 0.67 . Thus a tively. Thus, against what is usually be major part of the 0 2 uptake resistance in lieved, blood-gas CO2 equilibration in lungs appears to be located outside the red lungs may play an important role in limit cells, in the plasma and tissue barrier. ing the efficiency of CO2 elimination . This conclusion is not in good agreement with morphometric data, which show that diffusion distances within red cells are Site of Resistance to Gas larger than those across the air -blood tis Transfer: Red Blood Cells 71 sue barrier. But in red cells 0 2 transport versus "Membrane" appears to be facilitated by hemoglobin

(diffusion of 0 2-hemoglobin). Moreover,

The role of 0 2 transfer resistance of intracapillary hematocrit is generally the red blood cells in alveolar 0 2 uptake lower than large vessel hematocrit. Be

(and 0 2 delivery in tissues) has been dis cause 0 is defined for normal hematocrit cussed for many years. It was fortunate for (0.45), a lower hematocrit (lower 0) us that in 1981 Robert Holland from would lead to an increased DM for a Sydney, Australia, came to us for a sabbat given (measured) DL. Another factor that ical and initiated a number of studies on is difficult to assess is the convective mix

0 2 kinetics of red cells using an improved ing of red cell interior and plasma during stopped-flow technique. Our attention blood flow through pulmonary mi was directed toward determining the ex crovessels in vivo. tracellular resistance to 0 2 transfer in In other studies using the stopped stopped-flow experiments and to obtain flow apparatus we attempted to further ing, by subtraction of the extracellular re analyze the factors determining the 0 2 sistance, a better estimate of the true 0 2 transport within the red blood cells. Using transfer resistance of red blood cells or its a particular model for evaluation of mea reciprocal, the specific 0 2 transfer con surements, we concluded that the diffu 25 ductance, 0 . As expected the 0 0 values sion coefficients of 0 2 and hemoglobin corrected for perierythrocyte 0 2 transfer were the most important variables, but 0 2 resistances were considerably larger than reaction kinetics of hemoglobin also had a previously published values. 75 limiting effect. 23 In contrast, measure

Using the well -known Roughton- ments of 0 2 uptake kinetics at varied tern- 136 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

perature left very little space for a limiting explain the experimental data. This re role of the chemical reaction. 73 Both stud markable paper gave rise to a lively debate ies may be considered as evidence for a in which two discussants, Gabriel Laszlo minor role of the kinetics of the chemical (London) and Jack Hackney (Downey,

reaction of hemoglobin with 0 2 in limiting California) reported that they had not been

0 2 uptake. able to reproduce the negative blood-gas

Many years ago, I had tried to mea P co differences in alveolar gas-blood CO2 sure the red cell - plasma equilibration of eqJilibrium.

CO2-bicarbonate in vitro using the rapid In the wake of the Gurtner paper, a mixing-continuous flow technique com number of studies have been performed, bined with filtration for plasma sampling. most of them confirming negative mixed At that time I looked for a possible expla venous-to-alveolar or arterial-to-alveolar nation of the relatively large arterial P co differences in rebreathing equilibrium alveolar P co differences found in anesthe in 'varied experimental conditions (re 2 tized dogs. But the results showed the viewed in references 49 and 57). The ex kinetics of bicarbonate to be very rapid, citement about this finding was under leading to 90% equilibration in 0.11 s on standable. There was every reason to be the average. 47 Because the usually as lieve that this phenomenon of a negative sumed transit time of pulmonary capillar blood-gas P co difference would not be ies, 0.3 to 1 s, is longer, a discrepancy confined to r~breathing equilibrium but appears to exist: the in vitro results sug would be operative also in steady-state gas gest no measurable equilibration limita exchange (Fig. 9). But this would invali 13 tion in contrast to the in vivo C0 2 equili date the classical approach to the analysis bration results. But both in vivo and in of alveolar gas exchange in which the vitro techniques are difficult and fraught equality of P co between alveolar gas and with potential errors. A reevaluation using end-capillary tllood in equilibrium was a improved methods would be welcome. central , seemingly obvious, assumption. Indeed, soon Donald Jennings (King ston, Ontario) claimed that negative blood Blood-Gas Equilibrium of gas P co differences occurred in anesthe : CO2 "Anomalous" versus tized dJgs during steady-state gas exchange Conventional in hypercapnia. 25 Having spotted this pa per, my coworkers and I immediately set : In the Symposium on CO2 Chemical, out to repeat the experiments, essentially Biochemical and Physiological Aspects, duplicating the experimental conditions. which took place in Philadelphia in Au But we could not reproduce the results: gust 1968 (as a satellite to the International there were no negative arterial-to-alveolar Congress of Physiological Sciences in P co differences. 56 Soon after the comple Washington, D.C.) a remarkable finding tior'i.of these experiments, I had the oppor was presented by Gail Gurtner (at that tunity to present the results at the 1978 fall time in Buffalo). He showed experimental meeting of the American Physiological So data obtained in anesthetized dogs in re ciety in St. Louis. 48 Donald Jennings was breathing equilibrium, exhibiting large present, and our discordant experimental negative P co differences between alveolar results were discussed. After the session, gas and mi~ed venous blood, averaging we continued the discussion with some about 10 Torr but reaching up to 28 Torr. 15 beer. The outcome was a visit by Peter Moreover, he presented an elegant physio Scheid and myself to Jennings's laboratory chemical theory, which came to be known at Kingston , followed by joint experiments as the charged membrane hypothesis, to in Gottingen . Diffusion Limitation • 137

I. Rebreathing equilibrium II. Steady state gas exchange

Conventional v ------a,A

Pea, A------Anomalous v------a I

• Figure 9. Models for blood-gas equilibrium of CO2 In rebreathing equilibrium, conventionally an equality of mixed venous, arterial, and alveolar Pea is assumed; in the "anoma lous" case, mixed venous and arterial Pea are lower thafl alveolar Pea. In steady -state gas exchange, conventionally close to complete equilibration, with arterial close to alveolar Pea, is assumed; in the "anomalous " case , an equilibrium with Pea in blood lower than P c~ in gas is supposed to be approached, leading to arterial P co being 2 lower than alveolar Pco . 2

The experiments were performed on tions and reactions in this campaign fol awake dogs prepared with a chronic tra lowed. Steinbrook and coworkers 62 re cheostomy and exteriorized carotid loop ported large negative blood-gas P co differ (exactly as done in Kingston) but using our ences , averaging - 12 Torr in 178 m~asure mass spectrometer for alveolar -expired ments during long-lasting rebreathing in P co and our blood electrodes for P co . The awake goats. We repeated the experiments rest.It was that in hypercapnia no ~ingle on awake dogs in similar conditions but measurement in any dog had a negative found no significant blood-gas P co differ 2 value of the arterial-to-end-expired P co ence (average - 0.4 Torr in 266 m easure difference : with 5% inspired CO2 thJ men ts). 60 Because previously larger mean value was +0.9 Torr (significantly anomalous blood-gas P co differences had different from zero), with 10% CO2, +0 .1 been reported to occur \n exercise, we Torr (not significantly different from repeated measurements in dogs re zero). The results were published in a joint breathing while running on a treadmill. communication (26), although Jennings The result was the same: no negative was not quite convinced. We planned a blood-gas P co differences were ob - later continuation of the research in King served.30 2 ston, but it did not occur. During these years I frequently asked Thereafter another North American colleagues their opinions on the contro physiologist who had found indirect evi versial matter of negative blood-gas P co dence for negative blood-gas P co differ differences, or they approached me about ences in dogs in steady-state gas e:~change it. The opinions fell into two opposite came to us, initially with the intention of camps. Many encouraged us to continue restudying the phenomenon, but then he our efforts, with improved methodology , drifted to other experiments. Other ac- to reproduce this interesting phenome- 138 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

non, which we evidently had failed to (falling) alveolar plateau of CO2 (0 2) or of find. Others wondered why we wasted inert foreign gases previously inspired. time and effort trying to reproduce some These problems were investigated thing that was nonexistent because it evi half a century ago by, among others, my dently contradicted physicochemical teacher and predecessor, Wolf Schoedel, laws. In the last few years some reports of then at the Department of Physiology, Uni small negative P co differences have ap versity of Gottingen , headed by Hermann peared, but studi~s explicitly aimed at Rein. 41 ,59 It was realized that not only checking the phenomenon, with negative stratification proper, but also continuing results, have also been published. 8,12 gas transfer between blood and alveolar In a detailed analysis of potential gas and sequential emptying of lung areas sources of error it seemed that more fac with varied gas concentrations might be tors led to falsely negative than to falsely involved in producing sloping alveolar positive blood-gas P co differences, the plateaus (Fig. 10). With the advent ofrapid simplest and possibly ~ost important one gas concentration recording techniques being loss of CO2 from blood during sam like infrared absorption and mass spec pling or transfer into the electrode. 57 But it trometry, the shape of expirograms of vari was practically impossible to explain the ous gases could be recorded more accu large differences amounting to tens of Torr rately . P co . It seems wise to consider this inter The simultaneous measurement of estfng issue to be open, and I encourage all several gas species of different diffusivi students of CO/acid-base balance to look ties is of particular interest for the detec out for evidence pro or con. tion of diffusion limitations. Because of its It is important to point out that the great contrast in diffusivity, the pair He/ , equilibration kinetics of labeled CO2 dis SF 6 has been frequently used, the ratio of cussed in a preceding section, concerns a their diffusivities amounting to 6.0 from fundamentally different aspect: the kinet Graham's Law (diffusivity inversely pro ics of approach to an equilibrium that, in portional to the square root of molecular principle, is independent of the position weight) . After measurements in our labo of the equilibrium. Thus the kinetic data ratory, the ratio of diffusion coefficients of and their interpretation are compatible He and SF 6 in a gas mixture of 14% 0 2 , 6% 72 with any constellation of blood-gas P co CO2 , and 80% N2 was 7.2. For a simple differences in the equilibrium state. 2 diffusion resistance model, one expects the gradient per transfer rate to be in versely proportional to diffusivity. Be Diffusion Resistance in Gas cause the transfer rate is proportional to Phase: Conflicting Evidence the end-expired-to-inspired (or mixed expired-to-inspired) partial pressure dif There has been considerable contro ference , the relative slope of the alveolar versy, revived recently about what part of plateau (i.e., standardized to the above the overall diffusion resistance to move mentioned partial pressure differences) ment of 0 2 and CO2 between inspired gas should be inversely proportional to diffu and pulmonary capillary blood may be sivity, i.e., the SF/He ratio of standard located in the alveolar gas . The conse ized alveolar slopes should be about 7. quence of such a transfer resistance would Scherer's group in Philadelphia has be a partial pressure gradient in the termi studied the expirograms of CO2 and intra nal airways, often referred to as strati venously infused He and SF 6 in man . The

fication. This gradient could be detected reported SF 6/He ratios of the standardized during a prolonged expiration as a rising slopes were 3:13 58 and later, with im- Diffusion Limitation • 139

A. Series B. Parallel

Relatively Relatively Hyperventila ted, Hypoventilated, First Out Last Out

Figure 10. Alternative mechanisms of sloping alveolar plateaus . Density of stippling indicates gas concentration. A. Series inhomogeneity or stratification. Upon expiration, the sloping alveolar plateau directly reflects the stratification is alveolar space. B.

Parallel inhomogeneity , e.g., produced for CO2 by unequal distribution of ventilation to blood flow . If relatively hyperventilated lung areas expir e earlier and relatively hypo ventilated areas expire later , a sloping alveolar plateau is generated . proved technique, 1.85. 42 As pointed out to a central common compartment. The by the same group, due to the trumpetlike gas exchange between the central and shape of the lung airways (when consid each of the peripheral compartments was ered as total airways cross section as func implemented by both diffusion and venti tion of length), the expected ratio is con lation, characterized by a diffusive and a siderably smaller than the diffusivity ratio ventilatory conductance. 22 In subsequent and may reach the values that were experi experiments on dogs, the sloping alveolar mentally found . The authors concluded plateaus of CO2 , 0 2 , and intravenously that diffusion resistance in the airways is infused acetylene and Freon-22 were de the main factor in producing the alveolar termined.35 In another series, the alveolar

slope. slopes of He and SF 6 administered In our laboratory we found in anesthe through inspired gas and through venous tized dogs well-established alveolar blood were comparatively studied 38 (Fig. slopes, but SF /He slope ratios were much 11). In all cases only a minor dependence closer to unity, and in many conditions of the test gas alveolar slopes on diffusiv the ratios were even below unity. 34 This ity was found. finding indicated that the slopes were due The picture emerging from these ex to other factors besides incomplete diffu periments performed in Gottingen is that sional equilibration in gas phase. Because the alveolar slope is mainly due to contin the effects of continuing gas exchange uous gas exchange (particularly for well were compensated for by a special tech soluble gases, but also for little-soluble

nique , only sequential expiration of lung gases like He and SF 6 when intravenously areas of differing gas composition, due to infused), secondarily to sequential expira VA/Q or VA/VAinequalities, was a possible tion from lung areas with differing test gas explanation. The simplest model to ex composition (due to ventilation-perfusion plain the experimental data consisted of or ventilation-volume inequalities) . Fi two peripheral compartments connected nally , but to a lesser extent, the slope is 140 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

Inspired gos: 1% He• 1% SF6 in air - air

AIRWAY LOADING

0 o~--'"'----'-2---'---,....__.____.6 _ __._ _ _,_8_---'- Time Isl

50% He 11/min 50% SF6

] 0.5 & VENOUS LOADING

Vein 60ml/min Artery

Time Isl

Constant flow expiration (control: 100 ml /sec)

Figure 11. Simultaneous expirograms of He and SF6 obtained in anesthetized, artifi cially ventilated dogs during constant flow expiration. Airway loading: first breath after

wash-in equilibration with 1 % He and 1 % SF6 in air. Venous loading: continuous administration of He and SF 6 by equilibration of blood using an extracorporeal gas exchanger. The following findings are evident: larger dead space for SF6 than for Be; slightly higher alveolar slopes for SF 6 than for He; higher alveolar slopes for venous loading compared to airway loading. After Meyer et al. 38 due to diffusion resistance in gas phase (as tion in Gottingen). An interesting aspect of indicated by dependence on the diffusion this story should be mentioned: both the coefficient). Philadelphia group and the Gottingen The differing results from Philadel group had difficulty getting their papers phia and Gottingen have led to discus accepted for publication by a leading jour sions, reciprocal laboratory visits, and a nal of respiratory physiology, apparently joint symposium at a meeting of the Feder because the concepts, models, and inter ation of American Societies for Experi pretations of both groups were in disagree mental Biology (FASEB, Washington, ment with the views of influential refer D.C., April 1990) . What we could agree on ees. Indeed, other attractive lung models was that the source of the discrepancies producing sloping alveolar plateaus are might be sought in the species (humans in models with asymmetrically branching Philadelphia vs. dog in Gottingen) and in "trumpets" of different lengths leading to the experimental conditions (spontaneous locally varying diffusion resistances. 31 ,43 breathing in Philadelphia vs. artificial We have not tried to apply such models ventilation with prolonged, linear expira- because of their complexity and a lack of Diffusion Limitation • 141 information about the anatomy, preferring not differentiable from phase II of the nor simpler models composed of a few com mal expirogram. Moreover, the arterial partments as functional analogs. Pco was much higher than the peak ex According to model calculations, the pir~d Pea. relative alveolar slopes due to incomplete This'looked very much like a well diffusive mixing are expected to increase developed stratification. But the expiro with increased breathing frequency and grams of two intravenously infused gases of reduced total volume and have been equal solubility but different diffusivity, found to do so during rapid shallow acetylene and Freon 22, were close to iden breathing in humans. 42 An extreme form tical.61 (Fig. 12). Moreover, the multiple of rapid shallow breathing is panting in breath washout kinetics of helium and SF 6 the dog, with breathing frequencies of were very similar .18 This points to a rela about 5/s and tidal volumes close to ana tively small role for diffusion limitation, tomical dead space. Using a special tech and the prevalent role of convection, proba nique, expirograms during panting could bly a "stratified ventilation" in a serial be obtained. 33 They showed a very steeply system. But unequal parallel ventilation ) rising P co (falling PO during expiration, with relatively hypoventilated areas expir immediat~ly followea by a rapid fall of ing last could not be excluded . Similar ) P co (rise of PO during inspiration (Fig. results and conclusions were reached from 12)'. This couldlJe described in two ways: experiments with high-frequency ventila absence of an alveolar plateau or an ex tion in anesthetized dogs, with respiratory tremely steeply sloping alveolar plateau, frequencies varied from 10 to 40/s. 32

-----Expiration---<--- Inspiration----- 3· l'.f'

0.17 -CiH2 0.03 2- 10·' ...... F22 2·10"4

Fc,H, 0.18 FF22 0.02 F0i 10·' 10"' 0.19 Feoi

0.01 0.20 0 - 02 0 ...... CO2

0.21 0

0 100 200 300 Volume (ml BTPS)

Figure 12. Gas concentration profiles of intravenously infused acetylene (C2H2), Freon 22 (F22), and of0 2 and CO2 during a single respiratory cycle in dogs during panting (z 5 breaths /s), plotted against respired volume (abscissa) . Note reversed scale for 0 2 as compared to other gases . After Sipinkova et al.61 142 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

It is rather difficult to separate airway we expected and, what is at first less grati diffusion gradients proper (stratification) fying but more fruitful in the long run, from unequal distribution effects due to finding unexpected results. Of fundamen inhomogeneity of ventilation and diffu tal importance were personal contacts sion among parallel and serial airway ele with scientists from other laboratories. ments. Most of our contributions have arisen from such contacts, which gave rise to recipro Epilogue cal visits and joint projects. Acknowledgment: The work reported here could not This is a fleeting report of the main have been performed without the collaboration of many coworkers whose names appear as coauthors features ofmy meandering , erratic journey of the publications in the reference list . I am particu through diffusion problems in lungs. No larly grateful to Dr. Peter Scheid (now in the Depart aspect has been completely clarified, but ment of Physiology , University Bochum) and Dr. Michael Meyer , who participated , in many cases as my coworkers and I had in many cases the principal investigators in most of the recent studies pleasure of experimentally verifying what on which this report is based .

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