The Influence of Graded Degrees of Chronic Hypercapnia

on the Acute Carbon Dioxide Titration Curve

MARCB. GOLDSTEIN, F. JOHNGENNARI, and WILLIAM B. SCHWARTZ

From the Department of Medicine, Tufts University School of Medicine,and the Renal Laboratory of the NewEngland Medical Center Hospitals,Boston, Massachusetts 02111

A B S T R A C T Studies were carried out to determine theinfluence of the chronic level of arterial carbon dioxidetension upon the buffering response to acute changes inarterial carbon dioxide tension. After chronic adaptationto six levels of arterial C02 tension, ranging between35 and 110 mmHg, unanesthetized dogs underwent acutewhole body C02 titrations. In each instance a linear re-lationship was observed between the plasma hydrogen ionconcentration and the arterial carbon dioxide tension.Because of this linear relationship, it has been convenientto compare the acute buffering responses among dogsin terms of the slope, dH+/dPaco2. With increasingchronic hypercapnia there was a decrease in thisslope, i.e. an improvement in buffer capacity, whichis expressed by the equation dH+/dPaco2 = -0.005(Paco2) Chronic + 0.95. In effect, the ability to defend pHduring acute titration virtually doubled as chronicPaco2 increased from 35 to 110 mmHg.

The change in slope, dH+/dPaco2,was the consequenceof the following two factors: the rise in plasma bicar-bonate concentration which occurs with chronic hyper-capnia of increasing severity, and the greater changein bicarbonate concentration which occurred during theacute C02 titration in the animals with more severechronic hypercapnia. These findings demonstrate theimportance of the acid-base status before acute titrationin determining the character of the carbon dioxidetitration curve. They also suggest that a quantitativedefinition of the interplay between acute and chronichypercapnia in man should assist in the rational analysisof acid-base disorders in chronic pulmonary insufficiency.

Dr. Goldstein is the recipient of a Postdoctoral Fellowshipfrom the Medical Research Council of Canada.

Dr. Gennari is the recipient of a Postdoctoral Fellowshipfrom the National Institutes of Health.

Received for publication 12 June 1970 and in revised form2 September 1970.

INTRODUCTION

Recent studies of the "whole body" carbon dioxidetitration curve have provided a physiologic descriptionof the buffer characteristics of normal dog and man(1-5). They have left unanswered, however, the ques-tion of how, and to what extent, preexisting abnormali-ties in the acid-base status of the organism might influ-ence the ability to defend pH during acute changes inarterial carbon dioxide tension. In the present study,we make a first approach to this problem using chronichypercapnia as an instrument for creating change inbody composition. Chronic hypercapnia was chosen as apoint of departure not only because it is a potent toolfor altering the acid-base status of the organism but alsobecause it allows simulation of the interplay betweenacute and chronic respiratory acidosis that is fre-quently encountered in patients with chronic pulmonaryinsufficiency.

The experimental protocol consisted of, first, thechronic adaptation of normal dogs to one of six levelsof arterial C02 tension and, second, the acute titrationof these dogs over a range of carbon dioxide tensionsbetween 35 and 110 mmHg. The results indicate thatwith chronic hypercapnia of increasing severity therewas a progressive improvement in the acute defense ofpH. This improvement was a function of the initialplasma bicarbonate concentration and of the change inplasma bicarbonate concentration that occurred duringthe acute titration.

METHODSDogs to be studied during chronic hypercapnia were placedin an environmental chamber (6) that allows the percentageof carbon dioxide in the atmosphere to be controlled auto-matically within ±5-5%. The chamber was maintained atenvironmental carbon dioxide tensions designed to producearterial Paco2 levels of approximately 45, 55, 70, 90, and 110mmHg. The percentage of the oxygen in the environment

208 The Journal of Clinical Investigation Volume 50 1971

was maintained between 20 and 21%go in all studies. Theanimals were kept at a given level of arterial carbondioxide tension for 6 days, a period which has been demon-strated to be adequate for the development of a new steadystate of acid-base equilibrium (7). All dogs were fedcommercial dog chow with normal electrolyte content andallowed food and water ad lib. before and during the periodof chronic adaptation. Any dog which failed to eat spon-taneously was tube fed twice daily and dogs which vomitedwere excluded from the study. On the day of the acuteexperiment, food and water were withheld. Arterial bloodsamples were drawn percutaneously on the 5th and 6thdays of exposure to hypercapnia to insure that the acid-basecomposition of plasma was in the range characteristic ofthe chronic steady state (7). In a group of dogs studiedwithout prior exposure to hypercapnia (chronic Paco2 ap-proximately 35 mmHg), arterial blood samples were drawnon the 2 days preceding the acute study.

On the day of the acute study, arterial samples wereobtained from all dogs via a Teflon catheter placed in thefemoral artery. Dogs were considered acceptable for theacute titration study only if (a) the first arterial Paco2 onthe day of the acute study and the values obtained on theprevious days were within a range of 6 mmHg, and (b)the first plasma bicarbonate concentration on the day ofstudy did not differ by more than 3 mEq/liter from thevalue obtained on the previous day. 4 of 31 dogs failed tosatisfy these criteria and were therefore excluded.

Acute titrations with carbon dioxide. The acute titrationswith carbon dioxide were carried out over a range of carbondioxide tensions between 35 and 110 mmHg. The sequenceand direction of the titrations were varied, depending uponthe initial chronic Paco2 level (Table I). Those dogs withinitial arterial carbon dioxide tensions of 35 and of 45 mmHg were exposed to stepwise increments in Paco2 termi-nating with a Paco2 level of approximately 110 mmHg.Conversely, those dogs with initial chronic values of 110mmHg were exposed to stepwise decrements in arterialcarbon dioxide tension, terminating in exposure to room air.The dogs with intermediate chronic arterial carbon dioxidetensions were first titrated to one extreme and then under-went sequential titration in the opposite direction. Thetitrations were designed to limit the change in arterialcarbon dioxide tension between any two periods to no morethan 30 mmHg.

All the acute titrations were carried out in the followingmanner. Three control blood samples were drawn at inter-vals of 20 min. The carbon dioxide tension in the environ-mental chamber was then altered over a period of 15 minand an additional 30 min was allowed to permit the dogsto reach a new acute steady state.' Three further bloodsamples were then drawn at 20-min intervals. This entireprocedure was repeated for each subsequent period. A periodwas considered to be representative of an acute steady stateonly if (a) the range of plasma bicarbonate concentrationsin the three samples did not exceed 3 mEq/liter, and (b) therange of Paco2 values did not exceed 6 mmHg at Paco2levels less than 100 mmHg, and did not exceed 10 mmHgat Paco2 levels greater than 100 mmHg. Acceptance of theslightly less rigorous criteria for Paco2 at high carbondioxide levels was necessary because of the greater varia-bility encountered with severe hypercapnia. In 22 of 27studies all of the periods satisfied the above criteria. In

'Cohen, J. J., N. C. Brackett, Jr., and W. B. Schwartz.Unpublished data.

TABLE ISequence and Magnitude of the Acute Changes in Paco2

during Titration of Dogs Chronically Exposed toEach of Six Levels of Arterial CO2 Tension

Acute carbon dioxide titration,Approximate approximate Paco2 during each period

chronicGroup Paco2 level Period 1 Period 2 Period 3 Period 4

mmHg mmHg1 35 60 85 1102 45 60 85 1103 55 35 55 80 1104 70 100 70 50 355 90 110 90 65 356 110 90 65 35 -

each of the remaining five studies, a single period that didnot meet the criteria of the acute steady state was excluded.

Studies with ureteral obstruction. Preliminary studieswere carried out in dogs chronically adapted to a Paco2of 110 mmHg to determine whether significant renal alkaliexcretion occurred during acute reductions of Paco2 in dogswith a markedly elevated plasma bicarbonate concentration.These preliminary studies demonstrated an average netalkali excretion of 15 mEq during the acute C02 titration;net alkali excretion during an identical time interval 2 daysearlier (during which the C02 tension was maintained at aconstant hypercapnic level) was 6 mEq.

The following studies were undertaken to evaluate theinfluence of this renal alkali loss upon the acute C02response curve. Dogs in which Jacobson cuffs (Davol Inc.,Providence, R. I.) had been placed around both ureterswere chronically adapted to a Paco2 of 110 mmHg. Imme-diately before acute titration, bilateral ureteral obstructionwas produced by inflating the cuffs percutaneously. A groupof nonobstructed dogs was studied simultaneously. In dogswith ureteral obstruction all of the urine proximal to theobstructing cuffs was aspirated postmortem. In the nonob-structed dogs, all urine formed during the acute titrationwas collected via a bladder catheter.

Analytical methods. The pH of blood and urine wasmeasured anaerobically at 390C. (Radiometer Co., PHM26, with capillary microelectrode, Copenhagen, Denmark).The CO2 content of plasma and urine was determined usingthe Technicon Auto Analyzer (Technicon Co., Inc., Tarry-town, N. Y.) by a modification of the technique of Gambinoand Schreiber (8). The automated analysis of C02 contentwas monitored daily by duplicate determination of a ran-domly chosen specimen using the manometric technique ofPeters and Van Slyke. The automated system was consid-ered to be functioning satisfactorily if it differed from themanometric method by no greater than 1.0 mEq/liter forC02 values less than 40 mEq/liter and no greater than 1.5.mEq/liter for values greater than 40 mEq/liter. Beta-hydroxybutyrate and acetoacetate levels were measured bya modification of the method of Williamson and Mellanby(9). The remaining analytical methods (sodium, potassium,chloride, ammonia, phosphate, creatinine, and lactate) havebeen described previously (10, 11). The pH, pK', and solu-bility coefficient of C02 were corrected to the temperature ofthe dogs (which was measured by rectal thermometer at thetime each blood sample was drawn) employing the data-

Acute CO2 Titration Curve in Chronic Hypercapnia 209

TABLE I IPlasma Paco,, Hydrogen Ion, and HCO3 Values in Dogs

Adapted to Various Levels of Chronic ArterialCarbon Dioxide Tension*

No.of

Group dogs PacO2 H+ HCOs

mmHg nmoles/liler mEqiliter1 6 35-40 41-45 20-212 4 43-46 43-46 23-263 4 56-58 49-51 27-284 3 66-67 53-54 29-305 4 87-91 56-58 36-386 6 108-113 60-71 38-45

* The ranges are based on the mean chronic steady-state valuesfor each dog.

of Rosenthal (12) and Severinghaus, Stupfel, and Bradley(13, 14).

RESULTSAcid-base status before acute titrations with carbon

dioxide. The ranges of arterial Pacom, hydrogen ion,and plasma bicarbonate concentrations obtained beforethe acute titrations in animals studied at the six levelsof arterial carbon dioxide tension are presented in TableII. A regression line relating hydrogen ion concentra-tion and Paco2 calculated from these data yielded theequation, He = 0.27Pacom + 32.9; this equation is closelysimilar to that previously reported in dogs adapted tochronic hypercapnia (H' =0.32 Paco2+ 26.9 [7]).

Evaluation of the steady-state periods during acutetitration with carbon dioxide. To determine whetherthere was a unidirectional trend in either Paco2 or

bicarbonate concentration within the criteria establishedfor an acute steady state, the differences between thefirst and third blood values were analyzed for eachperiod. The periods after an acute increase in Paco2("upgoing") were considered separately from thoseafter an acute reduction in Pacom ("downgoing"). Inthe case of the Pacom, the mean difference was not sig-nificantly' different from zero, regardless of the direc-tion of the change. In the case of the plasma bicarbonateconcentration, the mean difference was not significantlydifferent from zero in the "downgoing" periods, but inthe "upgoing" periods, the mean difference was +0.5mEq/liter. This slight difference was ignored, and a

steady state was assumed to be present.Character of the acute carbon dioxide titration curves.

Fig. 1 presents two representative studies; in panel A isshown the carbon dioxide titration curve of a dog in

'Throughout this paper, the term "significant" will beused to describe a difference which has a P value of lessthan 0.01.

which the chronic Pacom level was approximately 40 mmHg, and 'in panel B (and Table III) is shown thetitration curve of a dog in which the chronic Paco2level was approximately 110 mmHg. Note that in bothstudies the relationship between the hydrogen ion con-centration and the Pacom appears to be linear, but thatthere was a smaller change in hydrogen ion concentra-tion for any given acute change in Paco2 in the dogwith chronic hypercapnia. It can also be seen that theanimal with chronic hypercapnia underwent the largerchange in plasma bicarbonate concentration during theacute titration.

Evidence for a linear relationship between hydrogenion concentration and Paco2. For each acute titration, alinear regression relating the hydrogen ion concentrationto the level of arterial carbon dioxide tension was calcu-lated using the method of least squares. The possibilitythat this linear function best described the relationshipbetween hydrogen ion concentration and Paco2 wasevaluated for each titration by the insertion of thequadratic term (15). In 24 of 27 studies, the insertionof this term did not significantly improve the goodnessof fit when compared to the linear function. In the threecases in which there was statistically significant im-provement, the introduction of the quadratic term didnot appreciably alter the predictive value of the linearfunction; the difference in predicted change in hydrogenion concentration in the worst case was, for a 70 mmHgchange in Paco2, less than 2 nmolesAiter.

Influence of the chronic level of Paco2 on the relation-ship between hydrogen ion concentration and Paco,.

TABLE II IAcute CO2 Titration of a Dog Chronically Adapted to a

Paco2 of Approximately 110 mmHg (Dog No. 581)

Time Ho pH Paco2 HCO3

min nmoles/liter mmHg mEq/literAmbient CO2, 14%

0 61 7.22 110 43.220 61 7.22 111 43.640 58 7.23 107 43.2

41-55 Ambient CO2changed to 12%85 54 7.27 94 41.8

105 54 7.27 94 41.7125 54 7.27 94 41.7

126-140 Ambient CO2changed to 7%170 43 7.37 69 37.9190 43 7.37 70 38.5210 44 7.36 66 35.9

211-225 Chamber opened to room air255 34 7.47 44 31.3275 32 7.49 44 33.2295 31 7.50 43 33.3

31Q M. B. Goldstein, F. J. Gerirari? and W, 13. Schwartz

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0

271

23F40 60 80 100 120

PaCo2(mmHg)

361-

321

40 60 80 100 120PCC02(mmHg)

FIGURE 1 Comparison of changes in hydrogen ion and bicarbonate concentra-tions during acute CO2 titration in a normal dog and in a dog with severechronic hypercapnia. Panel A represents the titration in a dog (No. 137) inwhich the chronic Paco2 was approximately 40 mmHg. Panel B representsthe titration in a dog (No. 581) in which the chronic Paco3 was approximately110 mmHg. The curves drawn through the observed bicarbonate values wereplotted using the bicarbonate values predicted from the corresponding He-Paco2 regression equations.

Fig. 2 presents the slope of the acute H' - Paco2 regres-

sion line, dH+/dPaco2, for each dog plotted against thechronic arterial carbon dioxide tension. It is evident byinspection that the acute slope decreased progressivelyas the chronic level of arterial carbon dioxide tensionincreased. The regression line calculated from thesedata, Y = -0.005X + 0.952, has a slope significantlydifferent from zero, and the insertion of the quadraticterm did not significantly improve the goodness of fit.

Influence of the chronic level of Paco2 on the acutechange in plasma bicarbonate concentration. Fig. 3depicts the relationship between the acute change inplasma bicarbonate concentration and the chronic arte-rial carbon dioxide tension. The delta bicarbonate con-

centration in each case was calculated for an arbitrarilychosen change in Pacom of 60 mmHg, i.e., for an acutetitration between 40 and 100 mmHg. The values forthese specific Pacom levels were determined from theindividual H - Pacom regression lines. Note that up toa chronic Pacom level of 60 mmHg the change inplasma bicarbonate concentration is virtually constant

(approximately 5 mEq/liter). Above this level, how-ever, delta bicarbonate concentration becomes progres-

sively larger with the result that at a chronic arterialCOs tension of 110 mmHg an acute change in Paco2 of60 mmHg results in a change of approximately 12mEq/liter in plasma bicarbonate concentration.

Acute carbon dioxide titrations after ureteral obstruc-tion. Studies of renal bicarbonate excretion duringacute reduction in Pacoa were carried out in seven dogschronically adapted to a Pacos of approximately 110 mmHg (four dogs with ureteral obstruction and three non-obstructed controls). In the course of acute titration(total reduction in Pacom of approximately 60 mmHg)the nonobstructed dogs demonstrated net alkali excre-tions of 7, 8, and 17 mEq, (mean, 11 mEq) and theobstructed dogs, excretions of less than 1.5 mEq. Themean reduction in plasma bicarbonate concentrationwas 10 and 7.5 mEq/liter, respectively, in the twogroups of dogs. The slopes of the H+- Paco2 regres-sion lines in the obstructed dogs, 0.459, 0.456, 0.468, and0.468, were not significantly different from the slopesof the nonobstructed dogs, 0.454, 0.412, and 0.460. Inaddition, there was no significant difference between theacute slopes of the cuffed dogs and the six dogs shown

Acute COt Titration Curve in Chronic Hypercapnia

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CHRONICARTERIAL CO2 TENSION(mmHg)FIGuRx 2 Relationship between the chronic arterial CO tension and the slope of theacute H+- Paco2 regression line, dH+/dPacos. The line drawn through the data wascalculated by the method of least squares.

in Fig. 2 which were also chronically adapted to a

Pacom of 110 mmHg.Miscellaneous. In the acute carbon dioxide titrations

in normal dogs, the increase in plasma bicarbonate con-

20

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40 60 80 100 120.CjRONIC ARTERIAL CO2 TENSION (mmHg)

FIGURE 3 Changes in plasma bicarbonate concentration induced byan arbitrarily chosen change in Paco2 (60 mmHg) in animalschronically adapted to carbon dioxide tensions ranging between 35and 110 mmHg. The curve through the individual data points wasdrawn by inspection.

212 M. B. Goklstein, F. J. Gennari, and W. B. Schwartz

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110 mmHg, the acute reduction in arterial C02 tensionand plasma bicarbonate concentration was not associatedwith any significant change in plasma electrolytes. Thechanges in plasma electrolyte composition in the dogstitrated from intermediate Pacom levels demonstrated atransition between the observations at the two extremes.

During acute hypercapnia in the normal dogs, theunmeasured anions (Na - [HCO3 + Cl]) decreasedfrom 11 to 7 mEq/liter, whereas during the acute re-duction in Pacoa in dogs chronically adapted to a Paco2of 110 mmHg there was an increase in unmeasuredanions from 13 to 18 mEq/liter. There was a meanincrease in the blood lactate concentration of 2.5 mEq/liter after acute reduction in Paco2 in the dogs withsevere chronic hypercapnia, a value almost identical tothe decrease in blood lactate concentration (1.8 mEq/liter) previously reported in normal dogs subjected toacute hypercapnia (1). Beta-hydroxybutyrate and aceto-acetate levels were also determined before and afteracute carbon dioxide titration in six dogs chronicallyadapted to a Paco2 of 110 mm Hg; no significantchanges were observed. No significant difference in thehematocrit was noted among the six groups of dogsbefore acute carbon dioxide titration. There was nosignificant change in hematocrit during the acute titra-tion except in the normal dogs in which the hematocritincreased from 39 to 45%. The blood pressure was moni-

tored in 12 dogs during the acute carbon dioxide titra-tions; regardless of the chronic Paco2 level or thedirection of the acute change in Paco2, no significantchanges in blood pressure were noted.

DISCUSSION

The present study demonstrates that the chronic levelof carbon dioxide tension in the body fluids has a majorinfluence upon the response to superimposed acutechanges in Paco2. As illustrated in Fig. 2, the abilityof the organism to protect extracellular pH againstacute changes in Paco2 increased progressively as afunction of the increasing degree of chronic hypercapnia.This behavior appears to be accounted for by twofactors: the level of bicarbonate concentration in theplasma before acute alterations in Paco2, and the changein bicarbonate concentration which occurred during theacute titration.

On the basis of the Henderson-Hasselbalch equation,it is evident that the rise in plasma bicarbonate concen-tration that accompanies increasing degrees of chronichypercapnia (Table II) in itself acted as an importantfactor in minimizing the change in pH in response toacute changes in Paco2. This effect is illustrated by thedashed line in Fig. 4, labeled "theoretical," which depictsthe situation which would exist if the plasma bicarbonate

1.2001-

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(ACUTE)

1.000k

0.800

0.600

0.400

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THEORETICAL

70 90 110

CHRONICARTERIAL CO2 TENSION (mmHg)

FIGURE 4 Theoretical and observed relationship between the chronicarterial C02 tension and the slope of the acute H+- Paco2 regression line,dH+/dPaco2. The dashed line, labeled "theoretical," was calculated for thehypothetical situation in which plasma bicarbonate at any given level ofchronic hypercapnia remains constant during acute titration with carbondioxide. The observed line was taken from experimental data shown inFig. 2.

Acute COr Titration Curve in Chronic Hypercapnia 213

100

801

601

40

20

30 50 70 90

CHRONIC ARTERIAL C02 TENSION (mm Hg)

110

7.00

7.10

pH

720

740

760

780

FIGURE 5 Predicted effect of acute changes in Paco2 on the plasma hydro-gen ion concentration in dogs with chronic Paco2 levels ranging between35 and 110 mm Hg. The horizontal lines represent the spectrum ofhydrogen ion concentrations which would occur after an acute titration tothe indicated Paco2 levels.

concentration were held constant at its chronic valueduring the acute titration. Note that in the presence ofa bicarbonate concentration fixed at the level appropriateto a given degree of chronic hypercapnia the slope of theHI - Pacow relationship, dH+/dPaco2, decreases sharply,the majority of the change taking place between chronicPacos levels of 35 and 70 mmHg.8

The influence of the second factor, the change inplasma bicarbonate concentration which occurred duringthe acute carbon dioxide titration, can now be readilyappreciated by a comparison of the dashed theoreticalline with the solid line which depicts the observeddefense of pH. The wide divergence of the two linesin the range of normal and slightly elevated arterialcarbon dioxide tensions indicates that the in vivo buf-fering response is markedly improved by the acutechange in plasma bicarbonate concentration. On theother hand, the close proximity of the lines above a

chronic Pacom level of 70 mmHg gives evidence thatin severe chronic hypercapnia the acute change inplasma bicarbonate concentration plays a relatively

'The curvilinear configuration of the theoretical linedepicted in Fig. 4 cannot be attributed solely to the factthat the bulk of the increment in plasma bicarbonate con-centration occurs with slight to moderate degrees of chronichypercapnia. Even if the plasma bicarbonate concentrationwere to increase in a linear manner in chronic hypercapniaof increasing severity, the "theoretical" relationship be-tween the chronic Paco2 level and the acute slope would stillhave the same general configuration, although, it would beslightly less concave.

small role in augmenting the buffer capacity of theorganism.

These findings, when viewed in light of the absolutechange in plasma bicarbonate concentration, pose aseeming paradox. In the severely hypercapnic state, thesmall improvement in the in vivo slope as compared tothe "theoretical" slope is achieved at the price of a

greater absolute change in plasma bicarbonate concen-

tration than is the large improvement in the mildly ormoderately hypercapnic animals. Of course, upon exami-nation of the Henderson-Hasselbalch equation the physi-cochemical explanation for this finding becomes clear.One must still ask, however, why the change in plasmabicarbonate concentration in response to a standardacute change in Pacoz is approximately 7 mEq/literlarger in animals with severe chronic hypercapnia thanin the normal dogs. The answer appears to lie in partwith the kidney. In the dogs with severe hypercapnia,2-3 mEq/liter of the acute reduction in plasma bicar-bonate concentration is accounted for by renal alkaliexcretion, whereas none of the acute increase in plasmabicarbonate concentration in the normal or mildly hyper-capnic dogs can be accounted for by renal acid excre-

tion (1, 7). The remaining discrepancy is not as easilyaccounted for, however, because the combined contri-bution of extracellular buffers and lactic acid in boththe normal and high C02 groups is about equal in mag-

nitude, though opposite in direction. In severe hyper-capnia, tissue buffering or production of some organicacid other than lactic must be invoked as the most

214 M. B. Goldstein, F. J. Gennari, and W. B. Schwartz

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35 mmHg

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likely sources for the unexplained increment in buffer-ing capacity.

The discussion thus far has concerned itself with thepattern of change in hydrogen ion concentration duringtitrations with carbon dioxide rather than with theabsolute levels of plasma hydrogen ion concentration.Fig. 5 depicts in an idealized fashion the spectrum ofanticipated hydrogen ion concentrations during acutetitration of dogs chronically adapted to a wide range ofarterial carbon dioxide tensions. The curves shown inthe figure were constructed from values calculated ateach chronic Paco2 level using the slope of the appro-priate H' - Paco2 regression lines. As would be ex-pected from the relationship between the acute slope,dH+/dPaco2, and the chronic arterial C02 tension (Fig.2), the range of predicted hydrogen ion concentrationsbecomes progressively narrower as the degree of chronichypercapnia becomes more severe. Thus, the change inhydrogen ion concentration during titration of the nor-mal dog is approximately 60 nmoles/liter whereas in themost hypercapnic dog it is only 30 nmoles/liter. Further-more, from this representation of the data it can be seenthat although severe acidosis is a feature of acute hyper-capnia in the normal dog (pH 7.0) severe alkalosis, atleast under our experimental conditions, is not a featureof acute reductions of Paco2 in dogs with moderate oreven severe chronic hypercapnia. As can be seen in Fig.5, the anticipated pH after acute reduction in Paco2 to35 mmHg is only slightly greater than 7.5 regardless ofthe level of chronic hypercapnia. Indeed, the highest pHin any dog after acute reduction of the Paco2 was 7.55.

Whether the interplay of acute and chronic changesin arterial carbon dioxide tension in humans with pul-monary insufficiency is the same as in the normal dogobviously cannot be deduced from the present study. Itis evident that the behavior of the patient with long-standing pulmonary failure might be influenced not onlyby species differences but also by many complicatingfactors that did not exist in our experimental setting.The presence of hypoxemia, potassium depletion, andother abnormalities might well lead to an He- Paco2relationship notably different from that observed here. Itis of interest, however, to note that in the one publishedstudy designed to assess the influence of chronic pulmo-nary insufficiency upon acute changes in arterial carbondioxide tension the gross behavior appeared to be similarto that which we have found in the dog, i.e., pH wasseemingly defended more effectively than in normal vol-unteers (16). Unfortunately, a detailed analysis of thesedata is not possible, because only mean values arepresented, because data demonstrating a chronic steadystate are not included, and because no effort was madeto relate the level of chronic hypercapnia to the char-acter of the acute carbon dioxide titration curve. It

seems reasonable to predict, however, that a rigorousquantitative definition of the interplay between acuteand chronic respiratory acidosis should provide a morerational basis for the analysis of mixed acid-base dis-orders than is currently available (17-20).

It will be recalled that the present study was under-taken as a step towards determining how and to whatextent preexisting abnormalities in the acid-base statusof the organism might influence the ability to defendextracellular pH during acute changes in arterial carbondioxide tension. The results have provided a clearanswer to this question for the specific case of chronichypercapnia. They have, in addition, suggested a rangeof factors which can well be expected to modify thecarbon dioxide titration curve in a variety of otheracid-base disorders.

ACKNOWLEDGMENTSWewish to thank Dr. Jonas H. Ellenberg for his valuableassistance in the statistical analysis of the data. The deter-minations of beta-hydroxybutyrate and acetoacetate werekindly performed in the laboratories of Dr. George F.Cahill, Jr.

This study was supported in part by Grant HE-759 fromthe National Heart Institute, National Institutes of Health.

REFERENCES1. Cohen, J. J., N. C. Brackett, Jr., and W. B. Schwartz.

1964. The nature of the carbon dioxide titration curvein the normal dog. J. Clin. Invest. 43: 777.

2. Brackett, N. C., Jr., J. J. Cohen, and W. B. Schwartz.1965. Carbon dioxide titration curve of normal man.Effect of increasing degrees of hypercapnia on acid-baseequilibrium. N. Engl. J. Med. 272: 6.

3. Michel, C. C., B. B. Lloyd, and D. J. C. Cunningham.1966. The in vivo carbon dioxide dissociation curve oftrue plasma. Resp. Physiol. 1: 121.

4. Brown, E. B., Jr., and R. L. Clancy. 1965. In vivo andin vitro C02 blood buffer curves. J. Appl. Physiol. 20:885.

5. Ichiyanagi, K., K. Masuko, N. Nishisaka, M. Matsuki,H. Horikawa, and R. Watanabe. 1969. Acid-base changesof arterial plasma during exogenous and endogenoushypercapnia in man. Resp. Physiol. 7: 310.

6. Schwartz, W. B., and L. Silverman. 1965. A largeenvironmental chamber for the study of hypercapnia andhypoxia. J. Appl. Physiol. 20: 767.

7. Schwartz, W. B., N. C. Brackett, Jr., and J. J. Cohen.1965. The response of extracellular hydrogen ion con-centration to graded degrees of chronic hypercapnia:the physiologic limits of the defense of pH. J. Clin.Invest. 44: 291.

8. Gambino, S. R., and H. Schreiber. 1966. Measurementof C02 content with the autoanalyzer. A comparisonwith 3 standard methods and a description of E newmethod (alkalinization) for preventing loss of CO2 fromopen cups. Amer. J. Clin. Pathol. 45: 406.

9. Cahill, G. F., Jr., M. G. Herrera, A. P. Morgan, J. S.Soeldner, J. Steinke, P. L. Levy, G. A. Reichard, Jr.,and D. M. Kipnis. 1966. Hormone-fuel interrelationshipsduring fasting. J. Clin. Invest. 45: 1751.

Acute CO, Titration Curve in Chronk Hypercapnia 215

10. Tannen, R. L., H. L. Bleich, and W. B. Schwartz. 1966.The renal response to acid loads in metabolic alkalosis;an assessment of the mechanisms regulating acid excre-tion. J. Clin. Invest. 45: 562.

11. Arbus, G. S., L. A. Hebert, P. R. Levesque, B. E.Etsten, and W. B. Schwartz. 1969. Characterization andclinical application of the "significance band" for acuterespiratory alkalosis. N. Engl. J. Med. 280: 117.

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