STUDIES OF ACID-BASE DISTURBANCES

(1)

E. Mead

Johnson

Award

Address,

October

1966

Robert W. Winters, M.D.

From the Department of Pediatrics, Columbia University College of Physicians and Surgeons,

and Babies Hospital, Columbia-Presbyterian Medical Center, New York

The original studies of the author have been supported by grants from the Health Research Council of New York City (U-1127) and from the U.S. Public Health Service (HD 00117).

R.W.W. is career scientist of the Health Research Council of New York City (I 309). ADDRESS: 630 West 168th Street, New York, New York 10032.

PEDIATRICS, Vol. 39, No. 5, May 1967

STUDIES

OF

ACID-BASE

DISTURBANCES

700

I

T IS A signal honor to be chosen as a

re-cipient of the E. Mead Johnson Award.

In accepting this award I wish to recognize

my debt to some of the outstanding

mdi-viduals with wllom I have studied and

worked. As a medical student at Yale

Uni-versity I was lucky to be exposed at the

same time to the wisdom of both Professor

J

ohn Peters in medicine and Professor

Dan-id Darrow in pediatrics-the best of all

worlds for a student struggling with the

nuances of acid-base and electrolyte

me-tabolism.

As an intern, I came to know Dr. Edward

Shaw, an eminent clinician and a past

pres-ident of the Academy. He set a high exam-ple for me and I think for all who have known him of the best there is in clinical

pediatrics.

As a research fellow my good fortune con-tinued. I worked in tile Department of

Med-icine at the University of North Carolina,

where Professor Louis C. Welt was carrying

on the Peters tradition of excellence in in-vestigation, teaching (largely by example), and patient care. Following this, I spent 3 profitable years in the Departments of Bio-chemistry and Physiology at the University

of Pennsylvania School of Medicine. In

bio-chemistry I was exposed to the mysteries of

ion transport under the guidance of

Profes-sor R. E. Davies, and in physiology, under

the far-sighted leadership of Professor John

Brobeck, I became better educated in tile

field of physiological regulation.

Finally, I am ilappy to acknowledge my good fortune in having been associated with Professor Edward C. Curnen for much of

my medical career-first as a student at Yale, continuing as a ilouse officer at tile

Univer-sity of North Carolina Hospital, and

pres-ently as a member of his department at

Co-lumbia University. He has made it possible for us to carry out the work which I shall

describe today.

Tile overall aim of our studics has been

to find answers to physiologically important

questions through the study of patients with

various acid-base disturbances. In doing

so we hope to advance the basic

tin-derstanding of acid-base disorders in a way

that will ultimately provide a sound physio-logical framework within which the clini-cian can manage patients with such disor-ders.

To this end, some 4 years ago we

es-tablished a research laboratory in the

Babies Hospital for the specific purpose of

studying acid-base problems in patients.

Since that time we have performed well

over 8,000 complete acid-base

determina-tions on the blood of infants and children

representing every conceivable acid-base

abnormality. Tile sheer mass of the data ac-cumulated over the years made it necessary

for us to take steps to facilitate efficient processing and retrieval. My colleagues-Drs. Ralph B. Dell and Knud Engel and, more recently, Dr. Fred Wiener and Mr.

Alan Zuckerman-have developed a series

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Plasma UsIa Blood

Respiratory Composes!: pCO2 pCO2 ARTICLES

in the memory of the computer for subse-quent retrieval.1 Additional computer

pro-grams have been developed to allow

selec-tive retrieval and statistical study of these

data.

METHODS

Blood acid-base equilibrium can be

qual-itatively conceptualized as illustrated in

Figure 1, where blood pH is shown to be proportional to the ratio of concentration of

the metabolic component over that of the

respiratory component. All authorities agree

that plasma pCO2 is the best measure of the respiratory component. The meta-bolic component, on the other hand, can be represented either in terms of actual plas-ma bicarbonate concentration, favored by

some, or as whole blood buffer base or its

derivative, base excess, favored by others.

There is, in fact, no fundamental

physico-chemical inconsistency between these two methods of representing the metabolic component, since buffers of the plasma are

in equilibirium Vitil those of tile

erythro-cyte and tile data from the plasma system are, hence, readily convertible to those of the whole blood system by use of appropri-ate nomographic methods.2 The original

claim for the superiority of the whole blood

system rested essentially on the assunlptiOll

that the metabolic component was

indepen-dent of pCO2 and, thus, that the buffer

properties of all fluid compartments of the body are the same as those of blood. This is now known not to be true, a point I shall deal with later. Both plasma bicarbonate

and whole blood base excess are dependent upon changes in pCO2, as well as changes produced by metabolic disturbances, and,

tiltls, both must be interpreted within a

physiological context when one is assessing the significance of changes in the metabolic component.

The analytical metilod we employ in our

laboratory is that popularized by Astrup and his co-workers.3 The principle of this method rests on the old observation of Dr. John P. Peters’ that the CO2 titration curve of blood in vitro when plotted logarith-mically is a straight line. As diagrammed in

BLOOD H

i istabstic C..piisit

1 p

LRsspiratsry C.mpsisuU

Metabolic Coinpomeut: Bicsrbouate hftsr Bass

I, Base Escess

FIG. 1. Interrelationship of acid-base variables in

blood and plasma.

Figure 2, one need only measure the pH of two samples of blood after their having been equilibrated in vitro with two known

CO2 tensions to establish the two points for the line. Then, by measuring the pH of a third non-equilibrated sample of blood col-lected anaerobically, one ascertains the point on this line which represents the pa-tient’s blood in vivo. From this the pCO2 of

tile blood sample is derived by i.nterpoia-tion. Other derived variables-actual plas-ma bicarbonate, whole blood buffer base, and base excess-may be read off the

ap-propriate scale of the log pCO2-pH

nomo-gram. Actually, with our computer

pro-gram, all derived values (including correc-tions for oxygen unsaturation) are calcu-lated by the computer from the primary

measurements, which are the CO2

concen-trations of the equilibrating gas mixtures and the three pH values. The total sample size required to establish the three points on the nomogram from which the acid-base data are derived is 0.2 ml of blood. In all patients, except those with poor peripheral

circulation, arterialized capillary blood can be used. If for some reason arterial blood is

required, the technique of temporal arterial puncture perfected by my colleague Miss Agnete Thomsen can be safely employed in the smallest of infants. The Astrup method

is obviously advantageous in the studies on

(3)

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FIG. 2. The principle of the Astrup method. Points A and B represent the pH values of tile two equilibrated samples, and the’ are joined b a line representing the in vitro CO2 titration curve of blood. Point C represents

the pH of the third sample; the pCO2 of that sample is derived by interpo-lation. Points D, E, and F represent values for base excess, buffer base,

and actual plasma bicarbonate concentration, respectively.

RESPIRATORY COMPENSATION IN

METABOLIC ACIDOSIS

One of our earliest studies dealt with the quantitative nature of the well-known

re-spiratory compensation which is evoked in

metabolic acidosis. This secondary, corn-pensatory hyperventilation reduces the plasma pCO2 so that blood pH tends to be restored towards normal in the face of the

primary reduction of the metabolic compo-nent. The first question we asked was: is

there a predictable relationship between

the severity of the acidosis as measured by the primary reduction of the metabolic component and the degree of respiratory compensation as measured by the

secon-dary reduction in the respiratory

compo-nent? To answer this question, Albert, Dell,

and I studied the acid-base displacement in 60 patients with untreated metabolic aci-dosis in which the disorder producing the

acidosis had been present for at least 1 day.

These patients were carefully selected so as

to exclude, insofar as possible, any factors which could compromise full respiratory compensation. The results obtained on

these 60 patients are shown in Figure 3.

The metabolic component, represented by either base excess or plasma bicarbonate concentration, is plotted against the plasma pCO2. Iso-pH lines are shown as the radiat-ing diverging lines across eacil of these graphs. The solid line on each graph

repre-sents the regression equation fitted to the

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PLASMA pCO2 (mm Hg) PLASMA pCO2 (mm Hg)

PLASMA HCO

(mEqA)

BASE EXCESS (mEq/I)

ARTICLES

of pCO. It is evident that there is a highly

predictable relationship between the

sever-ity of metabolic acidosis measured by the

re(luctiOfl in either base excess or in plasma bicarbonate and the compensatory reduc-tion in plasma pCO2; the correlation coefficients for both relationships are in ex-cess of 0.9. The comparison of the 95% confidence zones with the iso-pH lines on

either graph reveals that uncomplicated

metabolic acidosis will nearly always be

as-sociated with lower than normal blood pH

value. Furthermore, the greater tile

reduc-tion in metabolic component the lower the

pH will be.

We believe that such studies as these

may have clinical usefulness in assessing the degree of respiratory compensation pres-ent in any given patient with metabolic aci-dosis. For example, 95% of the patients

with metabolic acidosis presenting with a

given low value for base excess or for plas-ma bicarbonate should have values which fall in the shaded zone if they are making

the appropriate degree of respiratory

corn-pensation. A patient falling above this zone

is a suspect for the presence of some factor interfering with full respiratory

compensa-tion; a patient falling below this zone is

likely to have an independent stimulus for

respiration over and above that expected from metabolic acidosis alone-in other

words, a mixed disturbance composed of

metabolic acidosis and respiratory alkalosis. The pediatrician encounters this sort of mixed disturbance in the course of saucy-late poisoning in the infant and young child. Some years ago \Vhite, Hughes, Ord-way, and J7 concluded, on the basis of

studies of acid-base changes in salicylism,

that toxic amounts of salicylate exert a dual

effect upon acid-base equilibrium. The first

of these effects appears to be a primary stimulation of respiration through a direct

action on tile respiratory center, but in the

infant and young child (but usualiy not in

the older child or adult) salicylate in

addi-tion causes a simultaneous disturbance in

metabolism whereby strong acids-presum-ably ketone bodies and possibly others as

FIG. 3. Quantitative displacement of acid-base equilibrium in 60 patients with uncomplicated untreated

metabolic acidosis.’ The metabolic component represented either by blood base excess (right) or plasma

bicarbonate (left) is plotted against the respiratory component (plasma pCO). The shaded zone

en-compasses 95% confidence limits for estimate of pCO2 at any given value for metabolic component. The

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704 ACID-BASE DISTURBANCES

well-accumulate in the extracellular fluid. The resulting complicated disorder can best be described as mixed metabolic acidosis

and respiratory

alkalosis and can be recog-nized as such by comparison of the acid-base data of such patients with the stan-dards for uncomplicated metabolic acidosis shown in Figure 3.

The second question we raised concern-ing metabolic acidosis was: do the patients we have used for the definition of the stan-dards of respiratory compensation repre-sent any approximation of a respiratory steady state? This is a difficult question to answer unequivocally because serial studies at a constant level of acidosis are not easily carried out, and withholding treatment in seriously acidotic patients would hardly be justified. Accordingly, as an alternative ap-proach, we examined the factors which are believed to be important in establishing and maintaining respiratory stimulation in metabolic acidosis. In the past few years, Mitchell and his co-workers8’#{176} have pub-lished a series of provocative papers

sug-gesting that respiratory stimulation in

met-abolic acidosis results from two sets of stimuli-one set related to the altered acid-base composition of the blood and mediat-ed by the peripheral chemoreceptors and the other set of stimuli related to alterations in the acid-base composition of tile

cerebrospinal fluid (CSF) and mediated

by superficial medullary cilemoreceptors.

Thus, the time rate of change of the acid-base composition of the CSF relative to the acid-base composition of blood must be considered. Changes in CSF pCO2 rapidly follow those in arterial pCO2, whereas changes in CSF bicarbonate show a distinct time lag. Because of the difference in rate at which the CSF pCO2 and CSF bicarbon-ate attain equilibrium in early metabolic acidosis, initial respiratory stimulation rep-resents the stimulation from acid blood

pH and

inhibition

due to an alkaline CSF. The CSF is alkaline because the pCO2 is low, while the CSF bicarbonate is still nor-mal. With more prolonged metabolic acido-sis, the CSF bicarbonate falls and CSF pH

returils to normal, thereby removing tile

in-Ilibitioll to respiratioll. In sustained

meta-bolic acidosis a steady state of respiratory

compensation would include the attainment of a normal CSF pH. In such a steady-state

condition, the drive to the respiratory cen-ter would represent stimulation of the

pe-ripheral chemoreceptors by an acid blood

pI-I

exclusively.

\\ith this hypothesis in mind, we sought

to

examine the acid-base composition of cc-rebrospinal fluid in patients with metabolic acidosis of known duration. For this study we chose infants with gastroenteritis of 1 to 3 days’ duration. These studies were per-formed by Drs. Albert, Rahill, and Vega1

in Caracas, Venezuela. The results are shown in Figure 4. On the left are plotted the acid-base changes in blood of 11 infants arranged in order of decreasing plasma bi-carbonate concentration. On the right are shown the simultaneous acid-base data ob-tamed on tile CSF of these same infants. In all cases CSF pH was within the normal range. Thus, on the assumption that read-justment of CSF acid-base composition in-dicates achievement of a steady state, we conclude that clinical metabolic acidosis of

1 day’s duration or longer is accompanied

by an approximation of a steady state of

respiratory compensation.

This matter of the time lag in CSF

acid-base adjustment of bicarbonate is relevant to another aspect of metabolic acidosis, this one concerning pathways of recovery from this disorder. In 1958 Lovder, Ordway, and U1 published a paper in which was

report-ed the rediscovery of a very old observation

-namely, that during recovery from

meta-bolic acidosis most patients tend to go through a transient state in which blood pH is normal or even alkaline in the face of continuing low values for pCO2. We

pointed out that there must be a stimulus

other than blood pH to explain such

obser-vations and, indeed, suggested that this

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ARTICLES

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FIG. 4. Blood (left) and CSF (right) acid-base changes in 11 infants with metabolic aciclosis.” The

values for blood are plotted according to increasing severity of fall in plasma bicarbonate, and all are below normal values established by Albert and Winters.’1 The CSF data are plotted in the same sequence as the blood data. The shaded zones indicate normal CSF values established by Rahill and

Winters.’2

hypothesis, suggested at a time when

evi-dence concerning the importance of the

role of CSF pH in control of ventilation

was very much less complete than it is at present, has now been completely confirmed by the recent studies of Cowie,

et al.,1’ tile results of which are exactly as we predicted.

RENAL COMPENSATION IN CHRONIC RESPIRATORY ACIDOSIS

A second major area of our investigations has concerned the documentation of degree

of renal compensation in chronic

respirato-ry acidosis. In this acid-base disorder the

primary abnormality is, of course, the

ele-vation of pCO2, and the compensation to

705

this abnormality consists of an augmented

renal excretion of hydrogen ions, making “new” bicarbonate available to the extracel-lular fluid. The result is an increase in the plasma bicarbonate concentration and wilole blood base excess with an

ameliora-lion of the initial fall in blood pH. The

question we raised was: how complete is this process in clinical respiratory acidosis? This question could best be answered by studying the acid-base changes of normal man subjected to high CO2 tensions for the

periods of time required to achieve a new

steady state. On the basis of experiments in the dog, this period is of the order of 5 to 7 days.15 Although ideal in tileory, these

ex-periments simply callnOt be carried out,

BLOOD CEREBROSPINAL FLUID

. S.

(7)

PLASMA HCO (mEq/I) BASE EXCESS (mEq/1)

,/ /

16

12

.v7

PLASMApCO2

(mu

H5) 706

PIASIA pCO2(mmHg)

Fic;. 5. Quantitative displacement of acid-base equilibrium in 28 steady-state of chronic

hypercapnia.IG The respiratory component, represented by plasma pCO2, is plotted against the metabolic component represented either by blood base excess (right) or plasma bicarbonate concentration (left). The shaded zone encompasses 95% confidence limits for estimate of metabolic component at an given

value for respiratory component. Iso-pH lines constructed as in Figure 3.

since such high CO2 concentrations for such protracted periods of time are intolerable

to normal subjects.

Bearing this iii mind, Engel, Deli, Rahill,

1)enning, and I’ sought examples of

clirollic hypercapnia among our patients. As a result of tile long interest of the Babies Hospital ill cystic fibrosis, a large number

of hypercapnic patients with this disease

were available. During hospitalization seri-al, usually daily, acid-base determinations

are made Oil these patients. These data pro-yided tile potential source of the answer to

the question we posed.

In order to produce meaningful

stan-dards for renal compensation in respiratory

acidosis it is absolutely necessary that the

patients included in the study have docu-mented steady states of hypercapnia for pe-riods of time long enough to insure that the kidney has exerted its full effect. We used rather rigid criteria for duration (at least 5 days) and for stability of hypercapnia (no more than ± 10% variation in the daily pCO2 values from the mean of the entire period)-being guided by the experimental

data in dogs subjected to chronic

hyper-capnia.15 In addition, we excluded all

patients ‘iio might have had metal)olic

dis-orders superimposed upon respirato

aci-dosis. With such rigid criteria as these, it is hardly surprising that out of over 700

acid-base determinations of 72 patients we were

able to identify only 25 steady-state

pen-ods. Nonetileless, tilis was a large (‘Dough sample for analysis. The results are shown

in Figure 5, Wilere plasma pCO2,

repne-senting the primary abnormality, is plotted

on the abscissa and either base excess or

plasma bicarbonate, the components being

adjusted by the kidney, are plotted on the

ordinate. The regression lilles and the 95% confidence limits are shown as before. Over the wide range of pCO2 values observed in these patients it is obvious that there is a highly predictable degree of compensation, the correlation coefficients being in excess of 0.9. Comparison of the 95% confidence limits to the iso-pH of 7.37 shows that there is a progressive inability to achieve a

nor-mal blood pH as pCO2 rises and that above

a pCO2 of 80 mm Hg few if any patients with uncomplicated respiratory acidosis would be expected to achieve complete compensation.

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meta-BASE 0 EXCESS (m Eq/L)

-5

24

22

-30 40 50 60

PC02

70 80

(mmHg)

90 100

FIG. 6. In vitro CO2 titration curve of normal blood. The curve may be represented either as change

in plasma bicarbonate concentration (left) or in blood base excess (right) as a function of increasing pCO2.

30 40 50 60 70 80 90 $00

pc02 (mmHg)

ARTICLES

bolic acidosis, these standards may be use-ful in assessing the degree of compensation present 111 chronically hypencapnic patients. Thus, a patient with a given elevated value for pCO2 and maximally compensated re-spiratory acidosis has less than a 1 in 20 chance of falling outside of the shaded zone shown on Figure 5. If a patient falls above the upper limit, a complicating metabolic alkalosis ill addition to respiratory acidosis

is suggested. If he falls below the lower

limit, either compensation is less than maxi-mal or the patient has a complicating meta-bolic acidosis. Evidence for the latter state should then be sought.

ACID-BASE DISPLACEMENTS IN ACUTE HYPERCAPNIA

A third major area of our investigative effort which I should like to discuss con-cerns the quantitative changes occurring in acid-base equilibrium in acute hypercapnia -that is, hypercapnia of such short duration that there is no significant renal compensa-tion. These changes are of a special interest in neonatal medicine because this is essen-tially the acid-base disturbance presented by infants with respiratory distress syn-drome and related disorders. The question to which we addressed ourselves was sim-ply: What should be the expected changes in blood acid-base equilibrium when pCO2 is abruptly raised in vivo?

C02+H20 -H2C03

H2C03 +Buf. - HBuf. + HC03

32

PLASMA 30

HCO (mEq/L)

28

26

It is known that when CO2 is added to

blood in vitro (Fig. 6) it is hydrated to form carbonic acid; this is in turn buffered by non-bicarbonate buffers (abbreviated as Buf) to form bicarbonate. Therefore, plas-ma bicarbonate concentration rises as pCO2 rises, as is shown by the curve on the left of

Figure 6. Note that, in the buffer reaction

for every Buf consumed, one bicarbonate ion is produced. Since whole blood buffer base is conceptually the sum of the concen-trations of BuF and bicarbonate, it remains unchanged; and, since base excess is the change in buffer base from normal, it too is unchanged. A plot of whole blood base ex-cess against pCO2 thus yields a line with zero slope, as shown in the right of Figure

6.

If one “titrates” blood in vivo by adding CO2 to the inspired air of normal subjects, one obtains a different result, as shown in Figure 7. Thus, in vivo, plasma bicarbonate rises less than the comparable rise observed

in vitro; and base excess falls in vivo but remains unchanged in vitro. This difference, first described by Shaw and Messer in

1933,18 has often been overlooked despite the fact that it has been repeatedly confirmed since then.1922 It has sometmes

been assumed that the fall in base excess in acute hypercapnia indicates the presence of an independent metabolic acidosis in such subjects. This is now known not to be the

Buf. +HC03 - Butter Bose

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In Vitro

PLASMA

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FIG. 7. Comparison of in vitro and in vivo CO2 titration curves. The in vivo data on the left were deriyed from the study of Brackett, et al.’1 in normal man. The data for base excess were calculated

from the original data using the alignment nomogram.2

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TOTAL BODY WATER

Introcillulor

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40 50 60 70 80 90 100

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case. Rather, the difference is a manifesta-tion of the divergent buffer properties of tile several compartments of tile body fluids. Whether or not the fall in base excess is to

he called

metabolic acidosis is a problem of

22$ and I believe that this

ter-minological issue is quite adequately ne-solved by the recent recommendations of

the ad hoc committee Ofl acid-base

termi-nology of the New York Academy of

Sciences. This group has proposed that metabolic acidosis be defined as an

abnor-mal

physiological process produced by the gain of strong acid or loss of bicarbonate

by the extracellular fluid.25 In this light,

the fail

in base excess which is due to hicar-bonate redistribution in acute hypercapnia

is not synonymous with metabolic acidosis.

I might also add in passing that there

seems to be a great deal of

misunderstand-ing about the differences between the in

vivo and in vitro curves insofar as they apply to the validity of the so-called Astrup

method, since this method relies on an in

vitro CO2 titration (see Fig. 2). I have dealt with this matter in extenso elsewhere,26 and

I

would

simply

like to point

out

here that

these differences are not at all relevant to

the validity of this method. The method

yields accurate data, but these data must

be interpreted physiologically.

In Vitro

In V/va

I I I I I I

40 50 60 70 80 90 $00

PC02 (mmHg)

The causes of the differences between the in vivo and in vitro curves can be illus-trated with the aid of Figure 8. Addition of

CO2 to blood in vitro causes the production of bicarbonate para passu with the

con-sumption of Buf, but both of these

con-stituents of the buffer base are retained in

the tonometer in which the equilibration

occurs. In vivo, however, CO2 added to

blood causes a generation of bicarbonate in

8LOOD 002+ H20

H2C03

+

Buf

-HBuf

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FIG. 8. Models to explain the differences betveen

the in vivo and in vitro CO2 titration curves. The

nsodel on the left represents a system used to equilibrate blood 71 vitro (e.g., a tonometer). The model on the right is a three-compartment

repre-sentation of the body fluids, showing the bicarbon-ate redistribution occurring whei CO, is added

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pCO2

is raised. First, it is known that both

blood volume and hemoglobin

concentra-tion are proportionately greater in the

new-born than in the adult. Second, the volume of the interstitial fluid per kilogram of body

weight is much larger in the newborn, even

more so in the premature, than in the adult.

This means that per kilogram of body

weight not only does the infant have

sub-stantially more total non-bicarbonate buffer

with which to buffer CO2 than does the adult, but he also has a mulch larger volume

of distribution of the bicarbonate produced

by buffering.

Dell, Engel, and I’ sought to test the influence of varying body composition on the in vivo CO2 titration curve by con-structing a computer model of the in vivo

system using the available data on body composition and on the behavior of buffers

of blood along with an estimate of the

cel-lular contribution of bicarbonate.

Equa-tions were written incorporating all of these variables, and they were programmed for the computer such that the magnitude of

fall in base excess as pCO2 rises could be

predicted as a function of systematic

varia-the blood volume, some of which “leaks”

into the interstitial fluid (1SF). The intersti-tial fluid itself having little or no non-bicar-honate buffer, therefore, acts as a “sink” for

tile relatively large amounts of bicarbonate

produced in blood as well as for the smaller

amounts which cells add to this

compart-ment. Buf, being largely hemoglobin, is

confined to tile erythrocytes in the blood volume and, therefore, is restrained by

capil-larv membrane. Tile net result in blood will l)e a fall in concentration of Buf but a less-than-expected rise in bicarbonate. Buffer

base, being the sum of these two

compo-nents, falls in vivO; and base excess, being

defined as the change in buffer base,

there-fore also falls.

The degree of fall ill base excess in adult man is slight but definite, according to the data of Brackett and coworkers.20 We were specifically interested in the degree of fall

ill base excess in acutely hypercapnic new-born and Prelllatuire infants, particularly since certain differences in body

composi-tion between the newborn infant and the

adult might be expected to condition tile

magnitude of the fall in base excess as

0

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RANGE FOR BODY COMPOSITION OF ADULT MAN

B.V. (mi/kg) Hb(g/IOOmi) ECF (mi/kg)

INFANT

100 18

400-500.

ADULT

70

15

230-270

/

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PC02 (mmHg)

Fic;. 9. Predicted CO2 titration curves as a function of body composition. The tipper zone represents the expected result if the newborn or premature infant had an adult-type body composition; the lower curve represents ex-1)ected results for infants with body composition more appropriate to this age group. Both zones start at the average normal values for healthy neonates.21

ARTICLES

BASE EXCESS

(mEq/L)

RANGE FOR PROBABLE BODY

COMPOSITION OF NEWBORN

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0

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RDS data from

Kuldeberg, P

(Acta Ped. 53:505, $964)

BE.=-0.116 P,2 -1.02

- -0,73

n - 48

30 40 50 60 70 80

PC02

ROS

90 00 $10 $20 $30 140 150

(mm Hg)

Fic. 10. Comparison of predicted CO2 titration curves with data obtained by Kildeberg on infants with acute hypercapnia secondary to respiratory

distress syndrome (RDS) and related disorders.

BASE

EXCESS (mEq/L)

tion of interstitial volume, blood volume, or

hemoglobin concentration, either separately or in any combination.

Figure 9 shows the range of in vivo CO2

titration curves predicted for acutely

hyper-capnic subjects with an infantile body

com-position compared to those of a

hypothet-ical group with an adult-type body com-position. The actual ranges of values for body composition used for these particular

curves are shown for each group in the

lower left hand portion of the figure. The

normal point for both curves is set at the

average normal value found by Weisbrot and co.workers27 for healthy neonates. As is evident from the results, the computer model predicts a substantial difference be-tween these two groups. For example, if pCO2 were abruptly raised to 100 mm Hg

the computer model predicts that base ex-cess would fall to about -6.7 mEq/l in the

adult-type group, while the same degree of

hypercapnia would produce a considerably greater fall-to about - 10.2 mEq/l-in the infant.

I should like to emphasize that these

curves are entirely theoretical ones-valid

only insofar as the initial assumptions and

the primary data upon which the model is

based are valid. Direct substantiation of

this model by well designed experiments in

animals is needed. These are under way in

our laboratory. There is, however, a body

of information derived from the study of

babies with respiratory distress and related

syndromes which generally supports our predictions. Figure 10 shows the regression

equation fitted by Dr. Poul Kildeberg28 to

48 sets of data obtained on 29 infants with hypercapnia in which the duration was short enough to probably preclude any significant degree of renal compensation. The line representing these infants falls

below that predicted for the infantile CO2

titration curve. However, it has the same

general slope. It is likely that the

discrep-ancy between this line and the predicted

zone can be entirely accounted for by the increase in blood lactate occurring in such

infants. Indeed, this may resolve one of the

problems concerning the interpretation of

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Kilde-ARTICLES

berg’s data, for example, usually no more

tilall one third of the fall in base excess could be attributed to the measured rise in

lactate.2i This is about tile magnitude of the

difference between the predicted CO2 titra-tion curve and the actual data obtained on the babies. Clearly, further measurements of all relevant variables in infants with

acute hypercapnia are required to

demon-strate the validity of this hypothesis.

SUMMARY

In summary, the work which I have de-scribed here represents a quantitative

ap-proach to answering certain questions in

the acid-base field which are

physiological-ly important and practically useful as well. Encouraged by the results we have thus far

obtained, we hope to pursue this general

approach in answering other similar ques-tions in this general area.

REFERENCES

1. Dell, R. B., Engel, K., and Winters, R. W.: A computer program for the blood pH-log pCO2 nomogram. Scand. J. Gun. Lab. In-vest., in press.

2. Siggaard-Andersen, 0.: Blood acid-base align-ment nomogram. Scand. J. Clin. Lab.

In-vest., 15:211, 1963.

3. Siggaard-Andersen, 0. : The Acid-Base Status of the Blood. Copenhagen: Munksgaard, 1963.

4. Peters, J. P.: Studies of the carbon dioxide absorption curve of human blood. III. A further discussion of the form of the ab-sorption curve plotted logarithmically with a convenient type of interpolation chart.

J. Biol. Chem., 56:745, 1923.

5. Thomsen, A.: Arterial blood sampling in small infants. Acta Paediat. Scand., 53:237, 1964. 6. Albert, M. S., Dell, B. B., and Winters, R. W.:

Quantitative displacement of acid-base equilibrium in metabolic acidosis. Ann. In-tern. Med., in press.

7. \Vinters, R. W., White, J. S., Hughes, M. C., and Ordway, N. K.: Disturbances of acid-base equilibrium in salicylate intoxication.

PEDIATRICS, 23:260, 1959.

8. Mitchell, R. A., Carman, C. T., Seveninghaus,

J. W., Richardson, B. W., Singer, M. M., and Shnider, S.: Stability of cerebrospinal fluid pH in chronic acid-base disturbances in blood. J. Appi. Physiol., 20:443, 1965.

9. Mitchell, B. A., and Singer, M. M. : Respira-tion and cerebrospinal fluid pH in metabolic

acidosis and alkalosis. J. Appi. Physiol., 20: 905, 1965.

10. Albert, M. S., Rahill, W. J., Vega, L., and Winters, R. W. : Acid-base changes in cere-brospinal fluid of infants with metabolic acidosis. New Eng. J. Med., 274:719, 1966. 1 1. Albert, NI. S., and Winters, R. W. : Acid-base

equilibrium of blood in normal infants.

Psini-ATRICS, 37:728, 1966.

12. Rahull, W. J., and Winters, B. W. : Normal acid-base composition of cerebrospinal fluid in infants and children. Proc. Soc. Exp. Biol. Med., 122:935, 1966.

13. Winters, B. W., Losvder, J. A., and Ordway, N. K. : Observations on carbon dioxide ten-sion during recovery from metabolic acidosis.

J. Clin. Invest., 37:640, 1958.

14. Cowie, J., Lambie, A. T., and Robson, J. S.: The influence of extra-corporeal dialysis on

the acid-base composition of blood and

cerebrospinal fluid. Clin. Sci., 23:397, 1962. 15. Polak, A., Haynie, C. D., Hays, B. M., and

Schwartz, W. B.: Effects of chronic hyper-capnia on electrolyte acid-base equilibrium. I. Adaptation. J. Clin. Invest., 40:1223, 1961.

16. Engel, K., Dell, R. B., Rahill, W. J., Denning, C. R., and Winters, R. W. : Quantitative

studies of acid-base displacement in respira-tory acidosis. Unpublished manuscript.

17. Dell, B. B., Engel, K., and Winters, B. W. : A computer model of the in vivo CO2 titration curve. Unpublished manuscript.

18. Shaw, L. A., and Messer, A. C. : The transfer

of bicarbonate between the blood and tissues caused by alterations of carbon dioxide con-centration in the lungs. Amer. J. Physiol.,

100:122, 1932.

19. Siggaard-Andersen, 0. : Acute experimental acid-base disturbances in dogs. Scand. J. Clin. Lab. Invest. ( Suppi. 66), 14: 1, 1962. 20. Brackett, N. C., Jr., Cohen, J. J., and Schwartz,

\v. B.: Carbon dioxide titration curve of normal man. Effect of increasing degrees of acute hypercapnia on acid-base equilibrium.

New Eng. J. Med., 272:6, 1965.

21. Cohen, J. J., Brackett, N. C., Jr., and Schwartz, W. B.: The nature of the carbon dioxide titration curve in the normal dog. J. Clin. Invest., 43:777, 1964.

22. Brown, E. B., Jr., and Clancv, B. L.: In vivo

and in vitro CO2 blood buffer curves. J.

Appi. Physiol., 20:885, 1965.

23. Winters, R. W.: Terminology of acid-base

dis-orders. Ann. Intern. Med., 63:873, 1965. 24. Winters, R. XV.: Terminology of acid-base

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terminology, in Current Concepts of Acid-Base Measurements, Ed.: C. C. Nahas. Ann. N.Y. Acad. Sci., 133:251, 1965.

26. Winters, R. W.: Some comments on the valid-ity of the Astrup technique for the

measure-ment of acid-base status of blood. AS 36.

Copenhagen: Radiometer A/S, 1966. 27. Weisbrot, I. M., James, L. S., Prince, C. E.,

Holaday, D. A., and Apgar, V.: Acid-base homeostasis of the newborn infant during the first 24 hours of life. J. Pediat., 52:395, 1958.

28. Kildeberg, P.: Disturbances of hydrogen ion

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1967;39;700

Pediatrics

Robert W. Winters

October 1966