JOHN AND DefinitionsYALEJOURNAL OF BIOLOGY AND MEDICINE ratio, BHCO3, is a direct function, as Henderson37 showed, of the hydrogen-ion concentration. According to the familiar Hen-derson-Hasselbalch353equationl,~

ACID-BASE EQUILIBRIUM AND SALT AND WATEREXCHANGEJOHN P. PETERS

PHYSIOLOGICAL AND CHEMICAL CONSIDERATIONS

Definitions: Van Slyke72 has defined acidosis as a conditionin which the bicarbonate of the blood or serum, or, more exactly,the base available for combination with bicarbonate, is diminished.Alkalosis is a condition in which there is in the blood or serum anabnormal excess of bicarbonate, or base available for combinationwith bicarbonate. These definitions are quite restricted: they saynothing of the true reaction or hydrogen-ion concentration of theblood, nothing of abnormal accumulations of acid. Neverthelessthey have come to be accepted because they are expressed in termsof that function of acid-base equilibrium which is most frequentlydisturbed and which can be most easily and accurately measured.

The function of bicarbonate: Bicarbonates are salts of carbonicacid which is nothing more than the gas, carbon dioxide, in solution.Carbonic acid plays a peculiar role among acids in biology becauseof a special combination of properties: i. it is a weak acid and anexcellent buffer at physiological reactions; 2. it is produced in largequantities in the normal metabolic processes and is, therefore, alwaysavailable from endogenous sources; 3. it is volatile and can, there-fore, be excreted by the lungs. The reactions involved in the forma-tion of bicarbonate by combination of C02 and base, and the libera-tion of C02 from bicarbonate are:

produced in metabolism of tissue.

(I) CO2+ H20 = H2CO3(2) H2CO3 + NaOH = NaHCO3 + H20(3) NaHCO3 + HA* =NaA + H20 + C02 ->expired airUnder ordinary circumstances respiration is so regulated that

the excretion of carbon dioxide by the lungs not only keeps pacewith its production in the body, but also maintains the ratio ofcarbonic acid to bicarbonate in the blood relatively constant. This

*The terms "A" and "B" will be used to indicate, respectively, any mono-valent acid or base.

YALE JOURNAL OF BIOLOGY AND MEDICINE

ratio, BHCO3 , is a direct function, as Henderson37 showed, of

the hydrogen-ion concentration. According to the familiar Hen-3~ ~ ~ '1H2C03derson-Hasselbalch35 equationl, H = Kl BHCO3 or, in negative

logarithmic form, pH PpK' + log (H2CO) The concentra-

tion of H2CO3 is dependent upoIn the tension of C02 in the blood,and in turn, is determined by the rate of production of CO'2 in thebody and the pulmonary ventilation. It follows that, under anycircumstances, deviation of blood pH from the normal limits occursonly if the respiratory mechanism fails to respond quantitativelyto C02 production or bicarbonate changes. The pH rises (i.e.hydrogen-ion concentration falls) if respiration is too vigorous ata given blood bicarbonate concentration; pH falls if respiration is re-latively insufficient. The actual hydrogen-ion concentration affordsonly a mreasure of the adequacy of the respiratory response to dis-turbances of acid-base equilibrium and does not measure the degreeof the disturbance.

Van Slyke's definitions call attention to the fact that acidosis canresult not only from excessive accumulation of acids in the body,but quite as well from an absolute or relative deficiency of base.Gamble'9 has called bicarbonate (or carbonic acid) the "mendicant"acid because it is such a weak acid that it is at the mercy of all theother acids in the struggle for base. By the reaction pictured inequation (3) it is robbed of its base and forced to get out by itsmore powerful fellow acids, receiving its share only after all theothers are satisfied. It therefore serves as a measure of the differ-ence between the total base and the other acids of the blood and,at the same time, of the amount of base which can still be usedfor the neutralization of other acids.

The function of bicarbonate in the defense against acidosis hasbeen given great emphasis; its importance in preventing alkalosishas been less stressed. If, for any reason, more than the usualamount of base appears in the blood, it is immediately neutralizedby combination with C02 and is excreted in the urine as bicarbonate.

C02 iS, of course, ubiquitous in the organism and can freelypenetrate all membranes. From equation (2) it is evident thatstrong alkali can not exist in the presence of CO'2, but will be con-

I184

ACID BASE EQUILIBRIUM

verted to bicarbonate. Bicarbonate, furthermore, can not exist inthe absence of free C02 (or carbonic acid) because of the occurrenceof the reaction

(4) 2NaHCO3 Na2C&3 + H20 + C02.For these reasons, as Gamble"4 has pointed out, an alkaline urinemust contain bicarbonate and urine can not, on purely chemicalgrounds, have a pH more alkaline than is compatible with theexistence of bicarbonate, about 8.2, the point at which bicarbonate isconverted to carbonate. That this point can be approximated, butnot surpassed, has been demonstrated by Mainzer50 and others.

The function of ammonia: Just as bicarbonate may be con-sidered as an endogenous acid, so ammonia serves as an endogenousbase. It is formed from the neutral compound urea, a product ofnormal metabolism, by reactions which can be most simply expressedin the following manner,

(5) CO(NH2)2+ 3H20 + C02O 2NH4HCO3.urea

Even in the most highly acid urine strong acids can be excreted onlywhen they are neutralized by base. For this purpose ammonia isemployed, thus sparing the more essential mineral bases which canbe secured only from exogenous sources. The reactions involvedcan be represented in the following manner:

retained(6) NH4HCO3 + NaCl NH4C1 + NaHCO3.

urineGamble 19 was the first to point out, what has been amply sub-stantiated by subsequent workers, that ammonia is formed andexcreted, not in response to the pH of the blood, as had been sup-posed, but in accordance with the needs of the body for the con-servation of mineral bases. Unlike bicarbonate, ammonia does notplay any part in regulating neutrality within the body, but only infacilitating the excretion of acid in the urine. In fact, the burdenof evidence indicates that it is formned in the kidney5'6.

Urinary reaction changes: Among the other defenses againstdisturbainces of acid-base equilibrium one of the most important isthe ability of the kidney to produce urine that is either more acid ormore alkaliie than the plasma, from which it is derived. Thisenables it to excrete a certain proportion of weak acids a; free acid


and thus to conserve the base with which such acids were combinedin the body. Henderson36 estimates that in a highly acid urine aconsiderable amount of p-hydroxybutyric acid may appear as freeacid, while in the blood 99 per cent of it must be neutralized bybase. In the blood, at pH 7.4, 8o per cent of the inorganic phos-phate is composed of the alkaline salt, B2HPO4, only 20 per centof the acid, BH2PO4; in a highly acid urine almost all of thephosphate may be in the acid form. 'rhe conversion, in the processof excretion, of a molecule of alkaline phosphate to the acid formor of a molecule of organic acid salt to free acid saves for the organ-ism a molecule of mineral base, by the following reactions.

blood blood

(7) B2HPO' + H2CO3 = BH2PO'4 + BHCO3.

blood urine blood

(8) B (organic acid) + H2C03 H (organic acid) + BHCO3.

urineDiscussion of the buffering influence of weak acids, especially

proteins, organic and inorganic phosphates, and carbonates, in theprevention of changes of reaction in the internal environment, issomewhat outside the scope of this review. The chief value of suchbuffers lies in mitigating the effects on pH of sudden accessions ofacids or alkali, until the eliminative mechanisms described abovemay be brought into play.

Distinctive acid-base patterns in body media: The reactionswhich have been briefly summarized above are those which aregenerally recognized as immediate effects of, or specific responsesto, disturbances of acid-base equilibrium. However, the effects ofsuch disturbances are not strictly confined to a single system. It istoo generally assumed that certain functions in the body bear pe-culiar relations to one another to the exclusion of all other functions.Such exclusiveness seems to deny the most distinctive feature ofliving matter, its automaticity or tendency to continue its existence,something that one can admit without confessing himself a vitalist(cf. Henderson38). Only under restricted conditions has it provedpossible to demonstrate a consistent relationship between any twophysiological variables such as blood pH and pulmonary ventila-tion. If any one function such as the pH of the blood were favored

I86


to the exclusion of others, survival of the organism would be con-tinually threatened by relatively trivial disturbances. Factors whichalter the pH or the bicarbonate of the blood distort at the sametime the internal environment of the body in other ways; and eachone of these distortions provokes new counter reactions. Each func-tion which is squeezed or jostled resists the assault with one elbow

TABLE I.

Blood

Serum Cells Muscle

BasesSodium mg. per cent 3 30 0 8oPotassium " " 20 420 320Calcium " " I0 0 8Magnesium " " 3 3 2I

AcidsBicarbonate vol. per cent 6o 41Chloride mg. per cent 3 55 185Phosphate P " " 3.5 3.5 +Organic acid + +Protein per cent 7 32

and, with the other, makes itself more room by squeezing or jostlinganother neighboring function. Some kind of equilibrium or modusvivendi is attained only when a compromise has been reached amonga number of functions, each one of which has yielded as little as pos-sible to every other. Therefore, to appreciate the full effects of anydisturbance one must envisage the whole setting and observe the re-sponse in all its aspects and dimensions. Such a complete and com-prehensive view is, of course, unattainable; but our horizon in re-lation to acid-base disturbances has, thanks especially to Gamble, beengreatly extended to include the whole salt and water metabolism ofthe body. An adequate discussion of acidosis and alkalosis, therefore,involves a description of the general features of the inorganic internalenvironment and its responses to acid-base changes.

It must be recognized, first, that inorganic elements are notevenly distributed throughout all the media of the body. The factthat calcium salts exist in solution in most of the body fluids, butnormally attain a high enough concentration to precipitate out only

I87


in bone, is familiar to every one. The comparison of the con-centrations of acids and bases in blood serum, blood cells, and musclecells, in the table above, reveals the fact that hardly a single com-ponent is evenly distributed throughout the three media.

There is only half as much chloride in blood cells as in serum,and even less in muscle. Only questionable traces of calcium and sodi-um are found in blood cells, potassium predominating among bases;while in serum there is little potassium, and sodium is the chiefbasic element. Such peculiar distributions are, as yet, inexplicableOIn purely chemical grounds; nevertheless these distinctive patternsseem to be obligatory marks of differentiation between body mediathat are presumably connected with differences in function. Itfollows that no two elements, no matter how closely they may berelated, are mutually interchangeable in the bodily economy. At-tempts to modify these patterns are resisted by the organism.

Some implications of the data presented in the table have suffi-cient known bearing on clinical and physiological problems to war-rant special attention. It should be obvious to anyone that analysisof whole blood for inorganic elements can give no significant in-formation. The proportion of cells in blood is a more inmportantdeterminant of the amount of potassium, sodium, calcium, or chlorinein whole blood than is the concentration of any one of these in eithercells or serum. Anemia patients will have high whole blood cal-cium, sodium and chloride, not because the concentration of anv ofthese elements in either cells or serum is abnormal, but merely be-cause there is more serum in each unit of blood.

Uneven distribution of sodium and potassiumi: The restrictionof potassium to cellular and of sodiumn to fluid phases is probablynot characteristic of blood alone, but holds for tissue cells and in-terstitial fluids. Of this the muscle analysis given above is an ex-ample. Throughout the body, potassium appears to be the chiefbase of cells, and sodium of body fluids. Destruction of cellulartissues, then, should be attended by loss of potassium, while diminu-tiotn of the interstitial fluids of the body should result in increasedexc:-etioin of sodium only. Indirect evidence that this is the caseis found in Salkowski's66 studies of salt metabolism in disease and inthe study by Gamble, Ross, and Tisdall19 of the acid-base metabolismduring starvation.

I 8 8


In states of simple dehydration the body appears to guard tissuecells more solicitously than it does interstitial fluids. In vomiting,diarrhea, diabetic acidosis, etc., the loss of fluid from the bloodserum, for example, is greater than that from the blood cells andwith this fluid is lost its characteristic base, sodium. Because foodsare chiefly plant or animal cells, they contain mainly potassium saltsand only small amounts of sodium. The latter is contributed chieflyin sodium chloride which is added to food either in the course ofpreparation or after it is on the table. In states of dehydration,therefore, restoration of the normal internal environment can notbe secured as rapidly or certainly by the ingestion of food and wateralone as it can if, in addition, sodium chloride is given.

Magnus-Levy,48 Blum4 and others have shown that certaintypes of edemna, especially those of diabetes and nephritis, are ag-gravated by the administration of sodium chloride or sodium bi-carbonate. On the other hand, administration of the correspondingpotassium salts has no such unfortunate effect and may even causediuresis. From this one would be led to infer that the edema inthese cases affected only the interstitial fluids and not the cellularelements of the body.

Osmotic equilibriunm: Although the various body media differstrikingly in their individual chemical patterns, there are substan-tial reasons for believing that all of them, cells and interstitialfluids alike, are and must be in osmotic equilibrium, that isisotonic71' 74, 78. The osmotic pressure of a solution is determinedby the concentration of chemically active components (moleculesor ions) which it contains. Because of their small molecular sizeand the fact that they are electrolytically dissociated into ions, inor-ganic compounds are the chief determinants of osmotic pressure. Themaintenance, within narrow limits, of a constant osmotic pressure,i.e., a constant electrolyte concentration-throughout body mediaappe:.rs to be essential for the preservation of cellular structure andfunction. The alterations in salt solutions of different concentra-tion of the form of red blood cells, varying from crenation in ex-tremely hypertonic solutions to rupture with hemolysis in extremelyhypotonic solutions, is familiar to everyone. It is essentially forthe maintenance of cell structure that the surrounding fluid mediaremain always isotonic. The dangers attending disturbance of thisproperty can be illustrated by examples.

I89


Rowntree64' 65 and others54 have shown that the administrationto dogs by stomach tube of quantities of water far in excess of theirexcretory powers causes serious symptoms, finally culminating inconvulsions and death. That it is not merely the volume of fluidwhich is responsible for the intoxication is evident from the factthat the administration of an equal amount of isotonic salt solutionhas no similar effect. Moreover, if salt alone is given to the in-toxicated dogs, symptoms of intoxication rapidly disappear. Theblood and tissues in water intoxication are greatly diluted and, infatal cases, the blood cells are found to be hemolyzed54 6. Oneis forced to conclude that the deleterious effects of excessive waterare due to reduction of the normal salt concentration, the osmoticpressure, of the body fluids.

Although these experiments can not be exactly duplicated inman, at least with his consent, analogous conditions can be produced.Persons who have suffered depletion of both salt and water and whoare extremely dehydrated, possess a certain craving for water, evenwithout salt, which sometimes leads them into trouble. In certainmines and in stoke-holds men are forced to do heavy manual laborat high environmental temperatures. This entails the loss of sur-prisingly large amounts of fluid and salt as sweat. If large quan-tities of water are taken to satisfy the thirst which results, a con-dition known as miners' or stokers' cramps, characterized by severemuscular and abdominal cramps, may ensue. Moss55 has shownthat this may be prevented if salt solution, instead of water, is usedto quench the thirst. The harm appears to be done not by the ex-cessive sweating, not by chilling, as is so generally believed, but bydilution of the salts in the body, which have been reduced by theprevious loss of sweat.

To prevent changes of internal osmotic pressure, the excretoryfunctions of the organism are so regulated that, if the supply ofsalts and water is unlimited, their concentrations in the body re-main relatively unaltered. If reasonably large amounts of water aretaken in, salt will be retained until the excess of fluid is eliminated;if salt is taken water will be craved and will be used to dilute thesalt to normal concentration. If an excess of salt is excreted forany reason, an equivalent amount of water will be eliminated; ifwater is lost from the body, the salt which was dissolved in it willalso be excreted. These reactions, which may be called the defense

Igo


against disturbances of osmotic pressure, have been especially dem-onstrated by the studies of Gamble.

Constant fluid volume: The living organism, however, doesnot concern itself about osmotic pressure to the neglect of all otherfunctions. A sharp distinction must be drawn between the concen-tration and the content or total quantity of any substance in bodymedia. If two beakers hold, respectively, I00 and 200 cc. of aone per cent solution of the same salt, it is obvious that the secondcontains twice as much salt as the first, al-though analysis of samples from both beakers PH

without knowledge of the volumes of fluidmight lead to the erroneous conclusion that WQEboth contained the same amount. The bodydoes strive to maintain constant concentrationof salt more solicitously than it does totalcontent; but the latter is not entirely neglect- Naed. There is a demonstrable tendency to C1prevent extreme alterations of the volumeof fluid in the body. This has been alreadyillustrated in the discussion of miners' cramps.

Acid-base balance of body fluids: With-in the limits of variation of the hydrogen-ion l tconcentration of serum no significant quanti- FIG. I.ties of free acid or alkali can exist in the body; The relative concen-all acids and bases are found in combination trations of acids and basesas neutral salts. This is illustrated in figure in normal human serum.

IX which shows the concentrations of acids and bases in normal bloodserum. In this and subsequent figures the various acids and basesare evaluated not in the conventional gravimetric terms, as mg.per cent, but in chemical combining equivalents, as milliequivalentsper liter or cc. of O.I N acid or alkali per I00 cc. This method ofmeasuring all the components by a common unit, permits a balanceto be cast between acids and bases. Methods have recently beenproposed by which the total base concentration in terms of combin-ing equivalents, may be determined by a single analytical pro-cedure70. Because the concentration of total base is equal to thatof the combined acids of the blood, determination of total base gives

I9I


a measure of the total electrolyte concentration of serum; because, if[A] =[B], [A] + [B]=2 [B]

In normal serum 90 per cent of the base is composed of sodium.Two-thirds of the acid is chloride, one-fifth to one-sixth is bicarbon-ate, one-tenth protein. Organic acids and phosphates play less im-

I n m pi v VIExprz,d Air

HANANH;NA& A

Ui.FIG. 2.

A schematic representation of the acid-base balance of qerum during the developmentof diabetic acidosis. For description see text.

portant roles; sulfate is found in only negligible quantities. Sodiumand chloride, therefore, are the most important determinants ofosmotic pressure.

PATHOLOGICAL CONDITIONS.

Diabetic acidosis: Diabetic ketosis affords, perhaps, the bestexample of the effects of acidosis because it has been so completely

192


studied and because, in its most severe stages, it calls into play allthe reactions of the body against acidosis. The condition differs onlyin degree from the acidosis of starvation which Gamble, Ross, andTisdall"9 have analyzed so beautifully. In figure 2 an attempt hasbeen made to illustrate schematically the various disturbances ofelectrolyte, acid-base, and osmotic equilibrium that occur in severediabetic acidosis. In this figure the lower set of columns repre-sents the concentrations of electrolytes in the serum. The upperset represents the absolute quantities of the same components in thecirculating serum. The dot-and-dash line running along the topindicates the serum volume. Both sets of columns are drawn tothe same scale so that they may be compared easily and directly.Columns I represent normal acid and base concentrations and con-tents, and blood volume. On the base side potassium, calcium, andmagnesium have been grouped together, on the acid side, protein,sulfate, and phosphate, because they are of relatively little im-portance for the present purpose. Attention will be centered onsodium, organic acid, chloride, and bicarbonate.

The disturbance of acid-base equilibrium in diabetic acidosiscan be referred entirely to the production in the body of excessiveamounts of ketone acids (p -hydroxybutyric and aceto-acetic acids),which can not be burned unless carbohydrate is simultaneously oxi-dized. The increase of these acids is shown in columns II, wherethe concentration of organic acids has risen, displacing bicarbonate,which is shown above, as C02, escaping into the expired air. Atthe same time the kidneys are doing their part in restoring the nor-mal acid pattern by excreting the ketone acids, A, into the urine, part-ly as free acid, HA, partly neutralized by ammonia as NH4A. Noone of the reactions, thus far, has withdrawn from the body anyessential inorganic element. If, by the administration of insulinand carbohydrate, at this moment the excessive production of ketoneswere checked and the patient were enabled to burn the ketone acidswhich have accumulated in the blood, the process could be reversedand the normal electrolyte picture could be restored by internal re-arrangement of acids alone. C02 would be retained to form bi-carbonate with base liberated from the oxidized organic acid.

In subsequent columns it is assumed that all preceding reactionscontinue operative, although, to avoid confusion, only new reactionsare specifically illustrated. It must also be understood that, in

I93


life, these reactions do not take place as separate steps in the orderin which they are shown. In columns III the organic acid load hasbecome still greater; bicarbonate has been further reduced. Am-monia production is unable to meet the demands for the neutraliza-tion of acid in the urine; therefore base, sodium, is used for thispurpose (see NaA pouring into urine). Although this facilitatesacid excretion, it still further diminishes the amount of base avail-able for combination with bicarbonate and, at the same time, leadsto reduction of the total concentration of salt which can not exceedthe base. The result is shown in columns IV, where both electro-lyte concentration and content of serum are seen to have fallen belowthe normal level. This results in reduction of osmotic pressure, orhypotonicity. Unable to tolerate this the body excretes water toreduce the volume of the serum sufficiently to restore the properconcentration of salt. In columns V it will be seen that electrolyteconcentration has returned to normal, but electrolyte content hasfallen. Serum volume has diminished. Meanwhile, bicarbonatehas been almost extinguished.

Knowledge of subsequent reactions is somewhat less certain. Ithas been repeatedly demonstrated' 33,' 45S that in the most severestates of diabetic acidosis the concentrations of both base and Cl inthe serum are abnormally low. At the same time serum volume isdiminished8. Chloride appears to yield its base to neutralize theketone acids, thus saving bicarbonate from complete extinction58.Some of the Cl may be excreted with ammonia in the urine. Mostof these patients vomit, which would enable them to eliminate freehydrochloric acid. It has been suggested that Cl accumulates inhigh concentration in special tissues of the body6. Such local ac-cumulations are not compatible with what is known of electrolytedistribution and the forces which control it, and have not been ac-ceptably demonstrated. In other conditions similar hypotheses ofuneven chloride distribution, when put to the test of exact analysis,have proved false.

Cl is, therefore, shown passing into the urine as ammoniumchloride, NH4Cl, and into vomitus as free HCl, yielding a smallamount of base for bicarbonate. However, as all the other reactionscontinue to operate, electrolyte depletion becomes extreme; a pointis reached at which the body refuses longer to sacrifice fluid volumeto save salt concentration and the condition illustrated in the last

I94


column, VI, is reached. Though serum volume has diminishedgreatly, base concentration has fallen quite as far and the actual basecontent can be seen in the upper column to have become greatlydepleted. Proteins have increased slightly as a result of hemocon-centration.

Attention has been focussed on serum and urine alone, becausethey are the only materials available for direct analysis. Serummust, however, be regarded merely as representative of extracellularbody fluids which, presumably, suffer alterations of the same degreeand kind. BloQd cells,-and, it may be inferred, tissue cells-yieldless water and salt8' 58. They do, however, suffer in-another direc-tion. The diabetic organism, unable to burn carbohydrate or to secureits full fuel value from protein and fat, is forced to consume itsown tissues. The rate of nitrogen catabolism is greatly accelerated.This probably leads, as it does in starvation19, to the excretion ofcellular potassium, which aids sodium in the neutralization of urin-ary acid. Calcium and phosphate, derived from bones, probablyalso aid in the fight against acidosis.

To make the picture of the condition more complete, circulatoryand respiratory effects of acidosis should be included. Certainly someof them must be mentioned. Extreme dyspnea results from in-creased metabolism and the necessity of driving off the C02 liber-ated from bicarbonate by the action of the ketone acids. This over-ventilation may and, in fact, usually does fall somewhat short of itsmark. In this case the blood becomes more acid,.e., its hydrogen-ion concentration increases-because the ratio of free carbonic acid

to bicarbonate, BHCO3 rises. What is quite as important, butless often mentioned, is the fact that such dyspnea leads to loss ofbody heat by radiation and evaporation. Cooling plus reduction ofblood volume were shown during the war to be the most importantfactors in the production of the condition known as traumatic orsurgical shock. How far shock may be responsible for the symptomsand fatalities in diabetic acidosis is still uncertain; but its part hasprobably been greatly underestimated.

Although figure 2 is constructed from no particular case ofdiabetes, comparison with figure 3, which is made up from a groupof cases, shows that it gives a representative picture of the actualeffects of severq diabetic acidosis. In figure 3 the lower columns

I95


show concentrations of electrolytes in the serum of patients in dia-betic coma or threatened coma, shortly after admission to the hos-pital (from data of Kydd, Stetson, and Peters44).

Deaysa 2 20 " ) 6 4 1 3 5

140

~12 I

6100i

2

U 11

I

H1 m

-67p *o 59o 7250FIG. 3.

111

Imm

I m

I

5o4Z 22no 29s16

Serum electrolyte concentrations and contents in diabetic acidosis from data ofKydd et al44 and Peters, Bulger, Eisenman, and Lee'8. The lower set of columns

i4o140

in 1200

3.

.8t 6o

q, 4o_20

nm

II U

Cl

ICase co 11r1 W 2646 r

i96

_,-


shows the concentration of various acids in the sera of patients with severe diabeticketosis. In the upper set of columns an attempt has been made to estimate theactual deficiency of electrolytes in the serum. This has been calculated by as-suming that the difference between serum protein concentration at the height ofacidosis and after recovery was entirely due to change in serum water content.For example, in case no. 8I042, the serum protein concentration at the time ofthe first observation, when the patient was on the verge of coma, was I9.5milliequivalents. This is shown in the lower column. Two days later, when hehad recovered, the proteins had fallen to I 3.5 milliequivalents. Therefore, theconcentrations of all the serum electrolytes at the time of the first observationare multiplied by the factor 13.5/19.5 to determine the relative content of serumelectrolytes at this time. The values thus obtained are used in the constructionof the upper column. The total height of each column,-i.e., the sum of dll theacids, is equal to the total base.

The left hand columns present, for comparison, the e!i ctrolyte pattern ofaverage normal human serum.

In the upper columns an attempt has been made to estimate theactual serum electrolyte contents, using the serum protein valuesafter recovery as an index of the extent of initial blood dehvdra-tion. From the lower columns it will be seen that the concentra-tions of electrolytes are usually somewhat reduced, with bicarbonatethe chief sufferer and with variable deficits of base and Cl. Whenthe upper columns are considered it becomes at once apparent thatbase and Cl are invariably greatly depleted. Data of other ob-servers 33, 58 similarly treated, confirm these conclusions.

Comparison of columns I in figures 2 and 3 with column VI offigures 2 and columns 2 ff. of figure 3 permit certain deductions asto the treatment required to restore normal conditions in the shortestpossible time and in the most direct manner. Serum volume and,presumably, the total fluid content of the body, is low; the patientis dehydrated. However, the administration of mere water or glu-cose solution will only dilute further a serum that is already defi-cient in salt. Either; the fluid will not be retained or the osmoticpressure of the serum will be dangerously reduced. He must re-ceive base, sodium, in large quantities. Chloride must also be pro-vided. Neither of these can be secured from endogenous sourcesand must, therefore, be given in the form of sodium chloride. Bymeans of insulin and carbohydrate the production of ketones may bechecked and the ketones which have accumulated in the body maybe oxidized. All the base liberated from these acids is at oncerendered available for combination with carbonic acid to form bi-

I97


carbonate. It is apparent that this will, in most instances, provideenough base to restore almost completely the normal bicarbonatecontent of the serum.

Administration of sufficient water, sodium chloride, carbohydrateand insulin would, therefore, restore the electrolyte picture to normalexcept for a slight residual bicarbonate deficit. To overcome this,small doses of sodium bicarbonate may be of benefit. If the initial basedeficit were satisfied with bicarbonate alone, bicarbonate excess, oralkalosis, would inevitably result. Hartmann33 claims that, if nobicarbonate is given, but reliance is placed on chloride solution alone,base and bicarbonate deficit may persist for some time. The authorhas had no such experience, perhaps because he has given largerquantities of sodium chloride and water than did Hartmann. Eventhe latter does not advocate bicarbonate without chloride and recog-nizes that the latter is the more necessary of the two. If the fluidand salt content of the body is replenished and an adequate urineflow established the kidney will rapidly adjust the acid pattern ofthe body fluids by excreting Cl as the ammonium salt, retaining thebase to form bicarbonate; chloride must be provided from without.

Acids and acidifying salts: The administration of acids or acidi-fying compounds produces, by comparable reactions, disturbancesquite similar to those of diabetic acidosis, including dehydration. Theloss of water, in every instance, may be considered as a response onthe part of the body to depletion of base, which is swept into theurine to aid in the neutralization and excretion of the excess acid.This has been clearly demonstrated by Gamble and his associates15 20.Among the acids which may be used to produce acidosis are the min-eral acids and organic acids which can not be burned in the body.The administration of salts of the same acids with ammonia or withthe bivalent cations Ca, Mg or Sr is quite comparable in its effect tothe administration of the free acids. In the case of the ammoniumsalts, after absorption the ammonium ion is converted to urea by areversal of the reaction shown in equation (5), leaving the acid ionfree to combine with base and to displace bicarbonate, thus producingan acidosis. The acidifying and diuretic action of ammonium saltshas been repeatedly demonstrated'5' 20, 29, 42,, 5 Among the am-monium salts which are employed therapeutically to produce acidosisthe chief are amrnonium chloride and the acid ammonium phosphateNH4H2PO4.

i98


The acidifying effects of mineral acid salts of Ca, Mg and Sr de-pend on a slightly different mechanism. The basic ions of thesesalts are chiefly excreted in the stools as insoluble carbonates, phos-phates and salts of fatty acids, without appreciably draining the acidresources of the body. The acid ions are absorbed, combine withbase in the serum, displacing bicarbonate, and must finally be ex-creted by the kidney with a certain proportion of mineral base, chieflysodium'5' 20. 28 5t. Loss of earthy metals in the stools is not duemerely to lack of absorption. The calcium of injected calciumchloride is excreted chiefly by the intestines and, consequently, in-travenous injection of this salt may be quite as effective in produc-ing acidosis and diuresis as is peroral administration.49 Although agreat number of calcium and magnesium salts have been shown tohave acidifying and diuretic properties, calcium chloride is the onlyone which has been extensively employed for these purposes thera-peutically. Magnesium sulfate,- when given by mouth in acidify-ing doses has a drastic cathartic action; intravenously or subcutane-ously, because of the magnesium ion, it is a powerful sedative. Cal-cium sulfate is quite insoluble.

Perhaps the strongest evidence that ammonia production andexcretion are evoked by the need for conservation of base is found incomparative studies of the effects of ammonium chloride and calciumchloride on acid-base metabolism'5' 20,51. After doses of the twodrugs which contain equivalent amounts of Cl, ammonia excretionis the same. In the case of the ammonium salt more than half theadministered ammonia is converted to and excreted as urea; afterthe calcium salt a considerable quantity of metabolic urea is con-verted to ammonia. In both cases a large proportion of the adminis-tered chloride is excreted as sodium chloride. It is only after sodi-um has undergone a certain amount of depletion that ammoniaproduction reaches its height.

Hydroxides, carbonates, and bicarbonates of sodium and potassiumas well as salts of these metals with organic acids which can be oxi-dized by the organism produce alkalosis by increasing the concentra-tion of base and bicarbonate in the body. Among the alkalinizing saltswith oxidizable acids may be mentioned d-lactates, acetates and ci-trates. The administration of such alkalies increases serum bicarbon-ate, causes the urine to become more alkaline and suppresses the pro-duction and excretion of ammonia5'. The total base concentration of

199


the serum does not rise appreciably because water equivalent to theadministered base is retained with it. The results in dilution of serumCl. From examination of the serum alone one would gain the im-pression that the bicarbonate ion had displaced Cl from combinationwith base. Although such displacement may follow prolonged ad-ministration of bicarbonate, it does not appear to be its first anddirect result. Indeed bicarbonate seems, at first, to diminish Cl ex-cretion".

The effects of dilution or concentration on the one hand, andspecific ionic displacement on the other, in altering the concentrationof individual ions in the serum, must be carefully distinguished. Theeffect on the serum of bicarbonate administration is equivalent todilution of the serum with an isotonic solution of bicarbonate. Ifsufficiently large amounts of sodium chloride are taken serumchloride increases, while bicarbonate becomes proportionately re-duced. At first sight sodium chloride and ammonium chloride ap-pear to have identical effects. The Cl ion, in both instances, seemsto have displaced the bicarbonate ion. However, more careful studyreveals the fact that the serum becomes more dilute after sodiumchloride, dehydrated after ammonium chloride. The effects of thethree salts, sodium bicarbonate, sodium chloride, and ammonium(or calcium) chloride on acid-base equilibrium in serum are il-lustrated in figure 4.

In general, it can be said that the entrance into the body of baseand acid in combination as salt (and the introduction of base alone,because of the ubiquity of C02 which forms bicarbonate with thebase, is equivalent to the introduction of combined base and acid)evokes retention of water. Loss of base and acid together is at-tended by loss of water. Because in the excretion of acid a certainamount of base is withdrawn into the urine, acidosis is dehydrating.

Overventilation and oxygen want: Although bicarbonate usu-ally plays a mendicant role among the acids of the serum, it may,under certain circumstances, force other acids into secondary or com-pensatory reactions. Forcible overventilation of the lungs removesfrom the blood a certain amount of C02. This reduces the hydro-gen-ion concentration of the serum by diminishing the value of the

numerator of the ratio, NaHCO3 It furthermore, by the reaction

200


A

5

Ca

I

IH

c'

I I1X [I

"In

Ia

11W

I

I

-1 111111 --

b ar-- m

1 I I.

ILw

I

,1Efl

Ib

1

hID

IN N NNvriEfec ofi

FIG. 4.

The effects of the administration of NH4Cl, NaCl, and NaHCOs on serum

electrolyte equilibrium.

Ser

U111

I

fi

2

1

*

0

a

I20

I Ia b

I INaHiCO,

20I

7"

"*NaHcq


The effect of NH4C1. In "a" enough NH4C1 has been given to increasethe concentration and content by Io milliequivalents, displacing an equivalentamount of C02. In "b" one-half the excess Cl has been excreted as NH4Cl,the other half as NaCl (as indicated in "a") and the normal osmotic pressure hasbeen restored by the excretion of water equivalent to the Na lost.

The effect of NaCl. In "a" enough NaCl has been given to increase theconcentration and content of Na and Cl by IO milliequivalents. In "b" one-halfthe salt has been excreted as NaCl (as indicated in "a") and enough water has beenretained to restore the normal osmotic pressure.

The effect of NaHC03. In "a" enough NaHCO3 has been given to increasethe concentration and content of Na and HCO3 by IO milliequivalents. In "b"one-half the salt has been excreted as NaHCO3 (as indicated in "a") and enoughwater has been retained to restore the normal osmotic pressure.

shown in equation (4) causes the decomposition of bicarbonate withliberation of base. Under these circumstances, as Peters, Bulger,Eisenman, and Lee59 have demonstrated, serum Cl increases, pre-sumably because its excretion in the urine is depressed. At the sametime bicarbonate is excreted in the urine. Ketonuria is also ob-served after prolonged overventilation30 '7. Chloride and, to a less-er extent, ketone acids are provided to neutralize the base freed frombicarbonate by the pumping off of C02. Spontaneous overventila-tion alkalosis has been observed chiefly in connection with functionalnervous disorders and in the postencephalitic syndrome. It is partof the regular reaction to low oxygen tension in the inspiredair3 43' 59 When, however, oxygen want in the latter conditionbecomes sufficiently serious to interfere with oxidative processes inthe tissues, lactic acid accumulates in the tissues and blood. Thismay, at first, merely aid Cl and ketones in combatting the over-ventilation alkalosis. When the anoxemia becomes extreme lacticacid accumulation may become sufficient to produce an actual acidosis.

Asphyctic anoxemia: Primary retention of C02 was first dem-onstrated in emphysema patients by Scott89. In this condition and inother clinical states in which the exchange of gases in the lungs isimpeded by obstruction of the respiratory tract, an excess of C02accumulates in the blood12 57 69. This would increase the hydro-gen-ion concentration of the blood if it were not compensated by aproportionate increase of bicarbonate. Essen, Kauders, and Porges12,and Peters and Bulger57 have shown that compensation is establishedby the provision of base at the expense of Cl. Serum bicarbonate isfound abnormally high, while chloride is diminished to an equal

202


extent. The end result of these reactions is to enable the animal,without appreciable change of blood reaction, to maintain a hightension of C02 in the blood and in the respiratory air and, thereby,to excrete more carbon dioxide with a given respiratory volume.

Gastro-intestinal secretion: By a great variety of experimentsit has been established that the secretions of the gastro-intestinaltract are, almost without exception, in osmotic equilibrium withblood serum. Furthermore it seems to be a rule that alimentarycontents are brought into osmotic equilibrium with the serum be-fore or during the process of absorption' 16, 23, 47. This explains thefact that the rate of absorption of ingested sugar is independent ofthe amount or concentration of sugar given. After administrationof an isotonic solution of sodium sulfate MacLean found that theconcentration of S04 + Cl in the stomach remained constant. Gam-ble and McIver"6 have analyzed gastric, pancreatic, and hepaticsecretions. The results of these analyses are illustrated in figure 5.It is at once apparent that, with the exception of gall-bladder bile,which is greatly concentrated, all these secretions contain essentiallythe same total concentration of acids and bases as does serum; allare isotonic. They differ from one another only in the relativeproportions of different acids and base (chiefly sodium) which theycontain. In gastric juice almost all the acid is composed of Cl,which is balanced by sodium and hydrogen-ions in varying pro-portions. The amount of free hydrochloric acid present depends onthe extent to which Cl is neutralized by Na. Hepatic duct bile re-sembles serum very closely except that bile acids replace serumproteins. Pancreatic juice is alkaline, because most of its acid is inthe form of bicarbonate.

The acids and bases in these secretions are all derived from theblood serum in its passage through the secreting organs. Bulger7,by simultaneous analysis of gastric arterial and venous blood, hasshown that the blood serum in its passage through the stomach, loseschloride and water in approximately equivalent concentration.Dodds10, Hubbard4", and others have demonstrated that the "al-kaline tide" (increased urinary alkalinity) that follows the inges-tion of food is absent in patients with achlorhydria. It is, therefore,a reaction to the alkalosis caused by loss of hydrochloric acid fromthe blood to the stomach during digestion. During the alkaline

203


tide serum bicarbonate rises, while Cl falls. These normal post-prandial fluctuations of acid-base metabolism, although they areof physiological interest and may have some diagnostic value, aretoo trivial to influence appreciably the salt and water exchange.More profound changes of acid-base equilibrium may, however,follow continuous loss of gastro-intestinal secretions.

W -eq

El1Gcton !PWxkdW IpicDut uiI Id& BloodJuice Juke Dile Bile Plasm

Ftc. 5.Inorganic composition of digestive juices, illustrating the similarity of the

total electrolyte concentration of all except gall-bladder bile to that of the plasma.From Gamble and McIver".

Pyloric and intestinal obstruction: In animals with pyloric orupper intestinal stenosis the appearance of tetany was early noted.Through studies by MacCallum,- Lintz, et al.46 and others it wasdemonstrated that the spasmophilic tendency was due to loss of Cl

204


in the vomitus and resultant alkalosis and that the tetany could berelieved by parenteral administration of sodium chloride. Concern-ing the cause of the other symptoms and signs and the early deathof animals with intestinal obstruction there has been some controver-sy. Haden25 and others at first insisted that not only death, but alsothe hypochloremia and azotemia were due to the absorption of toxinsfrom the obstructed gut. It has also been claimed that vomitingalone could not explain the chloride depletion of the serum, whichwas, therefore, assumed to be partly due to transfer of Cl from theblood to repositqries elsewhere in the tissues. More exact investiga-tions have shown that hypochloremia, salt deficiency, dehydration,symptoms of intoxication, and death can all be referred directly toloss of fluid and electrolytes in the gastro-intestinal secretions. More-over, analyses of tissues by Haden and Orr26, have failed to detectin tissues excessive concentrations of chlorides.

Gamble and Ross'8, by studies of the complete acid-base meta-bolism of dogs with pyloric obstruction, have defined the electrolytedisturbances in this condition. The ultimate effects on the serumare: i. loss of fluid; 2. a greater loss of base, resulting in actualreduction of the serum base concentration as well as content; 3.extreme depletion of Cl; 4. the base liberated by chloride is chieflyneutralized by substitution of bicarbonate, aided to a slight extentby phosphate and sulfate2 (in man, organic acids, presumably ketonesresulting from starvation, also play a part). These disturbances ap-pear to be a direct result of loss in the vomitus of water, hydrochloricacid, and sodium chloride. A considerable amount of the chloridelost in the vomitus is neutralized by sodium. After pyloric obstruc-tion the stomachs of rabbits, which are unable to vomit, became rapid-ly distended with fluid, containing quite enough salt, hydrochloricacid and water to explain the serum electrolyte changes17. Miller53found that, if the obstruction was relieved within I5 hours the gas-tric contents were again absorbed and the animals recovered. If,however, the gastric contents were removed near the end of this time,death ensued even if an equal amount of water was placed in thestomach and the obstruction was relieved.

Foster'3 has shown that, if dogs are given for the first two orthree days after the production of intestinal obstruction, sufficientsaline solution parenterally to replace the salt and water lost in thevomitus, but nothing per os, they develop no signs of intoxication and

205


no hypochloremia. At the end of this period, when vomiting hasceased, if the saline injections are discontinued neither symptoms oftoxemia nor serum salt depletion develop. The animals live for aconsiderable time, finally succumbing to inanition. These resultshave been confirmed by Gatch, Trusler, and Ayres21. There can beno doubt, from all these observations, that acid-base disturbances,signs and symptoms of intoxication, and death after pyloric obstruc-tion are all alike referable to loss of fluid and salts in vomitus.

The urine in pyloric obstruction becomes extremely scanty be-cause of the dehydration; chloride excretion diminishes rapidly, ceas-ing entirely when serum chlorides have fallen to about 90 milli-equivalents; ammonia excretion is minimal. In the early stages theurine becomes alkaline, containing large quantities of bicarbonate.As intoxication becomes more severe, however, the urine may againbecome acid18 34 even though the bicarbonate excess (indication ofalkalosis) in the serum may be more extreme. Parenteral admin-istration of sodium chloride at this time causes the urine to becomealkaline. The paradoxical excretion of an acid urine when the serumgives evidence of alkalosis, seems to mark a state of extreme basedepletion. When base deficiency has reached a certain point theorganism becomes unwilling to part with more and thus further toexaggerate hypotonicity and dehydration, in spite of the fact thatfailure to do so aggravates bicarbonate excess. When, by admin-istration of chloride, it receives additional base, it reacts by excretingbicarbonate to restore the normal acid pattern. The course of thechanges in acid-base equilibrium after pyloric obstruction are il-lustrated schematically in figure 6.

One alteration of blood chemistry, which is not directly con-nected with electrolyte equilibria, but which invariably attends in-testinal obstruction, is increase of non-protein nitrogen. This is proba-bly to be ascribed to toxic destruction of protein or starvation, in-sufficient urine excretion due to lack of water, and circulatory changesattending reduction of blood volume.

The most serious effects of intestinal obstruction appear to bedue to the loss of salt and water. Administration of glucose solu-tion subcutaneously and intravenously, by promoting urine flow andsparing nitrogen may cause the blood non-protein nitrogen to fall,but does not prolong life. Ammonium chloride, although it over-comes hypochloremia and alkalosis, shortens life by furthering de-

2o6


a

'll"ll

b

NormeI Pyborba Obstruc10oo Diarrbea

FiG. 6.

The effect of pyloric obstruction and of diarrhea on the acid-base balanceof the serum.

In "a" vomiting has caused the loss of a large amount of Cl as free hydro-chloride acid. This has been replaced by HCO3. At the same time a certain-amount of NaCl with an equivalent amount of water has been lost. In "b"

inm

207


the same processes have continued further, but the loss of water has not been sogreat as that of salt. Serum volume has been spared to some extent at the ex-pense of osmotic pressure.

The end result of diarrhea is similar except that the alkaline character ofthe feces leads to greater depletion of HCO3 than of Cl. There is a considerablereduction of Cl content with only a minor deficit in Cl concentration.

hydration'17 21. Administration of isotonic sodium chloride pro-vides water and the ions which are chiefly lacking. It is not certainthat a mixture of NaCl and NH4Cl would not accelerate therestoration of the normal serum electrolyte picture. Grantedenough sodium chloride to restore its total water and salt content, thebody, through the kidney, will eliminate bicarbonate selectively, re-taining Cl, and thus make the necessary adjustment between indi-vidual acids.

Administration of water by mouth not only fails to alleviatesymptoms, but is positively deleterious because it maintains thesecretory activity of the alimentary tract and washes out of the bodyfurther salt'' 21

One of the points advanced by Haden in favor of the toxemicorigin of the hypochloremia in intestinal obstruction was the obser-vation of similar chloride deficits in animals with obstruction of thecardiac end of the stomach and of the pylorus27. The extent of theserum chloride deficiency in this condition is, however, relativelysmall. Its origin requires further investigation.

In obstruction of the pylorus by carcinoma associated with achlor-hydria, dehydration and salt depletion occur without specific chloridedeficiency and alkalosis22. Fistulae of the stomach with continuousloss of gastric contents produce effects quite similar to those follow-ing pyloric obstruction75. Fistulae of the pancreatic duct or thesmall intestine also cause dehydration and salt depletion. Becausethe contents of these organs are alkaline, however, acidosis withbicarbonate deficit and chloride excess develop76.

If obstruction of the alimentary canal is accompanied by impair-ment of the circulation (strangulation) or peritonitis, all the phe-nomena of obstruction are observed, and, in addition, symptoms andsigns of surgical shock'' 21,. In these circumstances, saline injections,though of service in improving the general condition of the patient,are of less benefit than in simple obstruction.

208


Vomiting without gastro-intestinal obstruction may, dependingon its severity and the nature of the vomitus (its content of free acid),produce disturbances of acid-base, electrolyte and water equilibriumvarying from simple starvation acidosis to pictures quite comparableto those of pyloric obstruction22 24,

Diarrhea: Carl Schmidt68, as early as I 850, in his classicalstudy of an Asiatic cholera epidemic in Mitau, Germany, demon-strated by analyses of serum both salt deficiency and hemoconcentra-tion. In some cases he found nine or more gm. per cent of proteinin the serum instead of the usual seven. The enormous losses offluid and salts, especially the monovalent bases, K and Na, in thestools of infants with diarrhea was pointed out by Holt, Courtney,and Fales40. Hartmann31 found in the serum of infants with di-arrhea deficits of base and bicarbonate with little or no chloride de-pletion and, occasionally, even a Cl excess. Administration ofsodium chloride alone failed to relieve the acidosis and sometimesproduced or exaggerated the chloride excess. This they interpretedas an indication for the administration of bicarbonate. Hoag andMarples39 have criticized Hartmann's conclusions, pointing out thathe did not administer enough sodium chloride solution to establisha free flow of urine. When this is done, they claim, hyperchloremiadoes not result because the kidneys excrete the excess Cl as NH4'Cl,retaining some of the base to form bicarbonate. As stools are usu-ally alkaline, even in diarrhea, the administration of some bicarbon-ate may be of advantage. It can not, however, compensate forfailure to supply fluid and sodium chloride to overcome dehydrationand to enable the kidneys to function properly.

Nephritis: Because of the frequent occurrence of edema whichis aggravated by ingestion of salt the problem of electrolyte meta-bolism in nephritis has long commanded attention. As investiga-tive studies have proceeded and multiplied it has become more andmore evident that no single conception can cover the phenomena ofthe disease. At least two clearly defined types of functional dis-turbance must be recognized, with intermediate mixed pictures pre-senting some characteristics of both types, whether such differentia-tion can be correlated with demonstrable anatomical distinctions ornot. In the first type, of which the condition often spoken of asnephro;is is the clearest example, are found profuse albuminuria, the

209

2YALE JOURNAL OF BIOLOGY AND MEDICINE

presence of or tendency to edema without evidence of circulatorydisturbances, litde impairment of renal function (no loss of theability to pass concentrated urine) and therefore no retention ofnitrogenous metabolites in the blood, and absence of hypertension.In the second, hypertension with attendant cardiac and vascular dis-turbances, polyuria and hyposthenuria with tendency to retention ofnitrogenous metabolites and finally the syndrome of "uremia" arethe most prominent features; edema seldom appears except as asymptom of heart failure.

In the nephrotic type the development of edema seems to bereferable chiefly to deficiency of serum proteins which, by their os-motic pressure, normally balance the hydrostatic force of the bloodpressure which tends to drive fluid from the circulating blood. Inmost instances, as has been mentioned above, sodium salts tend toaggravate the edema, while potassium salts have no such effect andmay, in fact, exert a diuretic influence4' 48. From this it may be in-ferred that the edema is confined to interstitial fluids and does notinvolve tissue cells. Electrolyte patterns are variously disturbed.The most common picture appears to be a moderate base deficit,often accompanied by relative or absolute chloride excess!' ` - 67.The serum Cl excess is balanced by a moderate bicarbonate defi-ciency. The changes can only be interpreted as an indication thatCl is retained in unusually large and Na in unusually small quantityin proportion to water.

This view is supported by the observation that ammonium chlor-ide produces a greater degree of acidosis in nephrosis patients than innormal persons61. Nevertheless, it is generally held that the edemais primarily due to retention of sodium, which secondarily provokesretention of equivalent amounts of water and of the acid, Cl. Thereasons for this theory are, first, that patients with nephrosis, whendeprived of salt, may excrete extra water without difficulty; sodiumbicarbonate often provokes more edema than an equivalent amountof the chloride; but both tend to reduce the volume of urine and toaggravate edema when the fluid intake is kept constant; while acidi-fying chlorides may induce diuresis. The force of the last argumentis lessened by the fact, mentioned above, that these chlorides se-cure their diuretic effects only by producing an unusually great dis-turbance of acid-base equilibrium.

210


Albright and Bauer' have recently presented an extremely in-teresting study of the total inorganic metabolism of a subject with"nephrosis", over a series of periods in which he received, suc-cessively, a salt-poor diet, added sodium chloride, ammonium chlor-ide and sodium bicarbonate. During the initial period serum basewas low. On the sodium chloride regime there was a continuous-ly positive salt and water balance and edema increased, serum baseremaining low, Cl rising somewhat. Ammonium chloride precipi-tated diuresis; but, at the height of diuresis, when base excretionwas maximum, serum base had risen to, and Cl had surpassed, thenormal limits. The diuresis ceased as soon as ammonium chloridewas discontinued. Under sodium bicarbonate there was initial re-tention of base and water, which later gave way to diuresis whichpersisted for some time after bicarbonate was discontinued. Againserum base was found to have risen to normal limits during theperiod of diuresis.

The facts hardly seem to permit one to place the chief or pri-mary responsibility for the disturbance of salt and water balanceupon any single component of the serum. Apparently the systemis by some means deranged so that an abnormal electrolyte patternis maintained. It is, so to speak, improperly set, most frequently sothat water and Cl are retained in the body in excess of Na. Withinthis setting, however, it reacts normally. Further Cl or water cannot be retained without Na. Therefore, water without salt is ex-creted comparatively freely and NH4C1 will produce diuresis. Nacan also be excreted if its concentration in the serum is forced up toor above the normal level. NaCl, however, does not essentiallyunbalance the electrolyte equilibria. Acidosis and alkalosis of seriousdegree seldom occur spontaneously in this condition.

In the types or stages of nephritis characterized by hyposthenuriaand hypertension, a very different picture is encountered. There isno especial tendency to edema; on the contrary these patients tendto become dehydrated. In the terminal stages of the disease bi-carbonate deficiency, acidosis, is extremely common. Electrolytestudies have revealed the fact that this acidosis is due to a variety ofcauses1, 32.67. Phosphate and sulfate accumulations play a definite,but not important role in its production. Organic acid increases mayoccur. Deficiency of base, however, appears to be the most importantsingle factor. This is shown by figure 7, prepared from the data of

21I1


Peters, Wakeman, Eisenman, and Lee80. It will be ten from thisfigure that serum bicarbonate is almost invariably reduced, base isusually low and chloride is more often low than high.

30

20

10

40

30

20

-10

IIs a

I 30

20

10

20

10

~ ~ m

0 5 10 15 20 25 30 35 40

P04 + Undeermined Acid weq

FIG. 7.A statistical analysis of the serum electrolyte changes in terminal stages of

nephritis. Distribution of values for base, Cl, HCO3 and P04 + undeterminedacid. White columns indicate normal values, black columns abnormal values.

These changes can be only partly explained. Accumulations ofphosphate and sulfate have been ascribed directlv to renal imper-

212


meability on presumptive evidence only. The chloride deficit mayresult from vomiting, usually a prominent symptom, which inter-feres with the ingestion of salt even if it does not cause absolute lossof Cl. Another factor is, however, instrumental in promoting Cldepletion. The patient in the terminal stage of nephritis is unableto pass chloride in high concentration in the urine. At the sametime he continues to excrete Cl even after its concentration in theserum has fallen below the level at which Cl excretion ceases innormal persons32 . For this reason, if he receives no salt or isunable to retain it, he has not the usual power of conserving thesalt stores of the body. Another element in the production of acid-osis and probably the chief cause of base depletion is the loss of theability to form ammonia, which has been demonstrated by VanSlyke73, Rabinowitch63, Linder45, and others. Without this abilitythe nephritic is unable to excrete any strong acid without an equiva-lent amount of mineral base. For the same reason his capacity toexcrete acids selectively is limited.

Ir~ ~I-so-

is i6o

~ 00

liios 11'tso4t7rXa ma. o 1

%0OcM+ 61?r0aCL+FIG. 8.

The concentration of electrolytes in the serum of a uremic patient as affectedby treatment. For description see text.

213


With this tendency to waste salt there is an inevitable tendencyto dehydration, often enough aggravated by vomiting. The logicaltreatment is the administration, subcutaneously or intravenously,if necessary, of fluids containing sodium chloride. The addition ofbicarbonate is often necessary because these patients have lost thepower by which persons with normal kidneys adjust the acid patternsof the body fluids. They can not excrete the Cl ion as the ammoniumsalt, retaining the base of NaCl to form bicarbonate.

The whole process is, perhaps, best illustrated by the examplein figure 8. The patient had a chronic nephritis aggravated byprostatic hypertrophy with partial urinary retention and a periure-thral abscess which had been drained, leaving a urethral fistula.When he was seen in medical consultation after the operation hewas unable to take fluids by mouth and had received but little byother channels. He appeared desperately dehydrated and was over-ventilating greatly. The total base concentration of the serum wasgreatly reduced. This, and increase of organic acid (or organicacid + sulfate), had almost extinguished bicarbonate. Chloridewas apparently normal. In spite of this he was given the therapyindicated below the figure, including i6 gm. of NaCl daily and asmaller quantity of bicarbonate, with carbohydrate to overcomestarvation acidosis and to mitigate protein destruction. Within 24hours there was noticeable improvement that was even more evidentthe next day. He was, however, still stuporous and breathingrather heavily. Treatment had raised the total electrolyte con-centration almost to the normal level, but chloride was too high andbicarbonate still too low. Bicarbonate administration was, therefore,pushed more vigorously, while chloride was continued. By thetime of the third study the patient was conscious, breathing quietlyand taking food and fluids freely. Examination of the serum re-vealed a normal electrolyte picture. The extra bicarbonate hadsupplied a specific deficiency. The continuation of chloride therapyafter the second study, when serum chloride was known to behigher than normal, at first sight seems illogical, although there isno escaping the fact that it had the desired effect. The reason onlybecomes obvious when one takes into consideration the serum proteinfigures. Serum proteins diminish in each successive study. Dehy-dration was extreme at the beginning. At the time of the secondobservation the concentration of chloride in the serum was high, but

214


the total chloride content of the body fluids was apparently stilllow. As the fluid content of the body was restored chloride wasdiluted. Besides this, urine flow increased greatly as had been de-sired. The beneficial effects of this are shown strikingly in the re-duction of blood non-protein nitrogen. Diuresis was stimulated bythe administered saline and presumably swept some chloride fromthe body. If salt had not been given to replace that which wasthus lost, chloride deficiency would have developed. Bicarbonatewas necessary because this man could not, like the diabetic or thepatient with diarrhea, make his internal readjustment when he re-ceived chloride alone, because he had lost the ability to form am-monia and could not, therefore, excrete Cl without Na.

In patients with true renal edema salt should be restricted. Inthe face of severe renal injury, however, with hyposthenuria -andno tendency to renal edema, it is desirable to establish and to main-tain a free urine flow by the administration of large amounts of fluid.If salt is withheld this inevitably leads to salt depletion, because thenephritic can not or does not conserve his salt supplies against renalleakage as the normal individual does. Forcing fluids without pro-viding salt is provocative of discomfort in any case; it is far moreserious in uremia. Salt restriction can and does lead only to dehy-dration, salt depletion and acidosis. Bicarbonate must often be pro-vided in addition because the ability of the kidneys to excrete indi-vidual acids selectively is impaired. It is, however, inadvisable touse bicarbonate alone to combat nephritic acidosis, because this veryloss of adjusting power, as Ellis" has shown, renders nephriticpatients peculiarly liable to alkalosis.

CONCLUSIONSAcidosis and alkalosis must not be looked upon as mere alter-

ations of the concentrations of bicarbonate or acids in the body. Theseconditions involve far more serious trains of consequences all ofwhich must be taken into consideration. The most important ofthese are changes in the salt and water content of the body, especiallydehydration and salt depletion. Although every derangement ofacid-base equilibrium should be fought with due attention to itsspecific cause and effects, regulation of salt and water intake is auseful weapon against them all. Attempts to provide individual ionsto supply deficits or to correct special disturbances of acid-base pat-

215

2I6 YALE JOURNAL OF BIOLOGY AND MEDICINE

terns are meritorious and sometimes essential, but can never be asbeneficial as measures which enable the organism to exercise its ownpowers of adjustment in the most effective manner.

BIBLIOGRAPHYI Albright, F., and Bauer, W.: The action of sodium chloride, ammonium chlor-

ide, and sodium bicarbonate on the total acid-ba3e balance of a case of chronicnephritis with edema. J. Clin. Invest., I929, 7, 465.

2 Atchley, D. W., and Benedict, E. M.: The distribution of electrolytes in dogsfollowing intestinal obstruction. J. Biol. Chem., 1927, 75, 697.

3 Barcroft, J., Binger, C. A. L., Bock, A. V., Doggart, J. H., Forbes, H. S.Harrop, G., Meakins, I. C., and Redfield, A. C.: Observations upon theeffect of high altitude on the physiological processes of the human body car-ried out in the Peruvian Andes, chiefly at Cerro de Pasco. Trans. Roy. Soc.of London, I 922, 2 IIX (B), 351.

4 Blum, Leon: Recherches sur le role des sels alcalins dans la pathogenie desoedemes. L'action diuretique du chlorure de potassium. Presse me'd., 1920,28, 685.

Blum, Leon, Aubel, E., and Hausknecht, R.: Le mecanisme de l'action duchlorure de sodium et du chlorure de potassium dans les nephrites hydro-pigenes. Compt. rend. Soc. de biol., I92I, 85, I23.

5 Blum, L., Grabar, P., and van Caulaert: L'azotemie par manque de sels dansle diabete grave. Ann. Med., 1929, 25, 23.L'azotemie par manque de sel son mecanisme. Ann. Med., I929, 25, 34.

6 Blum, L., Grabar, Pa., and Thiers: Teneur des organes en chlore et en sodiumdans le coma diabetique. Contribution a la physiopathologie du comadiabetique. Compt. rend. Soc. de biol., I927, 96, 643.

7 Bulger, H. A., Stroud, C. M., and Heideman, M. L.: Studies of the chemicalmechanism of hydrochloric acid secretion. I. Electrolyte variations in humangastric juice. J. Clin. Invest., I928, 5, 547.

Bulger, H. A., Duff, A., and Harrison; L. B.: II. Observations on the bloodpassing through the stomach of dogs. J. Clin. Invest., I928, 5, 56I.

8 Chang, H. C., Harrop, G. A., Jr., and Schaub, B. M.: The circulating bloodvolume in diabetic acidosis. J. Clin. Invest., I928, 5, 407.

9 Cori, C. F.: The fate of the sugar in the animal body. I. The rate ofabsorption of hexoses and pentoses from the intestinal tract. J. Biol. Chem.,1926, 66, 69I.

0 Dodds, E. C., and Smith, E. S.: Variations in the blood chlorides in rela-tion to meals. J. Physiol., I923-24, 58, 157.

Ellis, A. W. M.: Disturbance of the acid-base equilibrium of the blood to thealkaline side. Quart. J. Med., I924, 17, 405.

12 Essen, H., Kauders, F., and Porges, O.: Die Beziehungen der CO2 Spannungder Alveolarluft zu den Chloriden des Blutserums. Wien. Arch. klin. Med.,1923, 5, 499.

ACID BASE EQUILIBRIUM 217

13 Foster, W. C., and Hausler, R. W.: Acute intestinal obstruction. III. Simpleobstruction. Arch. Int. Med., I925, 36, 3I.

Foster, W. C.: Acute intestinal obstruction. The correlation of recent ex-perimental studies and clinical applications. J. Am. Med. Ass., I928, 9I,1523.

14 Gamble, J. L.: Carbonic acid and bicarbonate in urine. J. Biol. Chem., I922,51, 295.

15 Gamble, J. L., Blackfan, K. D., and Hamilton, B.: A study of the diureticaction of acid producing salts. J. Clin. Invest., 1925, I, 359.

16 Gamble, J. L., and McIver, M. A.: The acid-base composition of gastric se-cretions. J. Exper. Med., I928, 48, 837.

Gamble, J. L., and McIver, M. A.: Acid-base composition of pancreatic juiceand bile. J. Exper. Med., I928, 48, 849.Body fluid changes due to continued loss of the external secretions of thepancreas. J. Exper. Med., 1928, 48, 859.

17 Gamble, J. L., McIver, M. A., and Marsh, P.: A study of the effects ofpyloric obstruction in rabbits. J. Clin. Invest., I925, I, 53I.

18 Gamble, J. L., and Ross, S. G.: The factors in the dehydration followingpyloric obstruction. J. Clin. Invest., I925, I, 403.

19 Gamble, J. L., Ross, S. G., and Tisdall, F. F.: The metabolism of fixed baseduring fasting. J. Biol. Chem., 1923, 57, 633.

20 Gamble, J. L., Ross, S. G., and Tisdall, F. F.: Studies of tetany. I. Theeffect of calcium chloride ingestion on the acid-base metabolism of infants.Am. J. Dis. Child., 1923, 25, 455.

Gamble, J. L., and Ross, S. G.: Studies of tetany. II. The effect of ingestionof hydrochloric acid producing substances on the acid-base metabolism of aninfant and the probable manner of their action in the treatment of tetany.Am. J. Dis. Child., 1923, 25, 470.

21 Gatch, W. D., Trusler, H. M., and Ayers, K. D.: Acute intestinal obstruction;mechanism and significance of hypochloremia and other blood chemicalchanges. Am. J. Med. Sci., 1927, 173, 649.

22 Gatewood, W. E., Gaebler, 0. H., Montwyler, E., and Myers, V. C.:Alkalosis in patients with peptic ulcer. Arch. Int. Med., I928, 42, 79.

23 Goldschmidt, S., and Dayton, A. B.: Studies in the mechanism of absorptionfrom the colon. J. Biol. Chem., 19I7, I2, 29.

24 Haden, R. L., and Guffey, D. C.: Pernicious vomiting of pregnancy with lowblood chlorides and marked response to sodium chloride therapy. Am. J.Obst. Gynec., 1924, 8, 486.

25 Haden, R. L., and Orr, T. G.: Chemical changes in the blood of the dog afterintestinal obstruction. J. Exper. Med., 1923, 47, 365.Chemical changes in the blood of the dog after pyloric obstruction. J. Exper.Med., 1923, 37, 377.Chemical changes in the blood of the dog after obstruction of the esophagusand of the cardiac end of the stomach. -J. Exper. Med., I923, 38, 477.

26 Haden, R. L., and Orr, T. G.: The chloride content of the tissues of the dogafter experimental gastro-intestinal tract obstruction. J. Exper. Med., 1926,44) 435.

2I8 YALE JOURNAL OF BIOLOGY AND MEDICINE

27 Haden, R. L., and Orr, T. G.: Effect of sodium chloride on the chemical changesin the blood of the dog after obstruction of the cardiac end of the stomach.J. Exper. Med., I928, 48, 627.

Haden, R. L., and Orr, T. G.: Experimental dehydration. Chemical changesin the blood of the dog contrasted with those following obstruction of thecardiac end of the stomach. J. Exper. Med., I929, 49) 945.

28 Haldane, J. B. S., Hill, R., and Luck, J. M.: Calcium chloride acidosis.J. Physiol., I923, 57, 30I.

Haldane, J. B. S.: The production of acidosis by ingestion of magnesiumchloride and strontium chloride. Biochem. J., I925, I9, 249.

29 Haldane, J. B. S., Linder, G. C., Hilton, R., and Traser, F. R.: The arterialblood in ammonium chloride acidosis. J. Physiol., I927, 65, 412.

30 Haldane, J. B. S., Wigglesworth, V. B., and Woodrow, C. E.: The effect ofreaction changes on human carbohydrate and oxygen metabolism. Proc. Roy.Soc., I924, 96, Series B, I5.

31 Hartmann, A. F.: Chemical changes occurring in the body as the result ofcertain diseases. I. The effects of diarrhea, vomiting, dehydration and oliguriaon the acid-base balance of the plasma of infants with mastoiditis. Am. J.Dis. Child., I928, 35, 557.

32 Hartmann, A. F., and Darrow, D. C.: Chemical changes occurring in thebody as a result of certain diseases in infants and children. II. Acutehemorrhagic nephritis. Subacute nephritis; severe chronic nephritis. J. Clin.Invest., I928, 6, 127.

33 Hartmann, A. F., and Darrow, D. C.: Chemical changes occurring in thebody as a result of certain diseases in infants and children. III. The com-position of the plasma in severe diabetic acidosis and the changes taking placeduring recovery. J. Clin. InVest., 1928, 6, 257.

34 Hartmann, A. F., Scott, F. S., and Moser, A. E.: Chemical changes in the bodyoccurring as the result of vomiting. Am. J. Dis. Chi.'d., I926, 32, I.

35 Hasselbalch, K. A.: Die Berechnung der Wasserstoffzahl des Blutes aus derfreien und gebundenen Kohlensaure derselben und die Siurestoffbindung desBlutes als Funktion der Wasserstoffzahl. Biochem. Ztschr., I9I6, 78, I I2.

36 Henderson, L. J.: A critical study of acid excretion. J. Biol. Chem., I9II,9, 403.

37 Henderson, L. J.: Theory of neutrality regulation in the animal organism.Am. J. Physiol., I908, 21, 427.

38 Henderson, L. J.: Blood. A study in general physiology. Yale UniversityPress, I 928.

39 Hoag, L. A., and Marples, E.: Treatment of dehydration of diarrhea withparenteral fluids. I. Effect on acid-base status of blood. Proc. Soc. Exper.Biol. Med., 1929, 26, 374.

40 Holt, L. E., Courtney, A. M., and Fales, H. L.: The chemical composition ofdiarrheal as compared with normal stools in infants. Am. J. Dis. Child.,I915, 9, 213.

41 Hubbard, R. S.: The reaction of the morning urine. J. Biol. Chem., I929,84, 19I.

ACID BASE EQUILIBRIUM 2I9

Hubbard, R. S., and Steale, T. M.: Variations in the morning alkaline tideof normal individuals. J. Biol. Chem., I929, 84, I99.

42 Keith, N. M., and Whelan, M.: A study of the action of ammonium chloridand organic mercury compounds. J. Clin. Invest., I926, 3, 149.

43 Koehler, A. E., Behneman, H. M. F., Besell, 0. E., and Loevenhart, A. S.:The causes of death from anozemia. Am. J. Physiol., 1925, 74, 590.

44 Kydd, D. M., Stetson, R. P., and Peters, J. P.: Diabetic acidosis. (to appear).45 Linder, G. C.: The effect of mineral acid on acid-base regulation in health and

in nephritis. Quart. J. Med., I927, 20, 285.46 MacCallum, W. G., Lintz, J., Vermilye, H. M., Leggett, T. H., and Boas,

E.: The effect of pyloric obstruction in relation to gastric tetany. JohnsHop. Iosp. Bull., 1920, 31, I.

47 MacLean, H., and Griffiths, W. J.: The factors influencing the concentra-tion of hydrochloric acid during digestion. J. Physiol., 1928, 65, 63.

48 Magnus-Levy, A.: Natriumbikarbonat- und Kochsalzodeme. Zeitschr. klin.Med., 1920-21, 90, 287.

49 Mainzer, F.: Die Grundlagen des Sauretherapie mit Neutralsalzen. Klin.Wehnschr., 1927, 2, I689.

50 Mainzer, F.: Untersuchungen ilber die Bicarbonatausscheidung in Harn. III.Mitteilung. Theoretische und methodische Gesichtspunkte. Ztschr. klin.Med., I929, III, I.IV. Die Bicarbonatausscheidung des Gesunden. Ztschr. klin. Med., I929,I II) 9.

tber die obere Grenze Wasserstoffzahl und Bicarbonatkonzentration desHarns. Biochem. Ztschr. 1929, 207, I59.

51 Mainzer, F., and Joffe, A.: Zur Analyze des Saurebasengleichgewichts im Harn.Biochem. Ztschr., 1928, 203, 50.

52 Marrack, J.: Studies on oedema. I. The electrolvte concentration in thebody fluids in nephritis with oedema. Brit. J. Exper. Path., 1925, 6, 135.

53 Miller, G. H.: A study of interrupted duodenal obstruction in rabbits. Proc.Soc. Exper. Biol. Med., I926, 23, 835.

54 Misawa, H.: CJber das Wesen der sogenaunten Wasserintoxication. Japan J.Med. Sci., 1927, viii, Int. Med., I, 355.

55 Moss, K. U.; The effects of high air temperature and muscular exertion uponcolliers. Proc. Roy. Soc., London, 1923-24, Series B, 95, i8i.

56 Nash, T. P., Jr., and Benedict, S. R.: The ammonia content of the blood andits bearing on the mechanism of acid neutralization in the animal organism.J. Biol. Chem., 192I, 48, 463.

57 Peters, J. P., Bulger, H. A., and Eisenman, A. J.: Total acid-base equilibriumof plasma in health and disease. VIII. Bicarbonate and chloride in the serumof patients with heart failure. J. Clin. Invest., 1927, 3, 497.IX. High serum bicarbonate in heart failure. Asphyctic anoxemia. J. Clin.Invest., I927, 3) 5 I I

58 Peters, J. P., Bulger, H. A., Eisenman, A. J., and Lee, Carter: Total acid-baseequilibrium of plasma in health and disease. VI. Studies of diabetes.J. Clin. Invest., 1925, 2, I67.

220 YALE JOURNAL OF BIOLOGY AND MEDICINE

59 Peters, J. P., Bulger, H. A., Eisenman, A. J., and Lee, Carter: Total acid-baseequilibrium of plasma in health and disease. IV. The effects of stasis,exercise, hyperpnea, and anoxemia; and the causes of tetany. J. Biol. Chem.,1926, 67, 175.

60 Peters, J. P., Wakeman, A. M., Eisenman, A. J., and Lee, Carter: Total acid-baseequilibrium of plasma in health and disease. X. The acidosis of nephritis.J. Clin. Invest., I 929, 6, 5 I 7.

61 Peters, J. P., Wakeman, A. M., Eisenman, A. J., and Lee, Carter: Total acid-base equilibrium of plasma in health and disease. XII. A study of renaledema. J. Clin. Invest., I929, 6, 577.

62 Peters, J. P., Wakeman, A. M., and Lee, Carter: Total acid-base equilibrium ofplasma in health and disease. XI. Hypochloremia and total salt deficiency innephritis. J. Clin. Invest., I929, 6, 551.

83 Rabinowitch, I. M.: The origin of urinary ammonia. Second paper. Arch.Int. Med., I923, 33, 394.

Rabinowitch, I. M., and Bazin, E. V.: Studies concerning the origin of urinaryammonia. III. J. Biol. Chem., I926, 69, 283.

64 Rowntree, L. G.: Water intoxication. Arch. Int. Med., I923, 32, 157.65 Rowntree, L. G.: The effect on mammals of the administration of excessive

quantities of water. J. Pharm. Exper. Therap., I926, 29, I35.66 Salkowski, E.: Untersuchungen ilber die Ausscheidung der Alkalisalze. Arch.

path. Anat. Physiol., I87I, 853, 209.67 Salvesen, H. A.: Variations in the serum electrolytes in disease of renal origin

with special reference to the cause of renal acidosis. Acta Med. Scandinav.,I928, 69, i26.

68 Schmidt, Carl: Charakteristik der epidemischen Cholera gegenilber verwandtenT:anssudationsanomalien. Eine physiologisch-chemische Untersuchung. Leipzigund Mitau, 1850.

69 Scott, R. W.: Observations on the pathologic physiology of chronic pulmonaryemphysema. Arch. Int. Med., 1920. 26, 544.

70 Stadie, W. C., and Ross, E. C.: A micro method for the determination of basein blood and serum and other biological materials. J. Biol. Chem., I925, 65,735.

71 Van Slyke, D.D.: Factors affecting the distribution of electrolytes, water andgases in the animal body. J. B. Lippincott, Co., Philadelphia, 1926.

72 Van Slyke, D.D., and Cullen, G. E.: Studies of acidosis. I. The bicarbonateconcentration of the blood plasma; its significance and its determination as a

measure of acidosis. J. Biol. Chenz., I917, 31,I289.Van Slyke, D.D.: The carbon dioxide carriers of the blood. Physiol. Rev.,

192I, I, I41.73 Van Slyke, D. D., Linder, G. C., Hiller, A., Leiter, L., and McIntosh, J. F.:

The excretion of ammonia and titratable acid in nephritis. J. Clin. Invest.,1926, 2, 25 5.

74 Van Slyke, D.D.; Wu, H., and McLean, F. C.: Studies of gas and electrolyteequilibria in blood. V. Factors controlling the electrolyte and water dis-tribution in the blood. J. Biol. Chem., 1923, 56, 765.

ACID BASE EQUILIBRIUM 221

75 Walters, W., and Bollman, J. E.: Experimental acute gastric fistula. Arch.Surg., I926, I3, 578.

76 Walters, W., Kilgore, A. M., and Bollman, J. E.: Changes in the blood re-sulting from duodenal fistula. A clinical and experimental study. J. Am.Med. Ass., 1926, 86, i86.

77 Wigglesworth, V. B.: Studies on ketosis. I. The relation between alkalosis andketosis. Biochem. J., I924, I8, I203.

78 Wu, Hsien: Note on Donnan equilibrium and osmotic pressure relationship be-tween the cells and the serum. J. Biol. Chem., I926, 70, 203.

Documents

JOHN AND DefinitionsYALEJOURNAL OF BIOLOGY AND MEDICINE ratio, BHCO3, is a direct function, as Henderson37 showed, of the hydrogen-ion concentration. According to the familiar Hen-derson-Hasselbalch353equationl,~