MEDICAL LIBRARY QPO º CHEMICAL ANATOMY, iſoºl B 474361 PHYSIOLOGY AND PATHOLOGY OF ExTRACELLULAR FLUID A LECTURE SYLLABUS J. L. Gamble Department of Pediatrics The Harvard Medical School 1941 6) /* 4 / 22 , 4/7 . / 74// CHEMICAL ANATOMY, PHYSIOLOGY AND PATHOLOGY OF EXTRACELLULAR FLUID A LECTURE SYLLABUS J %- Department of Pediatrics The Harvard Medical School 1941 4 / 2. O / G / ? Y / 7.4// Third Printing Copyright 1941 by J. L. Gamble i : ; : i º PLANOGRAPH PRINT ED BY SPAULDING - MOSS CO. 42 FRAN Ki-I N ST. BOSTON, M ASSACH USETTS ...) 1 - 8 - #3 Tº do 5 "The living organism does not really exist in the milieu extérieur (the atmosphere if it breathes, salt or fresh Water if that is its element) but in the liquid milieu interieur formed by the circulating organic liquid Which surrounds and bathes all the tissue elements; this is the lymph or plasma, the liquid part of the blood which, in the higher animals, is diffused through the tissues and forms the ensemble of the intercellular liquids and is the basis of all local nutrit, iOn and the COmmon fact, Or Of all ele- mentary exchanges. The stability of the milieu interieur is the primary con- dition for freedom and independence of existence; the mechanism which allows of this is that which ensures in the milieu intérieur the maintenance of all the conditions necessary to the life of the elements." Claude Bernard "This theory of the constancy of the milieu interieur was an induction from relatively few facts, but the discoveries of the last fifty years and the introduction of physico-chemical methods into physiology have proved that it is well founded." Lawrence Henderson CHART 1 Extracellular fluid is composed of the plasma of the blood and the interstitial fluid (including lymph) which lies be- tween the vascular compartment and the tissue, cells. Functionally considered extracellular fluid is a particularly clear Cut entity. Its physiological role is as evident as that of the nervous system, for instance, and its organization to this end is quite as ingeni- ous. Extracellular fluid constitutes, as Claude Bernard appreciated, the immediate environment of the organism. It replaces, and in its essential features still closely resembles, the external environment (sea water) of the early forms of life. This aqueous medium which surrounds the tissue cells is the vehicle of transport of nutrient and Waste materials. Besides this simple service, it provides sta- bility of physico-chemical conditions, such as reaction in terms of hydrogen ion concentration, osmotie pressure, and temperature. The values for these properties in cell fluid rest on the values at Which they are held in the Surrounding medium and the successful Operation of Vital processes requires an approximate Constancy. Establishment of an internal aqueous environment in Which physical properties are held nearly stationary in the presence of a widely irregular demand for transport of many and various chemical substances, required, besides an intrinsic suitability of the medium itself, the invention of intricate apparatus of support and control. Movement of the medium throughout the body is accom- plºished by the cardio-vascular mechanism. A voluminous portal, the lungs, permits gaseous exchange With the external environment. A special vehicle, the red blood cells, containing a substance, hemo- globin, endowed with a reversible affinity for oxygen and carbon di- oxide, provides the necessary rapidity of transport of these two components of the largest metabolic transaction in the body, the ox- idation of food substances. A remarkable organ of regulation, the kidney Sustains the chemical structure of extracellular fluid. Mac- Callum, regarding the establishment of the enclosed aqueous medium as the largest forward step in the history of the animal organism, has described the kidney as the organ par excellence of evolution. The total quantity of extracellular fluid is about twenty per cent of body weight. As shown in the chart, one quarter lies in the vascular compartment and three quarters in the interstitial Space. The Volume of fluid in the tissue cells of the body is rough- ly fifty percent of body weight; two and one-half times the volume of the surrounding medium. Incoming substances enter the plasma and it is this more rapidly circulating portion which is directly dealt with by the mechanisms of regulation. On the arterial side 2-S —P STOMACH |NTESTINES → + + 4– SK |N <- BLOOD PLASMA —P 5% BODY WT. LUNGS * | K|DNEYS | º |NTERST |T| AL FLUID 15% BODY WT. * | | ~ |NTRA-CELLULAR FLUID 50% BODY WT. CHART | CHART 1 (Continued) of the capillary bed, fluid moves into the interstitial Space under hydrostatic pressure produced by the work of the heart. On the ve- nous side, the osmotic differential provided by the plasma proteins is unopposed and sustains a return flow into the vascular compart- ment. The chemical continuity of extracellular fluid is ShoWn in the next chart, , CHART 2 These diagrams describe the chemical anatomy of extracel- lular fluid (blood plasma and interstitial fluid) and also of Sea water and of cell fluid, in terms of acid-base equivalence. The individual values for the cations or potential base are superimposed in the left hand columns and those for the anions Or acid radicals in the right hand columns. The value for a component may be read On the Outer Side of the Ordinate. The Scale On the inner Side re- fers to the total of equivalence (the sum of the values in both col- umns). The values are per liter of Water; in other Words the space occupied by protein is discarded. The two middle diagrams make clear the almost identical chemical patterns of blood plasma and interstitial fluid. The Only large item of difference is the relatively very Small quantity of the non-diffusible component, protein, in interstitial fluid. This makes necessary adjustment of the concentrations of the diffusible ions which will preserve total cation-anion equivalence (Donnan equilibrium). This is accomplished, as shown in the diagrams, by a balanced reduction of cation and increase in diffusible anion, With the result that the total of equivalents in plasma Stands above that in interstitial fluid by approximately the base equivalence of plasma protein (16 milli-equivalents per liter). Owing to its multi- valency, the chemical equivalence of protein is about 8 times its concentration Value. The difference between the two fluids in the latter term is therefore approximately 2 millioSmols per liter. This Small difference has a large importance with respect to extracellu- lar fluid circulation (Chart 1). The presence of the device of a non-diffusible plasma component to propel fluid exchange between the two compartments does not, of course, disturb the conception of eXtracellular fluid as a continuous and essentially uniform medium. A total value for the non-electrolytes (nutrient sub- stances; glucose, amino-acids, etc., and Waste products of protein metabolism) is placed across the top of the diagrams. AS compared mEq/L H2O 2OO-T-40C) H.HCO3- 190+380 HCO3 | 80+36O EXTRACELLULAR FLU | D mEq/L 6OO-T |2OO | 70+340 NON-ELECTROLYTES =i-H.HCOs —H.HCO2 SHCO3 . | 6O-H-32O NON-ELECTROLYTES 550-F || OO —HHCOs |5 O-H-3OO HCO, 5OO-FIOOO | 4O- HCO, HPO, (ORG $º. AN1c) 450- |3O K |20- 4OO- 110- 35O- Na |OO - Na Cl a 90- g 3OO- Cl’ Na 8O- - * SO’ 4 25O- 7O- Cl 6O- 2OO- 5O- |50- K’ 40- Ca" | OO- 3O- 2HPO. ORG.AC SSO. Mo" —-HPo: “” • *-ºf- 5O- 3. * | O- K’ PRO /HP9. SO, ... ſcaſº Cº. K. —SO4. Mgs Mgº *LPROTEIN SEA BLOOD |NTERST |T|AL CELL WATER PLASMA FLUID FLUID CHART 2 CHART 2 (Continued) With the electrolytes, these substances occupy a relatively very Small amount of Space, in terms of concentration, although the total Quantity of them Carried to the tissue cells and into the urine over a unit of time is several times larger. The non-electrolytes de- mand only expeditious conveyance. The -electrolytes constitute a chemical framework on which rests the stability of the physical properties of extracellular fluid. Their transport is in terms of this requirement. This is the meaning of the large prominence of the electrolytes. The history of extracellular fluid is clearly indicated by the resemblance of its chemical pattern to that of sea water. In the Sea Water diagram may be seen the same four components of total base, the same dominance by sodium and chloride ion, and same pair of buffering substances, carbonic acid and bicarbonate. The chemical Skeleton of sea Water is clearly visible in extracellu- lar fluid. The total ionic concentration of sea water is several times that of extracellular fluid. Since the salinity of the sea is known to have increased continuously, the surmise is permissible that the electrolyte concentration found in extracellular fluid corresponds with that of Sea Water at the time of establishment of internal aqueous environment. That extracellular fluid is a surrounding and not a per- Vading medium is evident from the widely different electrolyte com— position of cell fluid. The data used in constructing this diagram are to some extent conjectural but will serve to present the extra- Ordinary phenomenon of apparently complete independence as regards ionic pattern in the two intimately adjacent and osmotically bal- anced fluids. An important feature is that the two largest compo- ments of extracellular fluid, sodium and chloride ion, are not per- mitted to pass the boundaries of protoplasm. With some slight res— ervation as regards sodium, an exclusively extracellular position Of these two iOnS has been dependably established. The foregoing description of the chemical structure of eXtracellular fluid is in terms of average values found in health, The basis of stability of physical properties is the degree of con- Stancy of chemical pattern which can be maintained. With a quite perfect constancy, hydrogen ion concentration and osmotic pressure Would be immovable. Since, however, Water and substances enter eXtracellular fluid intermittently and in Widely irregular quanti- ties and Since renal adjustments require an appreciable interval Of time, concentration values for the individual components of extra- CHART 2 (Continued) cellular fluid cannot be maintained with an ideal precision. Even under the most favorable circumstances, small oscillations will be unavoidable and, in the presence of obstacles imposed by disease, large deviations may develop. Inaccuracies in the control Of com- position are not, however, permitted to exert their full effect on physical properties. The regulatory apparatus governing extracel- lular fluid possesses mechanisms of adjustment behind the kidney Which do not prevent, but which greatly limit change in physical properties in the presence of change in chemical pattern. From the description of the operation of these mechanisms which follows (Charts 4–14) it will be noted that the extent to which their de- fense of physical properties falls short is roughly proportional to the initial error in control of chemical structure. Rigidity, then, is not to be expected either in chemical structure or in physical properties. The cardinal merit of any physico-chemical system in the body must be resiliency; otherwise it would be sure to be smashed by the rapidly changing currents of chemical events. In order to survive severely adverse circumstances, this recoverability from distortion must have a Width far beyond the usual requirement. The physico-Chemical System in extracellular fluid exhibits this neces— Sary elasticity very beautifully. Degree of Success of the regulatory mechanisms which guard the chemical structure of extracellular fluid may be judged by mea- Surements of the components of its accessible portion, the blood plasma. The plasma values Which have been established as average in health are given in the next chart. Except for carbonic acid Which is controlled by the respiratory mechanism and plasma protein Which is governed by a mechanism not yet visible, all of the items of plasma Structure shown in the diagram are under renal control. CHART 3 In this chart, the normal Values for the COmpOnents Of the electrolyte Structure in blood plasma are given as milliequivalents per liter of plasma instead of per liter of plasma Water, as in the preceding chart. Plasma water is obviously the correct basis for a Statement. Of COn Centrat, iOn. Its precise definition, however, re- quires that measurement of a plasma substance be accompanied by de- termination of plasma specific gravity or, as an approximation, the concentration of protein. Usage has, therefore, understandably cho- sen the much more convenient reference to plasma Volume. This method of statement is satisfactory for most purposes of plasma study. The value for millieguivalents per liter is obtained by dividing milligrams per liter by atomic Weight, and multiplying by Valency. In the case of the univalent ions, a milliequivalent is, of course, a milliosmol. The values given in the chart for the uni- valent components of the electrolyte structure, therefore, describe iOnic COncentrat, iOn as Well as Chemical equivalence., COncentrat, iOn of the divalent ions, calcium, magnesium and sulfate is one-half of their chemical equivalence. The base equivalence of HPoſ, is l. 8 times the concentration of this radical, because, at the reaction of blood plasma, it is carried as BH2PO4 and B2IPO, in the rat, iO Of l:4. The double Valency sign used in the diagram is, to this small extent, inaccurate. The base equivalence of protein, as determined by direct titration studies, is about eight times its osmotic value. The diagram in the chart is constructed by superimposing the values for the items of base in the left-hand column and those for the acid radicals in the right-hand column. The diagram pro- Vides a View Of the Various factors of the acid-base structure of the plasma in true perspective as regards their relative magnitudes. It may be noted that nearly all of the plasma base is sodium and that chloride ion is the large factor in the total acid value. The neXt large St. item Of Structure is the Concentration of bicarbonate iOn (HCOg) Which, together with the base which it covers, consti- tutes the plasma bicarbonate. At the top of the diagram the concen— trat iOn Of free Carbonic acid is indicated in Order to describe its magnitude in relation to bicarbonate. The line down the Centre of the diagram correctly indicates that we have to deal in the plasma, not. With Salts, but With separately controlled quantities of indi- vidual ions. Since about nine-tenths of the chemical skeleton of the plasma is built of univalent ions, the diagram provides an ap- Dr.OXimate descript, iOn in terms Of Concentration. ACID-BASE COMPOSITION OF BLOOD PLASMA mEq/ L BASE mEq/ L Na | 42. K. 5 Ca" 5 Mg 3. |55 ACID mEq/L HCO. 27 Cl’ |O3 HPO. 2 SO. | ORG AC. 6 PROTEIN | 6 |55 | 6O = Iso- |4O- | 3O- |2O- | | O- |OO- 90- 8O- 7O- 6O- 5O- 4O- 3O- 2O- -32O -3OO Cas —H.HCO3 Na HCO3 C!" HPO. ORGANIAC, `so. PROTEIN CHART 3 Mgs CHART 4 The range of hydrogen ion concentration compatible with life is approximately from one ten millionth to one hundred mil- lionth of a gram per liter. Although these are extremely minute quantities, they define a generous (almost ten fold) width of per- missible change. Using the pH notation system the extreme limits of reaction are pH 7.0 and pH 7.8. The entire physiological range of reaction thus lies on the alkaline side of neutrality, pH 7.0. In health hydrogen ion concentration is held within narrow limits which have been somewhat arbitrarily defined as pH 7.35 and pH 7.45. There is thus left on either Side Wide regions of change designated Acidosis and AlkaloSiS from Which hydrogen iOn concentration can return to its optimal position if the circumstances which caused its departure are removable. The basis of control of ionized hydrogen at the ultra- minute concentration Which biological processes require is the al- most uniquely small extent of hydrogen dissociation from the largest end product of metabolism, carbonic acid. This extremely weakly acid substance pervades the body fluids at a level controlled by the respiratory mechanism. In the presence of its salt, the slight eXtent of dissociation of hydrogen from carbonic acid becomes still smaller. This is due to "common ion effect" which consists in disturbance Of the disjogiation e uilibrium of carbonic acid by ad- dition of (HCO3) from bicarbonate. This makes necessary a new posi- tion of balance in Which the COncentration Of molecular Carbonic acid, (H.HCO3), is increased at the expense of (H) and (HCO3). By this process hydrogen ion concentration is reduced. * -ºm-º-º-º: sº N 9999999 ||N ACIDOSIS 3 || ALKALOSIS º M GRAMS à (H) PER LITER T - NG ` ſoooooooo." 1—1—1—1—1–1 | 1—1—1—1—" 7.O 7| 7.2 73 74 7.5 76 77 7.8 pH COMMON | ON EFFECT: -- & Le (H.HCO)= (H) (HCO) •+ {-> (B.HCO)=; (B)(HCO) CHART 4 CHART 5 Common ion effect explains the "alkaline salt" character Of bicarbonate and makes clear the relationship between hydrogen iOn Concentration and the ratio of the concentrations Of Carbonic acid and bicarbonate in a Solution containing these Substances, Moreover, owing to a proportionate increase of dissociation with dilution, a given ratio defines a fixed hydrogen ion concentration independently of change in the absolute values of its components. This direct determination of (H) by the (H.HCOg): (B.HCO3) ratio makes easily clear the method of reaction regulation in extracellu- lar fluid. Defense of reaction COnsists of maintenance of a normal ratio, Compensation for change in one component can be obtained by proportionate adjustment of the other. The relationship of change in the ratio to change in pH is not linear. It is described by the S shaped curve in the chart. The Henderson–Hasselbalch equation is derived from the curve and is a mathematical statement of the pH-ratio relationship. An important implication of the curve is that the buffering capacity of a carbo- nic acid-bicarbonate solution depends on its initial pH. The chem- ical transaction known as "buffering" consists in the substitution of a weak acid (from which H dissociates to a very slight extent) for a strong acid (from which H dissociates more or less completely) entering the solution, or, in the case of strong base, the substi- tution of a Weakly alkaline Substance. To illustrate the process Of the Se Substitutions: (l) HCl + NaHCO3 NaCl + H2003 (2) NaOH + H2003 = H2O + NaHCOg The effect of acid addition is to alter the ratio by increasing (H.HCOg) at the expense of (B.HCO3). Alkali addition Will alter the ratio in the other direction. The resulting change in pH will be determined by the extent of change in the ratio and also by the initial pH. This is illustrated in the chart. The physiological range of pH is at the upper part of the curve where it has begun to flatten Out With the result, that Small additions Of acid Or alkali cause relatively large change in pH. To produce the same width of pH change over the steep part of the curve, much larger additions are required. The buffering capacity of a carbonic acid-bicarbonate Solution of pH 6.1 is about four times larger than that of a solu- tion of pH 7.4. Apparently the position of physiological pH is un- fortunate. This, as Will presently be seen (Chart ll), is not the Ca,S6 e 2OH. 3OH. 4OH. 5OH. 6O 7OH. 8OH. 90|- |OO 5O 57 596. 63 65 7O 7274.76 78 - H.HCO3 - B.HCO3 . B.HCO3 pH =6|+ LOG. H.HCO3 (HENDERSON-HASSELBALCH EQUATION) 90 8O - 70 5O +4O – 30 2O - IO CHART 5 CHART 5 (Continued) At pH 7.4, the curve defines for (H.HCOg) and (B.HCO, ) a 3 l: 20 ratio. In extracellular fluid this ratio is, under normal cir- cumstances, provided by 3 volumes per cent (l.35 m-eq/L) carbonic acid and 60 volumes per cent (27 m—eq/L) bicarbonate. The steadi- ness of reaction depends on the accuracy of the mechanisms Which sustain these values. Carbonic acid is governed by the respiratory mechanism and so excellent is this control that clinically an ab- normality of reaction due to an incorrect concentration of carbonic acid is not often encountered. Occasionally acidosis or alkalosis does result from circumstances which disturb the respiratory center or which interfere with the mechanics of lung ventilation (Chart 13) but very much more frequently deviations of reaction are referable to change in the other component of the ratio, bicarbonate. CHART 6 The bicarbonate concentration rests on renal control, but not directly. If the kidney Succeeds in sustaining the other ionic components of the plasma at their usual values bicarbonate Will al- so be on the mark. If, however, change occurs in any other part or parts of the ionic structure, bicarbonate will change in the di- rection Which will preserve total anion-cation equivalence. The process of this adjustment is illustrated in the diagrams. With increase in the sum of the concentrations of the other anions (A) above the usual value (Diagram 2) bicarbonate ion, HCO, is to an equivalent extent dispossessed of base and released §§ Carbonic acid. With decrease of (A) there is corresponding increase of (HCO.) (Diagram 3), the additional bicarbonate ion being derived from the carbonic acid concentration sustained by the respiratory mechanism. In the event of reduction of plasma base (Diagram 4), the availability of base for the formation of bicarbonate is cor- respondingly reduced. Bicarbonate thus exhibits an adjustability to change in the extent to which total base (B) stands above the Other anions (A). An important feature of carbonic acid-bicarbonate buffer— ing in extracellular fluid is the control by the respiratory mech- anism of the concentration of carbonic acid. In ordinary in vitro buffering change in one component of the ratio reciprocal change in the other. The respiratory mechanism is capable of re- moving from extra-cellular fluid the carbonic acid released by bi- carbonate reduction, and of replacing the carbonic acid used in the process of bicarbonate extension, thus limiting alteration of the BLOOD ADJUSTMENT OF BICAREONATE. º PLASMA NORMAL ACIDOSIS ALKALOSIS ACIDOSIS H.HCOs H.HCOs H.HCOg º º e e • * * * * * * * * * * * e - " - s • * * : * : T | < * * * * * . . .” - * * > . • * * * * * s 15O- § § ; ::. š. § : : H.HCO |4O- Hºg º - § : 5 |3O- | 20- -> º - • * * * * * * tº a º & • * * & ... • * * ... • e s | | O- a • * º e e a * * * * g. • * * * * , |OO- 90- 8O- Nal Cl’ B | A B | A B | A B | A ro. 6O- 5O- 4O- 3O- AHPQ. -SOA". 2O- ORG. so: AC. to. K- PR Caº. TEIN M; BLOOD PLASMA | 2 3 4. CHART 6 \ CHART 6 (Continued) ratio to the change in bicarbonate with the result that the pH change Will be very much less eXtensive than Would occur in Vitro. But the respiratory mechanism does more than this. It undertakes to change (H.HCO, ) in the same direction as the change in (B.HCO3) and thus preservé the normal ratio (in vitro the change in (H.HCO.) is in the opposite direction). This is indicated in the diagramë. Usually, in the presence of bicarbonate change of considerable ex- tent respiratory defense of reaction falls short of the mark so that With bicarbonate receSSiOn there is acidos is and With extension al- kalosis, of Some degree. An ideally accurate control of the many individual parts of the ionic structure of blood plasma which would hold the B minus A Value in the diagram precisely Stationary Cannot be expected. The adjustability of (HCOſ) is therefore continuously exercised in health as Well as in dišease. By removal from, or addition to, plasma of (HCO3), gain or loss of anion (diagrams 2 and 3) is covered without disturbing total ionic concentration on Which the Osmotic value of extracellu- lar fluid almost entirely depends (Chart 2). Respiratory control of carbonic acid thus not only greatly amplifies plasma buffering but also defends the osmotic value, and so exhibits a remarkably com— prehensive functional ingenuity. CHART 7 Because of the control of carbonic acid by the respiratory mechanism, carbonic acid-bicarbonate buffering in blood plasma is enormously more effective than in vitro. This is illustrated by the diagrams in the chart. A reduction of bicarbonate by one-half of its usual value releases 30 vol. 3% carbonic acid. In vitro, the resulting change in ratio would produce a pH of 6.0, which is far beyond the physiological boundary. With removal of this carbonic acid by Way of the lungs, the change in pH is greatly limited and moves only as far as 7. l. The respiratory mechanism then undertakes to further limit movement of pH by changing (H.HCOg) in the direc- tion which Will restore the l: 20 ratio, as shown by the remaining diagrams. In the final one, (H.HCO3) is reduced to One-half of its usual value. This produces the usual ratio and pH is completely defended. The basis of this adjustment is the direct relationship between the concentration of carbonic acid in the plasma and the STEPS IN (H.HCO3-(BHCoy BUFFERING IN PLASMA VOL.7% pH 7.4 6.O 7| 72 73 74 CO2 T +3O –2O (B.H.Co.) RELEASED REDUCTION (H.HCO3) OF (H.HCO3) REMOVED. BELOW THE USUAL LEVEL. NORMAL. (B.Hcos) REDUCED BY ONE HALF. CHART 7 CHART 7 (Continued) carbon dioxide tension of the residual air of the lungs to which the plasma is exposed as it flows through the capillary bed of the lungs. The first and very large step in the respiratory defense of pH, the removal of excess carbonic acid requires no effort by the respiratory mechanism. This carbonic acid simply "flows" into the residual air Space until plasma concentration comes into balance With the usual CO2 tension in the residual air. The lungs and the mechanics of their ventilation Were designed to sustain this level Of CO2: The second step in defense of plasma pH which involves re- duction Of alveolar CO2 tension requires an extensive and laborious alteration of breathing, the method of which is shown in the next Chart. CHART 8 The diagrams describe the mechanism of respiratory ad- justment of CO2 concentration in residual air in the presence of reduction of bicarbonate concentration in blood plasma. In the up- per diagram the concentration of H.HCOg and Of B.HCO3 in plasma and Of CO2 in residual air have their usual Values. The Value for H.HCOg is one-half that of CO2 because Of the Circumstance that the absorption coefficient of cog is 0.52. The diagram implies what is approximately the case viz: that the transport and delivery of carbonic acid to the lungs is accomplished by the red blood cells and that carbonic acid in the plasma is not en route for excretion but is there simply as a physical consequence of eXposure of the plasma to the coe tension of the residual air. This is, , under norm— al circumstances, held closely stationary by adjustment of the rate and volume of lung ventilation to the rate of delivery of CO2 a.S prescribed by the energy metabolism. The respiratory adjustment to a reduction of (B.HCO3) to one-half of its usual value, as shown by the lower diagram, consists in doubling the capacity of the residual air space. This reduces CO2 concentration by one-half and, in consequence, the concentra- tion Of H.HCOg in the plasma falls correspondingly With the result that the normal (H.HCOg): (B.HCO3) ratio is preserved and pH is held at 7.4. The large increase in the depth of breathing which sustains RESPIRATORY REGULATION OF pH OF PLASMA PLAswa Hº - “º BHCO, 60Vol.% CORPUSCLES 2- -3 NORMAL BICARBONATE ALVEOLUS CORPUSCLES BICARBONATE /2 NORMAL CHART 8 CHART. 8 (Continued) the increased volume of residual air is described as hyperpnoea and is the one and only physical sign of acidosis. The concentration Of CO2 may also be reduced by increasing the rate of lung ventila- tion and in the presence of acidosis there is usually some increase in rate. The dominating and characteristic feature of the change in breathing is, however, the large increase in volume. When the plasma bicarbonate is above its normal value, respiratory adjustment is in the reverse direction. The breathing of alkalosis is characteristically extremely shallow. The capacity of the residual air space being thus greatly diminished, CO2 ten- sion and, in consequence, the concentration of H.HCO., in the plasma rise with the result that the (H. HCO its normal Value. 3 g): (B.HCO3) ratio approaches CHART 9 The preceding chart describes complete compensation for an extensive reduction of bicarbonate. Actually, in the presence of large change in bicarbonate, respiratory defense of pH falls con- siderably short of the mark. The data on this chart describe the extent of compensation found in two instances of extensive reduc- tion of bicarbonate. The first Set of measurements Of (B.HCo.) and of pH were obtained from a child with chronic nephritis and edema before and after ingestion of the diuretic agent CaClo. The other measurements are from an infant given hydrochloric aºid (in milk) with the purpose of relieving the symptoms of tetany. Ingestion of CaCl2, or of HCl increases the concentration of chloride iOn in the plasſia º corresponding replacement of bicarbonate. (Diagram 2, Chart, 6. The points marked by a circle and cross are values for pH as calculated for the reductions of bicarbonate in the absence of any compensating adjustment of carbonic acid. That is, using the 9. (B.H.9%), the found (H.HCO3) Value f-Or (B.HCO3) and the normal value for (H.HCO3), 3 vol. per Henderson–Hasselbalch equation, pH = 6.1 – lo cent, are taken. The directly determined fall in pH, in these two instances of large (B.HCO3) reduction, was of about half the extent measured by these calculated values. In other Words, respiratory defense of pH was roughly fifty per cent effective. NEPHRIT |S. BHCO, VOL. 9% • • * * - - CHART 9 CHART LO This chart records measurements obtained by Hartmann from a large series of infants suffering from severe disturbances of gastro-intestinal function. They provide further illustration of the extent of defense of pH in the presence of bicarbonate change. The pH value found for the individual patient is plotted with ref- erence to the accompanying bicarbonate measurement. The average val- ue for (B.HCO3) in health is, for infants, lower than is found in the plasma of adults and may be taken as 50 vol., per cent. This value prescribes at pH 7.4 a concentration of H.HCOg Of 2,5 Volumes per cent. The curved line in the chart defines the position of pH over the range of change in bicarbonate, in the absence of change in carbonic acid, i.e. in the absence of respiratory defense of pH beyond preserving the usual value for (H.HCO3). The values pro- ducing this curve were obtained from the Henderson-Hasselbalch equa- tion. On the basis Of (H.HCO3) Stationary at 2.5 volumes per cent. In the chart the limits of pH change in health are set at 7.35 and 7.45. Since the pH values for these infants, looked at en masse, are seen to drift downward with fall in bicarbonate, incompleteness of respiratory defense is clearly evident. The axis of this drift lies roughly midway between pH 7.4 ("complete compensation") and the curve defining pH in the absence of adjustment of (H.HCO3), SO that statistically respiratory defense of pH may be described as about fifty per cent effective. There is, however, a Wide vari- ability in the extent of pH change produced by a given change in (B.HCO3). In some instances large, and in others Small, departure of pH from 7.4 is permitted. It should be noted that the "no adjustment" curve rests on preservation by the respiratory mechanism of (H.HCO3) at its usual value. This in itself provides a large initial defense of pH, the extent of which is shown in the next chart. pH 7.6H. 7.5H. 77 (BHCO3). |LLUSTRATING DEGREE OF COMPENSATION FOR CHANGE IN .23% . ALKALOSIS 74 7.3H- 72 7 ||. 7ol. 6.9}- 6.8H *——-COMPENSATION- ACIDOSIS FROM HARTMANN'S S MEASUREMENTS OF PH S- $ $ AND BICARBONATE IN ASP PLASMA OF INFANTS. Io 20 30 40 50 60 70 80 90 100 PLASMA BICARBONATE, VOL. Z CHART |O CHART ll The buffering capacity of the blood plasma may be de- scribed as the extent, to which it can receive addition of acid or alkali Within the limits of reaction change compatible with life. This is measured by change in (B.HCOg) from its usual value, 60 vol. per cent at pH 7.4. The diagrams in the chart record the val– ueS for (B.HCO3) Over the physiological range of pH as computed by the Henderson–Hasselbalch equation; l) with reciprocal change in (H.HCO3), in vitro buffering; 2) with (H.HCO3) Stationary at its usual value, 3 vol. per cent; 3) with partial adjustment of (H.HCO3). By 50 per cent adjustment is meant change of such extent as to re- duce by One-half the movement of pH which a given Change in (B.HCOg) would cause in the presence of 3 vol. per cent (H.HCO3). The diagrams make clear the enormous increase in the buf- fering capacity of the plasma Which respiratory control of (H.HCo.) provides. Without this control, as shown in first diagram, the ad- dition of less than 2 m-eq. of acid per liter brings reaction from pH 7.4 to the physiological boundary and an even smaller addition Of alkali defines buffering capacity in the Other direction. In the second diagram respiratory control sustains (H.HCOg) at its usual value. Change in the ratio is thus entirely referable to change in (B.HCO3) which must therefore be of much larger degree to effect a given alteration than is required in the presence of reciprocal change in (H.HCO3). In consequence the Steps of bicarbonate change over the physiological range of pH are enormously increased and the buffering capacity of plasma is defined as (8 m-eq/L for acid and 29 m—eq./L for alkali. The further increase in buffering obtained by what may be roughly taken as the usual extent of respiratory ad– justment of (H.HCO3) to change in (B.HCOg) is shown in the third diagram. Here more than four-fifths of the normal bicarbonate of plasma may be utilized for the covering of acid addition and, on the other side of pH 7.4, progressively enormous increments of al- kali can be received. The much more extensible defense of the alkaline than of the acid boundary of plasma reaction seen in the diagrams is an in- teresting feature of carbonic acid-bicarbonate buffering under res— piratory control. Théºintimation which the titration curve of car- bonic acid (chart 5) provides, that the position of physiological CAPACITY OF CARBONIC ACID - BICARBONATE BUFFERING IN BLOOD PLASMA. ACIDOSIS ALKALOSIS ACIDOSIS ALKALOSIS 5r 707, 727374757677 7O 7| 72 73747576 77 707 727374757677 alo H.HCO3 | tº *:::::"...º.º.ºr- * = ... * *** B.HCO, 5 H- - IO º - |OH h t 2O | | . + 3O |5|- [. l t L 23 |- - I6 M-EQ/L +4O # 20H M-EQ/L. | H. ! |-h-hain t º : as || . . 50 s. # 25 || | : l 3 # cº -- - - - - - - - - | !--------- -- - 60 Hº- 90 3OH 2 z 1.8 K O.7 . . -70 § Lil M-EQ/L. M-EQ/L. || t a 35k - – É $ | +80 0- 3 § º 40H IN VITRO 490 * - BUFFERING : || B = 45k 27 loo 8 RECIPROGAL M-EQ/L. CHANGE ! . 55 - . . . . . . . . ." . . " * , * . . * * * # * e - e • * * - * * * * * * * * • " .. "... • - e. - * * * * * * • º o º ... • *. ... • * ... • * * * • - * * • * ~ * • * : * • * e • ... *-. te • . . • * ~ * • * ... • * * * * • . • ... • * * * * ... * * * . . "I" . . . . . . * • * * & e • * * * * * * • * • * * e - º e e º - - - tº e - * * * * * ~ * = * * * * * • *. • * g - * * * * , ... • . . - • * , º * = º º * - e. • * ... • , "... • . . . * * * * * . . . " tº e • * º ... • . * * : * ... • • * * • * * * * * * * : * * , * * * * • * * - - e - * * * * * s - - * s º * * * a * * * * • * * * * * * * ... • * * *.*, * • ... • * a * * - º º * - º e = • - - ... • * * . . . . . " " . • * * . . * * * • • * * * * * * ... • * r * , º • * * * * * * . . . . . * * * * * * - g - e. º º s e º - - • • *.* Q sº e - º e * , • a - - • * • * * * * ... • * * * * e * * * * - * , a • * g * e e • * g • * * . º • a * tº a g º 'º - - e º • * - - • . . . . . ... • * * * : . • * * * * * . * * º . . . . . . . “I”. “ e "... "... • * * "...". . . . . . . . " ... • • * e ‘º " * - "... • * ... • • . - * is e s w = • • * * * | * * * . . © ..". . . . . . . . . . ." . . " • . . * * • * * * • * * tº ſº * , • * tº • * * * tº o * - e tº * e º a • * * * * * * * * * * * * * • ". . * * * * * * * * * * * . . . . . " º * • * ~ * tº * . * * * * - e. • *s • * * * * * . . . . " ' " . . . . . . . . . * * * * . . . . . . . . - e * * º "... • * ~ * • * * * * * * * * g e -> * * s * • * * . * • * • * * e * * * * * * - - © & & - - º º • * * * * - º e (HHCO) ºf tº (B.HCO) | : • * . . * • . * * * • * * • * ... • . . .” * * * * * * º • * * * * • . ." . " ' ". "... • , , s * - e = * * * * * º • * * * * * . . . . * * * * *.*, *, * * * - - • * a * • * * • * : * > . I* . . . . . . . . . . ". . . ... • * * * . • * : * - a . . * * * * * * * * * * * * * * * * * * O.O - - º (B.HCO3) 60 VOL.7% * || || || || 1.5}. pH 7.O 7.1 72 7374 75 7.6 77 || ||. CHART 12 CHART 12 (Continued) extracellular fluid. This change in concentration could, however, be obviated by an additional adjustment, a corresponding retention of, or withdrawal of, extracellular water. Another and better meth- od of compensation for an incorrect (H.HCO3) by producing change in (B.HCO3) is suggested by the diagrams in Chart 6. Adjustment Of a Component Of the anion column would cause reciprocal change in (HCO3) and corresponding change in (B.HCOg) Without disturbing to- tal ionic concentration. Obviously, because of its relatively large size, (Cl") would be the suitable anion. Actually compensa- tory change of (Cl") is observed in situations which have caused a long Standing abnormality of (H.HCO3). Illustrations are given in the next chart. Apparently this ingenious mechanism of (B.HCO3) adjustment cannot be set up rapidly. It is not found in the acute situation caused by experimental overbreathing. Here the reduction Of (H.HCO3) is offset by direct removal of (B.HCOg) in urine ac- companied by diures is . CHART 13 The chart illustrates adjustment Of (B.HCO3) in the pres– ence Of an abnormal (H.HCO3), accomplished by alteration of the usual value for (Cl’). The values for the individual components re- corded on the diagrams are milliequivalents per liter. The first set of diagrams is from a patient with chronic emphysema. Owing to the impairment of ventilation which this con- dition imposes, CO2 tenSion in the residual air is established at a much higher than usual level and (H.HCO3) in the plasma is corres- pondingly increased. The diagram constructed from the measurements obtained from the patient shows (B.HCO3) eXtension approximately equivalent to (Cl’) recession. With reference to pH, this adjust- ment. Of (B.HCO3) in the presence of the increased (H.HCOg) is Of such extent as to place the patient's diagram midway between pH 7.4 and pH 7.2 which would have been its position in the absence of Change in (B.HCO3). The other set of data are from a patient with chronic hyperventilation (post encephalitic). Here there is a large reduction Of (H.HCO3). The patient's diagram shows an increase of (Cl’) with resulting reduction of (B.HCO3) of Such extent, as to 2O 25 3O 35 4O 45 7.40 1.35 ; 7.20 7.25 7.30 7.35 7.40 pH 7.35 74O 7.45 7.5o 7.55 I I ios ; NORMAL + - - - - Hi-j-i-li- - - - - - NO COM – PENSATION CHRONIC EMPHYSEMA | I | 2. 4 T I I I I O.96 43 9s s? C OMPLETE FOUND co, PENSATION 27 F • * * * * * * * * * *...* * *. * = & - - - - . . . . . " .. ". . ." ... - - - - - - - - - - - * * = & * * * * " * • * . • * * - * * ... •,• * g “. . .” | || * * • * , * • . . . . . • . ... * * . I* * * * * gº - & #. e * * • * * * * & * * & & • * tº 4. & * * * • * * : * = * a * * > . . * * * * * * * * * * * . " e & * * e - FOUND AN NO COM- COMPLETE PENSAT|ON COMPENSAT|ON CHRONIC OVER-VENT | LATION POSTE N C E PHALITIC CHART |3 CHART 13 (Continued) more than compensate for the lowered (H.HCO3) So that the diagram lies a bit. On the Other Side of pH 7.4. In the very much more usual situations of reaction dis– turbance Which are due to adjustment of (B.HCOg) to underlying de- fects of the ionic structure (Chart 6), and in which the method of compensation is by respiratory control of (H.HCO3), acid OS is is Cle- pendably indicated by reduction, and alkalosis by extension of (B.HCO3). It is important to note that when control of (H.HCO3) is at fault, the changes in (B.HCO3) have the reverse significance; the extension of (B.HCO.,) in emphysema results from a situation of aci- 3 dosis and the large reduction in chronic hyperventilation is a con- sequence of an initial alkalosis. Interpretation of a measurement of plasma bicarbonate therefore requires appraisement of the ac- companying circumstances of disease. If these suggest error in the C Ontrol Of (H.HCO3), a measurement of plasma pH is indicated. From the values found for pH and for total 002, (H.HCO3) and (B.HCO3) can be calculated by means of the Henderson–Hasselbalch equation and the Situation thus completely described. (Emphysema data from J.H. Talbott. Hyperventilation data from Peters, Bulger, Eisenman, and Lee.) CHART 14 The OSmOtic Value Of eXtracellular fluid is almOSt, en- tirely composed of the sum of the concentrations of its ionic com— ponents; the non-electrolytes make a relatively very small contri- bution (Chart 2). An important feature of the total ionic concen— tration is that it is determined by the sum of the cation values. This is because the adjustable part of the ionic structure is the aniOn (HCO’g). Change in other anion values Will be offset by re- ciprocal change in (HCO ...) and so will not alter the total ionic 3 concentration. This may be clearly seen in the diagrams in Chart 6. Since nearly all of the base is sodium, the stability of the osmotic value of extracellular fluid rests almost entirely on the accuracy Of renal C Ontrol Of this One component. Since the intakes of water and sodium have a widely ir– regular relationship and Since renal adjustment requires a consid— * WW7}{9\71C] 1BNNVÅ - NWOBHM-JVC) EHLt7| || ? JVHO Og Ov O2 O2 OI OOG Oț7 O2 O2 O|| OO9 Ot» O2 O2 OI O SMJELIT |I = Iſ]!UTT|U—||||JO | | 'WSO-\!\,įwsou'WSO-ul |WSO-ulWSO-ſulWSO-ul- O9 O98O|Hoog-O98 O||OO9+O98 O |O £79，7 || ſorsº|Ot> 2t>-H OOI ||*T G2*T +»! || ||+ OG I }–|-<--!-- `H#*-－-> ||+ OO2 |（14-0|| （T-I-O’T-I-O *T-B-O-WAHLNI |}V}}IXET3-0-vųLNI ||vulxā’T-I-O-VAJ LN|| RVXJ LXBfosz || |0 }| ||| --------------1-1------}+ OO2 awmoa GNV logº º l'OQN ’WSO-u.L OOG -¿O TVMVHQ HLINA º l'OQN ’WSO-ul OOG -¿O NO|1|00\/ NOI_1\/\）] LNB ONOO （JOH SETTVA TVW?JON §3. LIT & Ed STOWSOITITIW CHART 14 (Continued) erable time interval, the kidney cannot govern ionic concentration With a sufficient rapidity to meet the requirement for osmotic e- Quality between extracellular and intracellular fluid. There is therefore need for a supplementary mechanism of osmotic adjustment behind the kidney. This mechanism has been brought into view by the experiments of Darrow and Yannet. Its operation rests on the obligatorily extracellular position of Sodium and consists simply in the transfer of Water across the boundary between extracellular and intracellular fluid in the direction which will produce osmotic equilibrium in the two fluids. This adjustment is quantitatively illustrated by the diagrams in the chart. Volume is recorded On the abscissa and concentration on the ordinate. The first diagram gives the body fluid dimensions which may be taken as usual for an adult of average size. The next diagram describes the effect of a sudden large addition (about 15 gm NaCl) to extracellular electrolyte. Without volume adjustment, extracellular electrolyte concentration would rise far beyond the usual level. This is prevented by trans- fer of Water from the intracellular to the extracellular compart- ment to the extent shown by the vertical broken line. This produces OSmotic equality at the level shown by the horizontal broken line. This is considerably above the usual level but is only about one- third Of the initial increment in extracellular fluid. With the help of this initial adjustment, the kidney is permitted to remove the excess of extracellular electrolyte at its leisure and, as this is accomplished, body fluid dimensions move toward their usual val— ues. The third diagram describes adjustment to a sudden large loss of extracellular electrolyte. This Water transfer mechanism is con- tinuously in operation and provides immediate adjustment for irreg- ularities in tonicity of the Water-salt intakes CHART 15 This chart will serve to provide a general view of the task of the main organ of regulation of extracellular fluid, the kidney. The urine diagram describes a twenty-four hour specimen obtained from a subject on a usual type of diet. Renal defense of the chemical pattern of the plasma requires the production of a sol- ution of Substances widely and variably differing from blood plasma as regards the relative quantities of substances, osmotic value, and reaction. The great Width of renal control is shown by the large quantities in urine of substances which are relatively very Small components of plasma structure. These are many times concen— trated in the urine with respect to their plasma values. The small plasma concentrations minimize encumbrance of the Na-cl-Hco. frame 8OO- mEq/ L 750- UNDETER- MINED too. 65O- 600- 55O- UREA 5OO- 45O- CREAT- 4OO-H2OO |N|NE 350+175 NH, sche, “cºst-Tº: |||| HCOs. Cl’ 250412s . . . . . . . . . . . . Na 200floo 15O+ 75 Na | Cl HPO4 | OO-H- 5O - SO" * % e K 5O+ 25 K — gº - C V ‘. . . . . . . . . . CaS ORG. Mg protein MgS AC. BLOOD PLAS URINE pH 7.4 pH 5.4 CHART |5 CHART lü (Continued) Work on Which Stability of physical properties rests. This is es— pecially clear in the case of the non-electrolyte and unselectively diffusible Substance urea. Which is Serviceable neither in acid-base nor in Osmotic mechanisms. Although, as may be seen in the urine diagram, urea composes about one-half of the transport task of ex- tracellular fluid, its conveyance is, by renal efficiency, managed at a relatively extremely Small concentration. The total concentration of substances in this specimen is more than double that of blood plasma and its reaction, pH 5.2, is widely removed from the fixed plasma value. Several other items of difference may be noted. Three components of plasma, (protein, glucose, and bicarbonate, are not found in the urine. Protein does not enter glomerular filtrate in health. Glucose is completely re- absorbed from it. Bicarbonate in urine is a function of pH and is not found to an appreciable extent in urine of this degree of acid- ity (Chart 24). Urine contains the base onium which is (probab- ly) not present in plasma. The only substance which is found at ap- proximately the same concentration in both fluids is carbonic acid. CHART l6 The general features of renal control of the composition of blood plasma have been brought into View. The dauntless ingenu- ity of A. N. Richards has provided direct evidence that plasma fil— tration by the glomerulus is a simple physical process. An addi- tional process of direct tubular excretion of certain substances has been established. It is nevertheless clear that renal regula- tion consists essentially in selective reabsorption of Water and substances from glomerular filtrate by the tubule cells. Although the mechanisms of Selective reabsorption have not been uncovered, the outside dimensions of the renal process have been defined by the so-called clearance method of Study. The con- ception and development of the clearance measurement, which is of great usefulness clinically and to renal physiologists, rests chief- ly on the work of Addis and Barnett, and of Van Slyke. Obviously clearance does not imply complete removal of a substance from plas- ma. Only a fraction of the plasma is filtered and, in the case of urea, for instance, there is a large return from filtrate to plasma across the tubule cells. Clearance is an arbitrary, but quantita- tively valid, statement which refers the amount of a substance found in the urine over a unit of time to the volume of plasma which it Would occupy at the existing plasma concentration. This volume may be computed from the equation UV/P = C, in which U is concentration CREATININE DIODRAST UREA G LUCOSE | NUL|N D|ODRAST | NUL|N GLucose [] |} | | | | | | | | | | [] ! | | | | | Q <ſ ul 0， ~) 1 |- [] } | | |} | | —1— 7OOH- so |OOE | O O \ſ) E.10 NI W \! Ed C]B （JVE TO OO Įſ) VW SVT d ’O "O 2OO 3OO 4OO 5 OO 6OO | OO GLUCOSE 5 O 6O MGM PER CENT 4O | O 2O 3O PLAS MA D|ODRAST CONCENTRATION CHART FROM HomeR SMITH |6 CHART 16 (Continued) of the substance in urine, P its concentration in plasma, and V the volume of urine secreted per minute. If there is direct proportion— ality between the plasma concentration of a substance, P, and the rate of its removal, UV, clearance will have for the individual, a constant value and Will serve as a measurement of the capacity of the kidney in terms of plasma dealt with Over a unit of time . This capacity is determined by the total number of functionally active renal unitS Or ſephrons. Reduction Of Clearance therefore measures a loSS Of renal equipment. This does not, however, imply a reduc- tion of excretory capacity. The "smaller" kidney of Brights disease is able to excrete urea, for instance, as rapidly as the kidney in health by the Simple device of an increase in plasma concentration which produces correspondingly increased removal of urea from the reduced volume of plasma dealt with over a unit of time. P: UW pro- portionality is exhibited by a number of chemically inert, non- threshold Substances. A few of these are normal components of plas- ma; others are foreign substances. Since the concentrations of the most prominent components of plasma, the electrolytes, must be held closely stationary, a linear P: UV relationship Would not be expected. Their clearance values are found to vary Widely with change in the rate of intake and therefore have no utility as a measurement of Overall renal capacity. The clearance values (established for an adult of average size) for several substances, which are especially serviceable in this method of study, are recorded in the chart. The values differ and the reason for this is indicated in the diagrams. The substance inulin is believed to be removed from plasma exclusively by the process of glomerular filtration. The value found for inulin clear- ance therefore incidentally defines an important dimension of the renal process, the rate of glomerular filtration, as 125 cc. per minute. Under normal circumstances glucose is completely reabsorbed from glomerular filtrate and SO has a clearance value of Zero. Fol— lowing ingestion of creatinine, the value found for its clearance is l’5 cc. per min. Since, according to inulin, the limit of clear- ance by the process of glomerular filtration is 125 cc. per min. (the volume of plasma filtered), the additional 50 cc. of plasma must have been cleared by direct tubular excretion. Recent Studies Without administration of creatinine have produced measurements ap- proXimating the inulin value and therefore suggest that clearance Of endogenous Creatinine is accomplished entirely by glomerular fil— tration. The Clearance value for urea is below that for inulin be— CauSe Of return to the plasma of a large part of the urea in glom- erular filtrate. According to indirect evidence, urea is not ac- tively reabsorbed but crosses the tubule cells by a process of pas— Sive diffusion. For the substance diodrast, the enormous clearance CHART 16 (Continued) value of 740 cc. per minute has been found, which except for 125 cc. (glomerular clearance), must be accounted for by tubular excretion. This clearance of diodrast is regarded as ultimate in renal excre- tory achievement, a complete removal from the plasma during its passage through the kidney. On this premise it defines another basal dimension of renal activity, the volume flow of blood plasma. Comparison of this value for plasma flow With the value for glome— rular filtration defined by inulin clearance produces an additional datum of interest; about one-fifth of the plasma entering the kidney is filtered by the glomeruli. The direct proportionality between the plasma concentra- tion of a substance and the rate of its removal in urine On Which a stationary clearance value depends, may be expected to hold, re- gardless of increase in plasma level, for substances Which are dealt with by "passive" physical processes. When, however, "acti- vity" of the tubule cells is involved, a limit to the capacity of the process of transfer may be expected, beyond Which, rate of tu- bular absorption or excretion cannot follow rise in plasma concen— tration. This is clearly illustrated by the lower diagram in the Chart, , The Clearance Values for inulin and urea are Stationary at all plasma levels. With increa.Se in the 'concentration Of glucose in plasma, a level is reached which marks the limit of the capacity of the tubule cells to reabsorb glucose from glomerular filtrate and a progressively increasing remainder is found in the urine. Clearance of diodrast is stationary Only over low levels of plasma C Oncentration, With further increase, clearance falls rapidly and extensively, indicating that the maximal capacity of the tubule cells to excrete diodrast has been passed. According to Homer Smith, the plasma concentration of glucose beyond Which it enters the urine may be taken as 256 mg/100 cc. (arterial plasma). Using the Standard volume for glomerular filtration, the maximal rate of glucose ab- Sorption by the tubule cells is 256 x 1.25 = 320 mg/min. A value of 57 mg/min, has been established as the maximal excretory capacity f Or Cli Odra St. . Homer Smith and his associates have made ingenious application of the differing Ways in which the kidney deals with inulin, glucose and diodrast to appraisement of the extent and char- acter of Structural damage in renal disease . They designate maxi- mal glucose absorption, glucose Tm and maximal diodrast excretion, diodrast Tm. To very briefly indicate the scheme of this method of study: by reference to standard values; glucose Tm measures intact nephrons, since both glomerulus and tubule are required; diodrast Tim measures tubular excretory function, and since the glomerulus is not required, diodrast Tm minus glucose Tm measures aglomerular tu- bules; and since inulin needs only glomeruli, inulin clearance minus glucose Tm measures functionless tubules With intact glomeruli. CHART L7 The filtration-reabsorption method of renal control has rather Startling quantitative implications. The rate of glomerular filtration defined by inulin clearance, l25 cc. per minute, produces over the twenty-four hour period a volume of l80 liters. Since urine volume is usually not more than two liters, almost all of the water of the filtrate must be reabsorbed by the tubule cells, also, since only the surpluses of components of the ionic structure of the plasma are removed in urine, the greater part of these materials must be returned to the plasma from glomerular filtrate. This as– pect of control of the electrolytes is quantitatively described by the estimations of filtration and of reabsorption given in the table below. These are derived from the quantities found in a twenty-four hour urine specimen from a healthy adult on a usual dietary, assum– ing normal plasma concentrations and a glomerular filtrate volume of l80 liters. A B C D Per Cent, Pla.Sma. Reabs Orbed Found Filtered Reabsorbed Concentration (Axl80) in urine (B + C) B/D mM/L mM mM Na. l42 2556O lll 256'70 99.6 Cl 103 18544 ll.9 18663 99.4 K. 5 900 6O 96.O 93.8 HPO, l 18O 3O 2LO 85.7 SOA O. 5 90 23 ll3 79.6 Expressed in the more familiar term of Weight, the quan- tities of the two large components of plasma, Na and Cl, amount to— gether to more than a kilogram. The volume of the Specimen Was l.2 liters. Reabsorption of Water from the filtrate was therefore l78.8 liters (99.4%). The magnitude of the reabsorption task of the tu- bule cells is apparent in the table and in the chart. Which describes the filtration-reabsorption ratios. The volume flow of plasma through the kidney, as defined by the diodrast clearance value, 740 cc/min. , is also astonishingly large. This quantity of plasma corresponds to about 1300 cc. of blood which is more than one-quarter of the total cardiac output of the heart, under basal physiological C Ondit, iOnS. These definitions of the rate of glomerular filtration and Of plasma flow which the clearance method of study has produced make impressively clear the rapidity of operation of the renal process which maintenance of the integrity of extracellular fluid requires. PROPORTIONS OF COMPONENTS OF GLOMERULAR FILTRATE REABSORBED DAND EXCRETED IN URINEL |OO I- 90 H. 8OH 7OH 6OH 5OH 4OH 3OH 2O H. H2O Na Cl K HPO, SO, CHART |7 CHART 18 The history of the filtration-reabsorption method of re- nal control as related by E. K. Marshall and Homer Smith is an in- teresting tale of adventure of an evolutionary process. The glom- erulo-tubule kidney first appears in the vertebrate fishes. Ac- cording to recent interpretation of paleological evidence, the ver– tebrate fishes derive from fresh water ancestors and only in rela- tively recent geological times have fishes lived in the sea. The essential requirement for defense of extracellular fluid in a fresh water environment is conservation of substances in the presence of a very large removal of Water. This was excellently met by the de- Vice of filtration followed by reabsorption from a large surface provided by a long tube. This kidney was not equipped to secrete urine hypertonic to blood plasma, an accomplishment for which there is no need in an hypotonic environment (water intake X salt intake, with respect to extracellular fluid tonicity). When fishes under- took to live in the sea they encountered the reverse challenge to osmotic independence; a greatly hypertonic environment (salt intake X water intake). Plasma filtration was evidently a disadvantage and the glomerulus was permitted to atrophy, so that most present day Salt Water fishes are partially or completely aglomerular. The kidney being unable to secrete urine above the osmotic level of plasma, an extrarenal device for the removal of electrolytes in ex- cess of Water was necessary. This is described in the next chart. The marine elasmobranch (cartilaginous) fishes have developed an ingenious additional defense of the electrolyte level which consists in adding on top of it the physiologically inert substance, urea, to an extent which brings the total osmotic value of plasma to ap- proximately that of sea water. This permits the secretion of a much more concentrated, although still slightly hypotonic, urine. In- Cidentally this use of an unselectively diffusible substance clear- ly indicates that osmotic pressure per se is not physiologically Significant. Osmotic mechanisms in the body fluids rest on the Concentration level of the obligatorily extracellular electrolytes (Chart 14). It is also evident from these enormous concentrations of urea, that uremia is not by itself a poisonous predicament. In man, and in most other terrestrial animals, an econom- ical use of Water is imperative. Coinciding with the addition of the loop of Henle, the glomerulo-tubule apparatus became able to Secrete urine greatly hypertonic to plasma and thus meet Water: salt removal requirements which are the reverse of those for which it was Originally designed. As may be seen in the chart the plasma elec- trolyte concentration in man is almost exactly the same as is found in the fresh Water teleost (bony) fishes. As a result, however, of ELECTROLYTES IN PLASMA UREA |N PLASMA l-osM/L FRESH WATER SALT WATER TERRESTRIAL URINE – | 200 | | OO SALT PLASMA WATER [...] URINE |OOO : T- – .. 900 H. 8OOH 7OO H. sook PLASMA PLASMA ==3 URINE 4OOH PLASMA PLASMA º 3OO 2OOH FRESH WATER TELEOST ELASMOBRANCH TELEOST ELASMOBRANCH MAN FI SHES FISHES FISHES FISHES CHART |8 CHART 18 (Continued) having inherited a "fresh water" kidney, about 180 liters of water and more than a kilogram of Salt must be reabsorbed daily. Although this round-about method of control is, according to this account, fortuitous, it must be admitted that it works with a beautiful ac- Cura Cy. - CHART l9 Osmoregulation in the marine fishes consists in defense of the biologically prescribed value for the concentration of electro- lytes in body fluids against the three times superior osmotic pres– sure of present-day Sea Water. They have been provided with the obviously indicated impermeable cuticle. Sea Water enters the fish Only by ingest iOn. It has been shown that the gastro-intest inal tract is unable to selectively absorb Water. The requirement is, therefore, produced for the removal of salts of absorbed sea Water With an expenditure of Water no greater than sea Water provides. This the kidney, devised to suit an hypotonic environment, is unable to do. It cannot excrete urine of an osmotic pressure above that of the plasma, which is only one-third that of sea Water and is therefore obliged to spend three parts of the Water from ingested Sea Water On the removal of One part of salt. In other Words, the kidney not. Only is incapable of defending the osmotic value of the plasma, but actually operates in the reverse direction. The salt Concentrat, iOn Of intest, inal residue is lowered to that. Of the body fluids, So there is here the same loss of water With respect to salt as in the urine. These two items of Water Wastage produce the requirement for removal of the remainder of the ingested salt at a COn Centrat, iOn above that. Of Sea Water. Homer Smith has most inter— estingly shown that this feat is accomplished by the gills. His data, obtained from a fasting eel, have been used to construct the diagrams in this chart. Which give an approximately complete account of the Water and electrolyte exchange of a marine teleost. The di- agrams define the Water expenditures in excess of electrolyte in urine and intestinal residue and the compensat. Ory economy Of Water in the removal of electrolyte by the gills. The concentration val— ues Which the data in the diagrams produce are recorded at the foot Of the Chart,. From them it may be seen that the bulk of the elec- trolyte intake is removed by the gills at a concentration which is nearly One and One-half times that of the surrounding medium and four times the osmotic value of the internal medium (accepting the urine value as approximately that of blood plasma). Interestingly this fourfold osmotic gradient sustained by the gills also approxi- mately defines the concentrating capacity of the mammalian kidney equipped with the loop of Henle (preceding chart ). ExCRETION OF LITRE OF INGESTED SEA WATER BY A TELEOST FISH. | OOO WATER, CC. 900 ELECTROLYTES, m-osm 8OO 7OO 6 OO |NTESTINAL EXCRETION RESIDUE BY G|LLS SEA WATER URINE O97 M/L O36 M/L O4O M/L 1.41 M/L CHART |9 CHARTS 20 and 21 Although the mechanisms of selective reabsorption are still invisible, they require certain acid-base adjustments in the construction of urine which can be examined. Because of irregular- ity in the composition of the food intake, variably unequal quanti- ties of base and acid are presented for removal in urine. The per- missible range of reaction, from pH 7.8 to pH 4.8, is much wider on the acid Side than in plasma. But even a usual food intake re- quires excretion of an excess of agid_over base which, if uncon- trolled, Would produce a pH far beyond the limit of urine acidity. Occasionally When alkaline articles of food are predominant, base must be removed in exceSS Of acid. There is theref Ore Obvious need for defensive adjustments which will permit the process of selective reabsorption to Operate Within the boundaries which have been set for the reaction Of urine . The mechanism which manages the removal from plasma. Of acid in excess of base is composed of two interoperating parts; a direct, saving of-base– gained by secretion of urine of an acidity Within the prescribed limit and a regulated Substitution of ammoni- um for plasma base (fixed base) in covering acid radicals as they Těřitér the urine. 'Saving of base by secretion of acid urine can be accomplished only in the removal of the two weakly acid components of the acid excretion; phosphate iOn and the Several Organic acids, which, since they can be méâsured together by the titration method of Palmer and Van Slyke, are conveniently dealt with as a unit. As may be seen in Chart 20, HP0% is conveyed in plasma (pH 7.4) al- most entirely as dibasic phosphate, but can be removed in urine at the limit of acidity (pH 4.8) as monobasic phosphate. Its excretion may therefore be accomplished with an expenditure of only slightly more than one-half of the base which covers it in plasma. Similar- ly, in the case of citric acid, a prominent component of the group of organic acids, a considerable portion can be removed in acid urine base free, whereas in plasma it must be completely govered by base. The other two components of the acid excretion, Clſ and so". being radicals of strong acids must carry their full equivalence of base into the urine. A quantitative view of these two adjustments which defend plasma base is provided by the measurements given below Which were obtained from a twenty-four hour urine collection from a healthy adult on an ordinary diet. The values used for the base equivalence Of HPo”, and of the organic acids, according to the pH of urine, — Tl- Too TH 90 — 8O gº 7O — 6O ºmmemº - SO — &O – 3O — 2O BH,PO, — - || O -ULLLLL B,HPO, L - lo - 20 3O 40 | 5O ||||||||| - SO | 7O % Illlll l BO 50 T- Till 90 4O F- - |OO 3O H. Tl_ 2O H. T_ | O H. TH C|TRIC ACID | O H. CITRATE 2O H. 3O H. 4O H. 50 H. 60 | |-l- 7O Illll lill 8O Lill eok 1|| |OO *|||||||||||| T T T pH 4.8 5.O 5.2 5.4 56 5.8 6.O 6.2 64 6.6 6.8 7.O 72 7.4 7.6 7.8 URINE URINE BLOOD (LIMIT OF ACIDITY) (AVERAGE) PLASMA CHART 20 CHARTS 20 and 21 (Continued) derive from the ratios shown in Chart 20. For example at the pH of blood plasma the proportion of BH2PO4 to BełPO4 is 0.2: O - 8. The base equivalence of HP0; is therefore 0.2 + (2 x 0.8) = 1.8. In urine of the reaction of the specimen, pH 5.4, the proportion is 0.96: 0.04 and base equivalence is 0.96 + (2 x 0.04) = le04. A. Acid excretion in terms of base equivalence at pH 7.4 (plasma) Cl’ ll.9 m-M X l. O = ll.9 m—Eq. SO 4 23 m-M X 2. O = 46 m-Eq. HP0; 30 m-M X l. 8 = 54 m-Eq. *Organ. AC. 37 meg. X l. O = 37 m—Eq. 256 B. Fixed Base excretion Na" 108 m—M X l. O = 108 m—Eq. K” 60 m-M X le O = 60 m-Eq. Ca" 2.5 m–M X 2. O = 5 m-Eq. Mg” 4 m—M X 2. O = 8 m-Eq. 181 Aſ Acid excretion in terms of base equivalence at pH 5.4 (urine) Cl’ ll.9 m—M X l. O = ll.9 m—Eq. SO; 23 m—M X 2. O = 46 m-Eq. HPO 4. 30 m-M X 1.04 = 31 m-Eq. Organ. AC. 37 meg. X 0.8 = 30 m-Eq. 22g B. Ammonium product iOn NH; 44 m—M X l. O = 44 m-Eq. Acid excess at plasma pH, A-B = 75 m–Eq. Base economy by acid urine, A-A* = 30 m—Eq. Remainder of acid excess TET Ammonium, directly measured 44 m-Eq. # (The titration method of determination defines complete equivalence but does not measure molecular concentration. ) 64O º Hºco ACP.E.Tº mEq | | | |4OOO-T I I. I\ ^_^3 E EQUIVALENCE 62O : | Yūt-_CM. H 7.4 H 54 i - . p p tº gº tº BASE | FTT EXCRETION ..., |BASE} ~ y i 12OOO- 24O- HECON- \! OMY S-- I----- | \ - 22O- | | | | | | |OOOO- 2OO- CY NH, : : | tº- | 80- | : Cl’ | | 8OOO- | 60- | | (UREA sº | 40- º. | Nº. | & | 6OOO- | 20- & Na SO. | | * | OO- | tº ; : 4OOO- 8O- SO. | : | * 6O- HPO. | | HPO, g | | 2000- 4O- % K : | | | | | * OTHER 20- º ORG. . . . ACIDS AC. 2Ga. ___ 2Mg: ; ; A A. B CHART 2 | CHARTS 20 and 21 (Continued) This illustrative analysis of the process of removal from blood plasma of acid in excess of fixed base is graphically de- scribed in Chart, 21 Ammonium production is seen to be the larger of the two Control adjustments. The practically unlimited availa- bility of ammonium is shown by the last column in the chart. Which measures the urea excret iOn in terms Of potent, ial ammonium. Although the capacity of the base economy factor of control is relatively small, it has an immediate and very accurate adjustability. The larger ammonium factor moves much more slowly and, in consequence, With less precisi On. These two parts of the mechanism. Which Con- serves plasma base may be compared to the fine and the coarse ad- justments of a microscope. The relatively enormous value (about 2 pounds daily) of the largest end product of metabolism, carbonic acid, is shown in the Chart. Routinely this acid is removed, Without an expenditure of base, by the lungs. Under certain circumstances, however, an ad- justed quantity of carbonic acid carries base into the urine (Chart 24). CHART 22 The data on this chart. Will serve to illustrate the Opera- tion together of the two factors of regulation, base economy and ammonium production, which control the use of fixed base in the process of acid excret iOn. The measurements used in constructing the diagrams are from consecutive 24-hour collections of urine over a 4-day period of fast ing and a 2-day after period during Which a Small amount of carbohydrate Was given in the form of cane sugar. The subject was an epilept ic child Who Was fasted as a therapeutic meaSure, During fast ing HP0; and SO4 present ing for excretion de- rive from consumption of body protoplasm and Cl' from reduction of volume of extracellular fluid, and from these cources there is re- leased for removal in urine a roughly equivalent Quantity of base. A large excess of acid over base excretion develops, however, from extension of the excretion of organic acids due to addition of in- Completely Oxidized fatty acids. This ketosis is promptly removed by supplying glucose, which also, by its protein sparing effect, Causes a large reduct, ion in the quant, it ies of the other acid radi— SHOWING CONSERVATION OF FIXED BASE |N THE PROCESS OF ACID EXCRETION ACID EXCRETION BASE EXCRETION CARBO- CARBO- FASTING |ºp. FASTING T | * * * | *|mEq | | * * * | * | 80 | 6O BASE ECONOMY | 4O - ORGANIC ACIDS | 20 ... . . . . . . . . . . (AMMonium |OO ... . . . . . . . . . [.. 8O 6O 4O 2O O CHART 22 t CHART 22 (Continued) cals, and of fixed base presenting for excretion. There is, thus, over the two periods of this experiment, large and rapid change in the factors of acid-base excretion, requiring alert and extensive adjustment of the factors of regulation Which defend the fixed base content. Of eXtra Cellular fluid. The measurements obtained from the specimens Were Of the four factors of the acid excretion, of ammonium, and of base economy. The value for base economy can, as Was pointed out by LaWrence Henderson, be easily obtained by titrating the urine With standard alkali to pH 7.4, the reaction of blood plasma. The extent of plasma base conservation gained by secretion of acid urine is thus measured. In this study the four components of the fixed base excretion Were not directly measured. The values for fixed base, recorded in the chart, were obtained by subtracting the sum of the measurements of base economy and ammonium from the sum of the values found for the four components of acid excretion in terms of their base equivalence at the react iOn Of blood plasma. Reference to Chart 2]. Will make this computation Clear. The two factors controlling the use of fixed base in the process of acid excret iOn are thus given Quanti- tative description and it is seen that a total acid excretion Which, while being conveyed to the kidney, was completely covered by fixed base, is managed with an expenditure of fixed base amount ing to about. One-half ot, its plasma equivalence. The diagram shows very clearly the Wide adjustability of this control. CHART 23 In the preceding chart, the process of removing an acid excess in urine is described in terms of control of the total fixed base excretion. Obviously, this is an incomplete account of a mech- anism. Which must defend the several components of eXtracellular fluid base individually. In the situation produced by fast ing there is continuous release of K and Mg by consumption of protoplasm and an absorption of Ca from deposits, presumably caused by the acidosis of fast ing. The relatively small concentrations of these iOnS in extracellular fluid thus have the Support of an abundant intake. Sodium which composes 92% of the total base value, because of its exclusively extracellular position, has no source of support. MEQ. BASE –7 O ECONOMY (TITRATABLE ACIDITY) l -6O ACID-BASE coMPOSITION | "...” OF URINE -50 |2th TO |5th DAY OF FAST |NG AMMON IA -4O C l’É: -3O - HPO. -2O K. - |O SO. º- Ca" Mg". CHART 23 CHART 23 (Continued) Conservation of sodium is therefore the outstanding requirement in the regulation of fixed base excretion during fasting. This chart, describes the acid-base composition of urine during the later part of a prolonged fast. Sodium is found to be a Small fact, Or in the fixed base excret iOn. On the acid Side Of the diagram may be noted a corresponding restraint of the excretion of the other large factor of extracellular fluid structure, chloride iOn. It is probable that the presence in the urine of these Small quantities of sodium and chloride ion represent an appropriate re- duction of extracellular fluid volume along With the decrease Of total protoplasmic mass caused by fasting, rather than imperfect COnservat iOn. CHART 24 Not infrequently, instead of the usual excess of acid over fixed base claiming excretion in urine, the quantity of fixed base to be removed is larger than the sum of the acid radicals. There is here need for an acid analogue of ammonium; that is, an acid Sub- stance which is abundantly at hand and can be controllably placed in the urine. Carbonic acid Suits these Specifications ideally. Its availability is practically unlimited (Chart 2.l.). Routinely it leaves the body base free by Way of the lungs, but When needed can, to a regulated extent, be deflected into the urine. Measurements Of the COncentrat iOnS Of Carboni C acid and of bicarbonate in urine reveal the interest ing relationship shown in this chart. Carbonic acid is found to have a nearly stationary concentration of approximately the Value Sustained in blood plasma. Carbonic acid is unique in this respect; all of the other components of urine being found at Widely varying concentrations, usually above their plasma levels (Chart 15). Evidently the concentration of car- bonic acid in urine rests, as does its plasma value, on the carbon dioxide tension in the residual air of the lungs, and is not con- trolled by the kidney but simply diffuses into the urine. Since hydrogen ion concentration is determined by the ratio of the con- centrations of free carbonic acid and bicarbonate, this fixed value for the numerator of the rat iO prescribes the individual values for bicarbonate over the range of Urine reaction. These are recorded CARBONIC ACID AND BICARBONATE IN URINE. UR INE H BLOOD mEq/ L (AVERAGE) P PLASMA | Flo 5.6 5.8 6.O 6.2 6.4 6.6 6.8 7.O 7.2 7.4 7.6 7.8 (HHCO), I L O (B.HCO) ||||| - |O -2O T_ RATIO - 4O |N VITRO Tl -50 — (H.HCO3) - TH - (B.HCOs) | H. -6O -7O l Ill - 80 Ill LL *|| º – Hill|| - -90 5.4 5.8 62 6.6 7.O 7.4 7.8 CHART 24 CHART 24 (Continued) in the chart and it will be seen that, as reaction moves in the di- rection of alkalinity, the bicarbonate values rapidly become very large. The fixed numerator for the (H.HCOg): (B. Hoog) rat, iO thus provides a simple and excellent mechanism for the removal in urine of fixed base in excess of acid Within the alkaline boundary of urine react iOn. The extra base is removed as bicarbonate and, be- yond the reaction of blood plasma, progressively enormous quantities of base as bicarbonate can be placed in urine Within a very small range of reaction change. An alkaline boundary Which is Only a Small distance from plasma react iOn is thus ea Sily defended. Proper admiration for the device of a fixed value for car- bonic acid may be gained by inspecting the Smaller diagram which describes Ordinary unguided bicarbonate buffering. Here changes in the denominator of the ratio produce reciprocal change in the num- erator with the result that the steps in bicarbonate change, with respect to pH, are very much smaller than those found in the urine. The functional superiority of the urine ratio in providing a Wide range of control of base entering the urine as bicarbonate is clear- ly evident. This is especially conspicuous On the alkaline side of pH 7.4 where the uncontrolled ratio permits very small increments of bicarbonate to move pH to 7.8, and therefore would offer almost no defense Of the alkaline boundary of urine Which the urine ratio guards With an almost ideal effectiveness. The stationary value for (H.HCO3) rests, as has been mentioned, on the rapid diffusibility of carbonic acid. Depletion of (H.HCO3) by extension of (B.HC93) is immediately replenished and increase by release from (B. HCO, ) is Quickly removed. Diffusion from bladder urine is probably slow. Addition of urine of low pH to urine of high pH should release car- bOni C a Cid. This is the probable explanation of occasional large deviations from the usual value Which have been reported. CHART 25 y’ The removal of fixed base as bicarbonate in defense of the anion components of the plasma, particularly chloride ion, is il- lustrated by measurements obtained from an animal experiment and re- Corded in this chart. The CircumstanceS Of a Cid-base excret iOn which they describe obtain clinically when dehydration (reduction of extracellular fluid volume) caused by vomiting is treated by ad— ILLUSTRATING EXCRETION OF HCO, IN URINE IN DEFENCE OF (CI) IN BODY FLUIDS ACID EXCRETION. BASE EXCRETION. NaCl GIVEN. mEº NaCl GIVEN. I-I-I-1 7O 6O 5O 4O 3O CHART 25 CHART 25 (Continued) ministration of Salt solution. The experiment, COnsisted in obstruct- ing the pylorus of a female dog by ligature. Then, after permitting dehydration caused by loss of stomach secret ions to proceed for two days, large quantities of salt solution Were given by intraperitoneal inject iOn. OWing to the larger loss of chloride ion than of sodium in stomach secretions, the sodium deficit is replaced from the ad— ministered salt solution long before that for chloride ion. The kidney is then called upon to remove SOdium but to COnt, inue to re- t;a in Chloride iOn. Measurements of the individual acid radicals, ammonium and fixed base Were obtained from COnsecutive l?—hour Catheter Collect iOns Of urine. The values found for the acid rad- icals are superimposed in the left-hand diagram. The excret iOn Of chloride ion is seen to remain at a small value throughout the ex- periment, indicating that the quantity of salt solution given Was not enough to entirely replace the loss of chloride ion. In the other diagram, following the third injection of salt solution, an eXtensive rise in fixed base excret, iOn is found. This represents removal of surplus sodium. In the diagram of the acid excretion it is seen to be covered by a peak in total acid composed of bicarbon- ate iOn. CHART 26 The diagrams in this chart are constructed from the meas- urement, S Obtained from the urine Collected OVer the fourth l?—hour period of the experiment described by the preceding chart. This Specimen contained most of the sodium surplus and its pH value was 7. 9. The diagrams describe quantitatively the saving of chloride gained by the secret ion of urine at pH 7.9 instead of at the usual reaction of urine, pH 6. 0. Acid-base composition as directly de- termined is described by the first diagram. The measurement, S Of the Organic acid and phosphate ion excret ions are recorded in terms of their base equivalence at pH 7.9 (Chart. 20). The second diagram is constructed from the found values for the excretion of base, or— ganic acids, phosphate ion, and sulfate ion. The minute Value for bicarbonate ion is derived from the concentration found in urine at pH 6. O (defined in Chart 24). It will also be noted that the base equivalence of the Organic acids and of phosphate ion is consider- ably less than at pH 7. 9. There is thus left a large remainder, more than half, of the acid column in the diagram, which would have ILLUSTRATING CONSERVATION OF (CI) IN BODY FLUIDS mEq BY EXCRETION OF HCO, IN URINE. 7O- pH, 7.9 pH, 6.O NH. • * : * ... • . . . . . .” NH. F-1 HCO3 4. ... .....:::::: A. * - - - " " " . . . . ORGANIC ACI DS. 6O- HPO. 5O- HCO . . ... ". S O. FixED.º. FIXED 4O- ... . . . . 3O- BASEl BASE ORGANIC &P ACI DS. C) 2O- HPO #HCY CHART 26 CHART 26 (Continued) to be filled With chloride ion from the administered Salt, Solu- tion. By Way of emphasizing that the Word salt has no biological meaning, it may be noted that the kidney, dealing With plasma ionis in terms of their individual requirements, secretes in the above described situation an intensely alkaline urine following the ad- ministrat, iOn Of a neutral Salt. CHART 27 Returning to Chart 24, a point may be noted Which relates, not to removal of an excess of fixed base, but to base conservation. In urine of the reaction of blood plasma, the chart records a quan- tity of bicarbonate which is very large as compared with the bicar- bonate content of the urine at the average reaction of urine, pH 6. O. Since carbonic acid can be removed from the body base free by way of the lungs, b s bicarbonate—in the urine, under circum- stances demanding conservation of base, must be regarded as base Wasted. AVO idance of useless eXpenditure Of base as b iCarbonate Can therefore be recognized as a chief significance of , the usual reac- t; iOn Of urine. Obviously, there is here a saving of base separate from, and additional to, the economy of base gained by the removal of organic acids and the radical of phosphoric acid in urine of lower pH than blood plasma (A — A' Chart 21). The diagrams on the opposite page provide a quantitative view of these two items of base COnServat iOn. The first diagram describes the acid-base composi- tion found in a Specimen of urine Secreted at pH 5. 2. The Other diagram defines the much larger quantity of base Which Would have to be present if the same quant it ies of the acid radicals Were re- moved in urine of the reaction of blood plasma. This increment is composed of extension of the base equivalence of the Organic acids and phosphate ion and the presence of an even larger Quantity of base as bi Carbonate. The balance sheet of acid-base excret iOn given in Chart 21 defines a minimal expenditure of base required by the four acid radicals Which must be removed in urine. Carbonic acid therefore does not enter into this account ing and the item of base conserva- tion which consists in the absence of bicarbonate from very acid urine ClOeS not appeare SHOWING FACTORS OF REDUCTION OF BASE EXCRET |ON IN ACID URINE. mEq. pH 52 pH 74 | 80- - - | 6O- BASE AS BICARBONATE º | 4O- EXTRA BASE REQUIRED ORGAN.AC . FOR ORGAN. AC. AND HPO lm- | 20- = ~~ |º HP O - - %| |OO - HPO, BASE || 8O- TOTAL SO, SO, 6O - BASE H *-* 4O- | Cl Cl 2O- O CHART 27 CHART 28 The two items of base conservation shown in the preceding chart make clear the great advantage of the permissible range of pH in urine. The movement of pH, as Van Slyke and coworkers have pointed out , can be explained very simply and probably correctly as a consequence of the process of selective reabsorption of the com— ponents of glomerular filtrate. This chart is intended to illustrate in quantitative terms the (A): (BA) changes in the three sets of buf- fering substances in urine caused by adjustment of base return to the plasma. The (A) and (BA) values are computed for l. 5 liters of urine containing 30 millimols of phosphate ion and 40 millieduiva- lents of Organic acids. These are roughly average 24-hour quanti- ties. The COncentrations of Carbonic acid and bicarbonate are those given in Chart. 24. The individual values for the components of to- tal (A) and (BA) are superimposed. The relative quantities of the buffering substances in urine at the reaction of glomerular filtrate are shown in the Column at pH 7. 4. The columns on the alkaline side Of pH 7.4 describe the changes caused by reabsorption of anion in excess of fixed base. On the acid side this process is reversed by reabsorption of base from BA With consequent release in the urine of A. The values for (BA) over the range of urine pH will be easily understood if it be recalled that in the case of the phosphate ion and organic acid excretions, the steps in the removal of B from BA produce corresponding increments of A (Chart 20), whereas removal of base from bicarbonate does not alter the concentration of carbonic a Cid in urine. The stationary numerator for the (H.HCOg): (B.HCOg) ratio, which rests on the rapid diffusibility of carbonic acid, pro- duces the Wide range of values for (B.HCOg) Seen in Chart 24 and thus enables bicarbonate to contribute much more extensively to base adjustments than the BA fractions of the other two buffering sub- Stances. The effectiveness of this device is especially evident. On the alkaline side of pH 7. 4. Here the reabsorption of an ion in ex- cess of fixed base is accomplished almost entirely, and with only a Small movement of pH, by the large extensions of bicarbonate pro- Čuced by the perSistent, presence of free carbonic acid. At the out- set of the reverse process, base conservation by reabsorption of B from BA With release of A, bicarbonate is again the prominent factor and provides the greater part of the base until it approaches the point where it is completely removed from the urine. Thereafter, from the usual reaction of the urine, pH 6.0, onward in the direc- tion of acidity base is obtained in much smaller steps from the BA fractions of the phosphate ion and organic acid excret ions. OWing to the stationary value for (H.HCO3), increase in URINE (AVERAGE) mEq/L-30 J. III I l GLOMERULAR +2O ºf: FILTRATE | + |O • * * * T., "s" w "" "I gº .. " . . * * • *_ " ... • * *.*, *, *" - "... • , * * * * * * • *, *, *, *, * * - . . . . “. . . . . . . .” --- - - . . . . * - s = “ * . . . . . .”.”. * , - * . . . . *.*.* * * * * * *, * * • X • . * * * * ~ * , *.*.T. . . . . . . . . . . . . º.º.º.º.º.º. • - - - - * * - - * , , “ - X • , "... * * * * * ... ". . . . . . .” -º-º-º-º-º: *, *.*.*.*.*.*.* * * T. "... * * * * * * * *.*.*.*.*.*.*.*.*.*.*.* * * * * * * * * * * * * *, * * - - - -AT- * * * *_lº "." ". "... *, *.*.*.* •.*.*.* : *.*.*.* • *.*.*.*.*.*, * * * * * * * * * *• ". *..." . . . * • * * * * * * * * * * * • • * * • * * * * * * * *** *.*.* * = s * * * - • • . . ." . . . . . * * . . . . . . . . . . ." - tº ..… . . . . . . . . .'''-'l'- * * * . . . . . . . . . . .” - * , . . . . . . . . . . . . . . * *.*.*.*. .” -: - * * - *. * * ** - • . *, *. * - - º * * * * - º º ** - - • * * * * * * * * • • , " ". + 3O +5O +6O +7O +90 sº (BH2PO4) (ORGANIC ACIDs) . . . . . . . * | (HHCO) * (B.HPos) (B. ORGANIC ACIDs) (BHCo.) + l2O + |3O - pH as so gº sº. Es Es so sº. Tea es es ſo 7. T.T.T.'s CHART 28 CHART 28 (Continued) urine acidity is composed of acid phosphate and (beyond pH 6.0) free Organic acids. Although acid phosphate is the larger component, it may be noted that it is chiefly the increments of organic acid that carry the reaction of the urine beyond pH 6. 0. Economy of base in the removal of phosphate ion and the organic acids, as has been con- sidered (Charts 20 and 21), may be measured by titrating the urine With standard alkali to the reaction of blood plasma. The eXtent, of this saving of base at the acid limit of urine as defined by the data in the chart, is 26 millieduivalents per liter (obtained by subtracting (A) at pH 7.4 from (A) at pH 4.8). Since the Superim- posed values for acid phosphate and Organic acids define in the chart a roughly linear relationship between (A) and pH, and since the range of pH change is 26 tenths (7.4 — 4.8 = 2.6), it may be roughly stated that, according to these data from an "average" urine, each reduct iOn of pH by O. l produces a saving of one milliequiva- lent. Of base in the removal of these two COmponents of the acid ex- Cret, iOn. i CHART 29 t L^ The quantity of fixed base which can be taken from the BA fractions of the phosphate ion and organic acid content of glomeru- lar filtrate by the process of selective reabsorption within the acid boundary of urine (Chart 28), is usually less than half of the excess of acid over fixed base claiming excretion in the urine (Chart 21). The further reabsorption of fixed base, which is nec– essary to avoid plasma deficit, is provided for by the substitution in urine Of ammonium for fixed base to the extent. Of the remainder Of the acid eXCeSS. According to recent evidence, this regulated release Of *"...######". the ammonium is obtained, not ã, but from the amino acids of glomerular fil— trate. Jºne quantity of ammonium found in blood plasma is very mi- nute and, moreover, is possibly an artifact of the technic of meas— urement. It is a premise of acid-base metabolism that the base am— monium cannot be used to an appreciable extent in body fluids but can be used for the covering of acid radicals in the urine. It is this circumstance Which makes necessary the designation of plasma base as "fixed" base. As regards the interoperation of the two ad- justments which control fixed base removal in urine, direct base Saving (base economy) and the substitution of ammonium (Chart 21), it may be noted that they proceed together, and not en echelon, with | OOr------------- |NTAKE CaCl2 INTAKE. NH4C. 90H . TāAan dolgad agos aaoav ºbłu 24Or 2OOH | 80 H. 6OH- 4OH 22Ok <！---，！-• O O ī dolād agõ+ 3^5av ºbºu - CN) O <！－- N- TāAan doliad agos MoI38 % au 60. DAY CHART 29 OO O O CHART 29 (Continued) the result, that When the limit of base economy is approached ammon- ilum product iOn is in full St, ride. The adjustment S of base economy (Chart 28) are directly explained by the securely postulated but st ill invisible process of Select, ive reabsorpt iOn. MOt, iWat iOn Of ammonium production is also evidently referable t O this underlying process since increments of ammonium are seen to follow reduction of pH caused by fixed base reabsorption. The connecting mechanism Which produces a beautifully regulated release of ammonium is not, as yet, in View. The quantity of urea constructed from ammonium released by deaminization processes Within the body Will obviously not in- clude the ammonium taken from plasma amino acids by the kidney and placed directly in the urine. There is therefore a reciprocal re- lationship between urea and ammonium excretion. This is roughly de- scribed by the data in this Tchart, Which were obtained in the course of a study of the effects of the so-called "acid producing" salts, calcium chloride and ammonium chloride, on acid-base metabolism. The neutral salt, CaCl2, exerts an acid effect because relatively little of the Ca" Which it provides is absorbed from the gastro- intestinal tract— whereas nearly all of the Clſ is absorbed. When NH,Cl is ingested the base(NH) is absorbed Tbüt Is immediately con– Verted tº O t, he neutral substance (urea) Both salts thus place Cl’ a- lone in extracellular fluid and produce the requirement that the fixed base Which covers it during transport to the kidney be COm- pletely returned Tto the plasma. The amounts Of the Se Salt, S Which are used therapeutically produce a Very large addition to the usual excess of acid over fixed base claiming excret ion in the urine. Since increase in urine acidity beyond the usual value, pH 6.0, pro- duces only a small saving of base (Chart 20), the burden of cover- ing this large increase in acid excretion falls almost entirely on the ammonium production mechanism. The subjects of this study were healthy individuals. They Were placed On an accurately constant food intake Over a consider- able foreperiod during which daily excretion values for chloride, calcium, urea and ammonium were established. . The values recorded in the diagrams define the extent of change With respect to the fore period values found on three consecutive days of addition of "acid" salt to the constant food intake. The data in the first di- agram are from an eight-year-old child While receiving 100 milli– equivalents of Clſ as CaCl2 daily. The relatively very small quan- tity of the ingested base, Ca", is seen. The Clf increments over CHART 29 (Continued) the fore period value define the large addition to the total acid excretion. In response to this, ammonium production is extended in large StepS. The values for the urea excretion, recorded in terms of potential ammonium (twice the -iñelegular—value), progressively decline in rough correspondence With thiê 'amortium—increments. The data in the other chart are from an adult Who Was given 226 milli– equivalents of C1 as NH,Cl daily. That the ingested NH; is conveyed to the kidney as urea is clearly indicated by the increase in urea excret ion over the first two days. Reflection of the increasing ammonium production is not seen in these rough data over the first tWO ClayS. On the third day, however, the reciprocal relationship between the urea and ammonium excretions COmes into View. ; i : : ; i ; CHART 30 An item of evidence that the locus of regulated ammonium production in the kidney is the extensive impairment of this mech- anism found in chronic nephritis. This is shown by the data in this chart. Which were obtained by the plan of Study just described. The measurements in the upper diagram are from a child With normal renal function and those in the lower diagram from a child with chronic nephritis (and edema). Both children received 100 m—eq. C1ſ a.S CaCl2 daily. The values recorded are increments over fore peri- od levels on a constant diet. The pH of the urine over the fore periods Was below 6.0 So that Only slight increase in base economy was possible (Chart 20) and defense of plasma base therefore re- quired an almost complete covering of Cl’ increase by ammonium. As may be seen, even in the presence of normal renal function, ammoni- um response to this Sudden large addition to the acid excretion is not immediately adequate . The increments Of fixed base above the fore period level measure the resulting losses from the plasma. In the after period the ammonium increments surpass C1' excretion and produce replacement of the fixed base losses. In the case of the child With chronic nephritis the ammonium response is very much slower so that, over the CaCl2 period, Clſ is permitted to carry al- most its entire equivalence of fixed base into the urine with negli– gible recovery during the after period. Defense of the total ionic concentration of the plasma re- Quires that a Withdrawal of fixed base be accompanied by a corre- Sponding quantity of Water. This explains the diuretic action of CaCl2 (and of NH,Cl). On this premise it may be estimated that this child with chronic nephritis lost, over the four days of CaCl2 ingestion, l.4 liters of edema fluid. (Fixed base withdrawn, 220 m-eq. Fixed base in interstitial fluid, l06 m—eq./L (Chart 2). 220/156 = 1.4). As shown by this chart the diuretic effectiveness Of CaCl2 is greatly increased by disability of the ammonium mechan- iSm. Edema is a relatively infrequent event in chronic nephri- tis. The sluggishness of ammonium defense of plasma base produces the hazard of loss and, in consequence, the inverse change in ex- tracellular fluid volume; dehydration. That fixed base deficit does occur in chronic nephritis has been clearly demonstrated by Peters. Additional evidence of deficit is provided by Palmer's findings that, in chronic nephritis, ingestion of a much larger mEq. 2O = 3O. DAY 2 3 4 5 CALCIUM CHLoſ IDE PERIOD -I- 6 | 2 3 AFTER PERIOD B.K. RENAL FUNCT |ON NORMAL. CALCIUM CHLORIDE PERIOD —I * DAY 1 2 3 4. l 2 3 4. 5 AFTER PERIOD <) A.T. CHRONIC NEPHRITIS. AMMONIA RESPONSE TO A LARGE ADDITION TO THE ACID EXCRET |ON CAUSED BY INGEST ION OF CALC1 UM CHLORIDE. VALUES PLOTTED ARE INCREMENTS OVER FORE PERIOD LEVELS. CHART 3O CHART 30 (Continued) quantity of sodium bicarbonate is required to make the urine alka- line than in the healthy subject (the so-called alkali tolerance test). The rationale of the conventional low salt diet is there- fore clearly incorrect. An ample intake of Salt Should be Supplied. CHART 3L The Water balance of the body rests On Volume Control in the several body fluid compartments (Chart l). The mechanics of the circulation of the blood demand a fairly Stationary Volume . Re- quirement for an approximately constant volume of intracellular fluid may also be postulated. Although the usual Volume of inter- stitial fluid is presumably ideal for its services to the tissue cells, extensive change does not greatly disturb physiological proc- esses. The role of interstitial fluid as the adjustable segment in the total Water content of the body is clearly apparent. The ad- vantage of its extracellular position is evident from features of the Water exchange. Water expenditure, in the removal of Waste sub- stances in urine and of heat by the vaporization of water, is at the expense of extracellular fluid. There is no expenditure of intra- Cellular fluid. Actually there is a Small gain of Water from oxi- dation of food substances. The Water exchange therefore consists in replacement of losses of extracellular water. Since Water in- take is intermittent and expenditure is continuous and of variable degree, adjustment of interstitial fluid volume is constantly re- Quired. In the presence of abnormal circumstances obstructing the Water exchange, this adjustability of the interstitial compartment provides a wide survival margin. This defense of volume in the two adjacent compartments does not have the physiologically impossible attribute of rigidity. There is considerable permissible change in plasma volume and, as has been noted (Chart 14), the requirement for Osmotic equality makes necessary some degree of volume adjustment between intracellular and extracellular fluid. Considering, how- ever, that the boundaries of the body fluid compartments are elas- tically movable Within Wide limits the degree of success of the mechanisms in control of volume is very remarkable. According to the above considerations, the volume of ex- tracellular fluid, since interstitial fluid composes three-quarters of it, is necessarily fluctuant. Return to an approximately fixed value at the end of each twenty-four hour period, accomplished dur- ing the hours of sleep, might be expected. The data recorded on, this chart indicate, however, a much slower process of volume con- DAILY EXCRETION OF CHLORIDE AND OF WATER BY THE KIDNEY. INTAKE CONSTANT. M.EQ. C.C. 2OOH C - 2000 | 80 H. - 18OO | 6O H. + 16oo [ URINE VOLUME. º | 4O H. O 414oo | 20 F + l2OO º CHLORIDE. * . | OO H. - |OOO 8O H. - 800 * POTASSIUM. |- O-- °---o-s, --~"T"--o---o-> --o---9 6O H. * – & - 6OO C- A -O---O- -*---o -------------.” --~~ •O T°7′SULFATE. º 4O H. °--> M \,---------------------, -0--- 2^e - 400 so PHOSPHATE. Tº---o-Tº---of - 2O H. - 200 DAY 1 2 3 4 5 6 7 8 9 TO || 12 13 14 15 16 CHART 3| CHART 31 (Continued) trol. The measurements (taken from a study of electrolyte metab- olism by Atchley and Loeb) were obtained from consecutive twenty- four hour collections of urine from a adult. On an accurately COrl- stant food and water intake. They provide indirect evidence of day to day change in the volume of extracellular fluid. This consists in the wide irregularity of the daily quantities of the eXtracellular ion, C1, and the roughly stationary values for K, HP04", and SO4” which are large components of intracellular fluid but Which are conveyed in extracellular fluid at relatively very small concentra- tions (Chart 2). In the presence of a constant intake of Cl and as- suming that the relatively Small extrarenal excretion is approx- imately stationary, the irregularity of the daily quantities in urine defines fluctuation of Cl’ balance. If the concentration of Cl’ is held stationary in extracellular fluid, gain or loss must measure corresponding change in volume. This inference is supported by the large Changes in urine Volume Which roughly parallel the upS and downs of Cl’excretion (the scales of the ordinates are so ad- justed that m—eq: cc = O. l; l.0, approximately the concentration of Cl’ in extracellular fluid). Change in urine volume in the presence Of a fixed Water intake Cannot be taken as Ciependably measuring gain or loss of body water because of variability of the value for the large part of the water intake (1/3 – 1/2) which is removed by Way of the Skin and lungs. Close correlation of change in urine volume and change in Cl’ excretion would therefore not be expected. Extrarenal loss of Water by this subject was, however, not widely enough irregular to appreciably mask the urine volume – Clſ relation- ship. The data clearly permit the inference of a considerable day to day change in the volume of extracellular fluid. CHART 32 Day to day change in the total Water content of the body is fairly closely defined by change in body weight. A rough measure— ment of change in the balance of sodium, the dominant extracellular ion, can be obtained by comparing the quantity found in a twenty- four hour Specimen with Uhe average value for a period of days dur- ing Which Sodium intake is stationary. Irregularity in the rela— tively Small quantity of sodium lost in the feces and by way of the Skin is here ignored. The chart records daily measurements of gain or loss of body Weight and of sodium, obtained from an obese subject Who exhibited Weight fluctuation of rather unusual degree. Food (composition and quantity) and water intake were accurately con– stant. After an eight-day period, body fluid adjustments were placed under unusual stress by the ingestion of 20 gm; NaCl daily for three days, and in a final period 12 gm. NH4Cl were given daily. DAY TO DAY GAIN OR LOSS OF SODIUM AND OF BODY WE | GHT. BODY Na WT. meet GM. Q - 15OO 2OOH- SODIUM O BODY WEIGHT O |50 H. +|OOO |OOH- Ö - 500 5OH § t § $ !- O O 5O C 8 look 8 $ oo |- |50H - |OOO 2OOH SUBJECT PD. 2O GM. |2 GM. CONSTANT DIET. NaC) NH4C) -1500 25OH DAILY DAILY | I 1 I | 1– | | | | | | | I L | DAYS | 2 3 4 5 6 7 8 9 |O || 12 13 || 4 |5 16 ON BODY WEIGHT ORDINATE I.O GM. = O. |47 m-eq}sodium. CHART 32 CHART 32 (Continued) The scale of the sodium ordinate is so adjusted to that of body Weight that 0.147 m-eq. corresponds to l.0 gm. This is taken as the quantity of sodium in l.00 cc. of interstitial fluid (Chart 2). If body weight loss is composed of extracellular fluid, the two measurements should fall together on the chart. Over the eight-day period of quite usual water-salt intake, there is rough agreement. On the first day of additional Salt ingestion there occurs a large gain in body Weight and a much larger gain in SOdium. EXplanation of this discrepancy between the two measurements is provided by the Darrow diagram (Chart 14). The sudden large addition to extra- cellular electrolyte has made necessary a transfer of water from the intracellular to the extracellular compartment. The increase in eXtracellular fluid volume resulting from this transfer is not reg- istered by body weight change. Also, as seen in Chart lå, Water transfer does not entirely prevent change in total electrolyte con- centration. Both of these events interfere with correlation be- tween change in Water and sodium balances. By the third day of salt ingestion the measurements again coincide, indicating that the kidney has regained parallel control of Water and salt. But, with abrupt cessation of the high salt intake, discrepancy again develops in the presence of a large diures is accompanied by a larger loss of SOCl illm. These data make it clear that under ordinary circumstances change in water balance (as defined by body weight) is almost en- tirely referable to change in volume of extracellular fluid. When, however, extensive adjustment by Water transfer is necessary, change in Water balance does not closely follow change in extracellular fluid volume. This is more nearly defined by change in sodium balance, but with an unsatisfactory accuracy because of appreciable Change in Sodium concentration. Moreover the effect of another event, a large increase in the excretion of the intracellular base, potassium, during the periods of salt ingestion, must be appraised. In the next Chart a description of body fluid changes in this sub- ject, taking into account these several variables, is presented. The following table gives the measurements from which are derived the data recorded in this chart, and in the three charts Which follow it. CHART 32 (Continued) Day | BOCly Wt, gm, Sodium, m-eq. Potassium, m-eqe 97.386 + in urine. 4.93% in urine. +6l.4 | | 966.96 -690 186 –93 59, 9 + 1,5 2 |96386 –3LO 14l –48 66.9 - 5.5 3 || 965O6 +12O 97 — 4 64.5 – 3. 1 4 || 96336 —17O 86 + 7 69.9 — 8,5 5 || 96786 1450 42 +51 53.2 + 8.2 6 || 96676 – 110 8O +13 54.8 + 6.6 '7 | 96676 + O LO7 –l4 57.8 + 3.6 8 || 96226 —450 | 175 –82 64.3 – 2, 9 . . 9 96.896 +67O 22O +218 || 74.9 —l3.5 s s 10 | 96676 –220 509 –7]. 89.5 –28, l in loºse -ºo a -º 72.8 —ll, 4 12 | 94746 -1590 273 1850 52.8 + 8.6 13 94.866 + l2O 94 - 1 40,6 +20, 8 © 14 || 94526 –340 138 –45 89, O —l 7.6 º; 15 || 93976 –550 l44 –5l. 133 e O -71.6 r– 16 || 93726 –250 86 + 7 1OO ... O –36,6 * This quantity is taken as the daily intake of Na exclusive of the feces and Skin. small portion lost by Way of the from the m-e Q. Na. 345 = 438 m-eq. Total body weight loss, 914–170 = 744. tion the daily intake ll60 gm. iS Obtained total excretion in urine over the 8-day fore period cor— rected for Na lost from the body (Total Na excretion in urine, 914 lló0 X 0.147 = 170 m—eq. 744/8 = 93.) During the period of NaCl inges— of Na regulatable by the kidney becomes 93 + CHART 33 Using the Darrow-Yannet diagram (Chart l4), body fluid dimensions may be indicated as follows: C Bl = total extracellular electrolyte Vl = extracellular fluid Volume C = electrolyte concentration B2 = total intracellular electrolyte V2 = intracellular fluid volume In deriving the data recorded in the chart, the following approximations are used: change in total Water content of the body (V1 + V2) is measured by change in body Weight, change in total ex- tracellular electrolyte (E1) by change in sodium balance, and change in total intracellular electrolyte (B2) by change in potassium bal- ance. At the outset of the period of Study the Subject was provided with the following set of body fluid dimensions: vi = 16 liters 2 * 32 liters (50 per cent of pre-obesity weight, 64 kilograms); C = 310 (Chart 2); E1 = 4960 milliosmols (16 x 3.10); B2 = 9920 milliosmols (32 x 3.10). Change from these initial values was then additively computed day by day. The values for C, V1 and V2 Were obtained as follows: V1 + Ve/El Be = C, E/C = V1, E2/C = V2. The results of this process of description are shown in the chart. Over the eight days of normal circumstances, extracel- lular fluid Volume exhibits a large and slow moving fluctuation which corresponds closely with change in body weight. The slight eXtent of adjustment by Water transfer is shown by the small oscil- lations Of intracellular fluid Volume. With addition to extracel- lular electrolyte there occurs a large transfer of intracellular Water Which a CC Ounts for the increase of eXtracellular fluid volume beyond the extent defined by increase in body weight. (directly measured by the thiocyanate method); V | -1335 GM. - * C.C. -7 500 H. Nac / NHacı 20 GM. DALY.; 12 GM. DALY. O t 33O 5OO |OOO | +325 15OO | \ É | \ E ...] – INTRA-c-FL. | ; : —l 2OOO e—e EXTRA-C-FL. ...,’ É -----. Body weight 25OO | § 2, É | 'e-- ~ —l \ O | • > 3OOOH | \, 3 ! \ —l SUBJECT P D \ =! 35OOH c - Z tº | \ |= * 1315 4OOOH ,' - 314 NI à - 313 IO g con E - 312 2- | -|3|| é N-7 ~ 3|O J – 309 DAYS, O I 2 3 4 5 6 7 8 9 IO II 12 13 14 15 16 CHART 33 CHART 33 (Continued) In the lower part of the chart the calculated values for total electrolyte concentration are recorded. They show the excel- lent defense of the usual concentration level. Even during the periods of stress produced by salt ingestion, departure is only to the extent of 4 – 5 milliosmols per liter from the usual value of 310. The broken line shows the change in extracellular electrolyte concentration Which would have occurred in the absence of adjust- ment by Water transfer. CHART 34 The daily values for excretion of potassium in urine are given in the upper section of the chart. They show extensive in- crements during the periods of Salt ingestion. In the lower sec- tion, the calculated values for total ionic concentration in the body fluids, seen in the preceding chart, are again recorded. If the change in potassium excretion is omitted from the calculation of total ionic concentration, the values estimated from Sodium ex- cretion alone produce the broken line on the chart. A relationship of removal of intracellular electrolyte to preservation of the nor- mal total ionic level is clearly evident. Following the rise in Concentration at the outset of each of the periods of salt ingestion a return toward the uSual Value is seen to Coincide With an in- creased excretion of potassium. From this chart and the preceding One it is evident that neither the volume nor total electrolyte of intracellular fluid is maintained independently of events occurring in extracellular fluid. 120 4.6 OO Eºº 2 O POTASSIUM EXCRETION |N URINE. NaCl DA|LY NH2Cl DAll Y SUBJECT P.D. O |ONIC CONCENTRATION |N BODY FLUIDS. ASS 2 PRODUCED BY; Aſ •—e VOLUME ADJUSTMENTS TO CHANGE IN (Na) AND (K). e---e VOL. ADJ, TO CHANGE IN (Na) IN ABSENCE OF CHANGE IN (K). 3| 6 1— | ſ l | DAYS 7 8 9 |O || |2 [3 |4 |5 #TÉ 32O 3| 8 3| 4. CHART 34 Chart, 35 In order to place the changes in volume of extracellular fluid shown in Chart 33 in a proper perspective they are here re- COrded With reference to the initial total Volume. The fluctuations are seen to be relatively small, even When volume adjustments are under unusual StreSS. The diagram makes clear the great Width Of the reserve of extracellular fluid in the interstitial compartment. In the presence, however, of abnormal circumstances which interfere with the water exchange of the body, losses from this reservoir may be rapid and extensive. Water expenditures per twenty- four hours for an adult Ordinarily amount to 2–3 liters. The rate of loss is enormously increased by heavy work especially in a hot environment. Dill, in his studies at Boulder Dam, found expendi- tures of 8–12 liters daily; almost the volume of the interstitial reserve. It is thus clear that complete or partial absence of water intake will cause more or less rapid reduction of extracel- lular fluid volume. In many conditions of disease there is inci- dental interference with Water intake. Surgical procedures may re- quire the absence of water ingestion over prolonged periods. In addition to failure of replacement of water expenditures, direct withdrawal of extracellular fluid may occur under the circumstances described in the next chart. Loss of body fluid is described by the term dehydration. An important feature of any process of dehydration is that the Water loss is always accompanied by a corresponding loss of electrolyte. This is a consequence of renal control of total ionic concentration. In the presence of change in volume of extracellular fluid, the kid- ney attempts to defend the normal osmotic value by removing either water or electrolyte as circumstances may require. For instance in the simple situation of absence of water intake, the primary event is Water deficit in the body from continued Water loss by the lungs and skin. Preservation of the normal total iOnic Concentration re- quires removal in urine of an equivalent quantity of electrolyte. Dehydration is therefore an incomplete term since it does not in- dicate the accompanying loss of electrolyte. A therapeutic corol- lary of fundamental importance is that dehydration cannot be re- paired by Water alone; the lost electrolyte must also be replaced. 2O GM. 12 GM. SUBJECT P. D. ſº lº 12 H. | | H INTERSTITIAL |O H. FLUID 9 F ? & H —l 6 H 5 me 4 H. 3 - 2F BLOOD PLASMA | H. g DAY | 2 3 4 5 6 7 8 9 TO || 12 la lé. I5 16 CHART 35 CHART 36 Clinically, much the most frequent cause of severe de- hydration is disturbance of gastro-intestinal function to the ex- tent of producing continued vomiting or diarrhoea. The gastro-in- testinal secretions, aside from their enzyme content, are con– Structed from Water and elee trolytes taken from the blood plasma. Under normal circumstances, these materials are reabsorbed. Inter- ference with their return to the plasma will therefore cause a pro- gressive withdrawal of extracellular fluid. That loss of gastro- intestinal Secretions is a quantitatively adequate eXplanation Of eXtensive dehydration is clearly evident from the values given in this chart for the quantities of these secretions produced in twenty- four hours. Together they produce a total volume which is more than twice that of blood plasma or nearly two-thirds of the interstitial reserve. It is thus evident that interference With this circula- tion of water and electrolytes between the gastro-intestinal tract and the vascular compartment Will set up a rapid process of With- drawal of extracellular fluid. Moreover Circumstances Which pro- duce wastage of gastro-intestinal. Secretions usually also more Or less interfere with fluid intake, so that there is additional Water loss from failure of replacement of expenditures by the kidneys, lungs and Skin. TOTAL VOLUME OF DIGESTIVE SECRETIONS PRODUCED IN 24 HRs BY ADULT OF AVERAGE SIZE SALIVA, 15OOCC. GASTRIC SECRETIONS, 25OOCC. BILE, 5OOCC. PANCREATIC JUICE, 7OOCC. SECR. OF INTESTINAL MUCOSA, 3OOOcc. 82OOCC BLOOD PLASMA VOLUME, 3500CC. CHART 36 CHART 37 In these diagrams the relative amounts of Sodium, chloride ion, and bicarbonate ion in the digestive secretions are shown. The sums of the other anion and cation components are indicated at the foot of their respective columns. These remainders are estimated from incomplete data but are probably near the Values given. The total quantity of electrolyte in the secretions, as shown by the heights of the diagrams is closely the same as in blood plasma. Also, as in plasma, the large components of their structure are (Na), (C1) and (HCO3). The diagrams make clear that failure of re- absorption of these secretions will withdraw Water and total elec- trolyte from extracellular fluid in approximately plasma proportions and that the significant electrolyte loss will be almost entirely composed of sodium and chloride ion; the bicarbonate ion in the Se- cretions, derives from the circumambient H.HCOg and has no relation- ship to (HCO3) in extracellular fluid. The important feature of the composition of these secre- tions from the point of view of structural change in extracellular fluid is departure of the (Naſ); (CIſ) ratio from its plasma value. This is conspicuous in gastric juice and in pancreatic juice; in the other secretions the relative quantities of Na and Clſ are roughly the same as in plasma. It is clear from the diagram Of the gastric juice that loss of this secretion will cause a much more rapid With- drawal of Clſ than of Na' from plasma. It is probable that actually there is no Na in the acid secret iOn from the digestive glands Of the stomach. The small quantity shown in the diagram may be ex- plained by admixture of the alkaline secretion of the gastric mucosa, the composition of which is described by the next diagram. The specimen from which these measurements were obtained Was taken from an isolated pouch constructed in the pyloric antrum, in Which region there is no secretion of the true juice. Ordinarily the relative quantity of this secretion is small, but in the presence of irritative conditions Which provoke vomiting it becomes much larger and may reach a volume of about one-half that of gastric juice. There is therefore, with vomiting, a loss of Na’ which may be approx– imately one-half the loss of Clº. Because of the dominating rela- tionship of Na to total ionic content of extracellular fluid (Chart 6), it is this loss of Na’ which is significant as regards extent of dehydration. Diarrhoea causes loss of pancreatic juice which con– tains Na’ in much larger excess of Clſ than plasma. Gastric Juice, and all of the other intestinal secretions are, however, also ex- posed to loss, so that Na" and Clſ are withdrawn in roughly their plasma proportions. ELECTROLYTE COMPOSITION OF GASTRO-INTESTINAL SECRETIONS :..]--------------~~~~~~...~~~~~ |Éſ º TTTTTTTTE: "TTTTT. ::::::: . . . **** **, ::::::::: ::::::: Høg . . . . § :::::::: § ſº © e e & e º e s • :::::: . . ' ci' º: Cl’. * . . . * * TT|, . . . . . . ~ BLOOD GASTRIC GASTRIC PANCREATIC HEPATIC DUCT JEJUNAL PLASMA JU ICE MUCUS JUICE B|LE SECRET |ONS CHART 37 CHART 38 The data in this chart will serve to illustrate the rapid- ity of loss of eXtracellular Water and electrolyte When tº: tion of gastric secretions is prevented. They were obtained from rabbits following obstruction of the pylorus by ligature. Rabbits do not vomit and Secretions are not to an appreciable eXtent reab- sorbed by the gastric mucosa. The St Omach therefore collects and becomes enormously distended by the Secretions entering it follow- ing obstruction of pylorus. The animals were sacrificed near the end of the survival period and the quantities of water, fixed base, and chloride ion found in the St Omach Were measured and are recorded in the table. The fixed base is almost entirely composed of sodium (Chart 37). Estimations of the quantities of Water, fixed base, and chloride ion in the plasma before obstruction of the pylorus are also given in the table. As may be seen, the loss of fixed base is twice the initial plasma content and is accompanied by a somewhat larger loss of Water. These measurements describe an eX—, tensive depletion of interstitial fluid in support Of the blood plasma. The volume of interstitial fluid is about three times that of blood plasma (Chart l). These data therefore indicate a removal of two-thirds or more Of the interstitial reservoir. AS regards the rapidity of this process of dehydration by loss of stomach se– cretions, it may be noted that the survival period of these animals was from 36 to 42 hours . These measurements make Clear the dan– gerous situation of an infant suffering from diarrhoeal disease Who ** losing not only gastric but also duodenal and upper intestinal Secret iOnS. The quantity of chloride ion found in the Stomach is nearly four times the initial plasma content. This much more rapid loss Of chloride ion than Of fixed base Causes the Structural dis- tortion shown in diagram 3, Chart 6. So that, in addition to the volume change (dehydration) caused by loss of Water and fixed base, there is also reaction change (alkalosis). LOSS OF WATER, FIXED BASE AND CHLORIDE | ON IN GASTRIC SECRE- TIONS FOLLOWING PYLORIC OB - STRUCTION. (DATA FROM RABBITS) WATER LOST, 2O3 CC. INITIAL PLASMA VOLUME, 83 CC. FIXED BASE LOST, 27O CC, O.IN INITIAL PLASMA FIXED BASE, 14OCC. O.IN CHLORIDE ION LOST 3O9 CC. O.IN INITIAL PLASMA CHLORIDE ION, 85 CC. O.1N AV OF VALUES FOUND IN FOUR EXPERIMENTS CHART 38 CHART 39 This chart describes the results of an experiment. Which illustrate the defense of blood plasma Volume and composition by the interst, it idl fluid reservoir. Dehydration Was produced at a gradual rate by draining away the external secret ion of the pancreas through a fistula. The animal, a dog, was fed minced and Washed meat. Which provided almost no intake of sodium. Water was given freely. Dehydration resulting from the continued loss of sodium in the pancreatic juice is described in the chart by the fall in body Weight, which, it will be noted, began at the outset of the experi- ment. The Other Curve in the Chart, is COnStructed from a series Of measurements of plasma protein concentration. Regarding plasma pro- tein as an index of plasma volume, no change is observed until the tenth day of the survival period. Then, over the several remaining days, the curve rises extensively, indicating a rapid reduction of plasma VOlume. Other measurements showed an accurately sustained Composition Of the plasma Over the lC)-day period. Structural de- fects then developed rapidly and there was eventually severe acid— O Sis, The experiment illustrates the successful defense of the plasma Oy the interst, it ial reservoir until its Water and materials are exhausted, or nearly so. From the clinical point of view, this excellent support of the plasma explains the symptomless early stages of dehydration followed by the sudden development of the alarming manifestations Of failure Of the funct iOns of the blood When the volume of the plasma can no longer be sustained. CHART 40 In the presence of change in extracellular electrolyte, defense of the osmotic value of the body fluids may require not only Volume adjustment by Water transfer but also removal of intracel- lular electrolyte (Chart 34). It is therefore not surprising to find that dehydrating processes cause loss of potassium along With the much larger loss of sodium. Removal of intracellular base im— plies an accompanying Withdrawal of Water. It is thus evident that the interstitial reservoir does not completely defend intracellular Volume. Estimation of the extent of water loss from the body and of its partition as regards source may be obtained from measure- ments of loss of Na' and of K on the assumption that the accompanying EFFECTS OF CONTINUED LOSS OF PANCREATIC JUICE. WT. LOSS, PLASMA PROTEIN, KG. % I.O- FI2 2.O- -|| 3.O- -IO PLASMA PROTEIN. 4.0- -9 DAYS OF EXPERIMENT. iT:TâTAT5 T5 TFT & 5 to TTT2 TET: CHART 39 CHART 40 (Continued) losses of water Will be of Such extent as to preserve the normal concentrations of Na' and K in extracellular and in intracellular fluid respectively. This is not a precise premise because it ig- nores losses of the smaller components of the fixed base of the body fluids (Chart 2) and also the probability of Some degree of depar- ture of total ionic concentration from its normal Value in Situa- tions which place body fluid adjustments under unusual stress (Chart 33). Illustration of the rough description of body fluid water losses which this method of estimation provides is given by the di- agrams in the chart. The data are from the child with chronic ne— phritis and edema Whose losses of fixed base in urine during a pe— riod of CaCl2, administration are recorded in Chart. 30. In the first section, the increments (over foreperiod values) in the removal of Na and of K, the two chief components of the fixed base excretion, are Superimposed. The estimations of the accompanying Water losses are recorded in the Second Section. These are derived from the value for (Na) in interstitial fluid (0.147 m—osM/cc) and for (K) in intracellular fluid (0.150 m-osM) given in Chart 2. According to these data, removal of interstitial fluid by CaClo diures is also causes a considerable withdrawal of intracellular "fluid. Since, however, intracellular fluid volume is two and one-half times that Of eXtracellular fluid the eXtent of reduct iOn of cell Volume is proportionately Smaller. To illustrate application of this method of study to sit- uations of severe dehydration, data from an infant With diarrhoeal disease may be cited. Loss of Na’ in urine and stools over a 24– hour period was found to be l4.3 m-osmſ, defining a loss of 97 cc, of extracellular Water (14.3/0.147). The loss of K was 12.0 m-osm, indicating a loss of 80 cc. of intracellular water (lz.0/0.150). OWing to the Situation of starvation, however, consumption of body protoplasm Will cause a release of K" and of cell water which is not related to processes of dehydration. This quantity of water may be Computed from the nitrogen excretion; gm. N x 29.5 = gm. protoplasm of which 76% is Water. Using the value found for N loss; l.2 x 29.5 X 0.76 = 27cc . Subtracting this quantity from the total loss of intracellular Water estimated from K produces a value of 53 cc. of Water Withdrawn from the intracellular compartment along with the loss of 97 cc. of eXtracellular Water. Appreciation of the rate of dehydration is gained by referring this quantity of water lost per twenty-four hours, 150 cc, to the body weight of the infant which Was 2700 gm. REMOVAL OF EXTRACELLULAR AND OF INTRACELLULAR FLUID | N CaCl2 D1URESIS. EST IMATED FROM LOSSES OF Na AND K'. 6OO- 550- | OO- 5OO- 90- 450- 8O- :::::: 4OO- 7O- . . . . 35O- 3OO- 6 O - § Na. . . . . " 25O- 5 O * i 4O- - || | | | | 2OO- | 50- 5O- DAYS l 2 3 CHART 40 CHART 4.l. The immediate cause of deviation of hydrogen ion concen— trat iOn in extracellular fluid from the normal Value is almOSt. al- Ways change in the denominator of the (H.HCO3): (B.HCO3) ratio. De- crease in (B. HCO, ) causes an increase in hydrogen ion concentration which is described as acidosis, and increase the reverse change, alkalosis (Chart 4). This change in bicarbonate is, however, never a primary event. It is always a response to change in some other part, or parts, of the electrolyte structure and constitutes an alert and vitally important defense against reaction change of dis– astrous degree (Chart 6). Study of the pathogenesis of acidosis or alkalosis there- fore consists in ident ification of the underlying defect in plasma structure Which has made necessary the compensatory change in bi- carbonate and then in explanation of the development of this defect in terms of the accompanying abnormal circumstances. These are many and Various. They may conveniently be grouped under three headings : I. Impairment of Renal Function. With the exception of protein, carbonic acid and bicarbonate ion, the normal val— ues for the components of the electrolyte structure of extra- Cellular fluid rest directly On renal control. It is therefore not surprising to find that disease of the kidney may permit the development of Various defects. Another prominent cause of Structural change in extracellular fluid is a secondary dis– turbance of renal function found in the advanced stage of de- hydration. Eventual reduction of the Volume of blood plasma by the process of dehydration causes physical changes in the blood, and in the mechanics of its circulation, which greatly reduce Volume flow through the kidney With the result that ac- curacy of renal function is extensively impaired. In this group also may be placed the defect in renal control seen in Addison's disease Which seems to be due to a failure of horm- Onal as Sistance. II. Loss of Gastro-Intestinal Secret ions. Many condi- tions of disease may disturb gastro-intest inal function to the extent of causing continued vomiting and diarrhoea and thus set up a process Of Withdrawal of Water and electrolytes from extra- cellular fluid (Charts 36, 37, 38 and 39). Besides the changes in extracellular fluid directly caused by losses of its compo- CHART 41 (Continued) nent materials, the accompanying dehydration may eventually pro- duce, as mentioned above, further defects of structure by dis– abling renal control. III. Abnormal Acids in Extracellular Fluid. These are usually the ket. One acids Which appear in extracellular fluid Whenever carbohydrate metabolism falls below the level required for the Complete Oxidation of fat. The ket. One acids must be given place in the electrolyte structure While being carried to the kidney for removal in urine. Identification of the plasma defect which has caused an observed change in bicarbonate theoretically requires a complete dissection of the electrolyte structure. Fortunately, however, a falrly satisfactory account of the bicarbonate change can be ob- tained from three measurement, S. The sum of the values of Na’, K’, Ca” and Mg" (total fixed base) can be measured in a single pro- Cedure. Change in this value can be referred almost dependably to its dominating component, sodium. Change in the relatively very small concentrations of the other three cat ions of a magnitude which Would appreciably alter the concentration of bicarbonate ion is Very unusual. The other tWO measurements required are of bicarbon- ate iOn and Chloride iOn. If the sum of the Values found is Sub- tracted from the value for total base, a measurement of the combined base equivalence of HP0; 9 S04 , organic acids, and protein is ob- tained. The diagrams in this chart and in several which follow it are constructed from measurements of total base, bicarbonate ion, and chloride ion obtained from individual patient, S. Total base iS designated B, and the remainder of the acid column, which contains the relatively small and individually unmeasured anion values, R. The second diagram in the chart is constructed from meas— urements obtained from a patient suffering With the nephrotic type of renal disease and describes the changes in plasma structure which are fairly regularly found. These are a small reduction of base, a considerable extension of (Cl’) and a relatively large reduction of (R). The decrease in (R) is referable to the low plasma protein which is characterist ic Of this disease. Increase in (Clſ ) is a rather unusual structural change in plasma. It is possible that here this change and the inverse change in base are referable, not to renal control, but to preservation of the normal osmotic value in the presence of decrease of plasma protein. If the loss of multivalent i Ç : i ; CHART 41 (Continued) protein were completely replaced by univalent ions, total ionic concentration would be above the normal value (Chart 2). The net result of these changes, as regards (HCO3), is a moderate reduction. In chronic nephritis, a large variety of plasma defects have been Observed. The change which is perhaps most consistently present is an extension of (R). It has been found that this is com- posed of increased concentrations in the plasma of HP0; and S04, and probably of Organic acid radicalS. The increase in (R) as shown jn the diagram produces an approximately equivalent reduction of (H003) and explains the moderate degree of acidosis often found in the Course Of Chronic nephrit is. The measurements in the last diagram are from a patient in the terminal stage of chronic nephrit is. The very small bicarbonate concentration, which represents an extremely severe acidosis, is seen to be caused by two structural changes, an enormous extension of (R) and a large reduction of base. These changes result from errors in renal control in opposite directions. Extension of (R) represents failure to restrict the concentrations Of HP04 9 S04 , and organic acid to their normal relatively very small values. Reduction of (B), on the other hand, describes inad- equate support of the largest component of plasma structure, sodium. Renal disability conventionally connotes inadequate removal of ma— terials from the plasma ("retention"). It should, however, not be surprising to find the inverse error in control, especially if it be recalled that plasma values are not established by a process of direct removal of surplus, but by reabsorption minus surplus from tubular fluid. The relatively enormous requirement for the reab- sorption of sodium and its companion ion, chloride, is shown in Chart, 17. mEq/L NORMAL NEPHROSIS CHRONIC NEPHRITIS CHART 4| CHART 42 The measurements from an infant, who habitually VOmited a large part of his feedings show a moderate extension of (HC04) pro- duced by a corresponding recession of (C1'). The reduct iOn Of chloride ion is referable to a Small but continued Wastage Of gas- tric secret ions. This loss of chloride ion is a CCOmpanied by a much smaller but appreciable loss of sodium (Chart 37). OWing to the close relationship of (B) to the osmotic value of the plasma (Chart 6), the water content of the plasma is adjusted by the kidney to the loss of sodium with the result that, as may be seen in the dia- gram, the normal value for (B) is sustained. The diagram constructed from measurements from a patient with complete obstruction of the pylorus, shows as a result of pro- tracted vomiting of stomach secretions a reduction of (C1') to about One-third Of its normal Value. The compensatory extension of bi— carbonate represents an extremely severe degree of alkalosis. TWO other structural changes are recorded in the diagram, a considerable reduction of (B) and a large increase in (R). These two changes were seen in the preceding chart in the diagram describing plasma defects found in advanced nephritis. Their appearance in the plasma of the patient With pyloric obstruction indicates severe disability of renal control caused by advancement of the process of dehydra- tion, by loss of stomach secretions, to the stage of reduction of the Volume of the blood plasma and of volume flow through the kid- ney. In the early stages of dehydration plasma Volume is Well sus- tained (Chart (39) and, as seen in the preceding diagram, renal con- trol of (B) and (R) is accurate. In the diagram describing the plasma of an infant suffer— ing from severe diarrhoeal disease, these charges are again seen and are here also referable to an advanced stage of dehydration caused by loss of digest ive secret ions. Since in duodenal and upper inte St, inal Secret, iOnS there iS rather more Of SOClium than Of Chlor- ide ion (Chart 37), the recession of (C1') produced by loss of gas- tric secretions is not seen, and acidosis is found instead of alka- losis, the bicarbonate reduction being referable to the two changes, decrease in (B) and increase in (R), indirectly caused by the process of dehydration. It should be noted that the large extensions of (R),seen in the last two diagrams, are not entirely composed of increments Of HP04 9 SO; , and organic acids, as in chronic nephritis (preced- ing chart ), but are also to a considerable extent referable to in- crease in the concentration of protein caused by reduction of plasma volume (Chart 39). HABITUAL PYLORIC D|ARRHOEAL mEq/L NORMAL VOM |T|NG OBSTRUCTION DISEASE |6O 15O |4O |3O |2O | |O |OO 90 80 7O 6O 5O 4O 3O 2O |O S R CHART 42 CHART 43 In diabetes, ketosis results from a failure of the oxida- tive processes of carbohydrate metabolism. In many other condi- tions of disease, ketosis may result from a lack Or inadequacy of carbohydrate intake. Complete or partial starvation is often an in- cident of disease proCeSSes. Children exhibit, ket, O'SiS much more frequently than adults. Apparently, during childhood, even very short periods of carbohydrate deprivation may lower the level of carbohydrate metabolism to the point where incompletely oxidized fatty acids begin to appear in extracellular fluid. These ketone acids must be given space in the electrolyte structure of the plasma and this space is provided at the eXpense of the concentrat iOn Of bicarbonate iOn. The measurements used in constructing the diagram which describes the ketosis of fasting Were obtained from an epileptic boy Who Was fasted as a therapeutic measure e As may be seen, the only change in plasma structure is reduct iOn Of (HC04) to an extent corresponding to the base equiva- lence of the ketone acids. The next diagram shows the complete re- moval of the ketone acids, and return of (HCOg) to its usual value, produced by providing, over a l?-hour period, a small intake of carbohydrate (50 gm. cane Sugar). The last diagram in the chart describes the extensive structural changes found in the plasma of a child in diabetic coma, Which have together produced an extremely severe acidosis. Besides the very large accumulation of ketone acids, two other changes, de- crease of base and increase in (R), have contributed to the reduc- t iOn Of (HC04) to a very dangerously small value. These two changes are referable to renal disability caused by the rapid dehydration which is always a prominent feature of the situation in diabetic COIſla e * mEO, /L KETOSIS OF EFFECT OF D|AEETIC Q/ NORMAL FAST|NG GLUCOSE KETOSIS | 6O CHART 43 CHART 44 Since the Space Which the ket. One acids OCCupy in the elec- trolyte structure of the plasma is always at the expense of bicar- bonate, the inference is produced that ketosis regularly causes acidosis. This is usually, but not always, the case. The second diagram in this chart shows ketosis of severe degree in the presence Of alkalos is. The measurements are from a Child Who Was found tº O have an Obstruct iOn Of the duodenum. The ket, OS is is referable to StarWat iOn incident, al to the Obstruct iOn. The accumulat iOn Of ke— tone acids, although large, is not so large as the recession of chloride ion, caused by loss of stomach secretions by Vomiting. EX- tension of bicarbonate is therefore necessary. Not infrequently, especially in children, ketosis develops, as illustrated here, in the presence of other processes of distortion of plasma structure. It is therefore evident that the presence of ket. One acids in the urine does not dependably establish a diagnosis of acidosis. The next diagram in the chart shows the change in plasma electrolyte structure which is characteristic of Addison's disease; a very large reduction of base (at the expense of sodium). This is accompanied by an equivalent recession of chloride ion which almost completely preserves bicarbonate. The moderate Treduction of bicar- bonate, according to the diagram, is referable to an increase in (R). The findings in Addison's disease indicate that renal support of the normal osmotic pressure of the plasma by integration of Water and electrolyte removal is assisted in some Way by the adrenal cor- tical hormone. In its absence there is Wide discrepancy in the COn- trol Of Water and SOClium. The almost determining relationship of the backbone of the electrolyte structure, sodium, to the osmotic value of the plasma has been considered (Charts 6 and 14). The last diagram in the chart explains the reduction of plasma bicarbonate caused by ingest ion of (CaCl2, One Of the SO- called acid-producing salts. As has been considered (Charts 29 and 30), these salts introduce chloride ion into extracellular fluid un- accompanied by the ingested base. The amounts of these salts given for therapeutic purposes are so large as to require a very consid— erable increase in the level of chloride iOn transport in extracel— lular fluid. As may be seen in the chart, this extension of (Cl’) causes an equivalent reduction of (HCO4). In the instance described by the diagram, the therapeutic use of CaCl in a large dosage caused the reduct iOn Of the plasma bicarbonate to about one-third its usual Value. \94. . DUODENAL ADDISON'S CHLORIDE mEq/- NORMAL ošºon ºf ACIDOSIS CHART 4.4 CHART 44 (Continued) (The diagrams in Charts 41–44 illustrate (B.HCO3) adjustment to change in the components of the ionic structure under renal control. It should be remembered that, as shown in Chart, lº, Change in (B.HCO3) is occasionally compensatory for inaccurate respiratory C Ontrol Of (H.HCO3 gards initial direction of reaction change; i.e. increase of (B.HCO3) ) and it then has the reverse significance as re- indicates acidosis and decrease indicates alkalosis.) CHART 45 In situations of extracellular fluid disturbance Of Such severity as to require energetic parenteral therapy there is , as indicated in discussion of the several preceding Charts, nearly al- ways requirement for restoration of volume along With repair of a large variety of structural defects. Ideal therapy would therefore seem to consist in the use of a replacement; SOlution designed to repair the defects found in an individual situation Or, as an ap- proximation, a solution containing all of the materials used in plasma Structure. A solution of the elaborate type used in perfu- sion experiments, Ringer–Tyrode's solution, is described in the chart, and, as may be seen, it contains nearly all of the parts of the electrolyte structure of the plasma in roughly corresponding relat, iWe amount, S. It may, however, be dependably expected that, with the exception of the two extracellular ions, sodium and chloride ion, which have no source of replenishment, all of the other smaller structural parts Will be Supplied by the processes of metabolism which carry on even in a situation of starvation (Chart 23). It, therefore does not seem necessary to place them in a repair solu- tion. The apparent complexity of the therapeutic requirement, thus disappears and the indicated agent of repair is simple physiological salt solution, on the basis of the expectation that if Water, sodium, and chloride ion are supplied abundantly, the kidney Will so regu– late the retention of these materials individually (Chart 25), and of the materials contributed by metabolic processes, that extracel- lular fluid VOlume Will be rest Ored and all defects Of Structure re- paired, with the result that bicarbonate ion concentration will be permitted to resume its usual value. mE BLOOD º/- PLASMA REPAIR SOLUTIONS |50- HCO, |40- HCO LAC- |3O- TIC ACID 120- *| |NalCl Na Cl' | |Nal Cl’| |Na Cl' 4O- 3O- 2O- RGAc' to: K- PRO- K. S Cas TEIN CaS Caº Mg. M% 2HPO. M3S RINGER-TYRODE'S PHYSIOLOGICAL HARTMANN'S LACTATE- SOLUTION SALT SOLUTION RINGER'S SOLUTION CHART 45 CHART 45 (Continued) This expectation obviously requires an alert and Capable kidney. As has been considered, there is in advanced dehydration extensive impairment of renal function. A second and Very important therapeutic requirement is, therefore, restoration of renal accur- acy of COntrol over the parts of plasma structure. This requirement is very effectively met by the intravenous administration of an iso- t Onic Solution Of glucose. Glucose solution, besides assisting in the restoration of plasma Volume and Volume flow of blood through the kidney, provides a surplus of Water for removal by the kidney which presumably facilitates an accurate construction of urine. Glucose also inoident, ally demolishes an accumulation Of ket. One acids in the plasma, if present; the only defect of plasma structure which salt solution cannot repair. Nearly all situations of severe disturbance of extracel- lular fluid Volume and structure can be rapidly repaired by the use together of these two simple agents, salt solution and glucose sol- ut iOn. In the presence of very severe acidosis the use Of a third agent, sodium bicarbonate solution, is indicated as an initial pro- cedure With the purpose Of Sustaining the plasma bicarbonate until the reparative effects of Salt Solution and glucose solution have been Obtained. Instead of sodium bicarbonate, the ingenious solu- tion devised by Hartmann may here be appropriately used. The essen- tial feature of Hartmann's solution, as may be seen in the chart, is that it contains Sodium lactate along With sodium chloride. The lact, iC a Cid radical is OXidized after absorpt iOn and bicarbonate ion takes it, S place. CHART 46 º The means at hand for replacement Of the internal medium are, owing to the alertness and the capacity of renal regulation, eXtremely simple and practicable and are often quite dramatically life Saving. The diagrams in this chart will serve to illustrate the rapidity Of their effectiveness. The patient was a three-year- Old Child in diabetic coma, extremely dehydrated and with only a Small remnant of plasma bicarbonate. As shown by the diagrams, an almost complete repair of plasma structure was obtained in the course of eight hours. Unseen in the chart, there was an equally important large progress toward restoration of extracellular fluid VOlume. DIABETIC ACIDOSIS AND EFFECTS OF TREATMENT NORMAL 2 PM. 6 PM. |O PM. R’ R THERAPEUTIC AGENTS USED: Nsuki N 25 UNITs, 5% GLucose solution (INTRA V.) 300 cc., 2% SODIUM BiCARBONATE SOLUTION (NTRA V.) 200 cc., O.9% SODI UM CHLORIDE SOLUTION (SUBCU) 3OO CC. CHART 46 BIBLIOGRAPHY Atchley, D. W., Loeb, R. F. et al. On diabetic acidosis. J. Clin. Invest. XII, 297 (1933). Baldwin, E. An introduction to comparative biochemistry. Cambridge University Press (1937). Butler, A. M., McKhann, C. F. and Gamble, J. L. Intracellular fluid loss in diarrhoeal disease. J. Pediatrics. III, 84 (l.933). Clark, W. M. The determination of hydrogen ions. Williams and Wilkins Co. (1928). Darrow, D. C. and Yannet, H. The changes in the distribution of body Water accompanying increase and decrease in eXtracellular electrolyte. J. Clin. Invest. XIV, 266 (1935). Dill, D. B. Life, Heat, and Altitude. Physiological effect of hot climates and high altitudes. Harvard University Press Press (1938). Gamble, J. L. Carbonic acid and bicarbonate in urine. J. Biol. Chem. LI, 295 (1922). Ross, S. G. and Tisdall, F. F. The metabolism of fixed base during fasting. J. Biol. Chem. LVII, 633 (1923). Blackfan, K. D., and Hamilton, B. The diuretic action of acid producing Salts. J. Clin. Invest. I. 359 (1925). and Ross, S. G. The factors in dehydration follow- ing pyloric obstruction. J. Clin. Invest. I, 403 (1925). and McIver, M. A. Effects of pyloric obstruction in rabbits. J. Clin. Invest. I, 531 (1925). Body fluid changes due to con- tinued loss of external Secretion of the pancreas. J. Exper. Med. XLVIII, 859 (1928). Hastings, A. B., Salvasen, H. A., Sendroy, J., and Van Slyke, D. D. The distribution of electrolytes between transudates and serum. J. Gen. Physiol. VIII, 701 (1928). Henderson, L. J. The fitness of the environment. MacMillan (1913). Blood. A Study in general, physiology. Yale University Press (1928). BIBLIOGRAPHY (Continued) Macallum, A. B. The palaeochemistry of the body fluids. Physiol. Rev. . WI, 316 (1926). Peters, J. P. Body Water, C. C. Thomas (lS35). Peters, J. P. and Van Slyke, D. D. Quantitative Clinical Chem- istry, Vol. l, Interpretations. Williams and Wilkins (1931). Richards, A. N. Processes of urine formation. Proc. Roy. Soc. Bl26, 398 (The Croonian Lecture for l938). Sendroy, J., Seelig, S. and Van Slyke, D. D. The carbon dioxide tension and acid-base balance of human urine . J. Biol. Chem. CVI, 479 (1934). Shohl, A. T. Mineral metabolism, Reinhold Pub. Co. (in press). Smith, H. W. Water regulation and its evolution in the fishes. Quart. Rev. Biol. VII, 49 (1932). The absorption and excretion of Water and salts by marine teleosts. Am. J. Physiol. XCIII, 480 (1930). The physiology of the kidney. Oxford Uni- versity Press (1937). liii. 390.15068232456