·Surface Area m2 Percent Adult Dose 20 POUNDS TO SQ. METER (m2) 105 10o 16 94 98 14 82 12 71 65 39 3 OB 47 O 6 35 30 04 24 18 02 12 6 opum 20 40 140 160 60 80 100 120 Body Weight-Pounds Graph A, Relations between Body Weight IN POUNDS, Body Surface Area and Adult Dosage The surface area values correspond to those set forth previously (Crawford et al 1950) Note that the 100 per cent adult dose is for an individual weighing about 140 pounds and having a surface area of about 17 m' ·Surface Area Percent Adult Dose 2.0 KILOGRAMS TO SQ. METER (m2) 1.8 -105 roo I 6 94 88 | 4 B2 76 1 2 71 65 1 O 59 53 OB 47 41 0 6 35 30 o 24 18 Og 12 6 لسلسلسليبللسيا 0 10 20 30 40 50 60 70 Body Weight - Kilograms Graph B. Relations between Body Weight LIOGRINS, Nody Surface Arca and Adult Douage Except for the fact that the ahsual scale is in kilograms rather than rounds this graph is the same as that on the opposite rage

·Associate Professor of Pediatrics, Harvard Medical School
Physician, Children's Medical Service,
Massachusetts General Hospital
Instructor in Pediatrics, Harvard Medical School
Assistant Physician, Children's Medical Service,
Massachusetts General Hospital
Assistant Professor of Pediatrics, Harvard Medical School
Physician, Children's Medical Service,
Massachusetts General Hospital
Medical Artist,
Massachusetts General Hospital
cf

·METABOLIC HOMEOSTASIS
A Syllabus for Those Concerned with
the Care of Patients
NATHAN B. TALBOT, M.D.
ROBERT II. RICHIE, M.D.
JOIN D. CRAWFORD, M.D.
EDITII S. TAGRIN
Published for The Commonwealth Fund
By Harvard University Press
Cambridge, Massachusetts 1959
.

·For approximately a quarter of a century THE COMMONWEALTH FUND, through 11 T 11 : VARD UNIVERSITY PRESS became the publisher of Commonwealth Fund books, assuming responsibility for their production and distribution The Fund continues to sponsor and edit its books, and cooperates with the Press in all phases of manufacture and distribution Published for The Commonwealth Fund by Harvard University Press, Cambridge, Mass Distributed in Great Britain by Oxford University Press, London Library of Congress Catalog Card No 59-14732 Manufactured in the United States of America © 1959 by The Commonwealth Fund ·Acknowledgements Many colleagues past and present have helped indirectly and directly in the preparation of this volume We are particularly indebted to Drs. Allan M Butler and E Eugenc Yates for her many valuable suggestions and to Miss Gretchen Koch for her unstinting secretarial assistance This work has been made possible by grants from the Commonwcalth Fund of New York, by grants H 1529, A-808 and HITS-5139 of the National Institutes of Health, United States Public Health Service, and by the Medical Research and Desclopment Board, Office of the Surgeon General Department of the Army, under Contract No DA-49-007-MD- 437 In addition, we take particular pleasure in expressing our apprecia. tion to the Division of Publications of the Commonwcaith rund for the interest and care taken in the publication of this volume ז 8 א RIR.

·Table of Contents
Explanatory Remarks on
METABOLIC HOMEOSTASIS
Section A. Basic Considerations
WATER HOMEOSTATIC SYSTEM
1. Body Content and Distribution of Water at Various Ages
2. Components of Water Balance
3. Water Losses via Lungs and Skin
4. Water Homeostatic System
5. Dynamics of Water Homeostasis
6. Demonstration of Maximal Tolerance and Minimal Requirement
for Water
7. Symptoms and Signs of Water Deficit and Excess Relative to Solutes
8. Normal Ranges of Renal Capacity to Vary Urine Water-Solute Ratio
and Urine Volume at Various Rates of Solute Output
9. Normal Limits of Total Body Tolerance for Water
SODIUM HOMEOSTATIC SYSTEM
10. Body Content and Distribution of Sodrum at Various Ages
11. Sodium Homeostatic System
12. Dynamics of Sodium Homeostasis
13. Symptoms and Signs of Sodium Deficit and Excess
14. Development and Recovery from Sodium Insufficiency
15. Normal Limits of Body Tolerance for Sodium

·POTASSIUV HouCOSTATIC SYSTEM
16. Body Content and Distribution of Potassium at Varjous ABCS
17. Potassium Ilomeostatic System
18 Dynamics of Potassium Homeostasis
19. Symptoms and Signs of Potassium Lxcess and Dcficit
20. Limits of Body Tolerance for Potassium
HYDROGEN lov HOMEOSTATIC SYSTEM
21. Body Content of Ilydrogen lons Relative to Daily Turnover
22. Hydrogen lon Homeostatic System
23. Capacity of the Body > Buffer Systems to Take up Surplus
Hydrogen Ions or Surplus Bicarbonate lons
24. Dynamics of Hydrogen lon Homeostasis
25. Symptoms and Signs of Hydrogen lon Deficit and fress
26. Limits of Tolerance for llydrogen Ions and Bicarbonate lons
CULORIDE HOMEOSTASIS
27. Chloride Homeostasis
PIOSPHORUS HOMCOSTASIS
28. Body Content and Distribution of Phosphorus and Scrum Inorganic
Phosphorus Concentration at Various Arcs
29. Phosphorus llomcostalic System
30. Dynamics of Phosphorus Homeostasis
31. Symptoms and Signs of Phosphorus Lucess and Deficit
32. Normal Limits of Body Tolerance for Phosphorus
n B. Clinical Applications
INTANT T'riding
33. Infant I ecding
34. Cows Milk Tetany of the Newborn

·PARENTERAL FLUID THERAPY
35. Relative Importance of Homeostatic Adjustments versus
Composition of Solution Used in Recovery of Patients
Undergoing Parenteral Fluid Therapy
36. Correction of Hypovolemia
37. Solutions for Total Body Repair plus Maintenance Therapy
38. Maintenance Therapy with Multiple Electrolyte Solution
39. Maintenance of Patients Subjected to Major Gastrointestinal
Surgery
40. Treatment of Diabetic Ketoacidosis
41. Therapy of a Diarrheal Infant
42. The Water Intoxication Problem
43. Parenteral Fluid Therapy for Burned Patients
RENAL DISABILITIES
44. Nephrosis
45. Pannephritis
46. Pseudohypoparathyroidism
47. Nephrogenic Diabetes Insipidus of Petressin-resistant Type
REFERENCES
CONVERSION CHARTS
Graph A.
Relations between Body Weight IN POUNDS, Body Surface Area and
Adult Dosage See inside front cover
Graph B. Relations between Body Weight IN KILOGRAMS, Body Surface Area
and Adult Dosage See inside front cover
Graph C. Relations between Milliliters per Milliosmole Values and Their
Reciprocals, namely, Milliosmoles per Liter over the Range
Observed in Samples of Urine See inside back cover
Graph D.
ually

·Explanatory Remarhs on Metabolic Homeostasis Since Professor C H Starling of University College, London, and Profes. sor W B Cannon of llarvard University first expressed admiration for the marvelous manner in which the organism can maintain a steady state through suitable adjustments, physiologists hasc gathered a vast amount of information concerning the “Wisdom of the Body" The present sylla. bus is concerned with the application of this information to the diagnostic and therapeutic problems faced by those responsible for the care of pa tients The information presented here is basically very simple in nature Essentially, it is shown that the body contains a series of systems designed to hccp body composition within normal limits Each system has a "sens ing element' which detects abnormalities in the content or concentration of the substance for which st is responsible As directed by this element, the system acts to accumulate or climinate the substance in accordance with homcostatic needs for the systems to accomplish these tashs, they must be provided with certain essential raw materials at adequatc yet tol. crable rates Most of the metabolic disturbances encountered clinically arc due to failure to fulfill this important requirement Most subside spon tancously as soon as thus need is met Since it is as important for physicians to be familiar with the limits of capacity of the body s homeostatic systems as it is for surgeons to know the anatomy of the structures with which they are dealing, the first division of this syllabus will be concerned with descriptions of their functional characteristics in health and discase The second division of the syllabus then illustrates hy spxecific clinical erreriences the manner in which such infor mation can be used to improve and at the same time to simplify patient carc The task of presenting this information in clinically useful form has been cased greatly by the fact that most body requirements, turnover rates and limits of tolerance happen to be approximately proportional to body "surface arca" (16 to the two thirds power of body weight) This has it ·made it possible to express rates of intake and output for individuals of all ages and sizes with the aid of single per square meter (ma) values instead of the multiple values needed when weight or "basal energy expenditure" estimates are used as the basis for calculations This may be visualized with the aid of the accompanying chart, which shows that fluid allow ances, based on the series of milliliters per pound factors recommended by Oliver, Graham and Wilson,* correspond closely to a dosage of 2500 ml per ma per 24 hours Similarly, fluid allotments, calculated according to Darrow's recommendation that approximately 150 ml of water be given for each 100 calories of basal energy expended, differ little from those provided by prescribing 1600 ml per mº per 24 hours Incidentally, it is interesting to note that these authors differ by as much as 50 per cent in their recommended allowances The explana tion for the fact that both regimens are well tolerated by normal individuals is to be found in the observation that both lie within the range of free dom of choice normally provided by the body's homeostatic systems in this chart this range corresponds approximately to the area defined by the minimal requirement and maximal tolerance levels shown near the bottom and the top of the chart Surface area in square meters (mº) can be estimated easily from body weight with the aid of the charts shown on the inside of the front cover The scale shown along the right-hand ordinate of these charts also indicates relations between body weight and drug dosage expressed as percentages of ordinary adult dosage values If desired, these can be used to convert adult values to per square meter values and vice versa While rates of intake and output, which are related to homeostatic function, are expressed per m per unit of time, body content values, which are a function of mass, are expressed per kilogram of body weight Though a number of the limits of tolerance indicated in this volume must be considered approximate where definitive data are scanty, nonetheless they have been found satisfactory in orienting clinical therapy It is to be hoped, however, that these first approximations may in due course be replaced with more refined data as physicians and physiologists continue their explorations of these vitally significant phenomena While traditional methods of describing physiologic and medical phenomena usually are satisfactory, there are times when they may fail to place relationships in proper perspective Such appears to be the case with regard to the use of the term "milliosmoles per liter" in describing the * Oliver Graham and Wilson s miltliters per pound factors and Darrow $ factors for est;mating basal energy output are set forth in the table at the bottom of the chart ·BIRTH APPROX AGE YRS 12/21 70TT 3 5 12 14 16+ PPROXIMATE NAXIMAL TOLERANCE LEVEL 60- SO OLIVER, GRAHAM AND WILSON ALLOTMENTS LITERS PER PATIENT 40 2500 ml mt / 24 3.04 DARROW ALLOTMENTS 150 ml/100 cal 1600 ml/ m2/24 204 I OF APPROXIMATC WINIMAL MAINTENANCE LEYZ 1 SQ METERS 0 15 23 43 60 80 KILOGRAMS 0 25 ro 15 20 POUNDS OS 11 22 33 44 OLIVER.61 al.mi/16 60 60 60 50 45 DARROW, col/10 49 70 63 S) 45 105 JO 66 40 38 15 SO 110 33 33 1 65 60 130 40 88 35 33 35 31 Moses Based on Weight and on Basal Fnergy Expenditure in Relation to T'er Squarc Meter Doses and Body Limits of Tolerance ·function of the body's water homeostatic system This term appears to be the reciprocal of the variable with which this system actually is concerned, namely the ratio of water to solutes (ie milliliters per milliosmole) in body fluids Stated in other words, as individuals vary their fluid and food intake, this water system has the task of trying to prevent abnormal gains or losses of water relative to solutes, just as the various other homeostatic mechanisms strive to prevent pathologic gains or losses of the various sol utes for which they are responsible Accordingly, all water solute ratio values will be expressed as milliliters per milliosmole Those who wish to re express these values in terms of milliosmoles per liter can make the con version easily with the aid of graphs C and D (see inside back cover) In choosing references for this syllabus, no attempt has been made to quote all the pertinent literature On the other hand an effort has been made to give the sources of the original data on which the charts and text are based as well as to indicate the titles of publications which have been found particularly useful as sources of additional information The com plete bibliography is listed alphabetically by authors at the end of the syllabus References Starling (1923) Homeostatic concepts Talbot and Richie (1959) Use of surface area ·SECTION A. BASIC CONSIDERATIONS ·1. Body Content and Distribution of Water at Various Ages The accompanying chart shows the normal volume and distribution of the total body water at various ages These patterns are the product of recipro cal actions between the homeostatic systems which determine the electrofyte content of the body and the neurohypophyseal-renal system which normally keeps each milliosmole of solute encompassed by 3 5 to 37 ml of water* (chart 4) As a result of changes in the "setting' of the systems responsible for body sodium and chloride homeostasis, interstitial fluid and hence total water content per kilogram of body weight commence to diminish early in the neonatal period, reaching adult levels at about nine months of age Possibly these changes are explained in part by the fact that newborn infants are slightly hypoalbuminemic in comparison with older infants and children This could predispose to the accumulation of extracellular fluid much as it does in nephrotic children (chart 44) In addition, the newborn infant is apt to lose water out of proportion to solutes during the first two or three days, when he is obliged to obtain from his body stores most of the water needed to compensate for insensible and urinary losses As a result, the water-solute ratio of body fluids decreases until water becomes available in the form of mother's milk or other fluid of low solute content Technical Details Solutes are the substances in solution in the body fluids They are made up of the various electrolytes and of other substances including glucose, amino acids, urea and creatinine One millimole of any of these substances in solution exerts one milliosmole of osmotic pressure This is distinct from the electrical potential which is measured in terms of milliequivalents The osmolar content of a solution can be determined by measuring its freezing point A depression of the freezing point by 1 86° C below that of pure water signifies that there are 1000 milljosmoles of solute in each liter of fluid For reasons mentioned under Explanatory Remarks this method of expression 15 used instead of the reciprocal namely 270 to 285 mosM per liter Those wishing to con vert mulliliters per miljosmole values to their milliosmole per liter equivalents can do so with the aid of the graph shown on the inside of the back cover ·gm/kg 1000 800 SOLIDS ► American 1970 (10! ree INTRACELLULAR HOO سئل الدم ܝܕܨܐܪܓܢܕ,11y C-ide 200 PLASMA H2O INTERSTITIAL HOO НЕСУ 18 2 16 20 O 6 3 6 9 12 BIRTM WKS -- MONTHS-- 3 4 6 8 10 12 -- YEARS --- 1. Body Content and Distribution of Water at Various Ages Tracer doses of heavy water (DO) were used for determ ning tolal holy water bromide was employed for measuring curacellular space and the dye T1824 for cuumaling plasma Volume Solids were found as the afference between total bowy water and holy we ght and intracellular walcr as the dffcrence between extracellular volume and focal howly water no probably gyes very accurate informat on about total body water Though bromide lis chloride is located chicfly in extracellular Reference firings er al (1941) Puma Volume data Check (1954) Promide space data *) (ora et al (1950) Tital hoy valer data (0) I rus liansen (1957) Total dry wafer data (1 Arhols et al (1953) Chloride space as measure of extracellular companiment ·Components of Water Balance The water balance of the body fluctuates from positive to negative many times during the day as a consequence of the fact that the ingestion of water is intermittent Nevertheless, the organism usually is able to prevent major fluctuations in its water content by appropriate adjustments in rates of intake and output As the accompanying diagram shows, except for the relatively small quantity of water formed during the process of oxıdızıng carbohydrate, fat and protein within the body (about 200 ml per mº per 24 hours) we are almost totally dependent upon exogenous water as a source of intake Under conditions of fasting, destruction of body protoplasmic tissues may yield a small additional volume (about 120 ml per m² per 24 hours) Water is lost via a number of different routes Breast fed infants lose about 100 ml of water per m per 24 hours in their stools On the other hand, infants fed cow's milk formulae and older persons taking ordinary diets lose only about 50 ml of water per ma per 24 hours by this route Though such losses may increase markedly, reaching levels of 500 ml per m? per 24 hours or more as a result of diarrhea, they are not subject to homeostatic control and therefore do not vary much under normal circumstances The same may be said of the water losses which take place through the skin and especially of those which take place through the lungs Though these vary somewhat with age and size and may be influenced by factors such as environmental temperature, clothing, humidity and body temperature, they tend to remain essentially constant under ordinary conditions of living in a temperate environment (chart 3) The most important adjustments in the rate of water elimination are accomplished by the kidneys under the direction of the neurohypophysis (chart 4) The range over which this system normally can vary urinary output is indicated in chart 8 In the present chart minimal urine volume is indicated as "obligatory urine water," this being the smallest volume in which the kidneys can excrete the waste products presented to them for elimination Maximal urine volume is equal to the sum of the "obligatory urine water" plus the 'surplus urine water" Viewed as a whole, the body's minimal water requirement is approximately defined by bracket A and its maximal water tolerance by bracket B

·L/M2124"
ADULT
IntalOutput
o
A.MINIMAL WATER
REOVIRENENT
8. MAXIMAL NACR
TOLERANCE
1 WEEK INFANT
intole Output
Wole
Intake
Surplus
Water
Obl 99109
u in
Walet
IWL
$1001
water
Wor
GIOIA
2 Components of Waler Balance
The chart reproduce above shows the mn mal water requirement and the mat mal
water tolerance of a 1 noch olj inlant in marron with those of an adult The
following appropriate słucs has been used in consent of the dafram selute
In used in all the chans of the 13tlahus.

·2. Components of Water Balance The water balance of the body fluctuates from positive to negative many times during the day as a consequence of the fact that the ingestion of water is intermittent Nevertheless, the organism usually is able to prevent major fluctuations in its water content by approprate adjustments in rates of intake and output As the accompanying diagram shows, except for the relatively small quantity of water formed during the process of oxıdızıng carbohydrate, fat and protein within the body (about 200 ml per ma per 24 hours) we are almost totally dependent upon exogenous water as a source of intake Under conditions of fasting, destruction of body protoplasmic tissues may yield a small additional volume (about 120 ml per m" per 24 hours) Water is lost via a number of different routes Breast fed infants lose about 100 ml of water per mº per 24 hours in their stools On the other hand, jnfants fed cow's milk formulae and older persons taking ordinary diets lose only about 50 ml of water per miº per 24 hours by this route Though such losses may increase markedly, reaching levels of 500 ml per m” per 24 hours or more as a result of diarrhea, they are not subject to homeostatic control and therefore do not vary much under normal cir cumstances The same may be said of the water losses which take place through the skin and especially of those which take place through the lungs Though these vary somewhat with age and size and may be influenced by factors such as environmental temperature, clothing, humidity and body temperature, they tend to remain essentially constant under ordı nary conditions of living in a temperate environment (chart 3) The most important adjustments in the rate of water elimination are accomplished by the kidneys under the direction of the neurohypophysis (chart 4) The range over which this system normally can vary urinary output is indicated in chart 8 In the present chart minimal urine volume is indicated as "obligatory urine water," this being the smallest volume in which the kidneys can excrete the waste products presented to them for elimination Maximal urine volume is equal to the sum of the "obligatory urine water" plus the "surplus urine water" Viewed as a whole, the body's minimal water requirement is approximately defined by bracket A and its maximal water tolerance by bracket B ·ADULT Intake Output L/m2/24 13 21 10 A • MINIMAL WATER REQUIREMENT BWAXIMAL WATER TOLERANCE 1 WEEK INFANT intole Output Water Intake Surplus Uroe Water obl gatory Urne Water IWL Stool Wo er Growth Walar WOR 2 Components of Vater Balance The chart reproduced above shows the minimal water requ rement and the maximal water tolerance of a 1 week-old infant in comparison with those of an adult The following appropriate values have been used in constructing the degram solute load of 250 mos Vim/34 hours for both infant and adult maximal utine concen tration of 1 7 ml/most for the infant and of 1 6 ml/mos for the adult (conserva tive est males) mar mal urine d lution of 16 ml/most for the infant and of 50 ml most for the adult Wor-water of oxidat on IL * insens ble water loss Wm2/24 - liers per square meter per 24 hour period This form of abbrevia on is used in all the charts of the syllabus.

·References Ames (1953) Infant s maximal water tolerance Gamble (1958) General Hansen and Smith (1953) Infants minimal water requirement Newburgh et al (1945) Water of oxidation Shohl (1939) General 3. Water Losses via Lungs and Skin Infants, children and adults have approximately similar basal rates of insensible water loss via the lungs and skin However, basal conditions apply only to that small segment of the day when the individual is at rest Rates of loss are apt to be greater during periods of activity Consequently, except in persons living an inactive existence, total daily losses exceed the basal rate by a considerable margin These total losses may be higher in infants (average, 1200 ml per m² per 24 hours) than they are in children (average, 1000 ml per m² per 24 hours) or adolescents and adults (average, 700 ml per mº per 24 hours) The rate at which water is lost insensibly may become reduced al most to zero when the humidity is raised to 100 per cent as in a croup tent Contrariwise, insensible water losses are higher when individuals are nude and can be doubled by the hyperpnea of diabetic ketoacidosis or salicylate intoxication In addition to the water lost insensibly, individuals can lose a liter or more per day in the form of sweat, if they become overheated Because the neurohypophyseal-renal system can compensate for moderate fluctuations in insensible water losses by appropriate adjustments of urinary output, un estimating body water requirements and tolerances it suffices under most circumstances to assume that losses via the lungs and skin amount to about 1000 ml per m² per 24 hours It is important, however, to make a closer estimate of water losses via these routes when a patients homeostatic capacity (chart 45A) has become markedly reduced, as in pannephritic or anuric individuals or when it is obvious that the individual is sweating profusely References

·2/24
00
NON BASAL VALUES
600
1200
800
AVERAGE BASAL VALUES
16 20
400
8
10 12
6
YEARS
0
11
1
1
6 3 6 912 18 2 3 4
BIRTH WKS - MONTHS -
3. Insensible Water Losses via Lungs and Shin

·4. Water Homeostatic System The neurohypophyseal-renal or water homeostatic system is designed to keep the ratio of water to solutes* in body fluids within the range of 3 5 to 37 ml for each melhosmole This is an important physiologic variable be. cause elevation of the water solute ratio by as little as 10 per cent to 39 or 40 ml per mosM is apt to result in water intoxication Contrariwise, reduction of the ratio by 5 or 10 per cent to 3 3 ml per mosM, or less, tends to produce symptoms and signs of hypohydration (chart 7) The system functions somewhat like a feedback Circuit A tendency to abnormal lowering of the ratio of water to solutes in body fluids is recognized by osmoreceptors located in the hypothalamus As the ratio falls, they respond by creating a sensafion of thirst (chart 45C) and by causing the neurohypophysis to secrete antidiureic hormone into the blood stream The renal tubules react to this hormone by reducing the quantity of water accompanying each milosmole of solute in the unine Passage of urine, which is so concentrated that it contains less water for each mithos mole of solute than the plasma from which it was derived, tends to raise the water solute ratio of the body fluids When this approaches a physiologically satisfactory level, the sensation of thirst abates and the secretion of antidiuretic hormone ceases On the other hand, the reverse of these homeostatic reactions follows an abnormal rise in the water solute ratio of the body fluids Then the ratio in the body fluids falls as the ratio in the Utune rises The water homeostatic system, while closely concerned with the stability of the water solute ratio of body fluids, also is involved in the preservation of a satisfactory vascular volume Available evidence suggests that there are stretch or pressure sensitive elements, possibly located in the left atrium, which can promote thurst and antidiuretic hormone production irrespective of the water solute ratio of body fluids should the vascular volume become abnormally reduced in patients suffering from blood loss, hypoalbuminemia or extracellular electrolyte deficiency, this response can convulsions (chart 42) * Focusive of prea

·PHYSIOLOGIC KEY VARIABLE
0 Body Water-Solute Ratio
SENSING ELEMENT
Hypothalamic Osmoreceptors
MEDIATOR
Thirst and AOH Released by
Posterior Pituitory
0
EFFECTOR MECHANISM
Renal Tubules + Collecting Ducis
VARIABLE AFFECTED
01
Urine Water
Rolotive to Soluto
* This mechanism olso may be activated by hypovolemio
4. Water Homeostatic System
References
Smith (1957) General
Talbot et al (1952) General
Vemcy (1957) General

·5. Dynamics of Water Homeostasis As the accompanying chart demonstrates, the water homeostatic system normally reacts so nimbly to changes in intake that one can suddenly vary the intake rate all the way from the physiologic minimal to the physsologic maximal level without disturbing body water status (i e serum ml/mosM) to a major ettent There is apt to be a lag of approximately 45 minutes between the time when water load is first imposed and the time when urine water solute ratio and hence urine flow values commence to increase Nonetheless, adaptation is essentially completed within 2 hours The same as true when the water intake rate is reduced suddenly from a high to a low level Reference Crawford et al (to be published) General 6. Demonstration of Maximal Tolerance and Minimal Requirement for Water As has been menuioned in preceding sections, there are limits to the body's capacity to conserve and to eliminate water in accordance with needs More specifically, there is a physiologic minimal requirement, or floor, which represents the lowest rate of intake required to balance output and hence to prevent deficits when conservation forces are acting maximally Similarly, there is a physiologic marmal tolerance, or ceiling, which represents the largest amount of water that can be taken and elimi nated per unit of time without seriously disturbing body composition Rates of intale and output falling between these two extremes lie in what may be called the effectie or sale w orhing range of homeostatic function The subject of the accompanying chart was a 20-year-old youth with marked impairment of renal function, as evidenced by the fact that His urea clearance was only 5 per cent of nommai in the Icft-hand set of diagrams, it can be seen that his serum water-solute ratio was abnormally elevated when first measured This meant that he had at that aime a strong need to raise his urine water solute ratio to the highest level of which he was capable Accordingly, the urine water-solute ratio value found at that time, namely 7 ml per mosM, could be considered his ceiling value At ·100 URINE mi/mosM 8 OF 60- 40 20 J 8 3 7 SERUM ml / mos 3 6 NORMAL RANGE 35 34 10 000 INTAKE Hoo ml/m2/24 0 000 URINE OUTPUT 6 000 4 000 2 000 1 2 3 HOURS 5. Response to Water Loading and Deprivation The subject for the water loading experiment was a healthy young man who was given water orally at 15 minute intervals 4 5 6 11 ·hıs average rate of solute output (285 mosM per ma per 24 hours), this meant that he could not excrete more than 285 x 7, or about 2000 ml of urine per ma per 24 hours His upper limit of body tolerance for water, estimated by adding to this maximal urine value an approximate value for insensible water losses minus water of oxidation (1c 1000-200, or 800 ml per m" per 24 hours), was found to be 2800 ml per mi per 24 hours Inasmuch as he was already "over ceiling" with respect to rate of water intake when these measurements were made, there was no need to subject him to an additional water load in order to demonstrate where his ceiling was located on the other hand, it was necessary to restrict his water intake for a limited period in order to determine his minimal water requirement As can be seen in the right hand diagrams, thirsting caused his serum water-solute ratio values to fall rapidly to subnormal levels When this occurred, the neurohypophyseal system caused the urine wa. ter-solute ratio to fall to the lowest level possible, namely 2 5 ml per mosM This meant that while he was excreting solutes at the rate of 285 mosM per m² per 24 hours, his minimal urinary output would be 285 x 25, or about 700 ml per m² per 24 hours It followed that his over-all minimal water requirement, estimated as outlined above, was approximately 1500 mi per mº per 24 hours Thus, these observations indicated that, provided there was no change in total solute output, he should take at least 1500 but not more than 2800 ml of water per m² per 24 hours in order to avoid hypohydration on the one hand and hyperhydration on the other Reference herrigan et al (1955) Source of data ·WATER LOADING WATER DEPRIVATION SERUM WATER - SOLUTE RATIO ml / mosM PHYSIOLOGIC RANGE URINE WATER - SOLUTE RATIO GREAT THIRST ml / mosM PT'S RANGE OF URINE ml/mos M RATE OF URINE OUTPUT L/m2/24 PT S RANGE OF URINE VOLUME S RATE OF TOTAL WATER INTAKE AND OUTPUT INTAKE L/m / 24 OUTPUT PT'S RANGE OF WATER TOLERANCE URINE VOLUME OUTPUT 0 INTAKE HOURS 6 6. Physiologic Limits of Capacity to Conserre and Eliminate Water 0 1 2 3 4 5 6 HOURS ·7. Symptoms and Signs of Water Deficit and Excess Relative to Solutes Lowering of the ratio of water to solutes (other than urea) in body fluids below 35 ml per mosM results in thirst, concentration of the urine and, provided the solute output rate is not very high, a tendency to oliguria Lowering of the water-solute ratio below 3 2 mí per mosM is apt to result in fever Extreme lowering to levels below 2 9 ml per mosM can lead to central nervous system disturbances with lethargy, imtability, twitching, electroencephalographic changes, acidosis, respiratory or circulatory failure and death * When such hypohydration (ie low water solute ratio) is due simply to lack of water relative to solutes, the concentrations of sodium and chloride are apt to be increased in proportion to the increases in concentration of all other solutes Under such circumstances, serum sodium and chloride concentration measurements may serve as inverse indices of watersolute status Hence, it is not uncommon to find the serum sodium concentration elevated to 170 and the serum chloride to 130 mEq per liter, or higher, in patients with serum water-solute ratio values in the neighborhood of 2 9 ml per mosM The serum sodium and chloride values may not be elevated, however, in patients who become hypohydrated as a result of the accumulation in body fluids of many milliosmoles of ketone bodies (chart 40A) or other unusual solutes It follows that the finding of normal serum sodium and/or chloride concentration values does not rule out hypohydration Neither does the presence of gross edema, for patients with large accumulations of tissue flud may have even larger accumulations of solutes and therefore may suffer from lack of water in proportion to sol. utes This condition occurred commonly during the days when it was customary to treat patients with fluids of relatively low free-water content such as isotonic saline Elevation of the water-solute ratio in body fluids to 4 ml per mosM of non urea solutes is apt to result in headache, confusion, nausea, weakness, cramps, convulsions, coma and other manifestations of water in toxication, if 11 Occurs rapidly in the course of a few hours On the other band, very gradual elevation of the water solute ratio to equally high levels, as sometimes occurs in patients with nephrosis or pannephritis, may not produce overt signs * Such signs of dehydration as loss of subcutaneous tissue clasticity and softness of eyeballs are seen only of the total body water is subnormal 14 ·The elevation in water solute ratio responsible for signs of water intoxication may occur as a result either of an absolute gain in water relative to solutes or an absolute loss of solutes relative to water or both (chart 42A) Hence, water-intoricated persons do not necessarily show signs of water surplus such as edema The character and volume of the urine also may vary widely under different circumstances If the patient is suffering simply from an overload of plain water, he will put out large volumes of maximally dilute urine (chart 8) On the other hand, if he is suffering from hypovolemia, heart failure or the cffects of various other factors which can result in the uncontrolled release of antidiuretic hormone, the urine will tend to be highly concentrated and of small volume (chart 42A) Even if the urine is maximally dilute, the volume may not be very great unless there is a generous solute output (chart 47) As in hypohydration, serum sodium and chloride concentration values tend to fall as the water solutc ratio of the plasma rises On the other hand, they may become louered as the result of the fact that other substances such as ketone bodies, glucose and bicarbonate harc accumulated in body fluids It follows that the diagnosis of water deficit or excess rela. tive to solutes in body fluids can be made most dependably by direct measurement of the total solute content as revealed by freezing point depression or other suitabic index Symptoms and Signs of Water Deficit and Excess Relative to Solutes TOO LITTLE TOO MUCH Thirst Headache Concentrated urine Confusion Oliguria Nausea Fever Vomiting Irritability Weakness Lethargy Muscle twitching and cramps Muscle tustching Electroencephalographic changes Electroencephalographic changes Convulsions Acidosis Coma Respiratory or circulatory failure Serum water-solute ratio Scrum water solute ratio > 37 ml per mosli, < 35 ml per mosM, serum solutes < 270 scrum solutes > 285 mosli per liter mosM per liter References Crau ford and Dodge (1959) General Sotot et al (to be published) Waler deficit Weil and Wallace (1956) Water deficit Wyan (1956) Water cxcess ·8. Normal Ranges of Renal Capacity to Vary Urine Water-Solute Ratio and Urine Volume at Various Rates of Solute Output The upper curves of the accompanying diagrams represent physiologic maximal values and the lower curves physiologic minimal values It can be seen that the kidneys' ability to dilute the urine is greatest at low rates of solute output and least at high rates of solute output Maximal rates of urine flow, calculated by multiplying these maximal values for urine water-solute ratio by the corresponding values for rate of solute output, start at about 12 5 liters per m² per 24 hours and increase to about 15 liters per m" per 24 hours at high rates of solute output These ceiling levels are so high that normal individuals rarely reach them For instance, an adult weighing 70 ng would have to drink more than 5 gallons of water per 24 hours, or about one 250 mi tumbler every 15 minutes to overload the renal excretory mechanism Renal ability to concentrate urine in response to full antidiuretic hormone stimulus usually is not influenced very much by variations in rates of solute output * Concentrating capacity increases, however, as the ratio of urea to other solutes in the urine approaches 0 35 Al this osmolar racro, the kidneys can reduce the water content of the urine to 0 7 ml per mosM (specific gravity 1 030) If the proportion of urea to other solutes is much less than this value, the kidneys may not be able to reduce the water-solute ratio of the urine below 1 5 ml per mosM Patients also suffer partial loss of concentrating ability when their cellular potassium stores become depleted and are replaced by sodium (chart 19) Except for these factors, minimal urine volume varies directly with rate of solute output It amounts to about 150 ml per m* per 24 hours at the minimal rate of solute output (1 e 200 mosM per 24 hours) found in persons taking 100 gm of glucose per maper 24 hours together with an adequate quantity of water it increases to about 275 ml per mº per 24 hours in fasting individuals, who are apt to excrete about 375 mosM of solutes per m? per 24 hours Healthy persons eating a normal diet excrete 500 to 600 mosM of solutes per m² per 24 hours and hence have a minimal urine volume of 350 10 450 ml per m per 24 hours In patients whose solute output has risen to exceptionally high levels (ie A anap at very high rates of output when lute number of solutes ming nephrons Hence, mal persons per ma ·JOOH PHYSIOLOGIC RANGE URINE WATER - SOLUTE RATIO ml / mosM VAXINALLY DILUTE URINE 10 OH 1 001 41006 1010 MAXINALLY CONCENTRATED URINE + MOIN UREA MOIM NON-UREA HI012 APPROX. URINE SPECIFIC GRAVITY <OJS 1018 O 35 or more 024 OJO 1$ O MAXIWALLY DILUTE URINE 125 URINE VOLUME L/m2/24 10 OH 75 SOF 23 MAYINALLY CONC URINE 2 0 500 tooo 1500 TOTAL SOLUTE OUTPUT (mosM/m2/24) 2000 WIN TASTING ORDINARY Glucou No Bolate Ordinery No coloric diot falate 8. Normal Ranges of Renal Capacity to Vary Urine Water-Solute Ratio and Urine Volume at Various Rates of Solote Output HIGH DTOTC tetoecidosta ·about 1500 mosM per m2 per 24 hours) as a result of burns, other severe trauma or the glycosuria and ketonuria of diabetic ketoacidosis, minimal urine volume may amount to 2000-3000 ml per m* per 24 hours References Crawford et al (to be published) Source of data Talbot et al (1955) General 9. Normal Limits of Total Body Tolerance for Water Using the data presented in charts 2, 3 and 8, one can make approximate estimates of the maximal water tolerance and minimal water requirements of healthy individuals of various ages The limited information available indicates that because renal function is immature at birth infants have much less ability to diurese during the first days of life than they will after reaching four weeks of age Hence, the relatively low maximal water tolerance levels shown for the neonatal period Older individuals can tolerate as much as 12 to 13 liters per mº per 24 hours Because infants are apt to have larger insensible water losses per mº per 24 hours than children and adults, their minimal water requirements amount to about 1 6 liters per m² per 24 hours as compared with an adult's requirement of about 1 liter per m² per 24 hours These minimal requirements increase by 200 to 500 ml per ma per 24 hours of the infant is fed a cow's milk formula instead of human milk or if the adult cats a diet of or. dinary rather than exceptionally low solute residue Healthy persons can safely vary their water intake from 1500 to 12000 ml per mº per 24 hours under ordinary circumstances These limits may become narrowed by certain conditions, including the following CEILING LOWERED GE esthesia (chart 42A) Morphine-type drugs (chart 42A) Pannephritis (chart 45A) Diseases which transect the blood brain barrier in the region of the hypothalamus (chart 42A) Hypovolemia or circulatory failure (charts 4, 42, 44D) Neonatal period FLOOR RAISED Pitressin deficiency (diabetes insipidus) Pitressin resistance (renal diabetes insipidus) (chart 47A) Cellular potassium insufficiency plus sodium intoxication (chart 19) Pannephritis (chart 45A) 18 ·Lim2/24 14 13 IPL MXZVAL 101 FRANCE 7 2 AP --- GNS FISHY DIETRIMONCE 1 MINIMAL PEGUIFTA SNT 1 J 1 12 18 BIRTH KS - MONTHS... 3 4 6 9 Normal Limits of Total Body Tolerance for Water 8 -YEARS 10 12 16 20 References Ames (1953) Infant s maximal water tolerance Crawford et al (to be published) Minimal and matimal unnary output llansen and Smith (1953) Infants minimal water requirement Ilccley and Talbot (1955) Insens ble water loss Macy (1942) Normal water intake Shohl (1939) General ·10. Body Content and Distribution of Sodium at Various Ages Newborn babies have about 35 per cent more sodium for each kilogram of body weight than 1 year old infants and about 65 per cent more than adults Most of the infants' "extra' sodium is dissolved in the interstitial fluids at a concentration of approximately 140 mEq per liter Though the body's sodium is largely stored outside the cells, between 15 and 25 per cent is located within the cells and in bones Like the extracellular sodium, most of this intracellular sodium exchanges readily with tracer doses of the radioactive isotope Na" and hence is presumed to be readily available for metabolic processes The accompanying chart is based primarily on values for total exchangeable sodium per kg of body weight as determined with tracer doses of Na"The curve depicting the total exchangeable content is based on a formula proposed by Forbes and Perley The portion of this sodium which is located in the plasma and interstitial fluid was estimated by multiplying the plasma and interstitial volume values shown in chart 1 by a representative value for the concentration of sodium in an ultra filtrate of serum (1 e 143 mEq per liter) of the remaining sodium, about 2 5 mEq per kg are situated in protoplasmic cells at a concentration of approximately 8 mEq per liter and the rest is present in bone matrix References 20 ·nEq/ko SODIUM CONTENT 70 X 60 50 Nonexchangeable NO 1YPRICE LVLAN rour V RACE 40 30 ISTLASTITIAL Exchangeable 20 Na? - Extracellular Na 10 PLASMA 1 3 3 6 4 6 BIRTH WKS 9 12 18 2 MONTHS 6 8 10 12 16 20 YEARS 10 Body Content and Distribution of Sodium al Various Ages data of Forbes and Perley (1951) duty of Corsa cual (1956) ·11. Sodium Homeostatic System The sodium homeostatic system normally plays a major part in maintain ing vascular volume at physiologically satisfactory levels It accomplishes this task by functioning in a coordinated manner with certain other home ostatic mechanisms A decrease in the body s sodium content results in a diminution in extracellular solute content To maintain body water solute ratio values at normal levels the water homeostatic system (chart 4) eliminates about 72 ml of extracellular water for each milliosmole of sodium lost of this total 36 mi are accounted for by the sodium itself and 3 6 ml by the chlo ride bicarbonate and other anionic solutes which necessarily accompany sodium in extracellular fluid Such loss of extracellular fluid reduces plasma volume and hence blood volume The tendency to hypovolemia is detected by pressure or volume sensitive elements in the region of the carotid sinus These elements probably act indirectly by means of the adrenocorticalaldosterone mechanism and directly via neurologic pathways to cause the kidneys and sweat glands to conserve sodium They also may create a craving for salt which predisposes to increasing the sodium chloride in take For each milliosmole of sodium gained as a consequence of these re actions the neurohypophyseal system accumulates about 7 2 ml of water Because a portion of this newly formed extracellular fluid is attracted to the vascular compartment by plasma albumin the blood volume is in creased As this reaches satisfactory levels the stimulus for sodium con servation wanes and equilibrium is re established The reverse of these changes occurs when the body s sodium content rises above normal levels References Barger et al (1959) Neural control of Na excret on Leaf et al (1953) Vascular volume and Na excretion Selkurt (1954) General Smth (1957) General 22

·PRIMARY
PHYSIOLOGIG KEY VARIABLE
Extracellular No
li Solute) Content
COLLABORATED MEDIATOR
Water Retontion per
Water Homeostolic System
SECONDARY
PHYSIOLOGIC KEY VARIABLE
--
Vascular + Interstiliat
Fluid Volume
SENSING ELEMENT
Vosculos Volume Streich Receptors
MEDIATORS
Sodium Salt Hunger +
Adrenocorticol Hormones +
Autonomic System
EFFECTOR MECHANISM
Rengi Tubule
Reobsorption of No
VARIABLE AFFECTED
0 uninary Output of no
11. Sodium Ilomeostatic System

·12. Dynamics of Sodium Homeostasis When the sodium intake is increased abruptly, there may be a lag of one or more days before the urinary output of sodium increases to the point where equilibrium is re established The sodium accumulated during this interval leads to the retention of a physiologically equivalent volume of water, with resultant weight gain, and at times even to visible edema formation Provided the maximal capacity of the organism to eliminate so dium has not been over reached, most of this surplus sodium and its accompanying anions and water are unloaded eventually The healthy organism reacts to sudden restrictions of sodium intake within a day and can reduce its rate of sodium loss almost to nul within three or four days 24

·38
574
WEIGHT
kg
36
55
INTAKE
--- URINARY OUTPUT
300
No
mEq/m2/24
200
100
7
8 9 10 11 12 13 14 15 16
DAYS
12. Dynamics of Sodium llomcostasis
The source of the data in the shoic chart was a healthy young woman on a constant
normal dict who ingested added NaCl during the loading period and then changed
to a low sodium dict on day 9

·13. Symptoms and Signs of Sodium Deficit and Excess Most of the symptoms and signs in the accompanying list are explained by the changes in extracellular fluid volume, which usually take place as ex tracellular sodium stores become abnormally depleted or expanded As extracellular fluid diminishes, circulatory collapse is prevented up to a point by the transfer of water from the interstitial to the vascular compart ment and by compensatory reduction in the size of the vascular bed When further contraction becomes impossible, signs of circulatory failure are apt to develop rather abruptly (chart 14) They can be made to disappear by giving enough extracellular type fluid to expand vascular volume above the critical level On the excess side, rapid intravenous administration of sodium, in the form of an extracellular type fluid such as isotonic salıne, can lead to overexpansion of vascular volume and hence to congestive heart failure even in healthy individuals On the other hand, if the load is imposed more slowly and the organism has time to transfer surplus extracellular fuld into the interstitial spaces, surplus sodium is likely to show up as edema fluid Experience with nephrotic and cardiac patients indicates that double, triple and even quadruple the normal amount of sodium may be stored in the body as edema fluid without catastrophic results There comes a point however, where edema may so embarrass respiratory and other functions that it is incompatible with life Sodium also can accumulate in excessive quantities in the cells of individuals with potassium insufficiency and give rise to the cellular potassium lach-sodium intoxication syndrome (chart 19) Serum sodium concentration cannot be considered a reliable index of body sodium status Rather it constitutes an inverse index of the watersolute ratio of body fluids A high serum sodium concentration usually means that there is too little water in proportion to solutes in the body fluids, not that there is too much sodium in the body Conversely, a low serum sodium concentration usually* signifies that there is a surplus of water in proportion to solutes in the body, only occasionally is there an associated absolute sodium deficit It follows that one must judge body sodium status clinically either by means of isotopes, which are not generally available, or by estimating vas * In lipemic patients though the concentration of sodium per liter of serum may be abnormally low its concentration per liter of serum water may be within normal limits 26 ·cular and interstitial fluid volume The occurrence of signs of hypovolemia or of interstitial dehydration in an individual with a normal or subnormal scrum sodium concentration is indicative of sodium deficit (charts 14, 36) Conversely, the existence of signs of hyperolemia or of interstitial edema in an individual whose serum solium concentration is not grossly depressed ordinarily means that the sodium content of the body is greater than normal In judging body sodium status it is well to remember that extracellular sodium deficit is only one of a number of factors, including hemorrhage, hypoalbuminemia and certain forms of heart failure, which may act to reduce vascular volume and/or pressure in the region of the carotid sinus and thereby cause the body to retain sodium and form extra cellular fluid Unless this cxtracellular expansion "satisfies" the sensing clement, the tendency to fluid retention is apt to persist and to result in the development of edema Symptoms and Signs of Sodium Deficit and Excess TOO LITTLE TOO MUCH Dehydration Hypertension Loss of tissue clasticity Edema Soft eyeballs Congestive heart failure Microcardia See also the cellular potassium Tachycardia lack-sodium intoxication syn- Hypotension drome (chart 19) Hemoconcentration Prerenal azotemia Tendency to water intoxication Circulatory failure References Elkinton and Danowski (1955) General Talbot et al (1952) General ·14. Development and Recovery from Sodium Insufficiency The data in the accompanying chart were obtained in the case of a 13- year old boy whose desoxycorticosterone therapy was discontinued on day zero and whose sodium chloride intake was reduced on the third day to a low level (1 e 10 mEq per mº per 24 hours) for the purpose of certifying a tentative diagnosis of adrenocortical insufficiency (line A) Following this, he lost almost 9 mEq of sodium per kg, or about 20 per cent of his body's stores, together with a proportional quantity of extracellular fluid before he developed overt signs of circulatory insufficiency. Then, rather abruptly he became weak and hypotensive, developed a rapid, thready pulse and appeared to be on the verge of circulatory collapse These manifestations disappeared as soon as the patient was given 1 mEq of sodium per kg in the form of isotonic saline He remained symptom free throughout the remainder of the several days when he was replenishing his stores The fact that it was not necessary to correct his body sodrum deficit by more than one ninth part in order to eliminate most of the clinical signs of deficiency is worthy of note This seems to be generally true of many situations Thus, though it may be important to raise the body content of depleted patients promptly above the critical symptomatic level, it is not necessary or perhaps even desirable to attempt to repair deficits in toto within a few hours Once the critical level has been passed, patients usu ally do well if allowed to correct their residual metabolic disturbances in a smooth, asymptotic manner The present chart also is of interest in that it demonstrates that this same patient, when given desoxycorticosterone, could conserve sodium under conditions of low salt intake (line B) almost as efficiently as a normal person (line C) 28 ·SODIUM CUMULATIVE BALANCES OF SODIUM/KG BODY WEIGHT BALANCE mEq/ EXCHANGEABLE SODIUM LOST OO LOW SODIUN DIET STARTED 10 -NORMAL .C -20 B HYPO ADRENOCORTICAL PT ON DOCA -30 A -40H -SO 12 3% -60 - 70 HYPOADRENOCORTICAL PT DOCA DISCONTINUED DAYO DOGA + SODIUW ADDED BO -100 29 SYMPTOMS OF CIRCULATORY FAILURE 1 1 1 2 O 1 9 4 6 DAYS 7 fo 14. Development and Recovery from Sodium Insufficiency The source of the data in the above chart was a patient with hy roadrenocorticism (curve A) whosc desory corticosterone acctate therapy was stopped on day and whose solium intale was reduced to 10 ma per m' per day on day 3 The interval during which he manifested symptoms and signs of circulatory insufficiency is repre sented by the shaded area Curve B shows how the patient of cunc A responded to the lou solium regimen when being treated with DOCA Cunc C indicates the response of the normal individual to sendium restriction ใก ·15. Normal Limits of Body Tolerance for Sodium The scanty data available suggest that newborn infants are unable to take as much sodium as older infants, children and adults without becoming edematous Healthy children and adults usually can take and eliminate up to 250 mEq per m per 24 hours without difficulty Moreover, they may be able to manage loads of 500 or more mEq per m² per 24 hours of their sodium intake is increased gradually in a manner which provides ample time for adaptation In these connections, it is important to remember that tolerance even for moderate amounts of sodium is contingent upon having at least a moderate potassium intake Because the kidneys and sweat glands can reduce the rate of sodium output almost to zero when conservation forces are acting maximally, the body can maintain its sodium balance on an intake of less than 10 and maybe less than 5 mEq per m² per 24 hours This means that if one wants to prevent sodium retention and edema formation in a cardiac or nephrotic patient, it is necessary to restrict the salt intake drastically Among the conditions which may shift the limits of tolerance for sodium, the following may be mentioned CEILING LOWERED Zero potassium intake Hypoalbuminemia (charts 44B, 44C) Cardiac failure Severe stress Corticosteroid therapy Cushing's syndrome Renal disease FLOOR RAISED » Renal tubule disease Treatment with acetazoleamide, mercurial and other diuretics 30 ·mEq/m2/24 SODIUM 500 MAXIMAL TOLERANCE I with time for od optotion) 400 300 MAXIMAL TOLERANCE Cobrupt lood) V 70- ICO RAAF 410 411.17 3 1 1 1 1 6 9 12 18 --MONTHS A- 1 2 6 2 1 6 8 YEARS 1 16 20 3 10 12 BIRTH WKS 15. Normal Limits of Body Tolerance for Sodium Range of tolerance for sodium from birth to adulthood V indicales observed intakes above maximal tolerance A indicates obscncd solerable intake References Darrow and Pratt (1950) Noor values Gamble (1946–47) Adult floor values Gamble et al (1951) Infant ceiling values Leaf et al (1949) Adult ceiling values Macy (1942) Ordinary solum dict McCance and WidJou son (1957) Infant cclling values Shoht (1939) Ordinary sodium dict Smith (1958) Infant ceiling values Sicwart and Rourke (1942) Adult ceiling values Talbot et al (1952) Adrenocortical relations ·16. Body Content and Distribution of Potassium at Various Ages The body normally contains between 45 and 55 mEq of K39 per kg of body weight at all ages Most of this exchanges readily with its radioactive isotope, K", which can therefore be used to measure the size of body potassium stores Potassium is located chiefly in protoplasmic cells at a concentration of about 150 mEq per liter of cell water in the newborn infant about 60 per cent of this potassium is located in the musculature and about 20 per cent in the brain, the rest being divided among extracellular fluid, the skeleton and other organs In the adult the musculature contains about 80 per cent of the body's total potassium content, the remainder being distributed more or less evenly among extracellular Auid, brain, skeleton and other structures References Corsa et al (1956) Exchangeable K' data Elkinton and Danowski (1955) General Shohl (1939) Carcass analysis data 32 ·mEq/ kg POTASSIUM CONTENT 60 ADULT MALE NEWBORN 30 х x Other Drgons Stelelor 40 Bronn x x x XX х X х х х 30 х Muscle 20 10 Interstitio/ Plasmo 3 3 4 16 20 6 BIRTH WKS 6 9 12 10 2 -- MONTHS ----- 6 8 10 12 YEARS - (X- Exchangeable K42) 16. Body Content and Distribution of Potassium at Various Ages ·17. Potassium Homeostatic System * Though certain of the salient characteristics of this system can be dis cerned and described, many important details remain to be clarified It is clear that serum potassium concentration is one physiologic key variable worthy of note, for hyperkalemia per se results in various manifestations of potassium intoxication as described in the text accompanying chart 19 Moreover, it acts in some way, possibly in part via adrenocortical hormones, to stimulate excretion of potassium by the renal tubules into the urine Cellular potassium status is another variable which the body attempts to defend with considerable vigor Though the cells can store surplus po tassium in amounts equalıng between 5 and 10 per cent of their normal content (1e about 3 mEq per kg of total body weight), the organism normally eliminates such excess cellular potassium by way of the kidneys within a few hours, thereby rendering the cells capable of buffering a po tassium load once again The adrenal cortices play an essential role in this reaction The capacity to store surplus potassium temporarily within body cells constitutes a valuable defense against dangerous degrees of hyper kalemia and gives us the ability to handle much larger loads of potassium than would be the case if we had to depend exclusively upon the renal ex cretory mechanism to prevent hyperkalemia Hypokalemia per se does not necessarily result in maximal conserva tion of potassium by the kidneys On the other hand depletion of cellular potassium stores usually does lead to conservation of this ion by the kid neys However, the body is unable to conserve cellular potassium stores when deprived of potassium unless the sodium intake also is restricted sharply This is a fact of considerable clinical significance, for it means that one may be causing patients to develop cellular potassium insuffi ciency when one maintains them on potassium free, sodiu rich solutions such as isotonic saline Fortunately this danger can be minimized by pro viding both sodium and potassium in physiologically tolerable amounts * This is accomplished in large part at least by exchanging potassium ions within the cells of the renal tubules for sodium tons present in the tubular flud It probably ex plains why it is necessary to take at least moderate amounts of sodium in order to excrete large amounts of potassium by way of the kidneys 34

·PHYSIOLOGIC KEY VARIABLE
[Ken]
D
SENSING ELEMENT ----
MEDIATOR
-D
Adrenocortical
Harmonds et al?
EFFECTOR MECHANISM
0
Henan Tubule
Secretion of K
0
VARIABLE AFFECTED
0
Urinary Output of K
ID
17. Potassium llomeostatic System
References
Berliner (1952) General
Berliner et al (1950) General
Drescher et al (1958) Storage ol surplus
Laragh and Stocik (1997) Elfect of serum potassium on aldesicrone excretion
Spater eial (1939) Potassium deficiency

·17. Potassium Homeostatic System Though certain of the salient characteristics of this system can be discerned and described, many important details remain to be clarified It is clear that serum potassium concentration is one physiologic key variable worthy of note, for hyperkalemia per se results in various manifestations of potassium intoxication as described in the text accompanying chart 19 Moreover, it acts in some way, possibly in part via adrenocortical hormones, to stimulate excretion of potassium by the renal tubules into the urine Cellular potassium status is another variable which the body attempts to defend with considerable vigor Though the cells can store surplus po. tassium in amounts equalıng between 5 and 10 per cent of their normal content (ie about 3 mEq per kg of total body weight), the organism normally eliminates such excess cellular potassium by way of the kidneys within a few hours, thereby rendering the cells capable of buffering a potassium load once again The adrenal cortices play an esscntial role in this reaction The capacity to store surplus potassium temporarily within body cells constitutes a valuable defense against dangerous degrees of hyperkalemia and gives us the ability to handle much larger loads of potassium than would be the case if we had to depend exclusively upon the renal excretory mechanism to prevent hyperkalemia Hypokalemia per se does not necessarily result in maximal conservation of potassium by the kidneys On the other hand, depletion of cellular potassium stores usually does lead to conservation of this ion by the kid neys However, the body is unable to conserve cellular potassium stores when deprived of potassium unless the sodium intake also is restricted sharply This is a fact of considerable clinical significance, for it means that one may be causing patients to develop cellular potassium insuſliciency when one maintains them on potassium free, sodium rich solution such as isotonic salıne Fortunately, this danger can be minimized by providing both sodium and potassium in physiologically tolerable amounts • This is accomplished in large part at least by exchanging potassium ions within the cells of the renal tubules for sodium ions present in the tubular Alund I probably ex plains why it is necessary to take at least moderate amounts of sodium in order to excrete large amounts of potassium by way of the kidneys 34

·PHYSIOLOGIC KEY VARIABLE
0
[Ken]
SENSING ELEWENT --
HEDIATOR
Adrenocortica!
Hormones et ot?
) 0
EFFECTOR MECHANISM
-0
Renal Tubule
Secretion of K
O
VARIABLE AFFECTED
0
Urinary Output of k
n
17. Potassium llomeostatic System
References
Berliner (1952) General
Beclinet et al (1950) General
Drescher et al (1958) Storage of surplus+
Laragh and Stoerk (1957) Elfcct of serum potassium on aldesteronc excretion
Spater et al (1959) Potassium deficiency

·17. Potassium Homeostatic System Though certain of the salient characteristics of this system can be dis cerned and described, many important detajs semais to be clarified It is clear that serum potassium concentration is one physiologic hey variable worthy of note, for hyperkalemia per se results in vanous manifestations of potassium intoxication as described in the text accompanying chart 19 Moreover, it acts in some way, possibly in part via adrenocortical hor mones, to stunulate excretion of potassium by the renal tubules into the * urine Celular potassium status is another variable which the body attempts to defend with considerable vigor Though the cells can store surplus po tassium un amounts equalıng berneen 3 and 10 per cent of their normal content (ie about 3 mEq per kg of total body weight), the organism normally eliminates such excess ce}}ular potassium by way of the kidneys within a few hours, thereby rendering the cells capable of buffering a po tassium load once again The adrenal cortices play an essential role in this reaction The capacity to store surplus potassium temporarily within body cells constitutes a valuable defense against dangerous degrees of hyper kalemia and gives us the ability to handle much larger loads of potassium than would be the case of we had to depend exclusively upon the renal ex cretory mechanism to prevent hyperkalema Hypokalemia per se does not necessarily result in maximal conserva tion of potassium by the kidneys On the other hand, depletion of cellular potassium stores usually does lead to conservation of this on by the kid neys However, the body is unable to conserve cellular potassium stores when deprived of potassium unless the sodium intake also is restricted sharply This is a fact of considerable clinical significance, for it means that one may be causing patients to develop cellular potassium insuffi ciency when one maintains them on potassium free, sodium rich solutions such as isotonic salme Fortunately, this danger can be minimized by pro viding both sodium and potassium in physiologically tolerable amounts • This is accomplished ja targe part at least by exchanging potassium sons within the cells of the renal tubules for sodius sons present in the tubular flud It probably er plans why it is necessary to take at least moderate amounts of sodum in order to ctcrete large amounts of potassium by way of the kidneys

·SERUM K
mEq/L
NORMAL
RANGE
K
200
mEq/m2/24•
INTAKE
100
OUTPUT
10
STARKAS
0 6 12 18 24 30 36 42
HOURS
18. Dynamics of Potassium Ilomeostasis
The subject of these observations was a normal adult male

·18. Dynamics of Potassium Homeostasis The data presented in the accompanying chart were obtained in the case of a healthy adult subject who was given potassium in the form of a multi ple electrolyte solution A (chart 37A) at the rate of 185 mEq per m’ per 24 hours during the first 6 hours of each day and then allowed to fast and thirst for the remainder of the 24 hour period The abrupt increase in in tale from the zero level resulted in a small, transient elevation in serum potassium concentration It was followed within 6 hours by a compensa tory increase in urinary output of potassium which was sufficient to restore the body's potassium content and concentration values to - control levels It is thus apparent that the not is capable of reacting nromtolerance range Reference Neyzı et al (1958) Source of data for figure ·doxical in view of the fact that these signs usually can be presented by including a physiologically moderate allotment of potassium in the patient's daily intake Symptoms and Signs of Potassium Excess and Deficit TOO MUCH TOO LITTLE Hyperkalemia Without cellular sodium ercess Elevation and peaking of Twarcs Dehydration in ECG (lead II) With cellular sodium excess Muscle weakness Muscle weakness Paresthesias Ileus or diarrhea Cardiac arrest Loss of ability to concentrate urine Flattening of Twaves in ECG (lead II) Hypochloremic, hypokalemic alkalosis References Cookc et al (1952) Cellular potassium lack sodium excess Drescher et al (1958) Potassium intorication in rats Elkinton and Danowski (1955) General Goodman and Gilman (1955) General Spater et al (1959) Cellular potassium lack sodium ercess Winkler et al (1938) ECG changes with hyperkalemia ·19. Symptoms and Signs of Potassium Excess and Deficit Chronic loading experiments on rats indicate that the various manifesta tions of potassium infotication are due to abnormally high concentrations of potassium in extracellular fluids rather than to changes in the cellular content or concentration of this son It follows that sustamed hyperkalemia per se signifies that the organism is being subjected to a physiologically excessive load of potassium Because hyperkalemia characteristically re sults in changes in the electrocardiographic T waves, under most clinical circumstances the electrocardiogram can be used in lieu of the serum potassium measurement as an index of potassium intoxscation Digitalis iends to reduce myocardial potassium and therefore may interfere with the use of this index Acidosis also may cause changes in the T wases which can be confused with the characteristic peaking of potassium 10- toxication Potasstum depletion results m reduction of the potassium content of the cells in instances of simple cellular potassium deficiency, the cellular concentration remains al normal levels because there is a parallel loss of cell water Aside from producing evidences of dehydration, this type of potassium deficiency causes almost no Olert manifestations If the indevidual is placed on a generous sodium but negligible potassium intake. sodium and small amounts of hydrogen ion are apt to enter the cells and occupy the space normally filled by potassium This sodium acts as a sol ute to draw water into the cell, which reduces the potassium concentration at times to markedly subnormal levels Esther because of this or because of the associated fall in potassium sodium ratio, cell function deteriorates ---as may be evidenced by skeletal muscle weakness, sleus, a tendency to extracellular edema formation, loss of capacity to concentrate urine, flattening of the T waves in lead ll of the electrocardiogram, circulatory failure and other changes In addition, there is a tendency for the hydrogen ions to produce "cellular acidosis The kidneys react to this as if the pa tient were suffering from metabolic acidosis Hypochloremic, hypokalemic alkalosis results As may be inferred from the foregoing remarks, it is sometimes diffi cult for the clinician to recognize potassium insufficiency unless the patrent has developed cellular sodium intoxication as well This complication is often jatrogenic, arising as a consequence of maintaining patients on saline solutions or other fluids of generous sodium, but negligible potassium, content The common practice of withholding potassium from patients until they manifest some of the signs mentioned above seems para- 38

·600
500
mwy
Maximal Tolerance
(with time for
full adoptosion)
400
к
mEq/m21240
300
Maximal Tolerance
(conservative
estimate)
200
100
}
Ordinary Range of
Dietary Intoke
Minimal
Requirement
O
20. Limits of Body Tolerance for Potassium

·20. Limits of Body Tolerance for Potassium Healthy individuals can maintain equilibrium with respect to potassium while taking no more than 10 mEq per mº per 24 hours provided their sodium intake is low and their total caloric, carbohydrate and protein intake is large enough to maintain body protoplasm and glycogen stores As with sodium, individuals need more time to attain marimal rates of potassium excretion than to adjust urinary output to moderate sized potassium loads In recognition of this, iwo maximal tolerance levels are indicated in the accompanying chart The lower one at 250 mEq per m² per 24 hours is a rate which normal individuals can approach or attain within several hours (chart 18) The upper value at 500 mEq per m? per 24 hours is one which can be reached stepwise in the course of several days Both ceiling values presuppose that the individual is taking a moderate amount of sodium salts simultaneously As the insert shows, ordinary diets provide us with quantities of potassium which lie well within the body's safe working range of homeostatic function Among the conditions which may narrow this range, the follow. ing may be mentioned CEILING LOWERED Marked dehydration Circulatory failure Very low sodium intake Pannephritis with marked reduction in glomerular filtration rate (chart 45A) Hypoadrenocorticism Congenital adrenocortical vırılısm-sodium losing syndrome FLOOR RAISED Diarrhea 1 denen inhout 20 ) References Shohl (1939) Normal dietary potassium Talbot et al (1953) General Talbot et al (1956) General 40

·ht (mEq/kg)
10
Acute Bufter
Storage Capacity
9
B
(mEq/kg)
010
Body
Content
of free H+
PM 7.1
005
PH 74
Ordinary Daily
intake and Output
of 55 mEq/m2/24*
pH 76
0
Body
Content
of tree H
ALKALOSIS
NORMAL
ACIDOSIS
21. Body Content of Hydrogen Ions Relative to Daily Turnover

·21. Body Content of Hydrogen lons Relative to Daily Turnover As this heading indicates, the body contains a certain amount of hydrogen ions just as it contains certain amounts of water and the various other electrolytes discussed in previous charts The absolute quantity normally pres ent in free form in body fluids at any one moment is, however, very small, amounting to only 0 000,024 mEq per kg of total body weight when the serum pH is 74* Though the absolute quantity in body fluids is miniscule relative to ordinary daily hydrogen ion intake and output, which usually amounts to about 2 mEq per kg of body weight in a child having a surface area of 1 m*, it constitutes a very significant "physiologic hey variable " An increase in free hydrogen ion content to 0 000,048 mEq per kg results in marked acidosis (serum pH 7 1), while a decrease to 0 000,015 mEq per kg re sults in marked alkalosis (serum pH 76) The organism is usually able to keep its free hydrogen son content within tolerable limits despite wide variations in hydrogen ion intake be cause it is able to adjust output in accordance with need (chart 22) and because it contains buffers capable of temporarily absorbing up to 10 mEq of hydrogen ton per kg (chart 23) * PH = -log hydrogen ion concentration 42 ·wt intake 01 (1 HCO, latake 1) PHYSIOLOGIC KEY VARIABLE 1 CH+] of Body Fluds SENSING ELEMENT EFFECTOR MECHANISM HANISM K dney Tubutes VARIABLE AFFECTED Urinary + Output or Urnory HCO3 Output 1) BODY BUFFER SYSTEMS H+ + HCO3 = H2CO3 H+ + HDO? 1 11 HMOQ2 + + HPO4 =H2PO4 11 H+ + Proton =H Proten 111 OH HCO3 MPOA" etc of Skeletat Reservor 22 Hydrogen lon Homeostalic System ·22. Hydrogen Ion Homeostatic System The main purpose of the accompanying diagram is to call attention to the fact that there is an intake and output of hydrogen ions just as there is of water, protein, sodium, chloride, calories and so forth Acidosis develops when the intake of hydrogen ions exceeds the output and the body content increases (serum pH <7 35) Alkalosis ensues when the output of hydrogen ions exceeds the intake and the body content diminishes (serum pH > 745) To increase the hydrogen ion content of the body, hydrogen ons must enter body fluids in company with some anion other than bicarbonate or a precursor thereof such as lactate or citrate The reason is that brcarbonate "eliminates" hydrogen ions by combining with them to form water and carbon dioxide, which is excreted by way of the lungs Hydrogen ions presenting in company with anions such as chloride, phosphate, sulfate or mandelate constitute an intake load whether they are taken in the form of free acids or precursors such as ammonium chloride or methionine In the former instance, two molecules of ammonium ion are metabolized in the body to form one molecule of urea plus two hydrogen sons In the latter instance, the methionine molecule (which contains sulfur) upon being metabolized yields urea, hydrogen ions and sulfate ions and so forms the equivalent of sulfuric acid An abnormally large number of hydrogen ions also may be formed endogenously from lipid sources in company with two ketone anions, beta hydroxybutyrate and acetoacetate, under conditions of cellular carbohydrate starvation Unlike other forms of acidosis, this can be overcome simply by slowing the rate of ketone body formation to the point where the organism is able to metabolize the ketone acids completely to carbon dioxide and water. In nondiabetics this can be done by providing at least 50 gm of glucose per m” per 24 hours (chart 37B) and in diabetics by giving adequate doses of insulin (chart 40A) Pending their elimination by the kidney tubules, all but a tiny fraction of the free hydrogen ions entering body fluids are taken up temporarily by the body's buffer systems (chart 23) The few hydrogen ions which remain free create a tendency to acidosis This serves the useful purpose of stimulating the kidney tubules to accelerate excretion of hydrogen ions in the urine (chart 24) Hydrogen ions are made available for urinary excretion by hydration of carbon dioxide with the aid of an enzyme, carbonic anhydrase (CO: + H:0+ H+ + HCO3) Hydrogen ions thus produced in kidney 44 ·10 8 Cumulative H+ Balance 6 mEq/kg 4 2 150 H* --- Intake os NHACI un Urinary NH4+) Urinary Output Titrotable lacidity H+ intoko ond Output mEq/m2/24 100 50H 1 1 2 3 4 5 6 7 8 9 10 DOY 24. Dynamics of II; drogen Ion Iomeostasis The data for this diagram have been derived and recharted from Patts (1948) The urinary hydrogen ion excretion from the constant diet amounting to 50 mEq per m' per 24 hours evenly divided between titrablc acidity and NH.*has been climi nated from the dtagram The H+ output thus reflects the increase produced by the NH CI loud goren on days I through 5 The onginal data did not include the sub oct s size We have assumed the surface arca to bc 17 m' ·These data are of interest because they give an order of magnitude indication of the absolute capacity of the body as a whole to deal with abrupt loads of either of these ions pending their elimination by way of the urine As was indicated in chart 21, this capacity is generous in relation to the ordinary daily intake of hydrogen ions (about 55 mEq per m² or 2 mEq per kg per 24 hours or 07 mEq per kg per meal) It is also ample in relation to the individual dosages of sodium or potassium bicarbonate or dinarily used for alkalinization of the urine (i e about 72 mEq per mor about 2 5 mEq per kg per 24 hours) References Singer et al (1955) Bicarbonate loading in humans Swan and Patts (1955) Hydrogen ion loading in nephrectomized dogs Swan et al (1955) Bicarbonate loading in nephrectomized dogs 24. Dynamics of Hydrogen Ion Homeostasis It takes about 5 days for healthy individuals to adapt to a major shift in hydrogen ion intake During the initial period of adaptation a considera ble quantity of the hydrogen ions is retained and taken up by the body's buffer systems This probably provides the stimulus needed to accelerate hydrogen ion excretion by the kidneys Only a small portion of the hydro gen ions is eliminated by the urinary buffer mechanism Most are trans ported out of the body as urinary ammonium ions References Pitts (1948) Source of data Smith (1956) General 48 ·10 6 Cumulative H H* solonce mEq/kg 4 2 150 - - H* Intake as NH4C1 + W Urinary NH4 Urinary Output Tatratable lacidity ut Intake and Output mEq/m2/24 100 1 50 2 3 4 5 6 7 8 9 10 Day 24. Dynamics of Hydrogen Ion Ilomeostasis The data for this diagram have been derived and rechared from Pitts (1948) The urinary hydrogen son crcrction from the constant diet amounting to 50 mEq per mi per 24 hours evenly divided between titrable acidity and NH has been climi nated from the diagram The H+ output thus reflects the increase produced by the NH CI load given on dass I through 5 The original data did not include the sub. jects size We have assumed the surface area to be 1 7 m' ·25. Symptoms and Signs of Hydrogen Ion Deficit and Excess Lowering the concentration of hydrogen ions in the extracellular fluids (ie alkalosis) lessens calcium ionization and hence may lead to the development of tetany and convulsions It also can lead to mental confusion, coma and death It is thought that some of these manifestations may be due to spasm of cerebral blood vessels If the hydrogen ion deficit is pri marily metabolic in origin, as in patients who lose hydrochloric acid through vomiting or who gain bicarbonate through overloading with sub stances such as sodium bicarbonate or lactate, the respirations will be de creased in number and amplitude and the concentration of bicarbonate in the serum will be elevated On the other hand, if the alkalosis is primarily a disturbance in respiratory function as in patients with hysterical hyperventilation or with hyperventilation due to salicylate intoxication, the res pirations will be increased and the concentration of bicarbonate in the serum will be decreased Acidosis is associated with a tendency to increased respiratory ex change when it is primarily due to a metabolic disorder (such as fasting ketoacidosis), but with decreased respiratory exchange when due to a respiratory disturbance which interferes with the excretion of carbon di oxide via the lungs (such as pulmonary emphysema) The concentration of bicarbonate in the serum is subnormal in the former and is supranormal in the latter type of acidosis Apart from this effect, increase in hydrogen ion concentration per se may not produce obvious chnical manifestations until the pH of body fluids drops to 7 1 or lower Patients with this degree of acidosis are apt to become stuporous and comatose and may die if the pH falls below 6 9 It is difficult to be sure, however, to what extent these changes should be attributed to hydrogen ion excess per se, for such indi viduals are usually also suffering from other disturbances such as ketosis, hyperphosphatemia, hyperchloremia, azotemia and so forth

·Symptoms and Signs of 11; drogen lon Deficit and Excess
TOO LITTLE
TOO MUCI
If metabolic alkalosis
If metabolic acidosis
Decreased respiratory erchange Increased respiratory crchange
Plasma HCO,> 27 mEq/L Plasma HCO, < 24 mEq/L
If respiratory alkalosis
If respiratory acidosis
Increased respiratory exchange Decreased respiratory exchange
Plasma HCO3 < 24 mEq/L Plasma HCO, > 27 mEq/L
Tetany
Stupor
Convulsions
Coma
Mental confusion
Plasma pH <735
Coma
Plasma pH > 745
References
Elkinton and Danowski (1955) General
Lety and Schmidt (1948) Cerebral blood flow in alkalosis
Moorc (1958) General

·26. Limits of Tolerance for Hydrogen Ions and Bicarbonate Ions The largest amount of hydrogen ions that can be taken and eliminated without producing a sustained acidosis is approximately 200 mEq per m* per 24 hours Higher rates of intake result in higher rates of output, but at the expense of systemic acidosis While the lethal limit of hydrogen to! erance is not accurately known, it would appear to be in excess of 500 mEq per mº per 24 hours Alternatively, healthy individuals can take and eliminate as much as 250 mEq of bicarbonate per m* per 24 hours without elevating plasma bicarbonate concentration above 28 mEq per liter or becoming alkalotic By raising plasma bicarbonate concentration to higher levels, greater rates of output can be attained Though it is clear that one can take and climinate more than 250 mEq per mº per 24 hours, data defining where the lethal levels of intake may lie do not appear to be available References Følling (1929) Hydrogen son ceiling Gamble (1958) Bicarbonate ceiling Gamble er al (1951) Bicarbonate ceiling Pitts et al (1949) Bicarbonate ceiling Sartorius et al (1949) Hydrogen ion ceiling Shohl (1939) Dietary intake of hydrogen ons 52 ·RANGE OF TOLERANCE FOR ACID AND BASE INTAKE mEq/m2/24 200 Approximate Physiologic Maximal Toterance 150 H+ Nhạc 69m/m2/24• 100 INTAKE 50 Usual Range of Intake 1 - 50 NaHCO3 69m/m2/24 HCO3 INTAKE 100 150 200 250 Approximate Physiologic Maximal Tolerance 26. I imits of Tolerance for Hydrogen Ions and Bicarbonate Jons ·28. Body Content and Distribution of Phosphorus and Serum Inorganic Phosphorus Concentration at Various Ages There is a gradual increase in skeletal phosphorus and hence in total phosphorus per kilogram of body weight during the growth period It is interesting to note that protoplasmic phosphorus comprises about 20 per cent of the body's stores Approximately half of this, or 10 per cent of total body stores, is in the form of the vitally essential, energy rich phosphate compound adenosin triphosphate (ATP), which is present in all cells, and creatine phosphate, which is found chiefly in muscles Extracellular inorganic phosphate comprises less than 1 per cent of the body's content The concentration of inorganic phosphorus in the serum is about 5 6 mg per 100 ml at birth The values obtained during the first days of life are influenced markedly by intake, being much lower in babies fed human milk than in those fed cow's milk (chart 34) Apart from these neonatal phenomena, the inorganic phosphorus of the serum rises steadily after birth until a maximal value of about 6 5 mg per 100 mi is reached at 6 months of age It then falls somewhat, ranging between 40 and 5 5 mg per 100 ml in children aged 1 to 12 years and between 30 and 50 mg per 100 ml in children aged 12 to 20 years In adults it ranges between 25 and 5 0 mg per 100 ml References Elkinton and Danowski (1955) General Gardner et al (1950) Neonatal phosphorus concentration Shohl (1939) General 56 ·mmol/kg gm/kg PHOSPHORUS CONTENT Ho 300 9 8 250 7 2001 6 5 150 SKELETAL 4 100h 2 50 PROTOPLASMIC 16 20 6 3 BIRTH WKS Extracellular how inorgonic P Immol/kg 6 9 12 18 2 3 4 6 8 10 12 - MONTHS---------- YEARS ----- 28. Body Content and Distribution of Phosphorus at Various Ages The distribution of body phosphorus at birth and in adult life has been taken from carcass analysis The rate of increase in content w3s assumed to parallel the normal lincar growth rate ·29. Phosphorus Homeostatic System The accompanying diagram depicts serum inorganic phosphorus concentration as the physiologic key variable for which the phosphorus homeostatic system is responsible This undoubtedly is an oversimplification, since the parathyroids also have a responsibility for maintaining the concentration of ionized calcium in the serum within physiologically satisfactory limits Indeed, it is possible that the parathyroids sense changes in inorganic phosphorus concentration indirectly through the effects of alterations in this variable upon serum ionized calcium concentration Elevation of serum inorganic phosphorus results in a drop in jonized calcium concentration and there is no doubt that the latter change can lead to a marked increase in parathyroid secretory activity In the absence of parathyroid hormone the renal tubules tend to reabsorb essentially all the phosphorus contained in the glomerular filtrate, with the result that the urine is almost phosphate free By contrast, when parathyroid hormone influence is at maximal levels, the tubules stop reabsorbing phosphate almost completely Consequently, the urine now contains all the phosphate of the glomerular filtrate In healthy older children and adults, who form glomerular filtrate at the rate of about 100 liters per m² per 24 hours and whose serum inorganic phosphorus concentration ranges from 35 to 5 mg per 100 ml, the glomerular filtrate will contain between 3500 and 5000 mg of phosphorus per m² per 24 hours Because these figures are considerably in excess of the normal dietary phosphorus content, it is possible for normal persons to vary their intake from zero to 4000 mg of phosphorus per m² per 24 hours without becoming excessively hypo- or hyperphosphatemic Once this upper limit has been reached, the organism can no longer prevent accumulations of phosphorus in the circulation by suppressing renal tubule reabsorption of glomerular filtrate phosphorus Administration of larger quantities of phosphorus therefore inevitably produces hyperphosphatemia This automatically bungs into prominence the other mechanism for increasing the phosphorus output rate, namely elevation of the glomerular filtrate phosphorus content (left hand section of chart 29) This mechanism is rarely needed to any great extent by normal persons, but it may be of considerable importance in patients whose glomerular filtration rate has fallen to less than 10 or 15 per cent of normal as a result of kidney disease or circulatory failure or whose parathyroid-renal tubule system is defective and therefore unable to stop reabsorbing phosphorus (charts 45, 46) 58 ·Serum Concentronson O PHYSIOLOGIC KEY VARIABLE Glomerular Filtrate 0 Porathyroid Hormong 0 SENSING ELEMENT MEDIATOR Renal Tubular Reabsorption errECTOR WECHANISM of P O Urinary Output of PD VARIABLE AFFECTED 29. Phosphorus Ilomeostatic System Ir Nicholson has recently presented evidence which indicates that parathyroid hormone may control unnary phosphorus output by regulating renat tubule phos phorus ercrenon rather than renal tubulc phosphorus reabsorption as shown in this diagram Though this may mean that the mechanism by which parathyroid hormone crerts its influence upon urinary phosphorus differs from that indicated in the present diagram it does not alter the basic concept of the role of the parathyroid glands in body phosphorus homeostasis Reference Albright and Reifenstein (1948) General Crawford et al (1950) General Nicholson (1959) Parathyroid action Nicholson and Shepherd (1959) Renal phosphate output Talbot et al (1952) General ·30. Dynamics of Phosphorus Homeostasis When the phosphorus intake is increased abruptly, as it was in the normal subject of the accompanying chart, both of the mechanisms for augmenting phosphorus excretion mentioned in the preceding chart are brought into play Thus, it can be seen that raising the phosphorus intake rate from zero to about 2000 mg per mº per 24 hours at the fourth hour of observation resulted almost immediately in elevation of serum inorganic phosphorus concentration As indicated in the left hand section of chart 29, this led to an increase in glomerular filtrate phosphorus (GFP) and hence to a rise in urinary output of phosphorus (UP) In addition, the hyperphosphatemia stimulated the parathyroid mechanism (right-hand section of chart 29) to suppress tubular reabsorption of phosphorus (TRP), thus allowing more of the glomerular phosphorus to escape into the urine This effect is reflected in the values for TRP/GFP, which started to decline within 3 hours after the phosphorus load was imposed and reached minimal levels about 12 hours later Thus the organism was able by means of these two mechanisms to re equate output with intake within 8 hours and to return serum inorganic phosphorus concentration almost to normal levels within 18 hours after the rate of intake had been increased markedly Studies on patients whose phosphorus intake has been suddenly reduced indicate that downward adjustments in the rate of phosphorus output also can be completed in about 12 hours Reference Crawford et al (1950) Source of data 60 ·5 00 SERUM 4 00 INORGANIC PHOSPHORUS 300 CONC 2 00 mg / 100ml 100+ GFP 4000 TRP Inicke PHOSPHORUS 3000 mg/m2/24 2000H O'p 1000 100 80 TRP/GFP 60 40 20 O 2 6 8 10 12 14 16 18 20 22 24 TINE IN HOURS 30. Response of a Normal Subject to Phosphorus-Loading by Joiravenous Infusion The data in the above chart arc from Crawford et al (1950) ·31. Symptoms and Signs of Phosphorus Excess and Deficit Administration of phosphorus at physiologically excessive rates results in hyperphosphatemia Though any sustained elevation of serum inorganic phosphorus concentration above normal levels may be considered evidence that the individual is being subjected to a physiologically excessive load of phosphorus, slight to moderate elevations may not lead to grossly observable disturbances in body economy With marked hyperphosphatemia, serum ionized calcium values are apt to become depressed suffi ciently to result in tetany (chart 34) In other words, there is a consider able depth to the phosphorus ceiling zone, which starts at the level where the serum inorganic phosphorus concentration first rises above normal and ends at the much higher level (usually > 10 mg per 100 ml) where serious symptoms may occur This fact has a bearing on the management of nephritic patients whose physiologic tolerance for phosphorus has been reduced to such an extent that they can no longer eat diets of ordinary phosphorus content without becoming moderately hyperphosphatemic Though it is essential to restrict their phosphorus intake sufficiently to prevent marked degrees of hyperphosphatemia, it may not be of vital importance to reduce their phosphorus intake to the point where the serum inorganic phosphorus concentration is kept within normal limits Phosphorus deficiency is seldom accompanied by obvious clinical manifestations unless sustained for a considerable period of time It then results in hypophosphatemia, in reduction of the product of serum inorganic calcium and serum inorganic phosphorus and hence in failure to calcify the skeleton Osteomalacia (rickets) ensues Though this situation has been produced many times in laboratory animals, it is rarely encountered in clinical practice Symptoms and Signs of Phosphorus Excess and Defcit TOO MUCH TOO LITTLE Hyperphosphatemia Hypophosphatemia Hypocalcemia Osteomalacia (rickets) Tetany 7 other effects References 62 ·32. Normal Limits of Body Tolerance for Phosphorus As the accompanying chart shows the ceiling for phosphorus is low dur ing the neonatal period both because the glomerular filtration rate is about half as great in newborn infants as it is in persons over 1 year of age and because the parathyroid-renal system is relatively inactive at the time of birth During the neonatal period it is important to avoid fecding infants more phosphorus than they can handle in a physiologic manner (sec Cows Milk Tetany of the Newborn chart 34) Thercafter because the parathyroid-renal system rapidly acquires full functional capacity there is little likelihood that the normal individual will eat more phosphorus than he can eliminate without difficulty mmol/m?, 24- am/m2124 MAXIMAL TOLERANCE 140 40 120 35 100 30 80 25 20 60 I5 "LAY, THY A4 -- 40 IO 20 505 MIN REQUIREMENT 1 1 6 3 6 9 12 182 4 6 8 10 12 16 20 BIRTH WKS - MONTHS- ----- YEARS ------ 32 Normall imits of Body Tolerance for Phosphorus ·Because phosphorus is a common dietary constituent, normal persons almost always ingest enough to cover their minimal requirements About the only exception that one is apt to encounter clinically is the patient with vitamin D resistant rickets In such individuals the phosphorus floor may be artificially elevated by the large doses of vitamin D needed to facilitate calcium absorption by the gut Other conditions which may alter the range of tolerance for phosphorus are as follows CEILING LOWERED Normal newborn (chart 34) Pannephritis with marked reduction in glomerular filtration rate (chart 45A) TT none resistant, renal Circulatory failure FLOOR RAISED Vitamin D intoxication Hyperparathyroidism References Crawford et al (1955) Phosphaturic effect of vitamin D Macy (1942) Dietary phosphorus Rubin et al (1949) Renal limitations in infancy Shohl (1939) Dietary phosphorus Talbot ct al (1952) Phosphorus tolerance 64 ·SECTION B. CLINICAL APPLICATIONS ·33. Infant Feeding Infants tend to do well on any regimen which provides essential nutrients at rates which fulfill maintenance and growth requirements, yet do not overload the capacity of any of their homeostatic systems As would be expected, human milk is so composed that the nursling infant obtains all essential nutrients at adequate yet physiologically tolerable rates when he ingests a volume that satisfies his thirst and hunger (1 e about 2500 ml per m® per 24 hours) As charts 33A and B show, this quantity provides 1800 calories per m² of body surface per 24 hours and more than enough water, minerals and protein to cover growth and minimal maintenance requirements Any surpluses remaining after these primary needs have been met can easily be eliminated by way of the urine under the direction of the homeostatic systems Moreover, the infant can draw upon these surpluses, together with the quantities normally used for growth, when he needs to compensate for unusual or abnormal losses incurred as a result of sweating, diarrhea or vomiting The situation is quite different in infants fed whole cow's milk, because it contains per unit volume and per calorie much more sodium, potassium, chloride, phosphorus, calcium and protein than its human counterpart Unlike the calf, which can use most of the absorbed materials for growth purposes, the infant must excrete all but the small fraction that can be utilized for new tissue For one thing, this produces a urinary solute load which is much greater (about 600 mosM per mº per 24 hours) than that found in breast-fed babies (about 200 mosM per mº per 24 hours) This solute load in turn increases minimal urine volume and hence total body water requirements by 400 to 600 ml per ma per 24 hours, thereby eliminating the margin of safety with respect to water balance enjoyed by breast-fed infants For another thing, the load of phosphorus imposed when young infants are fed undiluted cow's milk exceeds their physiologic maximal tolerance Consequently, it is apt to result in hyperphosphatemia (chart 34) It is thus apparent that whole cow's milk is not well suited to the needs or tolerances of babies during their initial weeks of life The four right-hand columns of chart 33B are representative of the many clinical and commercial attempts to modify whole cow's milk in a manner that renders it more suitable for infant-feeding While none of these products resembles human milk exactly, all provide nutrients at rates which healthy infants should tolerate without difficulty after they are 3 weeks old During the first 3 weeks of life, when the capacity to conserve water and to eliminate phosphorus is relatively low, only formulae of low phosphate and other solute content should be used 66 ·2000 1500 WATER ml/m2/24 1000 Surplus Obligatory Insensible + Stoot + Urine Maintenance Needs Grorth 500 Normal intake of --Human Milk 23 L/m2/24 20 SODIUM mEq/m2/24 10 POTASSIUM mEq/m2/24 20 EINT 10 15H Ayolobis for mineralization of skolelon PHOSPHORUS mMot/m2/24 30 PROTEIN 20 m/m2/24 10 10 3 6 9 12 24 3 6 9 12 24 BIRTH MONTHS BIRTH MONTHS 33A. Approximate Requirements of Infants for later, Certain Flectrolytes and Protein ·Technical Details Each 100 ml of formula D contains 66 ml of whole cow's milk, 34 ml of water and a quantity of added carbohydrate sufficient to provide the cat ories contained in 34 ml of whole milk, namely 34 x 0 7 or 6 gm of sugar 4 Each 100 ml of formula E contains 50 ml of whole cow's milk, 50 ml of water and 50 x 0 7 or 9 gm of added carbohydrate 4 If evaporated milk is used instead of whole cows milk, the ratio of milk to water in formula D would be EM 33 ml water 67 ml and sugar 6 gm and in formula E it would be EM 25 ml water 75 mland sugar 9 gm No specific volume of formula is prescribed Rather, it is suggested that the infant be offered 2500 ml per m per 24 hours (170 ml per kg, 21/2 oz per lb) in six, five or four divided allotments and be allowed to take as much as he wants in a feeding period of approximately 20 minutes' duration By the time infants are about 2 or 3 months old, their homeostatic systems have developed to the point where it is safe to use whole cow's milk and to begin to add suitable prepared cereals, meats, eggs, fruits and vegetables as needed to give variety to the diet and to satisfy the appetite Infants given whole cow's milk should have access to plain water two or three times a day, especially in hot weather References Gamble (1958) General Gardner et al (1950) Neonatal tetany Nelson (1954) General Shohl (1939) Muk composition, growth requirements ·DO C E f G WEEK INFANT HUMAN WHOLE COW $ MILX -100 SNA' 를 STRENGTH COW'S MILKE CNO RANGE or TOLER Swat SIWILAC VILK H₂O W/m2/24 4000 I 2000 H I H! I Na 130 mEq/m2/24° 100- 50 M H, N 7 150 mEq/m3 124 1005 30 H H H 2 CI" 150 mEq/m2/24• 100F H H 30 H H IH P mg/m/24 2000 P mmol/m2/24 75 SOF 23 I H I н 1000 I ca 3000 mg/m2/24• 2000 1000 I M . PROTEIN g/m2124 75 $0 I ! ! H 25 - 1 CALORIES/ 3000 m2/24 rooo 2000W H н I 338. Provision of Infants' Nutritional Needs by Jluman Milk, Whole Con's Milk and Cow's still formulas ·34. Cow's Milk Tetany of the Newborn This is a condition usually seen between the fifth and twelfth days of life in infants fed whole cow's milk or other high phosphate mixtures As the accompanying chart shows, the high phosphate intake predisposes to hyperphosphatemia This lowers the concentration of ionized calcium in the serum Up to the point when the concentration of inorganic phosphorus in the serum is less than 10 mg per 100 ml, clinical signs of tetany usually are absent On the other hand, when the phosphorus concentration rises above 10 mg per 100 ml the baby usually becomes hyperirritable and jittery and may have localized twitchings or generalized convulsions The fact that the disease occurs rarely if ever in babies fed human milk indicates it to be a product of artificial feeding It can be avoided by keeping the phosphate intake within physiologic limits of tolerance during the neonatal period Once it has developed, an immediate attempt to stop convulsions should be made by slowly infusing 10 or 20 ml of a 10 per cent calcium levulinate or gluconate solution Thereafter, the most important step is to eliminate phosphorus from the infant's intake for a few days, which will enable him to excrete the surplus phosphorus that has accumulated in his body and will thereby restore his serum inorganic phosphorus concentration to normal levels This can be done most easily by feeding the infant water containing 10 per cent dextrose It also can be accom plished by feeding human milk One must remember that even the most highly diluted cow's milk preparations (chart 33B) have a generous phosphorus content They should therefore be omitted until the infant has re stored his serum inorganic phosphorus and ionized calcium values to normal levels Formulae containing minimal amounts of phosphorus can then be offered with safety References Gardner et al (1950) Source of diagram Talbot et al (1952) General 70 ·SERUM INORGANIC PHOSPHORUS mg/100 ml ܐܘ ܘܙ 50 FEO COW S MILK -- FED HUMAN NILK DIETARY PHOSPHORUS mMot/m/24 4BFmg/m/24 1500 32 41000 16 500 5 3 4 6 7 8 9 10 12 DAY OF LIFE 34 Relation between Dietary Phosphorus Intake and Serum Inorganic Phosphonis Concentration during the First Days of Life The data in the above chart are from Gardner et al (1950) ·35. Relative Importance of Homeostatic Adjustments versus Composition of Solution Used in Recovery of Patients Undergoing Parenteral Fluid Therapy It may be helpful to introduce these discussions of parenteral fluid therapy by summarizing observations of two infants who were treated for dehydration due to diarrhea In each instance the physician in-charge had calculated the baby's maintenance plus-repair needs and treated him accordingly In each instance, also, measurements were made which permitted one to judge in retrospect how the patient had responded to therapy. The results obtained were thought provoking, for they showed that though we had miscalculated these infants' needs by an appreciable margin and had given the largest allotments of various substances to the infant who needed them the least and the smallest to the infant who needed them the most, yet both had done well It then became apparent that the patients had recovered satisfactorily because, by good fortune, both had been given water, sugar, sodium, potassium, chloride and phosphate at adequate, yet physiologically tolerable, rates Consequently, it was possible for the infants to cure themselves by retaining or rejecting each of the ingested substances in accordance with needs as they sensed them This experience made one realize that the physician does not necessarily have to know exactly what his patient's specific maintenance and repair requirements are It is necessary only that he make a reasonably good estimate of his patient's homeostatic capabilities and provide him with raw materials at rates which fall within them Factors to be consid ered in the application of this homeostatic principle to the practice of parenteral fluid therapy will be considered with the aid of the charts that follow Reference Talbot et al (1955) Source of diagram 72 ·WATER 124 GLUCOSE SODIUM POTASSIUM CHLORICE PHOSPHATE 1/7/24 ave24.12. - 24. pan*124* APROXIMATE UPPEN LIMT Or MTS OLD TOLERANCE TOK SUBSTANCE ACTUAL INTAKE TOTAL AMOUNT AVAILAB YOR AVOUNT ACTUALLY USED FOR RCPAR NIN VAL AMOUNT NCCEED TO MAINTENANCE PT# 1) (5) 14) (5) (41 () 14 15) (°) (5) 35. Relation between Intake and Retention by Two Jalants Recorering from Dehydration Due to Serere Diarrhea The data in the above chart are from Talbot et al (1955) ·36. Correction of Hypovolemia Because circulatory insufficiency can result in marked functional impairment of the body's homeostatic systems, it is of prime importance to consider the cardiovascular status of each patient at the onset of parenteral fluid therapy Whenever a patient shows such signs of circulatory insufficiency as hypotension, weak thready pulse, cold clammy extremities or cyanotic mottling of the skin, the possibility that these changes are due to hypovolemia should be suspected As the accompanying charts indicate, blood volume may become markedly reduced by deficits in whole blood, plasma, extracellular fluid or total body water Because these fluids have different volumes of distri bution and comprise different fractions of total body mass, they vary considerably with respect to the absolute deficits needed to reduce blood volume to a given extent An approximately valid picture of these relations may be had by assuming that vascular volume shrinks in direct proportion to the loss of its main constituents from the body as a whole Thus the loss of either 120 ml of water alone, 83 ml of extracellular fluid, 17 ml of plasma or 16 ml of whole blood per kg of body weight would reduce the blood volume by approximately 20 per cent When water is lost, but solutes, plasma and red blood cells are re tained, the serum water solute ratio is subnormal, the serum sodium and protein concentrations are high and the hemoglobin is elevated (section I of chart 36) This is the type of situation which one may encounter in patients with diabetes insipidus When there is a loss of sodium and its companion anions in physiologic proportion to water, as may occur in patients suffering from diarrhea, vomiting, marked sweating or adrenocorti cal insufficiency, the serum water solute ratio and sodium concentration remain normal, but the total protein and hemoglobin concentrations rise there has not been a proportional loss of erythrocytes (sellion in on tilalle 36) It will be remembered that hypovolemia produces a tendency to expand extracellular fluid volume (chart 11) When this occurs, residual circulating albumin becomes diluted and hypoproteinemia results These same phenomena may be observed in patients whose blood volume has become reduced by hemorrhage (section IV of chart 36) 74 ·NORHAL 100 PLASMA VASCULAR CONTENT 60 H20 NO + PROTEIN RBC Vol 40 NORVAL 20 ROC BLOOD INDICES WIS N [Na] N TP N Hab N I PURE H2O DEFICIT (120 ml/ta) te Diabetes insipidus) coor DO Net 60 PROTEIN VASCULAR CONTENT 2 NORNAL PLASMA H2O 40H RBC Vol 20 RBC 0 BLOOD INDICES W/S (Na) TP HD t 36. Theoretical Types of Ily povolemia Calculations of the different types of deficits necessary to produce a 20 pcr con los of blood volume ucre based on the following values for normal total houy content water-60 per cent of body weight cxtracellular volume-25 per cent of holy weight, blood volume-8 pxr cent of body weight plauna volume-5 per cent of body weight ·Generally spcaking, it is not necessary or even desirable, to restore vascular volume to normal in a few minutes It is important, however, to increase blood volume promptly to a point where circulatory efficiency is regained (chart 14) In most instances this can be accomplished by the intravenous administration in two hours of a quantity of fluid equal to about a third of the deficits indicated in the various sections of this chart Unless plain water is clearly indicated (section 1 of chart 36), in which case 40 ml of 5 per cent dextrose in water would be appropriate, a dose of 25 ml of saline, 6 ml of plasma and/or 6 ml of whole blood per kg would be safer and more effective If such doses of saline, plasma or whole blood fail to restore circulatory efficiency, it is probable that the difficulty is due to cardiac or vascular failure rather than to hypovolemia Accordingly, unless there has been a rapid and continuing loss of extracellular fluid, serum or blood, such patients are not likely to benefit from the administration of additional doses of these fluids They are more apt to respond favorably to vasopressor agents such as levarterenol or aramine bitartrate 76 ·I EXTRACELLULAR HO + SOLUTE DEFICIT (75 mi/ig! leg Diarrhes or Vording voor 60 60- PROTEIN PLASNA VASCULAR CONTENT Z NORMAL ROC Yol 40 H2O NO 201 RBC 0 BLOOD INDICES W/$ N (NO) N TP 4 Hab PLASMA DEFICIT 115m1/agt leg Burn) 100r 80 VASCULAR CONTENT 60 RBC Vol PLASUA 40F но PROTEIN NORMAL 20 RDC o BLOOD INDICES w/S N (NO) N Mob TP NU X WHOLE SLOOD DEFICIT (16 ml/kg) legatule nomorthage) 100 80- 60 VASCULAR CONTENT 2 NORMAL PLASMA H2O PROTEIN 40F RBC Vol 20 AAC BLOOD INDICES W/S N [Na] M TP NU 36. Theoretical Types of Ilyporolemia: Contd ·37. Solutions for Total Body Repair plus Maintenance Therapy The three solutions shown in chart 37A are representative of many now available which can be used to provide glucose and extracellular and intracellular electrolytes in physiologically tolerable proportions As the black circles show, when these solutions are administered at a rate of about 1300 ml per m² of body surface per 24 hours, which covers the minimal maintenance need for water, they supply the organism with at least minimal maintenance allotments of the various other constituents Likewise, as the vertical bars indicate, one can safely provide the addıtional water and electrolytes which may be required to cover abnormal maintenance needs by increasing the intake rates of these solutions up to 3000 ml per m' per 24 hours All these fluids are hypertonic when administered, since they contain from 300 to 600 mosM of glucose and from 100 to 180 mosM of electrolytes per liter, but they become hypotonic in relation to body fluids when the glucose contained in them is metabolized within the body This is desirable because it means that only one quarter or at most only one half of the water infused will be needed to cover the electrolytes during their stay in the body (at 3 6 ml per mosM) or during their elimination from the body in the urine (at 0 7 to 1 5 ml per mosM) (charts 4, 8) The remainder of the water is therefore available to compensate for insensible water losses and to eliminate endogenous waste products via the kidneys Patients undergoing parenteral fluid therapy are apt to need potassium as much as they need sodium (chart 40) Despite this and the fact that body tolerance for potassium under most circumstances greatly exceeds the doses used, most parenteral fluids contain much less potassium than sodium Of the fluids shown here, solution A contains approximately equal amounts of these two ions (K 35 mEq, Na 40 mEq per liter) while solution B has less than one third as much potassium as sodium (K 12 mEq Na 40 mEq per liter) and solution C about half as much potassium as sodium (K 25 mEq, Na 60 mEq per liter) Because maintenance and repair needs for chloride may parallel and even exceed those for sodium (chart 39), it has seemed appropriate to use thus as the chief anion of parenteral fluid solutions Under many and perhaps most circumstances, it might be as well not to dilute the chloride with bicarbonate (or lactate) or phosphate Though commonly included, **n than its bio- North American or European diet The quantities ul Didi Wullum qui iutate) 78 ·MULTINC ELECTROLYTE SOLUTIONS IN 1 DEX A 0 H2O L/m2/24 PNTS HOL 0616 KAYSE or TOLERANCE LOKOINART DIET RANCE pomy ) 300 Not mEq/ml 1342004 100TILI kt 300F megim?/24• 2001- 100F 11-14 CI" 300 mEq/m/24• 200 thi tel нсо, 130 mEq/m2/24• 100 30 H Ho! 150 P Moum/24° 100 30 CALORIES/ 3000 2000 1000 PROTEIN m/m2/24 79 SOF • Atcovuc OCD WARTENANCE DOSE I USUAL REPAIR PLUS VAINTENA*CE DOST RANSE 37A. Multiple Electrolyte Solutions for Parenteral Huid Therapy NE Mis C7 Last HIPO. Solution A 40 35 40 20 15 Solution R 40 1: 35 17 Solution C co 25 $3 12 The electrolyte concentrations are crpressed in ml g/l. Scc sferences for suste ថ្មី ·of sugar provided by the present solutions should, however, be well tolerated because they do not pose an excessive load on the body's hydrogen ionbicarbonate son homeostatic system Likewise, though the phosphate may not be necessary, it provides the depleted organism with readily available phosphate, which it can use either for glycogen formation, cellular fluid repair or urinary buffer purposes Even when given at minimal maintenance rates, fluids containing 50 or more gm of glucose per liter deliver more than the 50 gm needed per per 24 hours to prevent hetosis and to reduce protoplasmic catabolism to minimal levels (chart 37B) Such fluids do not, however, fulfill the body's total caloric requirements This is not important to wellnourished patients, who will be able to resume oral feedings within a week or 10 days On the other hand, it may be of vital importance to patients who are severely depleted or who must be nourished parenterally for longer periods of time (chart 37C) Under these circumstances, it may be desirable to fortify the multiple electrolyte solution with calories in the form of additional glucose (up to 250 gm per ma per 24 hours), fat, alcohol and/or amino acids Though fat preparations have not been entirely satisfactory, they may be worth considering in cases of marked caloric deficit Amino acids are well tolerated and can be given as 2 5 or 5 gm/100 ml solution They may also be of value in providing the organism with material from which protein can be formed Available data indicate, how ever, that the body is apt to use amino acids largely as a source of energy unless its caloric needs are being provided for by adequate allotments of carbohydrate and fat (chart 37D) In view of the difficulties inherent in making it possible for debilitated patients to synthesize protein, it sometimes is important to administer preformed protein as plasma or crystalline albumin and/or erythrocytes in the form of a whole blood transfusion These are strongly indicated in patients who, because of hypovolemia, are manifesting circulatory insufficiency (chart 36), water inte catic 42A) or edema (chart 44C) Such signs are apt to occur only after pro longed or very severe illnesses in older children and adults However, they can appear in infants within a few days after the onset of a major infection or nutritional upset 80 ·7.5 5,0 URINEN gm/m2/24 25 - 0 1 75 0 25 50 100 125 ISO 175 1.0 URINE KETONE BODIES g/m2/24ost 175 25 50 75 100 125 150 GLUCOSE INTAKE gm / m2/24 378. Amount of Glucose Needed to Suppress Ketonuria and Reduce Urine Nitrogen Output to Minimal levels Reference Butler dial (1945) Source of data, chart 3713 1Tettel al (1949) Solution 1 (1 rart Darrow s solution, 2 parts 5 per cent D). chart 37A Lowc (1955) Solution C. chart 37A Shohl (1939) General, chart 37C Talhot et al (1952) Source of diagram chart 37D Talhot at al (1953) Solution A, shan 31A Tallet anu Rxhie (1958) Source of datam, chart 37C ·provided by the present solutions should, however, be well tolerated because they do not pose an excessive load on the body's hydrogen ionbicarbonate ion homeostatic system Likewise, though the phosphate may not be necessary, it provides the depleted organism with readily available phosphate, which it can use either for glycogen formation, cellular fluid repair or urinary buffer purposes Even when given at minimal maintenance rates, fluids containing 50 or more gm of glucose per liter deliver more than the 50 gm of sugar needed per mº per 24 hours to prevent ketosis and to reduce protoplasmic catabolism to minimal levels (chart 37B) Such fluids do not, however, fulfill the body's total caloric requirements This is not important to wellnourished patients, who will be able to resume oral feedings within a week or 10 days On the other hand, it may be of vital importance to patients who are severely depleted or who must be nourished parenterally for longer periods of time (chart 37C) Under these circumstances, it may be desirable to fortify the multiple electrolyte solution with calories in the form of additional glucose (up to 250 gm per m per 24 hours), fat, alcohol and/or amino acids Though fat preparations have not been entirely satisfactory, they may be worth considering in cases of marked caloric deficit Amino acids are well tolerated and can be given as 2 5 or 5 gm/100 ml solution They may also be of value in providing the organism with material from which protein can be formed Available data indicate, however, that the body is apt to use amino acids largely as a source of energy unless its caloric needs are being provided for by adequate allotments of carbohydrate and fat (chart 37D) In view of the difficulties inherent in making it possible for debilitated patients to synthesize protein, it some times is important to administer preformed protein as plasma or crystallıne albumin and/or erythrocytes in the form of a whole blood transfusion These are strongly indicated in patients who, because of hypovolemia, are manifesting circulatory insufficiency (chart water intoxication (chart 42A) or edema (chart 44C) Such signs are apt to occur only after pro longed or very severe illnesses in older children and adults However, they can appear in infants within a few days after the onset of a major infection or nutritional upset 80 ·750 50 URINEN am/m2/24 25 25 50 75 100 125 150 175 1 5 10 URINE KETONE BODIES am/m2/245 175 25 50 75 100 125 150 GLUCOSE INTAKE gm/m2/24 378 Amount of Glucose Meeded to Suppress hetonuna and Reduce Urine Nitrogen Output to Vinimal levels References Butler et al (1945) Source of data chart 370 Fett et al (1949) Solut on 3 (1 part Darrou s eclut on ? pants Sper cent DA ) char 37A Love (1955) Slut on C chant J7A Shohl (1939) General chart 37C Tahol tal (1952) Sower old stan shart 370 Talhot at al (1953) Salut cart 7A Talhot and Rahe (1958) Source of dagram cham 37C ·38. Maintenance Therapy with Multiple Clectrolyte Solution The data recorded in the accompanying charts were obtained from pairs of healthy adults who were maintained on a total of 1500 ml of multiple electrolyte solution A (chart 37A) per m per 24 hours for a total of 3 days As chart 38A shows one pair of subjects received their allotments steadily at a rate of 125 ml per m per hour throughout the 24 hour period of observation (left hand division) The second pair of subjects received their allotments in the first 12 hours of each day* (middle division) while the third pair of subjects received their allotments in the first 6 hours of each day (right hand division) All individuals were then fasted and thirsted for the remainder of each 24 hour interval Those on the 24 hour regimen were able to keep body water and electrolyte content and concentration values close to normal control levels with a minimum of homeostatic effort On the other hand the 12 hour and particularly the 6 hour subjects had to male wide adjustments in rate of output to prevent body content and concentration values from fluctuat ing to an important extent This is documented in chart 38B where it can be seen that the individuals on the 24 hour regimen utilized less than 20 per cent of adult capacity to excrete water sodium potassium chloride and phosphate by way of the urine By contrast those on the 12 hour and especially those on the 6 hour regimen varied their rates of output from the physiologic minimal to almost the physiologic maximal level Had the subjects been infants instead of adults the loads imposed by the 12 and 6 hour regimens would have over reached homeostatic capacities The effects of over reaching homeostatic capacities can be visualized by comparing the solid with the interrupted lines of chart 38C The former represent the changes in body content which actually occurred The latter indicate the changes which would have occurred in 12 and 6 hour sub jects during each infusion period if concomitant adjustments in rate of output had failed to take place Those on the 12 hour regimen would have augmented their body water and electrolyte stores by 1 to 3 5 per cent and those on the 6 hour schedule by 3 to 5 per cent by the end of the in take periods One cannot abruptly increase the body s total water or potas sium by much more than 5 per cent without intoxicating the subject These observations show that it is physiologically safest to spread the darly maintenance allotment evenly over the 24 hours This form of ther * To compensate for the reduct on in t me the rate of adm n strat on was increased to 250 ml per m per hour n the 12 hour subjects and to 500 ml per m per hour in the 6 hour subjects 84 ·she has OUTPUT 0 O ment of homcostatic function Morcoser i results 17:21 of body water and clcctrolyte stores and practically im. CICS to wcalness headache nausca hunger and the her Encn their days allotment in 12 or 6 hours and then ir Continuous infusions can be carried out in the room INTAKE AND OUTPUT $UDJECT NI SLET I SC 6000 H2O 4000 mi/m/24*2000) INTAKE 700! Na mtaim'124 100 700- K 00- mEq/m/24 zoor CL 100! mEq/m*124 0 TIME IN HOURS 38 Maintenance by Multiple Ilectrolyte Solation T for 12 or 18 hours. For Li bri LII பட்ட O Lan apy imposes so little strain on the body s stabiluing for and adults without difficulty by means of ordinary ses aux pics bulb delivers i ml per 15 to 20 drops in dealing w5r. infants it is preferable to use a set containing a dnglesse ime about 1 mlret (O drops Relences Anaria! (1958) Sure of data and spams chamike ak1987) touwluutilants ·24° 12° 6° 20 15 REGIMEN H20 L/m2/24 10! 5 11 O 400 Na mEq/m2/24° 200 0 400 K mEq/m2/24º 200 II 0 400 CI mEq/m2/24º :3! YEARS 38B. Maintenance by Multiple Electrolyte Solution: Conta Relations between rates of output observed for subjects on various regimens (righthand section) and physiologic ranges of excretory capacity (left hand section) The Anna and the ottien har traversino them the al (1958) 86 ·TOTAL BODY CONTENT SUSJECT BP SUBJECT M* SUBIECT PC 109 H20 100- * NORMAL 103 NO % NORMAL 100 05 K % NORMAL 100% 93 at w 105 CI % NORMAL 100H INTAKE 1 24 12 72 TIME W HOURS 38C. Effects of the 24., 12- and 6-]lour Regimens on Rody Content Values These measurements were made on suhects similar to the represented in charta 38A and The soltu lines in this diagram represent watu dernc from balance measurements The interrupted lines represent the parts for low) haruld have occurred during the prints of administralien if no homentale aj ustmortin tale of output had occurred during these periods where the lines are atuent data con cerning output rutes immediately before the infuvon rein are lacking Irom Neun et al (1958) ·39. Maintenance of Patients Subjected to Major Gastrointestinal Surgery It has become customary in many clinics to maintain patients undergoing surgery with dextrose in water or dextrose in saline solutions Though these forms of maintenance may be innocuous if used advisedly and for a short time only they do impose a considerable and at times excessive burden upon the homeostatic systems Thus most individuals given elec trolyte free dextrose in water must reduce their rates of electrolyte Output from ordinary dietary levels to essentially zero within a short time if they are to escape serious depletion of the extracellular and intracellular solute stores Moreover they are likely to develop water intoxication unless the dosage of this electrolyte free solution is carefully controlled (chart 42A} Those given approximately isotonic saline solutions are not apt to develop water intoxication but they must eliminate the sodium contained in them with high efficiency if they are to avoid developing the cellular potassium insufficiency-sodium intoxication syndrome (chart 19) As others have shown this is a diffcult accomplishment for persons undergo ing the stress of anesthesia and surgery since stress acting via the adreno cortical system produces strong tendencies to sodium accumulation and to cellular potassiunt depletion The accompanying chart sets forth data which indicate that this problem may be avoided by giving surgical patients ordinary allotments of both potassium and sodium together with the main intracellular and extracellular anions The subject of this diagram was one of a series of five adult patients who were followed closely during the hours preceding and the days following an extensive subtotal gastrectomy for control of peptic ulcer A nasogastric tube was inserted and all food and Nuds by mouth were stopped approximately 16 hours preoperatively Anesthesia was in duced with thiopental (pentothal) and the surgery performed with the patient under ether anesthesia The operation lasted about 5 hours About 200 ml of saline 700 ml of 5 per cent dextrose in water and 1000 ml of whole blood were given intravenously during the operative pe riod Thereafter the patient was given by vein 1200 ml of multiple electro lyte solution A (chart 37A) per mº per 24 hours as a basal maintenance allotment To this was added an amount equal to the volume of fluid cur rently being lost by way of the nasogastric tube In the present case this instially amounted to about 500 ml per m' per 24 hours and then gradually diminished 88 ·H2O Na 110 TOTAL BODY CONTENT > NORMAL 100 too 90 mI/AP/24 100 IN TAKE AND TODO OUTPUT 1000 JDT 0 1 4 102 к 10, CI I10 IO TOTAL BOOY CONTENT NORMAL tootoo 0 90 INTAKE AND OUTPUT +00 100 LETE Som 30 UU PALAB O o 1 2 3 TIME IN DAYS αυ INTAKE RESECTED T1330E BLODO (03sts SAITRIC SUCTION LONICS INSINO VEINARY LOS113 39. Maintenance of a Patient Subjected to Gastrointestinal Surgery These data are from studies by Florder, Talhet, Lincoln and Terry (to be published).

·39. Maintenance of Patients Subjected to Major Gastrointestinal Surgery It has become customary in many clinics to maintain patients undergoing surgery with dextrose in water or dextrose in saline solutions Though these forms of maintenance may be innocuous if used advisedly and for a short time only they do impose a considerable and at times excessive burden upon the homeostatic systems Thus most individuals given elec trolyte free dextrose in water must reduce their rates of electrolyte output from ordinary dietary levels to essentially zero within a short time if they are to escape serious depletion of the extracellular and intracellular solute stores Moreover they are likely to develop water intoxication unless the dosage of this electrolyte free solution is carefully controlled (chart 42A) Those given approximately isotonic saline solutions are not apt to develop water intoxication but they must eliminate the sodium contained in them with high efficiency if they are to avoid developing the cellular potassium insufficiency-sodium intoxication syndrome (chart 19) As others have shown this is a difficult accomplishment for persons undergo ing the stress of anesthesia and surgery since stress acting via the adreno cortical system produces strong tendencies to sodium accumulation and to cellular potassium depletion The accompanying chart sets forth data which indicate that this problem may be avoided by giving surgical patients ordinary allotments of both potassium and sodium together with the main intracellular and extracellular anions The subject of this diagram was one of a series of five adult patients who were followed closely during the hours preceding and the days following an extensive subtotal gastrectomy for control of peptic ulcer A nasogastric tube was inserted and all food and fluids by mouth were stopped approximately 16 hours preoperatively Anesthesia was in duced with thiopental (pentothal) and the surgery performed with the patient under ether anesthesia The operation lasted about 5 hours About 200 ml of saline 700 ml of 5 per cent dextrose in water and 1000 ml of whole blood were given intravenously during the operative pe riod Thereafter the patient was given by vein 1200 ml of multiple electro lyte solution A (chart 37A) per mº per 24 hours as a basal maintenance allotment To this was added an amount equal to the volume of fluid cur rently being lost by way of the nasogastric tube in the present case this initially amounted to about 500 ml per m per 24 hours and then gradually diminished 88 ·H2O Na 110 TOTAL BODY CONTENT X NORMAL 100- 100 ml/m2/24 90 mEq/m2/24 FLE 100 IN TAKE AND 2000 OUTPUT 1000 30H Q 0 O 10p for CI I10 10 TOTAL BODY CONTENT % NORMAL 100F 100 90 90 INTAKE AND OUTPUT 100H TOOF 11 UE JOH SOF 123* 0 O 2 3 TIME IN DAYS DO INTAKE RESECTED TISSUE & BLOOD LOSSCS GASTRIC SUCTION LOSSCS INSENSIBLE & URINARY LOSSES 39. Maintenance of a Patient Subjected to Gastrointestinal Surgery These data are from studies by Border, Talbot, Lincoln and Terry (to be published) ·By the end of the fifth day the patient was able to resume oral feed. ings It can be seen that he kept his body water, sodium, potassium and chloride content values close to the normal starting levels Though they are not recorded here, he maintained extracellular and intracellular electrolyte concentration values equally close to normal control levels He did so by making such adjustments in urinary output as were needed to maintain equilibrium The results obtained in this case are reasonably representative of those found for four of the five individuals studied in the case of the fifth patient, gastric suction losses amounted to more than 500 ml per mº per 24 hours during the first postoperative days The chloride contained in these gastric fluids exceeded that being provided by the multiple electro lyte solution (about 70 mEq per mº per 24 hours) by a small margin Consequently, though the patient reduced his extragastric losses of chloride to zero, he was unable to maintain his body chloride stores at normal levels This trend was reversed by an added intake of 50 mEq of sodium chloride per m² per 24 hours From these experiences it may be concluded that patients can maintain metabolic normalcy with considerable efficiency even while undergoing the homeostatic stresses of anesthesia major surgery and postoperative gastrointestinal drainage if they are provided with water and the chief extracellular and intracellular electrolytes in reasonable amounts The multiple electrolyte solution used here appears adequate for patients losing up to 500 ml of gastrointestinal fluid per ma per 24 hours For those losing more than this amount, it would seem advisable to cover losses in excess of 500 ml per per 24 hours with isotonic saline References Border et al (to be published) Source of data Moore (1958) Postoperative sodium and water retention Moore and Ball (1952) Postoperative sodtum and water retention grading surgical stress 90 ·40. Treatment of Diabetic Ketoacidosis The subject of the accompanying charts was a 15-year-old girl who presented with diabetic ketoacidosis of 3 days' duration When first scen she was markedly dehydrated and had the rapid, deep respirations characteristic of severe ketosis The urine was found to have high sugar and ketone-body content An electrocardiogram did not reveal any changes in the T waves suggestive of potassium intoxication Serum chemical measurements showed her to be moderately hyperglycemic (blood sugar 420 mg per 100 ml), very acidotic (serum pH 6 9, serum bicarbonate 5 mEq per liter) and markedly hypohydrated (serum water-solute ratio 30 ml per mosM) In spite of all this, her pulsc was strong and her blood pressurc satisfactory Accordingly, it appeared unnecessary to crpand vascular volume prior to intravenous infusion of a multiple electrolyte solution which contained potassium Shortly after admission, therefore, she was given 150 units of crystalline insulin * At the same time an intravenous infusion of multiple electrolyte solution A (chart 37A) was started and given at a rate of 4000 ml per mper 24 hours Initially, this solution was made up in water without dextrose Two hours later, when the blood sugar had fallen to 200 mg per 100 ml. a multiple clectrolyte solution containing dextrose (5 gm/100 ml) was substituted for the sugar-free solution At the end of 6 hours the rate of infusion was reduced to 2900 ml per ma per 24 hours The patient was able to take sips of water by mouth by the fifteenth hour, and it became possible to feed her entirely by mouth by the eighteenth hour From the second day, her intake was maintained at previous levels by giving her measured quantities of food and fluids of Inown composition It can be seen in the right-hand diagrams (chart 40A) that the blood sugar fell and that serum płt and bicarbonate values commenced to rise shortly after this therapy was instituted, reaching normal levels in less than 20 hours Serum pH values overshot normal levels slightly during the pe. riod of equilibration Serum bicarbonate values approached normal levels in a smooth, steady manner These changes in acid base balance were duc in part to the provision of base bicarbonate in the form of sodium and potassium lactate, they were duc mainly to the fact that hetonc acids disappeared as the administered insulin made it possible for cells to use car. bohydrate instead of fat as a source of energy . She had been given 30 units cach of protamine zinc and crystalline insulin 6 hours por lo admission It was on this account that no longacung insulin was given at the lime of entry ·The left-hand diagram of chart 40A shows that the ratio of water to solutes in body fluids also rose promptly to the physiologic range This rise was due in part to the 500 ml gain in total body water indicated in sections B and Cand in part to the reduction of approximately 800 mosM in body solutes which occurred as the hyperglycemia and ketosis were overcome Insofar as the water-solute ratio was concerned, this reduction in solutes was equivalent to the addition of about 2 5 liters of solute free water to the intake during the first half day of therapy During the same period, when there was a deficit of water relative to solutes in the body fluids, the patient passed urine of minimal water content Thereafter, in close accordance with rapidly changing needs, she began to dilute her urine with the surplus water which became available as repair needs and insensible losses diminished Chart 40B shows that the patient conserved sodium until she had re tained a quantity equal to about 9 per cent of the normal content of the body This was the amount needed to restore the extracellular sodium content and concentration to normal Thereafter she eliminated sodium as fast as she received it Potassium was stored in relatively larger quantities and for a longer period of time This too appeared to be governed by need, for calculations indicated that the patient still had an intracellular potassium deficit at the close of the 5 day observation period Despite the fact that she had lost almost 20 per cent of her potassium stores, she never was hypokalemic Almost all the phosphorus offered was retained There was, however, no retention of chloride ions This appeared appropriate, since the serum chloride concentration was normal and there was nothing to suggest extracellular fluid volume insufficiency These observations are representative of many recorded in the literature which demonstrate that patients with diabetic ketoacidosis have a very real capacity to overcome their various metabolic disturbances when provided with insulin and reasonable allotments of water and electrolytes They accomplish this by retaining and rejecting water and extracellular and intracellular ions in close accordance with rapidly changing requirements In other words, the organism reacts according to its specific needs The fact that it can do so largely eliminates the necessity to obtain an extensive series of chemical measurements of serum and urine constituents This is fortunate because it may take several days even for a well equipped team to determine exactly the specific status and hence the maintenance and repair requirements of a given individual at a given moment In practice, it usually suffices to certify the diagnosis by demonstrating that the patient is hyperglycemic and ketonemic or ketonuric In this 92 ·40 WATER SOLUTE RATIO ml/mosM NESIOLOSIC RANGE JO 100 INSULIN UNITS 309 Crystalline Insel B TOTAL BODY WATER * ESTIMATED NORMAL 10! ** Bw wmns 20079 tod US! 100 10 + INTAKE C 10 o 40 + zo HOURS WATER INTAKE ANO BALANCE L/M/24 2 1 MCO, +1 o 2S BALANCE 3000 pH NORMAL RANOL 0 URINARY OUTPUT Lim./24 PM mEq/L TOTAL URINE WATER -RECURINE WATER OBLIGATORY URINE WATER tooof HCO, 10H 1000 0 2000 INSENSIBLE WATER LOSS 1000 L/m/24 0 to BO 10 10 30 40 HOURS DAYS 40A. Insulin and Multiple Electrolyte Therapy The above chart shows the effects of insulin and multiple electrolyte solution therapy upon the body water (leſt section) blood sugar (night upper), scrum pil and bicarbonate (right lower) status of a patient with severe diabetic ketoacidosis The patient weighed 51 kg and had an estimated body surface of 15 m From Talbot et al (1955) ·clinic, it is customary to treat these manifestations of insulin lach by giv. ing, for each square meter of body surface, 75 units of crystalline insulin intravenously plus 75 units subcutaneously as an inital dose At the same time, the anticipated daily maintenance dose of a long acting insulin such as protamine zinc (ie about 20 units per m²) is given subcutaneously Thereafter crystalline insulin doses are repeated at intervals of 2 to 4 hours, as indicated by urine and/or blood sugar determinations, until normal values arc attained If the patient appears to be suffering from circulatory collapse, he is given by vein a vascular volume expansion dosc of sugar free salıne within the first 90 to 120 minutes * If he is not suffering from circulatory insufficiency and there are no signs of potassium intoxication (chart 19), a mul. tiple electrolyte solution (chart 37A) is given intravenously at the rate of 2500 to 3500 ml per m per 24 hours until such time as he can take this solution or its equivalent by mouth The lower rate should suffice for patients who are only mildly acidotic and dehydrated, even in severely depleted and acıdotic patients, it rarely is necessary to exceed the higher rate The patient is shifted to ordinary foods and fluids by mouth as he can tolerate them •The recommended dose is 25 ml per kg (chart 36) However initiation of therapy with sugar free electrolyte solution may be considered a nonessential refinement References 94 ·too TOOL TOTAL BODY CONTENT % ESTIMATED NORMAL 901 90 Na к 80 140 80 PHYSIOLOGIC RANGE SERUM CONC mEq/L 130 +100 +100 INTAKE AND BALANCE 0 mEq/m / 24 -100F O -100 1001 100% TOTAL BODY CONTENT % ESTIMATED NORMAL 90F 90 SERUM CONC mEq/L 110 Ioa 90: PHYSIOLOGIC RANGE + 2 +100 INTAKE AND BALANCE mEq/m / 24 -100 gm/m! 124 -2 1 1 O 1 4 5 2 3 DAYS 1 2 3 DAYS 5 40B. Insulin and Multiple Electrolyte Therapy: Conta The above chart shows the effects of insulin and multiple clectrolyte solution therapy upon the body clectrolyte status of the dishetic patient of chast 40A From Talbot et al (1955) ·41. Therapy of a Diarrheal Infant The pafient of this chart was a 1-month old infant weighing 38 kg who became depleted and dehydrated as a result of severe diarrhea of several days' duration In contrast to the diabetic girl of chart 40A, he showed signs of circulatory insufficiency when first seen Accordingly, his therapy consisted initially in the administration of saline in dextrose at the rate of 2300 ml per m² per day for the first 6 hours By the end of that time, his circulatory status was considered to be satisfactory and he was started on multiple electrolyte solution A of chart 37 at the rate of 3000 ml per ma per 24 hours, a rate closely similar to that used for the diabetic patient of chart 40A Balance measurements showed, however, that the infant used the nutrients thus provided in a quite different manner This was most strikingly evident with regard to sodium and potassium Whereas the diabetic girl retained much more potassium than sodium, the diarrheal infant retained more of the latter than the former ion Both adjusted their balances in a smooth, asymptotic manner, well suited to their specific mainte nance plus repair needs and both did well clinically Reference Talbot et al (1955) General 96 ·SODIUW POTASSIUM 1101 110 100 TOTAL BODY 1001- CONTENT NORMAL 90 OF 10 10 SERUM NO SERUM K LL 130 INTAKE 300 Joo INTAKE AND BALANCE 200 BALANCE 800F 10O2 +10o O o -100 -1004 O + 3 $ 0 3 9 DAYS DAYS 41. Selective Retention of Sodium and Potassium by an Infant Recovering from Dehydration Due to Diarrhea The subject of this chart was a l-month-old male infant weighing 38 kg and having a surface area of about 02 m ·42. The Water Intoxication Problem The subject of chart 42A is representatne of many patients in whom water intoxication has developed accidentally while they were being main tained on parenteral fluids following general anesthesia and surgery In this case, an intravenous infusion of solution A (chart 37A) was started a few hours before surgery at a rate approximating 2400 ml per m' per 24 hours During the preoperative period the patient had no diffi culty in maintaining water and electrolyte homeostasis The picture changed, however, when he was subjected to ether anesthesia and surgical exploration of his craniopharyngioma The urine water solute ratio then fell abruptly from the 5 ml per mosM level required to maintain equilibrium to levels characteristic of maximal antidiuretic hormonc activity Between the fifth and tenth hours this produced an increase in body water relatsve to body solutes At about the tenth hour, the patient stopped gain Ing water and started to lose solutes This led to further elevation of body water solute ratio values, here represented by the serum measurements Unfortunately, these trends were not suspected clinically until the patient commenced to have generalized convulsions 14 hours postoperatively When emergency studies carried out at that time revealed that these convulssons were probably due to water intoxication, the patent was given by vein 4 ml of 0 5 molar (3 per cent) solution of sodium chloride per kg of body weight His response was prompt and favorable He had commenced to dilute hes urine shortly before this treatment was given, and from then onwards he had no more difficulties It is now known that many general anesthetic Agents and morphine type drugs, as well as injury to the blood brain barrier in the region of the hypothalamus can result in uncontrolled release of antidiuretic hormone and hence can predispose to the events recorded above It also is known that water loading by expansion of the vascular volume can cause an extracellular solute diuresis of the sort observed between the tenth and twenty ninth hours in the present instance These difficulties can be avoided by giving only a minimal maintenance allotment of water to patients who are undergoing general anes thesis receiving repeated doses of narcotics or suffering from encephalrers, meningitis or severe brala trauma If electrolyte free dextrose in water solutions are used, the rate should approximate 1200 to 1300 ml per m2 per 24 hours For half isotonic solutions such as solution A of chart 37A, from 1300 to 1500 ml per mº per 24 hours would be suitable Though the 98 ·CONVULSIONS 3% NACL IV SURGERY 4 25+ ANESTH SERUM WATER-SOLUTE 400- RATIO 375 ml/mosM 11 NORMAL RANGE 3 50 INTAKE OUTPUT +2 WATER BALANCE ml/m2/ min yokumppa: - 15 URINE WATER SOLUTE RATIO ml/mosM Required to Maintain Equilibrium 101 Am PATIENT'S DEMONSTRATED RANGE 52 SOLUTE FREE WATER 500 400 1500 100 300 TOTAL BODY WATER DOO 00 + 500H CUMULATIVE WATER BALANCE mi 090 200 CUMULATIVE +100 SOLUTE BALANCE 0 mos -100 200 300 500 TOTAL BODY toooh SOLUTES ? 1 400 O 6 12 18 36 42 48 24 30 HOURS 42A. Water Intoxication following Partial Surgical Removal of a Craniopharyngioma The subject of the above chart was a 14 year-old boy from Crawford and Dougc (1959) 09 ·danger of water intoxication can be avoided entirely by using isotonic saline, one is apt to produce sodium intoxication if one gives enough of this solution to cover insensible and urinary losses of water The therapy used for the control of this patient's convulsions was based on the following assumptions and calculations First, it is known that the body contains normally about 600 ml of water and 170 mosM of solute per kg of body weight It follows that in order to lower the water solute ratio of body fluids by 0 1 ml per mosM the patient must either lose approximately 17 ml of water or gain about 6 mosM of solute per kg of body weight While there are times when it is reasonable simply to discon tinue fluid intake and allow a water intoxicated patient to cure himself by eliminating surplus water when serious manifestations such as convul sions are present it is preferable to correct the disturbance promptly by administering solutes This can be accomplished by administering intra venously, for each kilogram of body weight approximately 6 ml either of 05 molar (3 per cent) saline solution or of 1 0 molar (18 per cent) man nitol solution both of which contain 1 mosM of solute per ml Unless the patient s sodium stores are depleted it is preferable to use mannitol and thereby avoid sodium intoxication Hypertonic saline is indicated how ever, when there are signs of sodium depletion (charts 13, 36) The initial dose, which is designed to reduce the ratio of water to solutes in body fluids about 01 ml per mosM often suffices Should it fail to control the manifestations of water intoxication the dose can be repeated once Elevation of the serum water solute ratio and hyponatremia may be observed also in patients suffering from left heart failure or from hypo volemia due to lack of red blood cells plasma proteins or extracellular electrolytes This is illustrated by the nephrotic child of chart 42B, who was found to have serum water solute ratio values of approrimately 4 0 ml per mosM and serum sodium concentration values approximating 120 mEq per liter He was at this time grossly edematous and was exhibiting signs indicative of circulatory insufficiency (weakness rapid thin pulse, pallor, cold extremities, mottling of the skin) Inasmuch as he had no evi dences of cardiac disease it was concluded that these signs of circulatory casufliciency were due to hypovolema It was further presumed that the hypovolemia was caused by hypoproteinemia (total serum protein 2 gm per 100 ml) rather than by lack of red blood cells (blood hemoglobin 17 gm per 100 ml) or of extracellular electrolytes (edema fluid +++) Accordingly, he was given a series of albumin infusions together with corti sone in doses sufficient to control his albuminuria Perhaps because he reached this elevated water solute ratio gradually he did not show clear- 100 ·140 SERUM (Na+) mEq/L IJO 120 61 SERUM TOTAL PROTEIN om/100m! 41 2 CORTISONE mg/24 400 200 O ALB INFUSED om/24 30 20- 10 o 10 15 Water Intoxication as Revealed by Hyponatremia in a Patient with Mephrotic llypoproteinemia The subject of the above chart was a 5 year old boy with an average we ght of 28 kg DAYS 20 25 cut clinical manifestations of water intoxication though a disturbing tremulousness may have represented warning symptoms The signs of circulatory insufficiency disappeared shortly after the first plasma infusion was started Later as serum protein stores were rc plenished serum sodium concentration values which were used here as an inversc index of body water solute relationships also returned to normal The patient was losing water and sodium (ie cdema fluid) as the serum sodium concentration was rising Thus the rise in sodium concentration was due to the shedding of water in cicess of sodium rather than to an absolute gain in body sodium content This phenomenon is casily crplained of one accepts the thesis that the neuroly pophyseal system is designed basically for the purpose of sus taining circulations effemine lescls (charts 4 44B) for the system to 101 3 ·fulfill this purpose by maintaining the ratio of water to solutes in boc fluids within the range of 3 5 to 3 7 ml per mosM, it is essential that bod stores of red blood cells, plasma protein and extracellular electrolytes be at least at minimally satisfactory levels and that the person be capable of an adequate cardiac output A deficiency in any of these ancıllary factors results in a chronic tendency to circulatory insufficiency and hence in a continuous stimulus to the neurohypophyseal system to conserve and store water relative to solutes Among other things, this induces a tendency to hyponatremia When this is due to extracellular solute deficiency (eg in patients who have lost large amounts of sodium as a result of sweating or hypoadrenocorticism), sodium chloride administration constitutes ap propriate treatment On the other hand, hyponatremia consequent to hypoproteinemia and/or anemia are best treated by administering plasma or whole blood or by taking such other steps as appear indicated to raise the oncotic pressure of the blood to satisfactory levels Likewise, hypona tremia due to cardiac failure will disappear spontaneously if cardiac output can be restored by means of digitalis and other standard remedies Additional information concerning the etiology and management of water intoxication will be found in the sections which deal with pannephrstis (charts 45A-C) References Crawford and Dodge (1959) General and source of diagram chart 42A Leaf et al (1953) Solute diuresis caused by water retention Talbot et al (1957) General chart 42B 102 ·43. Parenteral Fluid Therapy for Burned Patients Physicians may find the following description of the guides to therapy cur. rently being used by this service of help in deciding about the management of severely burned patients These remarks will be concerned only with steps aimed (a) al sustaining vascular volume by replacing blood con. stituents lost as a result of the burn in accordance with need (chart 36) and (b) at providing maintenance allotments of water and sugar (charts 37A, 38A) They cover the first 48 hours By that time most patients are ready for an ordinary maintenance regimen In considering vascular replacement needs, it is helpful to estimate the area of the burn in square meters This can be donc by first determin. ing the patient's total surface area in square meters from body weight measurement (graphs A and B. see inside front cover) The proportion of this area which has been damaged can then be estimated with the aid of chart 43 Generally speaking, it is advisable to institute parenteral fluid therapy in all patients who have had more than 5 per cent of their skin burned An indwelling urcthral catheter is inserted in most cases because it cn ables one to record urine Now at hourly intervals in a dependable manner The airway is kept clear, with artificial aids if necessary, both to assure oxygenation and to prevent the occurrence of respiratory acidosis secondary to inadequate ventilation Morphine demcrol and similar narcotics are avoided if possible because they predispose to water intoxication (chart 42A) Patients are apt to need for each square meter of area burned approximately 4000 ml of plasma during the first 8 hours after the injury, 4000 ml during the next 16 hours and 4000 ml during the ensuing 24 hours Accordingis, an intravcnous infusion designed to deliver plasma at the indicated rate is started promptly At the same time, a separate in travenous infusion of 5 per cent dextrose in water is initiated at the rate of 1500 ml per mof total body surface per 24 hours Blood pressure, urine fox, urine specific gravity, blood hemoglobin, total scrum protein and if possible serum water-solutc ratio measurements are made every hour for the first scieral hours and thereafter as often as necessary to keep aware of the patient's needs Arruks are used to indicate that changes in value may be of importance as well as absolute leucis • 11 the urine and serum are visibly discolorat sih hemoglobin and/or the patient I found to have a low hematocrit reading is recommend that whole too instead of plasma be rettitally ·Ordinary normal standards of reference may be used with respect to blood pressure and blood and serum concentration measurements There are no single ideal values for urine flow or urine specific gravity Roughly speaking, it is desirable to maintain urine flow above 40 ml per m" per hour since this may consutute the least amount needed to eliminate the large mass of waste products created by the burn injury It also may be ad vantageous to keep the specific gravity below 1 025, since this should re duce the likelihood of tubular cast formation Though these measurements are intended as an aid to physicians in estimating the status of the patient's blood volume, none give direct information concerning this vitally important variable It follows therefore that one must deduce from clinical observations and such measurements as these whether the patient is hypovolemic, euvolemic or hypervolemic Since individuals are apt to show alterations in blood pressure which correlate quite closely with alterations in blood volume, serial measurements of this index are helpful It must also be remembered that both hypovolemia and simple water deficit tend to reduce the flow and increase the specific gravity of usine (chart 44D) Hypervolemia and simiple water excess tend 10 produce opposite changes Once it has been ascertained that a patient has hypo- or hypervolemia, the nature of the deficit or excess responsible for this abnormality can be told with considerable dependability by blood hemoglobi, serum protein and serum water-solute measurements (chart 36) The resultant Information can then be used as a basis for deciding whether the patient needs more or less dextrose in water, plasma or whole blood After 48 hours have passed, it usually is possible to initiate ordinary feedings and to give plasma or blood intermittently as indicated Bedside Gordes for Modifying Burn Therapy Blood Vrine Urine Blood Serum Serus {pressureflow sp gr hgb protera (ml/mos Change yodicated Speed up D/Winfusion N 1 1 fum References Cope et al (1948) Magmtude of plasma losses in burns Luad and Browder (1944) Body surface area proportions at various ages 104

·NEWBORN
MEAD
3 YEARS
16 %
6 YEARS
TRUNX
40 2
15 %
12 + YEARS
ARMS
40%
LEGS
402
26 Z
163
16*
29*
32%
38
26
43. The Relative Proportions of the Major Areas of Body Surface at
Various Ages
The percentage figures in the above chart refer to front and back for crample, if an
individual suffered a burn of the whole anterior chest, this would comprise 10 per
cent of his body surface
105

·44. Nephrosis Chart 44A shows the manner in which a mildly edematous nephrotic child adapted to an abrupt increase in sodium intake Except for a slight delay, her response was essentially the same as that observed in the healthy sub ject of chart 12 The same was true with respect to water homeostasis Taken together, these observations show that this girl's edema was the result of facultative adjustments in salt and water balance rather than the product of an absolute inability to excrete sodium and its companion anions or water Indeed, if she had lost as much sodium during the period of low intake as on the fifth day of sodium loading she would have drained sodium from her body at the rate of 200 mEq per ma per 24 hours and shed edema fluid at the rate of 700 ml per mº per 24 hours Patients with nephrosis do not always remain in such a homeostati cally balanced condition As chart 44B demonstrates, there are times when they tend to retain all the sodium ingested and to use it to form ever increasing quantities of edema fud These trends can be reversed by re peated infusions of plasma protein supplemented by corticosteroid therapy in dosages sufficient to suppress albuminuria (chart 44C) The etiologic and therapeutic implications of these findings may be summarized with the aid of chart 44D The initial step in the pathogenesis of nephrotic edema is an antigen antibody reaction involving the glomerular basement membrane, which becomes attenuated and discontinuous This results in leakage of albumin into the urine Rates of loss in excess of 5 gm per mº per 24 hours produce a tendency to hypoalbuminemia The resultant loss of oncotic materials leads to diminished vascular volume This in turn stimulates the sodium homeostatic system to conserve sodium (chart 11) As sodium and its companion extracellular anionic solutes accumulate, they prompt the water homeostatic system to retain a physio logically equivalent amount of water (chart 4) Hypovolemia also acts di rectly to promote water retention, thereby creating the tendency to hypo natremia shown in chart 42B Because there is a deficiency of oncotic material in the plasma, much of this newly formed extracellular fluid escapes into the interstitial spaces, where it accumulates as edema and ascites If the quantity retained in the vascular tree is sufficient to restore blood volume to satisfactory levels, equilibrium is re established (chart 44B) If not, water and salt retention continues (see days 13 to 17, chart 44B) It would thus appear that edema is the product of a series of physio logic reactions designed to counteract the tendency to hypovolemia, which 106 ·20 BODY WEIGHT (kg) 19 JC 628539 19.51 18 +100 Na INPUT + 50 AND BALANCE 0 mEq/day - 50 INPUT BALANCE -- 0 5 15 20 25 30 DAYS 1 35 40 44A. Sodium Homeostasis in a Nephrotic Patient Essentially normal adaptation to increase and to decrease in sodium intake by a nephrotic girl aged 7 years in these studies body w cight was used as an inder of changes in extracellular fluid volume and thus of hody sodium content From Talbot et al (1957) 45 50 55 develops when large amounts of albumin are lost from the plasma It may therefore be considered "normal" for the abnormal circumstances These observations provide a useful frameword for considering the level of action of various forms of therapy As indicated at the right in chart 44D, corticosteroids crert their influence by facilitating the healing of the pathologic process responsible for albuminuria Consequently, it allows the organism to replenish its albumin stores As they become rcplenished, the edema is shed by normal homeostatic processes In most patients this type of diuresis can be initiated within 21 days by giving orally from 150 to 200 mg of cortisone or its cquivalent per m' per 24 hours in three divided doses at 8 hour intervals This diuresis is considered a fortunate by-product of the cortisone therapy, the chief 3im of which is to suppress the pathologic process in the kidneys There is substantial chidence that relapses are less frcquent if cortisone is continucd for a period 107 ·29 205 - + 450 Paracentesis 27 Paracentesis +300 26 4+150 BODY WEIGHT kg 25 CUMULATIVE Na BALANCE mEq O 24 -150 23 --300 22 -450 21 -600 20 90C mg 24" EL ACTH --750 DOCA 3mg +100 INTAKE BALANCE + 50 Na INTAKE 0 AND BALANCE mEq/24• - 50% -100 -150 3 513 1 20 1 O 5 10 15 35 40 45 50 25 30 DAYS 44B. Sodium Retention and Diuresis after ACTH Therapy that the sodium diuresis which occurred during these days was not influenced by a major increase in sodium intake but was slowed for 1 day following the administration of a single dose of desoxycorticosterone acetate From Talbot et al (1957). 108 ·ALBUMIN gm 75 234 LI 75 mg at PREDNISONE SERUM PROTEIN gm/100ml 2. Or -305 ORAL NO INTAKE MINUS -100F URINE NA OUTPUT mEq/24 - 1501 -2001 XX -250F 608 PARACENTESIS 4 liters 50 BODY WEIGHT kg 404 30F EDEMA 20 ---- 10 NORMAL BODY SUBSTANCE 3 6 9 12 15 DAYS 18 21 44C. Induction of Sodrum Diuresis by Intravenous Administration of Albumin Negatne sodium balance and loss of edema fund following repeated intravenous in fusions of albumin in the nephrotic girl of chart 441 It became unnecessary to ad minister albumın intravenously for the pumose of sustaining axular volume after the albuminura had been brought under control hy prednisone therapy from Tal bot et al (1957) 109 ·of weeks or months after the edema has subsided until such indices of nephrotic activity as urinary albumin output, serum cholesterol concentration and the serum protein level have returned to normal Albumin (plasma) infusions and blood transfusions constitute phys- 1ologically appropriate emergency measures to overcome extreme degrees of hypovolemia and edema (chart 44C) However, they usually are effective only temporarily up to the time when albuminuria has been sup. pressed by corticosteroids One can slow the rate of edema formation in nephrotic patients by reducing the sodium intake to minimal maintenance levels—1 e about 10 mEq per m² per 24 hours (chart 15) On the other hand, it is practically impossible to reduce body sodium or edema by restricting the sodium intake when sodium conservation forces are acting maximally There is no need to restrict the sodium intake below ordinary dietary levels after the plasma protein has been restored to satisfactory levels by corticosteroid treatment (see days 35 to 45, chart 44B) Indeed, patients may derive considerable benefit from liberalization of the sodium intake if it results in improved appetite and hence in more positive caloric and nitrogen balances Though patients do tend to retain water out of proportion to solutes, they rarely take enough water by mouth spontaneously to cause convulsions or other overt manifestations of water intoxication Hence, for the reasons mentioned above in connection with sodium, it rarely is necessary or desirable to impose restrictions on the water intake of nephrotic patients Of all the procedures listed, paracentesis is the least physiologic, for it removes some of the fluid which the body has accumulated for the purpose of sustaining the circulation Paracentesis may therefore result in circulatory failure unless steps are taken to maintain vascular volume with plasma or whole blood It is now used only for the relief of serious mechanical difficulties due to gross fluid accumulation References Riley et al (1959) Cortisone therapy Spiro (1959) Renal pathology Talbot et al (1957) Pathologic physiology and source of data charts 44A-C 110 ·LEVEL OF ACTION OF THERAPY STEP 1 CORTICOSTEROIDS FIBRINOID DEGENERATION OF GLOMERULAR BASEMENT MEMBRANE STEP 2 ALBUMINURIA STEP 3 HYPOALBUMINEMIA ALBUMIN INFUSIONS STEP 4 HYPOVOLEMIA BLOOD TRANSFUSIORS STEP 5 RENAL SODIUM CONSERVATION LOW SODIUM DIET SODIUM DIURETIC AGENTS STEP 6 BODY SOLUTE (SODIUM, ETC) STORES INCREASED STEP 7 RENAL WATER CONSERVATION RESTRICTED WATER INTAKE STEP 8 PARACENTESIS EXTRACELLULAR VOLUME INCREASED (EDEMA, ASCITES, ETC) 44D. Outline of the Pathogenesis of Nephrotic Edema, with the Levels of Action of Various Therapeutic Maneuvers ·45. Pannephritis The patient of the accompanying chart was a young man with chronic nephritis of serious proportions as evidenced by the fact that he was at various times hyperhydrated, hypohydrated, edematous, hyperkalemic, hypokalemic, acidotic, hyperchloremic, hyperphosphatemic and azotemic with a glomerular filtration rate less than 10 per cent of normal In an effort to find out how these disturbances might best be overcome, a survey was made of his ranges of tolerance for water and certain other dietary constituents in accordance with the principles set forth in chart 6, the survey was based on simultaneous consideration (a) of rates of urinary output and (b) of his metabolic status * These measurements were made promptly after admission so as not to waste opportunities to locate limits of tolerance provided by the fact that the patient had over reached a number of his "ceilings' and "floors” spontaneously Individual data expressed in terms of intake are presented in chart 45A The ranges of tolerance indicated by these individual measurements are represented by the right hand column of each pair shown in chart 45B Comparison of the columns representing the patient with the adjacent columns indicating normal tolerance and ordinary dietary ranges gives a fair idea of the practical problems faced by this individual His ranges of tolerance were narrowed to a degree where he could not eat and drink ad libitum in an ordinary manner without developing metabolic disturbances, but it was not so narrowed that it would be practically impossible for him to attain and maintain metabolic normalcy by taking food • The urinary excretion rate measurements usually were made on carefully tumed collections of at least 6 hours durafton The oral intale equivalents of these urinary output values were calculated on the basis of the following extrarenal loss rates per m per 24 hours water 1000 ml sodium potassium hydrogen bicarbonate and chloride ions zero phosphorus 10 mMol protein zero The following were used as indices of status for water serum ml per mosM (chart 7) for sodium evidences of extracellular fluid lack (ie dehydration) or ercess (ie edema) (chart 13) for potassium serum potassium concen tration and the T waves of lead Il clectrocardiographic tracings (chart 19) for hydrogen ion serum pl and bicarbonate concentration (chart 25} for chloride serum chloride concentration (chart 27) for phosphorus serum inorganic phosphorus concentration (chart 31) for protein blood NPN concentration in the case of phosphorus the maximal tolerance was estrated from measurement of his glomerular flirahon sale by assuming maximal urinary output to be equal to glomerular filtration rate (assumed to be equal to creatinine clearance) unes maximal allowable serum inorganic phosphorus concentration here arbitrarily set at 5 mg per 100 ml (chart 31) The same principle was used in estimat ing his maximal protein tolerance on the assumption that his urinary output would be equal to his urea clearance rate times an arbitrarily selected maximal allowable blood urca nitrogen (or NPN) concentration of 100 mg per 100 ml 112 ·and ſuid at rates which fell within his residual ranges of homeostatic tolcrancc. Experience with the present and similarly handicapped patients has shown that this usually can be accomplished without too much difficulty while the individual is living in a hospital where his intale can be controlled by trained personnel It is a different matter, however, when the patient is living at home where he and his family must play a major role in the management of the disease Under these circumstances, one may find that dietary and other recommendations are ignored in whole or in part becausc thc patient is unaware of their importance, or lacks the motivation to lnc cffectively as a person, or finds the restrictions so irhsome or impractical that he is more inclined to suffer the disabilities of the discasc than he is to cope with the discomforts inherent in his therapy It follows that patients with this type of enduring handicap need help from their physicians not only with respect to the management of the metabolic disorder, but also with regard to striking the best possible balance between that which may be good for the disease and that which is best for the per. son who has the disease In fulfilling this larger responsibility, in certain cases one may come closer to controlling the disease itself by granting libertics compatible with survival and passably cffective living than by attempting to impose the regimen most ideally suited to control of somatic disturbances For instance, though one would prefer to see scrum inorganic phos. phorus concentration values within normal limits, it does not appear that mild degrees of hyperphosphatemia are necessarily very harmful Accordingly. If onc can Accp the phosphorus intake within residual physiologic limits of tolerance only by giving distressingly large doses of alumi. num hydroxide gel or by fccuing a dict which is so unpatatable that the patient fails to cat enough to satisfy his caloric needs, it may be better to liberalize the diet at least to the point where body weight measurements indicate that he is in caloric balance Dictary protein also may deserve consideration both with regard to phosphorus, nitrogen, potassium, sullate, hydrogen jon and total solutc. loading and with regard to its influence upon the palatability of the diet When a diet is so unpalatable that the patient cats littic and is in negative caloric balance, he is art to stop anabolizing protein and may start con. suming his own body stores as a source of energy Since rifiye caloric balance predispoves to protein anabolism (chart 37D), liberalization of protein intale to the point where the appetite for calories is stimulated paradorically may result in loucting instead of raising blond NP values ·(A) Hao Nat x+ H+ HCO3 CI P CALORIES PROTEIN L/m424 mEq/m2/24 Mom? 24. omim 24 24 12 300 1504 6000F $07 (B) 10 2501 125- 3000 123) Body Fat 4000 Stores 100 200 Edema 1001- (113) 6 1504 75 3000+ 754 0440100 13 91 50 20004 so 100% (39) 2103 31 504 25- 1000+ 25 (89) &31 Oro Olie (311 (84) (C) SERUM mimosM H₂Oe [K*s (HCO3-)s [C), [P]g BODY FAT INPN), * Estimated from GFX (A) SUBSTANCE (B) RATE OF INTAKE (C) INDICATOR OF STATUS O EXCESSIVE YOLERABLE O INADEQUATE CREAT CLEARANCE : 97 L/m2/24 45A. Tolerance of a Pannephritic Patient for Water and Certain Other Nutrients Each of the circles in the top division represents a measurement of rate of intake of the substance named in section (A) at a time when the patient's status had been assessed per the indicator of status named in section (C) If the indicator of status revealed the patient to be within normal limits, it was concluded that the corresponding rate of intake was physiologically tolerable Under this circumstance a solid black circle was used On the other hand, if the indicator of status showed that the patient had a surplus of the substance in his body, the correspondiog rate of intake was considered to be physiologically excessive for that individual at that time Under this circumstance a horizontally shaded circle was used to represent the rate of intake Finally, of the indicator of status showed that the patient was deficient with segard to the substance, the intake was considered to be inadequate and a circle con taining a solid dat was used The actual value of the "status indicator" is shown in the adjacent parenthesis ever, when he took water at the rate of 4 hters per m' per 24 hours, nis serm watercontinued on opposite page 114 ·/m2/24 mEq/m2/24 mmol/m²/24 om/m/24 12H soor tor 150r 11 ORA' INN 250 123 125 200 100) 100F WOW ro so Tournur RATE ORAL INTAKE ISO 75 75 ODERY ORT nett 100F 30 30 PTS 1 100 30 25 23 PATIENT NORMAL 1 i Twto TOI CARE H2O Not K+ HCO3 CI P PROTEIN **STATUD 45B. Tolerance of a Pannephritic Patient for Water and Certain Other Nutrients The left-hand column of each pair shows the normal limits of totcrance for certain nutrients and the ordinary dietary range The right hand column of cach pair shows the tolerance of the pannephritic patient of chart 13A The columns representing the patient are hounded at top and bottom by solid black bars if the ceiling and/or floor is focalized by the data of chant 454, they are serrated if these data show only that the patient could raise or lower his intake to the indicated level without hecom ing intoxicated or depleted solute ratio was abnormally high at 40 ml per moll Contranwise, the fact that his scrum water-solute ratio was subnormal at 3 3 ml per most when he was taling water at the rate of 18 liters per m' pxr 24 hours indicated that this rate was physio logically inadequate The other abbreviations used in section (C) have the following meaning 11,0, - extracellular fluid volume, ( Kl. krom porastum concentration in max liter, [}ICO. 1. - serum bicarbonate concentration in mater liter. (C). - scrum chlonde concentration in mca per liter. It). * serum inorganic phoxphorus concenitation in mg per 100 ml, INPX), xrum non protein nitrogen concentration in mg x 100 ml The body surface of this 22-car-old male patient #11 estimated to le 16 m'. 115 ·H2O INTAKE PRESCRIBED H2O INTAKE AD LIB SE RUM WATER ml/mosM Physiologic Range 45C. Body Water-Solute Ratio Status of Two Nephritic Patients The left hand data were obtained during periods when their water intake was being prescribed by physicians who lacked exact knowledge about the patients limits of tolerance The right hand data were obtained when they were allowed to take water in accordance with thirst The shaded zone indicates the normal range From Kerri gan et al (1955) Of the variables under consideration potassium is probably the one most likely to produce a fatal degree of intoxication Consequently, it ap pears essential in patients with very low tolerance for this electrolyte to emphasize the dangers of potassium excess and to give specific direction as to how to avoid it It has been noted empirically that most nephritic patients can excrete up to 1 5 times their glomerular filtrate content of po tassium without becoming seriously hyperkalemic Thus a patient with a glomerular filtration rate of 5 liters per m² per 24 hours and a serum potassium concentration of 4 mEq per Itter would have a glomerular filtrate potassium of 5 x 4, or 20 mEq, and an estimated tolerance for this son of 20 x 15, or 30 mEq per ma per 24 hours This can be expressed to the patient in meaningful terms by making him aware of the potassium con tent of common foods In these connections, it has been found that thirst may constitute a A pal a homan. t 3 down" with water since the volume taken in this manner may by itsef overload the individual s residual homeostatic capabilities and lead to 116 ·water intoxication It also is important that patients with a lou ceiling of tolerance for water should eat a relaticly dry diet and then satisfy their thirst with plain water or suectened, clectrolyic free fluids rather than with milk, soup or other solutions of high fixed soluic content References Talbot et al (1956) General Acrogon et al (1955) Water homcostasis and source of data chart 45C 46. Pseudolypoparathyroidism The patient of this chart presented at the clinic during infancy with laryngospasm and other manifestatrons of tetany The concentration of calcium in his serum was found to be marhedly depressed and that of inorganic phosphorus to be markedly elevated The clevation in phosphorus con centration could be traced to a failure on the part of his kidncys to shed surplus phosphorus in the normal manner in accordance with homeostatic requirements Indeed, as this chart shows his ceiling of tolerance for phos phorus was so low that he could not fake even a minimum of thc ordinary dietary alloiment of this substance without becoming hyperphosphatomic However, in contrast to the pannephritic patient of chart 45A he appeared not to havcany other important limitations in renal function Though his specific disturbance could not be overcome by the ad ministration of parathyroid hormone it could be aftesiated by oral ad ministration of 100,000 10 400 000 units of vitamin D. daily These doses raised his maximal tolerance for phosphorus to leicls which were compart ble with an ordinary phospliorus intake It is not known whether this therapy also raised the level of his physiologic minimal requirement for phos phorus, a possibility which would be interesting to crpiore The administranon of units of poteni rasathy to J cutact xrm caprs sharp and distinct increase in phosphorus clearance in hyrpataikyou or normal in Januals but not in patients with nephrogenic hypparathyroidism This 1 an interesting dat not on hut one that has ne kating on therapy for both types of hypoparathy tuism are treated similarly References Albright et al (1943) General Talbot (tal (1953) Gencral 117 ·(A) H20 Na K H нсо, CI P PROTEIN L/m2/24 ImEq/m²/24 Mal/m2, 24° 24 12 300 150 150 (B) 10 250 125 125 200) 100 100 6 150+ 75 BEFORE VIT DE AFTER 75 100F 50 50H (50) 1 50 25 25 198) is 0)* (c) SERUM ml/mosM H2OE [K*Is CHCO3). [CI] СРIs (NPNIS (A) SUBSTANCE * Estimated EXCESSIVE from GFR (B) RATE OF INTAKE TOLERABLE (C) INDICATOR OF STATUS CREAT CLEARANCE 42 L/m2124 46A. Tolerance of a Patient with Pseudohypoparathyroidism for Various Nutrients The body surface area of this 22-year old patient was estimated to be 1 43 m'. The design of the chart corresponds to that of chart 45A 118 ·L/m2/24* mEq/m2 124 mmol/m%124 am/m 124* 12H 300 ISO- 150r ))) ONL) 125 room 250 125 27 # ON 200 100H 100+ no pe Pocenom RATE ORAL INTAKE 150F 75 75 ONEY Ontar 441 100 so 501 ri With or FK 50F 25 25 i PATIENT NORMAL H2O trert FIT Nat H+ HC0, CI" Р PROTEIN CKTAY CLCARANCE 420/124 . *Tico oy av 46B. Tolerance of a Patient with Pseudohypoparathyroidism for Various Nutrients as Defined by Data of Chart 46A Note the increase in the patient's tolerance for phosphorus after vitamin D. therapy had been started The design of the chart corresponds to that of chart 45B 119 ·47. Nephrogenic Diabetes Insipidus of Pitressin-resistant Type This patient tended to become severely hypohydrated, as evidenced by loss of weight and skin elasticity, dryness of the mucous membranes, hemoconcentration, lowering of the serum water-solute ratio and hypernatremia unless he was allowed to take large quantities of solute free water This disturbance was due to the fact that his kidneys were vorespon sive to antidiuretic hormone * As a consequence of this, he needed a minimum of about 15 ml of water to eliminate 1 mosM of solute from the body by way of the kidneys This meant that when he was taking whole cow's milk, which produced a urinary solute load of about 600 mosM per ma per 24 hours, he needed about 9000 ml of solute free water to cover urinary needs plus 1000 to equalize extrarenal water losses or a total of about 10,000 ml per m² per 24 hours (chart 47A and column a of lefthand division of chart 47B) This requirement could be lessened only by reducing the solute content of his diet, the effects of lowering his urinary load to 400 or to 200 mosM per mº per 24 hours are indicated by columns band c of the left hand division of chart B In all other respects, his renal function appeared to be well developed (charts 47A, B) Such an isolated congenital defect in homeostatic function can have far reaching effects on body economy (chart 47C) For instance, when this child was taking whole cow's milk, he needed on the average to drink every 24 minutes and to void every 50 minutes Since he awoke for each of these activities, the duration of uninterrupted sleep was never greater than about 20 minutes This made it impossible for him to fulfill his sleep requirements at night and hence necessary for him to nap intermittently during the day As a result, there was little opportunity for social contact, play and learning The clinical manifestation of this was gross retardation in mental and emotional development When the solute load was reduced by substitution of an isocaloric dilute formula made up by mixing equal parts of whole cow's milk and 15 per cent dextrose in water, the rate of water turnover slowed so much that he could go for about 66 minutes without drinking or voiding Fol lowing this change, his daily pattern of activities became almost normal for a child of his age and he commenced to grow and mature physically, intellectually and emotionally at a markedly accelerated rate * Intravenous administration of a test dose of 2 units of aqueous posterior pituitary extract per m' failed to produce a normal faff in fine water solute ratio to levels of approximately 2 ml per mos 120 ·H20 Not M HCO CI P CALORIES PROTEIN 4001 Tum2/240 24 JOM LOV 12 10 oot ISO 190H 600 Ots) 129 3000 B) 10 250 125 Body 2001 100 4000 Steret 100 OK 09 150F 75 3000 75 30 2000: 90) TO2) 100 FO13-11 OUD 30 1000) 29 SERUM mimosM HOC [Kg CHCO3). ccui, CP), BODY FAT (NPN), (A) SUOSTANCE Eatinale EXCESSIVE from CIR (D) RATE OF INTAXE TOLERABLE Calimololo (C) INDICATOR OF STATUS O INADEQUATE Splate Output 350 W/m2/24* CREAT CLEARANCE 01.1124 474. Nephrogenic Diabetes Insipidus of the Patressin-resistant Type The body surface of this 213-year-old patient was estimated to be 0.45 m Thc dc. sign of the chart corresponds to that of chart 45A. It is interesting to note that he dorised about as much benefit in terms of his activity pattern from this dilute formula regimen, which was com. patible with normal growth and desclopment, as he did from the much morc drastic nutritionally inadequate dextroscand water regimen References Hillman et al (1958) General and source of data chart 47C Wanng et al (1945) General 121 ·400r L/m2/24 350 mEq/m2/24 3004 mmol/ m2/24 am/m2/24• 150r 150C 250 125 125 200 100F 100F NORNAL ANYSIO LOSIC RATE ORAL INTAKE TOLERANCE 150 754 75 01111111111 ܢܠܚ 100F ORDINARY OIC TARY MANGE 30 50 1 Nat ZPTS FRANSE OF 50 254 TOLERANCE 25 PATIENT NORMAL H20 ** H+ HCO3 C1 P PROTEIN WINIMAL MO REQUIREMENTS CALCULATED FOR SOLUTE OUTPUT CREAT CLEARANCE BOL/m2/24 + ESTIMATED FROM GFR 600 2. 72/24* 400 200 47B. Tolerance of a Child with Nephrogenic Diabetes Insipidus as Defined by Data of Chart 47A Note in the left-hand section that the patient's minimal water requirements are set forth relative to rates of solute output The design of the chart corresponds to that of chart 45B a D ·PERCENT OF OBSERVATION PERIODS ACTIVITY OF PATIENT AVERAGE VALUES FOR FLUID INTAKE URINE OUTPUT VOLUME INTERYAL | VOLUVE VOLUME INTERVAL VOLUNE PER BETWEEN PER PER OCTWEEN PER HOUR DRINKS MOUR VOIDINCSI VOIDINC AJA ml DRINK SLEEP (51) DRINK (2821 370HM S.MOO 247 24 120 135 50 112 MILK PLAY (219) SLEEP 1452) DRINK (62) 0 120 66 141 77 66 102 PLAY (492) DEXTROSE OILUTE a WATER FORMULA DRINK SLEEP (372) 89 66 127 74 90 132 PLAY (56%) ACTIVITY OF NORMAL 15 mo 12 g DRINK 172) SLEED (29%) 370H SHOJ o 50 288 240 25 240 100 PLAY (642) 470. Effects of Limitation in Capacity to Conserve Wafer Duc to Pitressin Resistance The chart shows the daily life pattom of the patient a 15 month-old infant weighing 66 kg while taking (a) whole cou s múk (b) a diluie low solute formula and (c) * solute frec dextrose in water solution These patterns may be compared with those of a normal infant of similar age shown at the bottom of the chart. I tom Hillman et al (1958) 123

·No text on this page.

·REFERENCES ·GAMBLE,J L Chemical Anatomy, Physiology and Pathology of Extracellular Flud A Lecture Syllabus (6th ed) Harvard Univ Press, Cambridge, 1958 GAMBLE, JL. WALLACE, W M, ELIEL, L, HOLLIDAY, MA, CUSHIMAN, M, APPLETON, J , SHENBERG, A , and PIOTTI, J Effects of large loads of electrolytes, Pediatrics 7 305, 1951 GARDNER, 1, MAC LACHLAN, E A, PICK, W, TERRI, ML, and BUTLER, A Etiologic factors in telany of newly born infants, Pediatrics 5 228, 1950 CINANDES, GJ, and TOPPER, A Insensible perspiration in children }} Statistical correlation of insensible perspiration and various body measurements, proposed basal standards for children, Am ) Dis Child 52 1335, 1936 GOODMAN, L S, and GILMAN AZ The Pharmacologic Basis of Therapeutics (2nd ed ) Macmillan, New York, 1955 M HANSEN, D L, and 5011TH, CA Effects of withholding fluid in the immediate postnatal period, Pediatrics 12 99, 1953 HIEELEY, A M, and TALBOT, N B Insensible water losscs per day by hospitalrzed infants and children, Am ) Dis Child 90 251, 1955 HILLMAN, DA, NEYZI, O, PORTER, P, CUSHVAN, A , and TALBOT, N B Ronal (vasopressin resistant) diabetes insipidus, definition of the cffects of a homeostatic limitation in capacity to conserve water on the physical, intellectual and emotional development of a child, Pediatrics 21 430, 1958 KERRIGAN, GA, TALBOT, N Band CRAWFORD, JD Role of the neurohypophyseal antidiuretic-hormone renal system in every day chnical medicine, Clin Endocrinol 15 265, 1955 LETY, S S, and SCHVIDT, C F The effects of altered arterial tensions of carbon droxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men, 1 Clm Invest 27 484, 1948 LARACH, J H, and STOERK, H C A study of the mechanism of secretion of the sodium retaining hormone (aldosterone), ) Class Inves! 36 383, 1957 LEAF, A, COUTER, W T, and NEWBURGH, L H Some effects of vanation in sodium intake and of different sodium salts in normal subjects, 1 Chr inest 28 1082, 1949 LEAF, A , BARTTER, FC, SANTOS, A F, and WRONG,O Eudence in man that urinary electrolyte loss induced by Pitressin is a function of water reten tion, J Clin Iniest 32 868, 1953 LEVINE, S Z, KELLY, ay, and WILSON, J R The insensible perspiration in infancy and chưdren if Proposed basal standards for infants, Am I Dis Child 39 917, 1930 128 ·LOWE, C U: Practical thoughts on clectrolyte and Nuid administration, Pedaalries 15.498, 1955 LUND, C. C, and BROWDER, Ac, The estimation of areas of burns, Surg. Gynec & Obst 79 352, 1944 MACY, I G Nutrition and Chemical Growth in Childhoorl Vol 1 Evaluation Thomas, Springfield, III, 1942 MC CANCE, * A, and WIDDOU SON, F M Hypertonıc expansion of the cxtracellular hurds, Acta Pediat 46 337, 1957 ATOORE, F D Common patterns of water and electrolyte change in injury, surscry, and discase, New England 1 Med 258 277.325, 377, 427, 1958 MOORE, F.D. and BALL, M R The Metabolic Response to Surger) Thomas, Springfield, 111, 1952 NABARRO, J D N. SPENCER, A G. and STOWERS, J M Metabolic studies in sesere diabetic ketosis, Quant 1 Mied 21 225, 1952 NELSON, W E (cd ) Texibook of Pediatrics (6th ed ) Saunders, Philadelphia, 1954 NEWBURGII, L H. JOHNSTOV, AL W. and NEW BURGIT, JO Some Funda mental Principles of Metabolism Eduards Bros, Ann Arbor, 1945 NCYZI, O, BAILEY, M, and TALBOT, A Cliccts of varying infusion time in maintenance fluid therapy, en England / Med 258 1239, 1958 MICHIOLS, C, JR, NICHOLS, A, WEIL, W , and WALLACE, * M The direct measurement of the extracellular phase of tissues, 1 Clin Invest 32 1299, 1953 NICHOLSON, T F The mode and site of the renal action of parathyroid ertract in the dog, Canadian / Biochem & Physio4 37 113, 1959 NICHOLSON, TF, and SITE PIERD G1 The effect of damage to various parts of the renal tubule on the excretion of phosphate by the dog's didney, Canailian / Biochem & Physiol 37 103, 1959 OLIVER, WJ, GRAITAV, , and WILSON JL Lack of scientific validity of body surface as basis for parenteral fun dosage, JAVA 167 1211. 1958 ORLOFF, J The role of the Ajdncy in the regulatuon of acid his balance, ale 1 Bol Ned 29 211, 1956 rits, R F Renal cicrction of acid Fed Prix 7 418, 1948 PITTS, R F, AYER, L, and SCHIESS WA The ional regulation of acid base balance in man II The reabsorption and ctcreiken of bicarbonate, / Clin Iniest 23 35, 1949 139

·No text on this page.

·TALDOT, N B, SORCL, E II, MCARTHUR, J W, and CRAWFORD JO Funccional Endocrinology from Birth through Adolescence Harvard Univ Press, Cambridge, 1952 TALBOT, N B , CRAWFORD, J D, and BUTLER, A M Homeostatic limits to sale parenteral fluid therapy, Nex England ) Med 248 1100, 1953 TALBOT, N B. KERRIGAN, G A , CRAWFORD, J D, COCHRAS, H. and TERRY, MI L Application of homeostatic principles to the practice of parenteral fluid therapy, New England J Med 252 856,893, 1955 TALBOT, N D , CRAWFORD, J P, KERRIGA, GA, HILLVAN, D, DERTL CIO, M, and TERRY, M L Application of homcostanic principles to the manage. ment of nephritic patients, en England 1 Med 255 655 1956 TALBOT, N 1 , CRAWFORD J D and cook, CD Application of homeostatic principles to the management of nephrotic patients, en ensland / Ved 256 1080, 1957 TALBOT, N B, and RICHIE R The effect of age on the body's tolerance for fasting, thirsling and for oscrloading with water and certain clectrolytes, Ciba Foundation Colloquia on Ageing 4 139, 1958 TALBOT, N 8, and RICHIE, * The advantages of surface area as a common de nominator in calculating pediainc dosages l'ediatrics (in prese), 1959 VERNEY, E B Renal excretion of water and salt Lancer 2 1237, 1957 WARING, A J, KAJDI, L, and TAPPAV V A congenital defect of water metat olism, Am I Dis Chuld 69 323, 1945 WEIL, W o, and WALLACE, E AL Hypertonic dehydration in infancy. Pedealrics 17 171, 1956 WINKLER, A *, JOTF, F, and SMITH P K Electrocardiographic changes and concentration of potassium in serum following intricnous injection of potassium chloride Am I Phys101 124 478 1938 WINY, V Wałcr intoxication and scrum hypofonicity, Metabol sm S 490. 1956

·No text on this page.

·No text on this page.