Acute symptomatic hyponatremia

MEDICAL PROGRESS

Acute symptomatic byponatremia Hyponatremia is a laboratory finding which reflects several different physiological ad)ustments. The diagnosis o[ symptomatic hyponatremia is based on clinical findings, laboratory data, and the response to appropriate therapy. Laboratory data alone do not distinguish children with low plasma sodium concentrations and symptoms o[ water intoxication [rom those with hypotonic dehydration unassociated with central nervous system dys[unction. Data [rom 17 children with acute symptomatic hyponatremia are presented. These patients had satis[actory clinical and biochemical responses to in[usions containing sodium at concentrations o] 500 to 1,300 mEq. per liter.

Wandee Varavithya, M.D., and Stanley Hellerstein, M.D.* KANSAS CITY, MO.

A c v w ~ hyponatremia is frequently encountered in seriously ill children, whereas chronic hyponatremia is predominantly a problem of adult medicine. The latter subject has been examined in a number of excellent articles and will not be considered here. 1-9 THE S I G N I F I C A N C E OF PLASMA SODIUM CONCENTRATION The major clinical value of a plasma sodium determination is its reliability as an indicator for the concentration of body fluids. I n general, a significant alteration in plasma sodium concentration provides in[ormation concerning an abnormality in body water From the Department o[ Pediatrics, University o[ Missouri School o[ Medicine, at The Children's Mercy Hospital. Supported in part by National Institute o[ Health Grant HD 01004-01A1. *Address, The Children's Mercy Hospital, 1710 Independence Ave., Kansas City, Mo. 64106.

content, not in body sodium content, s, 10 Sodium is the most abundant ion in extracellular fluid, accounting for about 90 per cent of the total cations. Since most of the plasma anions are also univalent, twice the plasma sodium concentration is equal to about 90 per cent of the total concentration of ions in plasma (Table I). 11 Sodium and its anions also contribute most of the osmotically effective plasma solute. Twice the plasma sodium concentration, or 90 per cent of the total plasma ion concentration, is a good estimate of effective plasma osmolality because the osmotic coefficient of solute in body fluids is about 0.93.12 An increase in plasma sodium concentration reflects an increase in body fluid osmolality and a decrease in body water relative to body solute. With two exceptions, a decrease in plasma sodium concentration refleets a decrease in body fluid osmolality and an increase in body water relative to body Vol. 7I, No. 2, pp. 269-283

270

Varavithya and Hellerstein

The Journal of Pediatrics August 1967

Table I. Ionic structure of plasma r Cations

mEq. per L.

Na K Ca Mg

142 ~4 5 3

Total ~After

154

Anions

mEq. per L.

C1 HCO3 PO4 SO.~ Organic anion Protein Total

103 27 2 1 5 16 154

Table II. Pathogenesis of acute hyponatremia I. Excessive solute loss (usually associated with low solute replacements)

A. Skin 1. Cystic fibrosis19-21 2. Heat stress22, 23 B. Gastrointestinal tract 1. Protracted vomiting, e.g., pyloric stenosis 2. Diarrhea C. Urinary tract 1. Salt losing renal states--untreated adrenal insufficiency24-26 2. Solute diuresis during treatment of intoxications, e.g., salicylate 3. Subarachnoid ureteral anastomosis27

P i t t s . 11

solute. One of the exceptions is the result of a decrease in the water fraction of.plasma, as in patients with hyperlipemia or hyperproteinemia. 13 Although the concentration of sodium in plasma is low in these situations, the concentration of sodium in plasma water is normal, if body fluid osmolality is normal. Plasma sodium concentration may also be reduced in the presence of normal or increased body fluid osmolality when the extracellular space is expanded by the accumulation of nonionic extracellular solute such as glucose, urea, or mannitol. 14-18 Excluding these conditions, plasma sodium concentration is a reliable index for effective body fluid osmolality.

II. Excessive administration of water

A. Oral--usually associated with defects in water excretion, particularly in acute renal failure-~S B. Rectal, e.g., tap water enemas in patients with megacolon29, a0 C. Parenteral 1. Therapeutic accidents 2. "Usual therapy" in patients with diminished ability to excrete water 31-3* D. Transplacental in newborn infanta3 III. Abnormality in excretion o[ water (associated with positive water balance)

A. Acute renal failure B. Nonosmotic stimulation of antidiuretic hormone secretion or activity 1. Associated with infections36-41 2. Associated with anesthetic agents and other drugs 31, 42 3. Associated with surgery, head injury, and other trauma.43-4s

C L I N I C A L P A T T E R N S OF ACUTE HYPONATREMIA Hyponatremia is not a diagnostic term. It is a laboratory finding which reflects several different physiological adjustments. Patients with acute hyponatremia usually present in one of the following clinical patterns: 1. Asymptomatic acute hyponatremia. 2. Acute hyponatremia with dehydration. 3. Symptomatic acute hyponatremia or water intoxication. These forms of acute hyponatremia are the result of one or several of the processes listed in Table II. Asymptomatic acute hyponatremia. This has been encountered during severe infections, after surgery, and following trauma. It occurs in the absence of an overt disturbance in water and electrolyte metabolism and appears to have little bearing on the patient's clinical course. T h e occurrence of low plasma electrolyte concentrations during

IV. (?) Increase in available body water associated with the increased metabolism of inflammation~9 _

V. (?) Decrease in osmotic activity o/ ionic solute due to sequestration or binding49

acute infections has been recognized for m a n y years. One of the early studies on children was reported by D a r r o w and H a r t m a n n 36 in 1929. Children with pneumonia were found to have lower total plasma ion concentrations before the crisis compared with later in convalescence. D a r r o w and H a r t m a n n concluded that these changes could be explained by the increase in plasma volume and the tendency to retention of water associated with the infections. Gonzalez and associates 38 have recently examined serum electrolyte concentrations in

Volume 71 Number 2

pediatric patients with acute infections. There were 126 children classified as severely ill. Serum sodium concentrations were below 131 mEq. per liter in 50 per cent of 65 children with bacterial infections, in 30 per cent of 43 with viral infections and in 33 per cent of the 15 children with infections of undetermined etiology. Hyponatremia was present in a smaller fraction of the children with less severe infections. Finberg and Gonzalez a9 infected rats with pneumococci to develop a model which might be used in the study of hyponatremia associated with acute infections. T h e y found serum sodium concentrations below 131 mEq. per liter in 18 of 24 severely infected rats. T h e hyponatremia appeared to be the result of two processes, an increase in available body water and a decrease in urine volume. The increase in available body water appeared to originate from the extra water of oxidation resulting from the increased metabolism in response to infection. The mechanism causing diminished urine volume in the severely infected rats was not clarified. The decreased urine output led to greater water retention than in control animals, but the quantity of retained water was not in itself sufficient to account for the degree of reduction in serum sodium concentrations. There were striking alterations in the composition of muscle tissue in the severely infected rats. Muscle water content was increased, sodium content decreased, and potassium content unchanged. Although these rats had positive sodium balances, the sodium transferred out of the muscle tissue could not be accounted for in inflammatory exudate or gastrointestinal fluid. It was assumed that the sodium was taken up elsewhere in the body. The significance of hyponatremia during acute infections, after trauma, and following surgery is not understood. It probably reflects an adaptive process triggered by these stresses. Although the low plasma sodium concentrations usually revert to normal without specific therapy, the presence of hyponatremia usually indicates that the patient's ability to excrete water is impaired. This is clearly the case in central nervous system

Acute symptomatic hyponatremia

271

(CNS) infections in which symptomatic hyponatremia has been observed in patients who were receiving water and electrolytes at usual rates, ar Unless contraindicated by dehydration or other factors, patients with asymptomatic acute hyponatremia should receive maintenance water at about 80 per cent of the usual rate of administration. The solutions infused should contain sodium and chloride at about half isotonic concentrations. Even in the absence of hyponatremia, the plasma sodium concentration should be followed closely in patients with CNS infections and injuries. These patients should receive water at the same rate as those with asymptomatic hyponatremia unless more fluid is specifically indicated.

Acute hyponatremia with dehydration. This is indicative of the loss of extracellular solute out of proportion to water.2, ~. s, 5o This state is usually encountered in patients with abnormal losses of both water and electrolytes. The clinical features due to the electrolyte disorder result from the contraction of extracellular volume and inadequate perfusion of tissues21-~4 Although total body water is usually decreased, a significant fraction of the deficit in extracellular volume is the result of osmotic transfer of water into the cells. Darrow and Yannet55, 56 were able to produce hypotonic dehydration in experimental animals without altering total body water. The removal of extracellular electrolyte led to a fall in effective plasma osmolality and in the movement of water into the cells. Extracellular volume and plasma volume fell, and clinical dehydration was evident. This form of extracellular volume depletion may be produced clinically in pediatric patients by the administration of hypotonic fluids by hypodermoclysis. Acute hyponatremia with dehydration is treated by the expansion of extracellular volume with solutions containing extracellular electrolyte24 The infusion of hypotonic solutions for hydration of patients with hypotonic dehydration may precipitate symptomatic hyponatremia. 57 Symptomatic acute hyponatremia or water intoxication. This is the most dramatic of the hyponatremic syndromes. It may occur

272

Varavithya and Hellerstein

in patients who were previously normonatremic or as a complication of chronic hyponatremia. Weir and colleagues 5s used the term, water intoxication, to describe the symptom complex which occurred during treatment of patients with diabetes insipidus. While receiving injections of posterior pituitary extract, the patients were instructed to continue the level of water intake to which they had become accustomed. During an 8 hour period 1 patient ingested 5.25 L. of water and excreted 800 c.c. of urine. "In the course of 3 to 4 hours he became very ill, was nauseated, developed severe headache, and was forced to go to bed. Physical examination revealed only puffiness of the lower eyelids and slight edema of the ankles. Repetition of this experiment on the same and on another patient gave similar results, that is, nausea, vomiting, and headache which forced the patient to go to bed. In one instance definite ataxia appeared." Rowntree 59 followed these clinical observations with careful studies on the effects of the administration of excessive quantities of water on mammals. These studies led to the following concepts : 1. Ingestion of water in excess of the ability of the organism to excrete it leads to water intoxication. 2. Water intoxication is manifested by restlessness, asthenia, nausea, vomiting, diarrhea, polyuria (and at times, oliguria), convulsions, coma, and, unless the process is terminated, death. 3. The symptom complex is probably a manifestation of disturbance in salt and water equilibrium of the body and of the CNS. 4. "Water intoxication can be prevented, alleviated, or cured by timely intravenous administration of a hypertonic solution of sodium chloride." Relatively little has been added to this conceptual framework in the past 40 years. Helwig and associates 6~ reported a human fatality due to water intoxication in 1935. A 50-year-old woman, following an uneventful cholecystectomy, was administered tap water by proctoclysis. During a 30 hour period, she absorbed 9,000 ml. of water rectally, voided 1;050 ml, and vomited about 300 ml. Some

The ]ournal o[ Pediatrics August 1967

18 hours postoperatively she complained of severe headache, was perspiring freely, and had tremors of the right arm. She later became stuporous, developed convulsions, and died 41 hours after the operation. Helwig and his co-workers 6~ recognized that features of this patient's history and course resembled those described in water intoxication of animals. They were successful in reproducing the clinical picture of water intoxication in rabbits by rectal administration of tap water. The histological findings in these animals were similar to those in the fatal human case. Many aspects of the pathophysiology of water intoxication have been clarified by the clinical and experimental observations of Dodge, Crawford, and ProbstY Using rabbits, they showed that the clinical signs, electroencephalographic alterations, and elevated cerebrospinal fluid pressure observed during water intoxication could be reversed with hypertonic solutions of mannitol, urea, or saline. The infusions of mannitol and urea produced increased effective body fluid osmolalities and further depression of the Iow concentrations of plasma sodium and chloride. These observations showed that low plasma electrolyte concentrations per se are not the cause of water intoxication. The electroencephalographic changes of water intoxication could not be reproduced by artificial elevation of cerebrospinal fluid pressure in the absence of hypotonicity nor were they prevented by lowering the spinal fluid pressure in the presence of hypotonicity. In these acute experiments, the signs of water intoxication were correlated with increases in intracellular water. P A T H O G E N E S I S OF SYMPTOMATIC ACUTE HYPONATREMIA

The clinician is frequently confronted with a dilemma in the evaluation of patients with hyponatremia. One patient with a plasma sodium concentration of 125 mEq. per liter and an effective plasma osmolality of 250 mOsm. per kilogram may have striking symptoms of water intoxication while another with identical plasma findings may

Volume 71 Number 2

have no clinical evidence of CNS dysfunction. Baskin and colleagues 61 expressed the view that the absolute concentration of body electrolyte is not as important as the rate at which body tonicity is reduced. They suggest that it is the sudden expansion of cell water which results in symptoms of water intoxication. Stormont and Waterhouse 4~ produced hyponatremia in 10 adult subjects by overhydration and noted a rough correlation between the level of serum sodium and the degree of symptomatology. Mild symptoms were seen with serum sodium levels in the range of 120 to 130 mEq. per liter, moderate symptoms with serum sodium values of 114 to 120 mEq. per liter, and severe symptoms when serum sodium was below 114 mEq. per liter. According to Wynn and associates, 1, 2 the syndrome of water intoxication is the result of water retention, but the symptoms may be acute or gradual in onset. With acute retention of water, the symptoms are sudden in onset with disturbances in mental activity, disorientation, delirium, convulsions, and coma. In the gradually developing cases, the symptoms are insidious in onset; they begin with lethargy, muscle weakness, sleepiness, apathy, and disorientation, and progress to extreme prostration. Crawford and Dodge 31 observed that water intoxication may develop in the presence of deficits of body water if there have been extensive losses of solute. These observations are consistent with our experience (Table I I I ) . Edelman and his associates3, s2 have pointed out the role of potassium depletion in hyponatremia. Potassium and its associated anions contribute the bulk of intracellular milliosmols. A decrease in cellular potassium which is accompanied by a fall in intracellular osmolality is reflected by decreased tonicity of extracellular fluids and a reduction in plasma sodium concentration. The hyponatremia due to depletion of potassium tends to result in a relatively chronic state. In pediatric practice, this is most frequently encountered with protracted vomiting or following gastrointestinal losses which have been replaced with fluids containing insuf-

Acute symptomatic hyponatremia

273

ficient potassium. Clinically, this chronic low sodium syndrome seems to limit the patient's ability to tolerate water loads and to make him particularly susceptible to symptomatic hyponatremia. Symptomatic acute hyponatremia has been described in three newborn infants whose mothers had asymptomatic hyponatremia, s~ On the day of delivery, the maternal serum sodium concentrations were 117 to 119 mEq. per liter. One of the infants was cyanotic and flaccid at birth and required endotracheal intubation and resuscitation. Another infant had irregular heart sounds immediately before delivery and was covered with meconium at birth. She developed progressive weakness, intermittent cyanosis, and convulsions. During the second day of life, these two infants had serum sodium concentrations of 120 and 124 mEq. per liter. The mother of the third infant had been on salt restriction and received diuretics for eclampsia. During the 24 hours prior to delivery, she received 3,600 ml. of 5 per cent dextrose in water intravenously. At delivery the maternal serum sodium concentration was 117 mEq. per liter, and the infant's was 122 mEq. per liter. The infant was flaccid and gray during the first 14 hours of life. Following the administration of hypertonic sodium chloride by gavage, the infant's color and muscle tone improved and she seemed normal by 24 hours of age. T H E D I A G N O S I S OF SYMPTOMATIC HYPONATREMIA

The diagnosis of water intoxication is usually made because of the abrupt appearance of CNS symptoms in a clinical situation in which symptomatic hyponatremia may be anticipated, or because a low plasma sodium concentration brings the possibility to mind. Pertinent information concerning 18 children diagnosed as having symptomatic acute hyponatremia is presented in Table III. In some instances the diagnosis of symptomatic hyponatremia was suspected clinically and then confirmed by laboratory studies and by the outcome of treatment. In others, the finding of a low plasma sodium concentration led to clinical review and the

Table IlL Patients with symptomatic hyponatremia

Patient No.

Age (years)

Primary diagnosis

Probable cause of hypotonicity

1-6/12 Meningocele of thoracic, Inappropriate renal respine, hydrocephalus, sponse--probable nonventriculo-atrial shunt osmotic stimulus for ADH secretion Gastrointestinal losses; low 3 Gastroenteritis due to solute intake unknown cause Gastrointestinal losses 4-5/12 Gastroenteritis due to unknown cause 3 Meningitis, acute due to Inappropriate renal reHemophiIus influenzae s p o n s e - p r o b a b l e nonosmotic stimulus for ADH secretion Inappropriate renal re6/12 Subdural hematoma, s p o n s e - p r o b a b l e nonchronic; subduralpleural shunt, pneuosmotic stimulus for ADH monia secretion 3/12 Gastroenteritis due to Gastrointestinal losses; low solute intake unknown cause 2-10/12 Fever of unknown origin Unknown; marked renal solute excretion renal glycosuria

'10/12 Pericarditis, acute due to Unknown; marked renal

10

2/12

unknown cause Vomiting due to unknown cause, chronic hydrocephalus, subarachnoid-ureteral shunt Meningitis acute, due to

solute excretion Continuous solute loss-spinal fluid

Immediate ] clinical response to in[usion o[ hypertonic solution

Follow-up

Dramatic

Died suddenly, 45 hours after hypertonic infusion

Dramatic

Recovered

Dramatic

Recovered

Good

Recovered

Good

Died 14 days after hypertonic infusion ; septicemia due to H.

Good

Recovered

staphylococcus

Dramatic

Recovered from acute illness. Glycosuria persisted No change Died 16 hours after evident hypertonic infusion Good Recovered

Inappropriate renal reGood sponse--probable nonosmotic stimulus for ADH secretion Good 2/12 Meningitis acute, due to Inappropriate renal response--probable nonD. pneum,oniae osmotic stimulus for ADH secretion 9/12 Gastroenteritis due to un- Gastrointestinal losses; low Dramatic known cause; pneusolute intake monia, interstitial; renal tubular necrosis Gastrointestinal losses ; Dramatic Gastroenteritis due to hypodermoclysis of hypounknown cause tonic fluid Tap water enema Good 11/12 Hyponatremia~ acute symptomatic. Anemia due to iron deficiency 8/12 Meningitis, acute due to Excess low solute infusion; Satisfactory inappropriate renal reD. pneumoniae s p o n s e - p r o b a b l e nonosmotic stimulus fer ADH secretion Gastrointestinal bleeding; Dramatic 11-6/12 Typhoid fever low solute infusion Gastrointestinal losses; low Good 3/12 Gastroenteritis due to solute intake unknown cause Gastrointestinal losses; low Good 5/12 Gastroenteritis due to solute intake unknown cause

Recovered

D. pneumoniae

11

12

I3

14

15

I6 17 18

Recovered

Died 8 hours after hypertonic infusion

Recovered

Recovered

Recovered

Recovered Recovered Recovered

Volume 71 Number 2

Acute symptomatic hyponatremia

appropriate diagnosis and treatment. Selected case summaries are presented later in this paper. The outstanding clinical features were lethargy, convulsions, and marked pallor. There were 2 patients in whom the hypertonic infusions did not produce marked improvement in CNS function. Patient 8, a child with unsuspected pericarditis, probably did not have symptomatic hyponatremia. The hypertonic infusion m a y have been harmful to this child. Patient 15, an 8month-old boy with pneumococcal meningitis, showed improvement in skin color, loss of opisthotonus, and lightening of his comatose state following the hypertonic infusion. The other 16 children responded to the hypertonic infusions more dramatically, with cessation of convulsions, marked improvement in mental status, and striking loss of pallor. Laboratory data were examined for characteristics which might distinguish patients with asymptomatic acute hyponatremia from those with symptomatic acute hyponatremia. The laboratory data from the patients with symptomatic hyponatremia were compared with similar data from 18 infants with hypotonic dehydration. The latter children were dehydrated because of acute gastrointestinal disorders, but none of them had symptoms of water intoxication, and all recovered. Comparison of plasma electrolytes, osmolali-

Table IV. Initial laboratory data (symptomatic and acute hyponatremia)

Effective Plasma plasma sodium osmolality* (mEq./L.) (mOsm./Kg.) Symptomatic

hypo-

natremia (No. 18) Asymptomatic hyponatremia (No. 18) Normals--1 mo. to 15 yr. (No. 77)

123 + 5

246 + 16

126 • 4

251-2-10

139 +- 2.9

273-+ 5.4

*Effective plasma osmolality ---- total plasma solute concentration by freezing point depression minus the ineffective milliosmols contributed by glucose and urea. Wlth plasma sugar < 180 ms. per cent: [mOsln]~EF 7_. [mOsm]Fi" Sugar ms. per cent Urea N mg. per cent~ 18

2.8

275

ties, C02-contents, urea-nitrogen and sugar values, blood pH's, urine osmolalltles, and urine electrolyte concentrations failed to reveal characteristics which distinguished the children with symptomatic hyponatremia from those with asymptomatic hyponatremia. Total body water was not measured in these children, but it seems unlikely that this determination would have identified the patients with symptomatic hyponatremia since many of the children with clinical water intoxication were also water depleted. The plasma sodium concentrations and effective plasma osmolalities of these two groups of patients are shown in Table IV. T R E A T M E N T OF S Y M P T O M A T I C ACUTE HYPONATREMIA

The clinical manifestations of water intoxication respond promptly to the addition of effective milliosmols to extracellular water. Although hypertonic solutions of sodium chloride are generally used, hypertonic mannitol may be preferable when body sodium content is increased. 68 When infusions of hypertonic saline are used, the patient with symptoms due to water intoxication will usually have distinct clinical improvement when the plasma sodium concentration has been increased by about 10 mEq. per liter or to 130 to 135 mEq. per liter. The quantity of sodium needed may be estimated with the following formula: mEq. Na ~- ( [Na]f - [Na] l) x (TB-H~O) where: mEq. Na • milliequivalents of sodium required to raise the plasma sodium concentration from [Na]l to [Na] f. [Na] ~= the final or desired plasma sodium concentration. Either 130 mEq./L, or 135 mEq./L., depending upon the initial plasma sodium concentration and the clinical situation. [Na]~ = the initial plasma sodium concentration.

(TB-H~O) • total body water. 0.7 x body weight in kilograms may be used in infants through five months and 0.6 x body weight in kilograms in older children, a4

276

Varav~thya and Hellerstein

D a t a p e r m i t t i n g comparison of the effects of various concentrations a n d rates of infusion of hypertonic saline on children with s y m p t o m a t i c h y p o n a t r e m i a are presented in Tables I I I a n d V. T h e solutions infused contained sodium in concentrations from 526 to 1,312 mEq. p e r liter and were infused at rates of 10 _+ 4 ml. p e r kilogram p e r h o u r delivering sodium at 8 +_ 3 mEq. per kilog r a m per ho.ur. I n every case there was a satisfactory biochemical response with elevation of the p l a s m a sodium concentration into the desired range. O f the 18 children, 17 showed distinct clinical improvement, and in none were adverse effects recognized. T h e r e a p p e a r e d to be no clinical a d v a n t a g e in the use of solutions with sodium in the concentration range of 500 mEq. per liter

The ]ournaI of Pediatrics Au,~ust 1967

r a t h e r than 1,000 mEq. per liter nor was there evidence of undesirable side effects due to the use of solutions in either of these concentration ranges. I n these studies, as well as in the literature, solutions containing 3 p e r cent to 6 per cent sodium chloride ~ a p p e a r to be suitable for rapidly increasing body fluid osmolality?, s, 31, 3z C H A N G E S IN B O D Y COMPOSITION DURING HYPERTONIC INFUSIONS

Analysis of balance d a t a obtained during the hypertonic infusions shows that changes in effective body fluid osmolality were determ i n e d by the rates of infusion and the e515 to 1,030 mEq. of sodimn per liter,

T a b l e V. A c u t e s y m p t o m a t i c h y p o n a t r e m i a - - h y p e r t o n i c infusions

Patient No.

Duration of infusion (hours)

Plasma sodium Initial Final (mEq./L.) (mEq./L.)

Concentration of sodium in infused fluid (mEq./L.)

1

1-y2

122

140

548

2

1

123

133

720

3

1

128

143

1140

4

1-V2

122

128

526

5

1

125

138

807

6

1

130

141

630

7

I-~

125

139

630

8

1-y~

131

136

640

9

1-~

127

136

664

10

I

126

137

597

11

2

123

134

604

12

1-~

106

130

638

13

1-V2

121

131

1014

14

1-~

121

138

746

15

2

126

138

1312

16

1- 89

126

135

1014

17

1

121

140

98O

18

1

119

134

608

123 •

136 •

Means • SD* *Standard deviation.

768 • 227

Volume 71 Number 2

Acute symptomatic hyponatremia

tonicities of the infused solutions (Table V ) . These changes occurred because the renal excretion and extrarenal losses of water and electrolyte were small during the infusion periods, making the retentions of water and electrolyte proportional to the rates of administration of these substances. Other studies on infants with hypotonic dehydration have shown that rapid infusion of isotonic solutions causes a slight increase in plasma osmolality, whereas similar administration of hypotonic solutions causes a fall in effective plasma osmolality. This is shown diagrammatically in Fig. 1 in which changes in effective plasma osmolality in hyponatremic children are compared following 1 to 2 hour infusions of hypertonic, isotonic, and hypotonic solutions. The effect of the retained solute on

Rate o[ in[usior~ (mEq./Kg. (ml./Kg. per hour) per hour)

plasma osmolality is plotted upward from the baseline while the effect of the retained water is indicated by the stippled areas plotted down from the top. The alterations in plasma sodium concentration, and in effective plasma osmolality, are the result of the opposing effects of solute balance relative to water balance. The increase in effective osmolality of extracellular fluids resulting from hypertonic infusions leads to an osmotic transfer of water out of the cells as osmotic equilibrium is approached by body fluids2 ~, 66 Data bearing directly on the redistribution of body water in response to hypertonic infusions were obtained from the study of plasma and red blood cell water in 12 of the 18 children treated for symptomatic hyponatremia. These

Volume in[used (ml./Kg.)

Sodium balance (mEq./Kg.)

Water balance (Gm./Kg.)

14

8

21

9

0

9

7

9

7

7

I1

13

11

13

6

8

4

13

6

7

14

11

14

11

9

I0

6

10

6

6

8

6

10

6

2

8

5

12

7

9

8

5

9

6

1 8 0

13

8

13

7

7

4

14

7

16

10

20

16

7

7

10

0

12

12

16

9

10

4

6

9

4

4

5

0

9

9

9

-6

17

10

17

10

10.+

8 +

277

12_+

7_+2

5.+5

278

Varavithya and Hellerstein

The Journal o{ Pediatrics August 1967

Table VI. Alterations in plasma and red-blood-cell water (per 100 ml. whole blood) ~

Patient

A[mOsm.] ~e.,,~cTlv~, mOsm./Kg.

A Weight Gm/I.25 Kg.

I I

3 5 6 7 8 9 10 12 13 14 17 18

39 28 23 20 21 16 16 43 43 39 29 30

7.5 11.3 7.5 2.5 11.3 1.3 10.0 20.0 0 --7.5 12.5

14.7 23.3 9.0 4.1 12.0 7.8 11.2 21.9 12.0 4.3 19.2 8.3

-4.7 -2.2 -1.9 -I.0 -0.7 -2.5 -0.5 -4.4 -1.7 -2.2 -3.3 -1.5

M e a n -+ SD

29 -+ 10

6.9 +- 7.5

12.3 +- 6.4

- 2 . 2 + 1.3

A

Plasma H~O I A RBC H~O Gm./lO0 Gin. Whole Blood

"~'Abrupt increases in effective plasma osmolality (A [mOsm.] NrFEO'rlVJ~) cause a transfer of water from the cells into the extracellular volume. Taking blood volumes as 100 ml. per 1.25 Kg. prior to the hypertonic infusion, the increase in plasma volume (A plasma H.~O) was greater than the sum of the water retained (A weight) plus the shift of water out of red blood cells (A RBC H.~O).

o.;cow -10

k

HYPOTONIC

Fig. 1. The effect of retained water and solute

or~ body composition.

data are presented in Table VI. For the calculations, the initial blood volumes were taken as 80 ml. per kilogram, so 1.25 Kg. of body weight was associated with 100 ml. of whole blood. It was assumed that the absolute amounts of plasma solids and red blood cell solids did not change during the infusions. Calculations were made from initial and final measurements of plasma and red blood cell solids and from the initial hematocrit. A specific gravity of 1.10 was assumed for the red blood cells. The total weight increase in these patients amounted to 6.9 • 7.5 Gm. per 1.25 Kg. of body weight while the increase in plasma water exceeded this, amounting to 12.3 +_ 6.4

Gin. per 1.25 Kg. (Table V I ) . This means that an internal source, presumably the cells, provided some of the water added to plasma in response to the increase in effective plasma osmolality. Similar increases in water occurred through the entire extracellular space, so the total increase in extracellular water must have been several times as great as that calculated for plasma. The abrupt increase in effective osmolality of extracellular fluids caused an osmotic transfer of water out of the cells. The concentration of solutes in cell water was increased while the volume of extracellular fluid was expanded. The changes in red blood cell water were relatively slight, indicating that red blood cells achieve osmotic equilibrium in vivo by shift of both water and solute. 67-~~ Although both the water and the solute content of brain cells may be altered in response to changes in body fluid osmolality, there is little data on this feature during treatment of symptomatic hyponatremia. 71-75 Muscle cells achieve osmotic equilibrium by transfer of water alone. TM Since muscle tissue usually accounts for the major mass of body cells, muscle cells are probably the major source of fluid for expansion of extracellular volume in response

Volume 71

Acute symptomatic hyponatremia

2 79

Number 2

to hypertonic infusions. 77 The probable effects of hypertonic infusions on the distribution of body water are shown in Fig. 2. CLINICAL SUMMARIES Children with symptomatic hyponatremia.

Patient No. 4. This 3-year-old Negr o boy was admitted with meningitis due to H. influenzae. He was acutely ill, lethargic, and mildly dehydrated. His sensorium seemed more obtunded after a 12 hour period during which he received 730 ml. of an intravenous mixture containing sodium at a concentration of about 75 mEq. per liter. The presumptive diagnosis of SAH was supported by laboratory data. The plasma Na = 122 mEq. per liter, K = 5.2 mEq. per liter, C1 = 94 mEq. per liter, CO2-content = 17.1 raM. per liter, sugar = 318 rag. per cent, urea N = 9 mg. per cent, and total solute concentration = 260 mOsm. per kilogram. At this time the urine specific gravity

"~

was 1.028 and the total urine solute concentration = 674 mOsm. per kilogram. Following administration of hypertonic NaCI, he became alert and responded to verbal stimuli. His subsequent course was uneventful. Patient No. 8. This 10-month-old Caucasian girl had a history of a high fever and draining ears of three days' duration. She had been treated for meningitis due to H. influenzae six weeks prior to the present illness. On admission she was cyanotic and dyspneic. Her heart rate was 160 per minute. Her lungs were clear by clinical and roentgen examinations and her heart was of normal size. Despite treatment with oxygen, antibiotics, and the usual maintenance fluids, her condition remained critical. The plasma chemistries, 22 hours after admission, were: Na = 131 mEq. per liter, K = 7.4 mEq. per liter, C1 ---- 93 mEq. per liter, CO2-content = 16 mM. per liter, sugar = 72 mg. per cent, and urea N = 32 mg. per cent. Hyper-

HYPERTON IC ~I INFUSION ~---.

HYPERTONIC INFUSION

PLASM~

EXTRACELLULAR

EXTRACELLULAR

WATER

WATER

WATER

PLASMA i W A T ER

CELL WATER

CELL WATER

RBC

RBC WATER

WATER

I=

INITIAL

FINAL

BLOOD

INITIAL

FINAL

WHOLE

BODY

Fig. 2. Alterations in body composition during hypertonic infusions.

2 80

Varavithya and Hellerstein

tonic NaC1 was given with no change evident. She died 16 hours later. The autopsy revealed fibrinopurulent pericarditis, the cause of which was not discovered. Patient No. 9. This 2-year-old Caucasian boy was admitted because of severe dehydration. At three and one half months of age bilateral subdural hematomas were found and later communicating hydrocephalus was diagnosed. He subsequently had a subarachnoid-ureteral shunt. Despite the oral intake of extra salt, he had numerous admissions because of hypotonic dehydration. On this occasion he was admitted following vomiting for eight hours. He was severely dehydrated, extremely lethargic, and pale. After initial hydration consisting of 40 ml. per kilogram of lactated Ringer's solution given over two hours, his circulation was improved, but he remained very lethargic. Initial plasma chemistries were: Na = 127 mEq. per liter, K ---= 5.6 mEq. per liter, C1 = 91 mEq. per liter, CO~-content = 17.4 mM. per liter, sugar = 111 mg. per cent, urea N = 47 mg. per cent, and total plasma solute = 289 mOsm. per kilogram. The initial urine had a specific gravity of 1.010, total solute concentration of 402 mOsm. per kilogram, Na = 88 mEq. per liter, K = 67 mEq. per liter, C1 = 84 mEq. per liter, and urea N = 315 mg. per cent. Following infusion of hypertonic NaC1 his pallor vanished and his state of consciousness was markedly improved. Intravenous fluids were discontinued after 48 hours and he was subsequently dismissed on a diet appropriate for his age plus supplementary sodium chloride. Patient No. I2. This 9-month-old Mexican boy had been followed in the outpatient clinic because of diarrhea. He was given low solute fluids with some improvement. Upon starting solids he developed severe diarrhea which persisted for the week prior to admission. Upon admission he was pale, lethargic, and had poor skin turgot. Parenteral fluid therapy was initiated with a hydrating solution which contained 75 mEq. of Na per liter. The initial plasma chemistries were: Na = 113 mEq. per liter, K = 3.9 mEq. per liter, C1 =- 69 mEq. per liter, CO2-

The Journal o[ Pediatrics August 1967

content = 12.7 mM. per liter, sugar = 190 mg. per cent, urea N --- 85 mg. per cent, and total plasma solute -- 254 mOsm. per kilogram. At the end of one hour, after receiving 25 ml. per kilogram of the initial hydrating solution, he appeared more lethargic. Blood was again obtained and the intravenous infusion changed to hypertonic NaCI. The second blood sample showed: Plasma Na = 106 mEq. per liter, K = 2.4 mEq. per liter, C1 = 67 mEq. per liter, CO~-content = 18.4 mM. per liter, urea N = 73 rag. per cent, sugar = 245 mg. per cent, and total plasma solute -- 250 mOsm. per kilogram. By the time the hypertonic infusion was absorbed his color was markedly improved, he was alert, cried, recognized, and was soothed by his parents. He ran a high fever, developed r~les in both lungs, and died eight hours later. Postmortem examination revealed generalized interstitial pneumonia and bilateral renal tubular necrosis. Patient No. 13. This 2-year-old Mexican boy was transferred from another hospital with a presumptive diagnosis of lead intoxication. Vomiting and diarrhea had been present for 10 days. There was a history of eating plaster which was confirmed by roentgenographic evidence of opaque material in the intestine. Prior to transfer he had received a hypodermoclysis of 500 ml. of a solution containing 54 mEq. per liter of Na, 25 mEq. per liter of K, and 50 mEq. per liter of CI. On admission he was lethargic and pale. The plasma chemistries were: Na = 121 mEq. per liter, K = 5.3 mEq. per liter, C1 -= 82 mEq. per liter, CO2-content = 22.5 raM. per liter, sugar = 163 rag. per cent, urea N = 29 rag. per cent, and total plasma solute = 240 mOsm. per kilogram. The urine specific gravity was 1.004, total solute concentration = 153 mOsm. per kilogram, Na -= 8 mEq; per liter, K = 21 mEq. per liter, CI ----= 13 mEq. per liter, and urea N = 360 rag. per cent. He had good response to administration of hypertonic NaCI and made a satisfactory recovery. The blood lead level was 50 /~g per liter. Patient No. 15. This 8 ~ - m o n t h - o l d Caucasian boy was transferred to this hospital

Volume 71 Number 2

with a confirmed diagnosis of pneumococcal meningitis. H e had received 500 ml. of 5 per cent dextrose in water over the 7 ~ hour period prior to admission and had one grand mal convulsion. O n admission the infant was well hydrated, comatose, opisthotonie, and pale. T h e plasma chemistries were: N a = 126 mEq. per liter, K = 7.7 mEq. per liter, C1 = 83 mEq. per liter, CO2-content = 25.9 m M . per liter, sugar = 75 mg. per cent, urea N = 13 mg. per cent, and total solute concentration = 238 mOsm. per kilogram. There were 61 ml. of urine in the bladder. T h e specific gravity was 1.024, total solute concentration = 570 mOsm. per kilogram, N a ---= 64 mEq. per liter, K = 58 mEq. per liter, C1 = 48 mEq. per liter, and urea = 710 mg. per cent. H e had a fair response to the administration of hypertonic NaCI with improvement in color, disappearance of opisthotonos, and lightening of his comatose state. H e had a second convulsion ten hours after admission which was not related to hyponatremia. After a few stormy days, he made a satisfactory recovery. He appeared to be entirely normal at follow-up visits at 13 and 20 months of age. Patient No. 18. This 5-month-old Caucasian boy was admitted with a 1 week history of diarrhea and vomiting. H e was severely dehydrated, weak, lethargic, and pale. He was initially hydrated with lactated Ringer's solution, 40 ml. per kilogram in one and one quarter hours. After the initial infusion his circulation was improved and he had good urinary output, but the pallor and lethargy persisted. Admission plasma chemistries were: N a = 118 mEq. per liter, K = 4.8 mEq. per liter, C1 = 94 mEq. per liter, CO2content = 6.9 m M . per liter, sugar = 79 mg. per cent, urea N = 10 mg. per cent, and total solute concentration = 261 mOsm. per kilogram. During the infusion of lactated Ringer's solution, 10 ml. of urine was collected by catheter. T h e specific gravity was 1.012, total solute concentration 405 mOsm. per kilogram, N a = 3 mEq. per liter; K ---2.9 mEq: per liter, C1 = 29 mEq. per liter; and urea N = 580 rag. per cent. Following infusion of hypertonlc NaCI his pallor van-

Acute symptomatic hyponatremia

28 1

ished and he became alert and responsive. His subsequent course was uneventful. SUMMARY

T h e major clinical value of a plasma sodium determination is its reliability as an indicator for the concentration of body fluids. Plasma sodium concentrations may be low as a result of several different physiological adjustments. Asymptomatic acute hyponatremia is usually self-limited, occurring during severe infections, after surgery, and following trauma. Acute hyponatremia with dehydration results from the loss of body solute out of proportion to the loss of body water. T h e clinical features are those of extracellular fluid depletion. Symptomatic hyponatremia may occur as a complication of either acute or chronic hyponatremia. It is characterized by central nervous system symptoms and pallor, both of which respond promptly to infusion of a suitable hypertonic solution. T h e outstanding features of acute symptomatic hyponatremia in 17 pediatric patients were lethargy, convulsions, and marked pallor. These patients had satisfactory clinical and biochemical responses to infusions of solutions containing sodium at concentrations from 500 to 1,300 mEq. per liter. REFERENCES

1. Wynn, V., and Rob, C. G.: Water intoxication. Differential diagnosis of the hypotonic syndromes, Lancet I: 587, 1954. 2. Wynn, V.: Water intoxication and serum hypotonicity, Metabolism 5: 490, 1956. 3. Edelman, I. S.: The pathogenesis of hyponatremia: Physiologic and therapeutic implications, Metabolism 5: 500, 1956. 4. Elkinton, J. R.: tIyponatremia: Clinical state or biochemical sign, Circulation XIV: 1027, 1956. 5. Orloff, J., Walser, M., Kennedy, T. J., Jr., and Bartter, F. C.: Hyponatremia, Circulation XIX: 284, 1959. 6. Orloff, J., and Burg, B. B.: The pathogenesis of hyponatremia in congestive heart failure, in Friedberg, C. K., editor: Heart, kidney and electrolytes, New York, 1962, Grune and Stratton, Inc. 7. Mattty, R. H., and Edelman, I. S.: The role of sodium, potassium, and water in the hypoosmotic states of heart failure, in Friedberg, C. K., editor: Heart, kidney and electrolytes, New York, 1962, Grune and Stratton, Inc.

282

Varav~thya and Helierstein

8. Leaf, A.: The clinical and physiologic significance of the serum sodium concentration, New England J. Med. 267: 24, 77, 1962. 9. Bartter, F. C.: Regulation of the volume and composition of extracellular and intracellular fluid, Ann. New York Acad. Sc. 110: 682, 1963. I0. Berliner, R. W.: The regulation of water balance and plasma sodium concentration, Arch. Int. Med. 102: 986, 1958. 11. Pitts, R. F.: Physiology of the kidney and body fluids, Chicago, 1963, Year Book Medical Publishers, Inc. 12. Wolf, A. V.: Aqueous Solutions and Body Fluids, New York, 1966, Harper and Row, Publishers. 13. Albrink, M. F., Hald, P. M., Man, E. B., and Peters, J. P.: The displacement of serum water by the lipids of hyperlipemic serum. A new method for the rapid determination of serum water~ J. Clin. Invest. 34: 1483, 1955. 14. Sunderman, F. W., and Williams, E. S.: Studies in serum electrolytes. IX. The change in total quantity and osmolal concentration of glucose and chloride in the serum after the ingestion of glucose by diabetic patients, J. Clin. Invest. 14: 245, 1935. 15. Wynn, V.: Electrolyte disturbances asociated with failure to metabolise glucose during hypothermia, Lancet 2: 575, 1954. 16. Wright, H. K., and Gann, D. S.: Hyperglycemic hyponatremia in nondiabetie patients, Arch. Intl Med. 112: 344, 1963. 17. Dodge, P. R., Crawford, J. D., and Probst, J. H.: Studies in experimental water intoxication, Arch. Neurol. 5: 513, 1960. i8. Wise, Burton, L.: Effects of infusion of hypertonic mannitol on electrolyte balance and on osmolarity of serum and cerebrospinal fluid, J. Neurosurg. 20: 961, 1963. 19. Darling, R. C., di Sant'Agnese, P. A., Perera, G. A., and Andersen, D. H.: Electrolyte abnormalities of the sweat in fibrocystie disease of the pancreas, Am. J. M. Sc. 225: 67, 1953. 20. Kessler, W. R., and Andersen, D. H.: Heat prostration in fibrocystie disease of the pancreas and other conditions, Pediatrics 8: 648, 1951. 21. Barbero, G. J., and Sibringa, M. S.: The electrolyte abnormality in cystic fibrosis, Pediat. Clin. North America I1: 983, 1964. 22. Corm, J. W.: Aldosteronism in man, J. A. M. A. 183: 775, 1963. 23. Reeves, J. E.: Acute renal tubular necrosis due to water intoxication, California Med. 104: 203, 1966. 24. Williams, A., and Robinson, M. J.: Addison's disease in infancy, Arch. Dis. Childhood 31: 265, 1956. 25. Scherz, R. G., and Geppert, L. J.: Recognition and treatment of adrenal crises in the newborn infant, J. PEDIAT. 53: 645, 1958. 26. Bongiovanni, A. M.: Fluid therapy in adrenocortical failure, Pediat. Clin. North America I1: 971, 1964. 27. Matson, Donald D.: Hydrocephalus treated

The Journal o/ Pediatrics August 1967

28. 29. 30. 31.

32. 33. 34.

35. 36.

37.

38. 39. 40.

41.

42.

43.

44.

45.

by arachnoid-ureterostomy; report of 50 cases, Pediatrics 12: 326, 1953. Bewley, T. H.: Acute water-intoxication from compulsive water-drinking, Brit. M. J. 2: 864, 1964. Richards, M. R., and Hiatt, R. B.: Untoward effects of enemata in congenital megacolon, Pediatrics 12: 253, 1953. Ziskind, A., and Gellis, S. S.: Water intoxication following tapwater enemas, Am. J. Dis. Child. 96: 699, 1958. Crawford, J. D., and Dodge, P. R.: Complications of fluid therapy in neurologic disease, Pediat. Clin. North America 11: 1029, 1964. Whalley, P. J., and Pritchard, J. A.: Oxytocin and water intoxication, J. A. M. A. 186: 601, 1963. King, T. M,, and Hall, D. G.: Water intoxication in obstetrics, Missouri Medicine 63: 359, 1966. Buhler, U. K., Savary, A., Krauer, B., and Stalder, G. R.: Water intoxication in a cretinoid infant, J. Clin. Endocrinol. 26: 11t, 1966. Aitstatt, Leslie B.: TransplacentaI hyponatrem[a in the newborn infant, J. PEDIAT, 66: 985, i965. Darrow, D. C., and Hartmann, A. F.: Chemical changes occurring in the body as a result of certain diseases. IV. Primary pneumonia in children, Am. J. Dis. Child. 37: 323, 1929. Nyhan, W. L., and Cooke, R. E.: Symptomatic hyponatremia in acute infections of the central nervous system, Pediatrics 18: 604, 1956. Gonzalez, C. F., Finberg, L., and Bluestein, D. D.: Electrolyte concentration during acute infections, Am. J. Dis. Child. 107: 476, 1964. Finberg, L., and Gonzalez, C.: Experimental studies on the hyponatremia of acute infections, Metabolism 14: 693, 1965. Mangos, J. A., and Lobeck, C. C.: Studies of sustained hyponatremia due to central nervous system infection, Pediatrics 34: 503, 1964. Posner, J. B., Kossmann, R. J., and Scheinberg, L. C.: Hyponatremia in acute polyneuropathy, Trans. Am. Neurol. A. 90: 67, 1965. Moran, W. H., Jr., Miltenberger, F. W., Shuayb, W. A., and Zimmermann, B.: The relationship of antidiuretic hormone secretion to surgical stress, Surgery 56: 99, 1964. Ariel, I. M.: Effects of a water load administered to patients during the immediate postoperative period, Arch. Surgery 62: 303, 195I. Wynn, V., and Houghton, B. J.: Observations in man upon the osmotic behavior of the body cells after trauma, Quart. J. Med. XXVI: 375, 1957. Scott, J. C., Jr., Welch, J. S., and Berman, I. B.: Water intoxication and sodium depletion in surgical patients, Obst. & Gynee. 26: 168, 1965.

Volume 71 Number 2

Acute symptomatic hyponatremia

46. McLaurin, R. L.: Metabolic changes accompanying head injury, Clin. Neurosurg. 12: 143, 1964. 47. Knochel, J. P., Osborn, J. R., and Cooper, E. B.: Excretion of aldosterone in inappropriate secretion of antidiuretic hormone following head trauma~ Metabolism 14: 714, 1965. 48. Joynt, R. J., Afifi, A., and Harbison, J.: Hyponatremia in subarachnoid hemorrhage, Arch. Neurol. 13: 633, 1965. 49. Stormont, J. M., and Waterhouse, C.: The genesis of hyponatremia associated with marked overhydration and water intoxication, Circulation XXIV: 191, 1961. 50. McCance, R. A.: Experimental sodium chloride deficiency in man, Proc. Royal Soc. London 119: 245, 1935. 51. Nadal, J. W., Pedersen, S., and Maddock, W. G.: A comparison between dehydration from salt loss and from water deprivation, J. Clin. Invest. 20: 691, 1941. 52. Hopper, J., Jr., Elkinton, J. R., and Winkler, A. W.: Plasma volume of dogs in dehydration, with and without salt loss, J. Clin. Invest. 23: 111, 1944. 53. Elkinton, J. R., Danowski, T. S., and Winkler, A. W.: Hemodynamic changes in salt depletion and in dehydration, J. Clin. Invest. 25: 120, 1946. 54. Elkinton, J. R., Winkler, A. W., and Danowski, T. S.: The importance of volume and of tonicity of the body fluids in salt depletion shock, J. Clin. Invest. 26: 1002, 1947. 55. Darrow, D. C., and Yannet, H.: The changes in the distribution of body water accompanying increase and decrease in extracellular electrolyte, J. Clin. Invest. 14: 266, 1935. 56. Darrow, D. C., and Yannet, H.: Metabolic studies of the changes in body electrolyte and distribution of body water induced experimentally by deficit of extracellular electrolyte, J. Clin. Invest. 15: 419, 1936. 57. Hellerstein, S.: Dehydration in infants and children, General Practice. In press. 58. Weir, J. F., Larson, E. E., and Rowntree, L. G.: Studies in diabetes insipidus, water balance, and water intoxication, Arch. Int. Med. 29: 306, 1922. 59. Rowntree, L. G.: The effects on mammals of the administration of excessive quantities of water, J. Pharmacol. & Exper. Ther. 29: 135, 1926. 60. Helwig, F. C., Sehutz, C. B., and Curry, D. E.: Water intoxication, J. A. M. A. 104: 1569, 1935. 61. Baskin, J. L., Keith, H. M., and Scribner, B. H.: Water metabolism in water intoxication, Am. J. Dis. Child. 83: 618, 1952. 62. Edelman, I. S., Leibman, J., O'Meara, M. P., and Birkenfeld, L. W.: Interrelations be-

tween serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water, J. Clin. Invest. 37: 1236, 1958. Finberg, L.: Dehydration in infants and children, New England J. Med. 276: 458, 1967. Friis-Hansen, Bent: Changes in body water compartments during growth, Copenhagen, i956, Ejnar Munksgaard Forlag. Wynn, V.: The osmotic behavior of the body cells in man. Significance of changes of plasma-electrolyte levels in body-fluid disorders, Lancet 2: 1212, 1957. Robinson, J. R.: Metabolism of intracellular water, Physiol. Rev. 40:112, 1960. Yannet, H., Darrow, D. C., and Cary, M. K.: The effect of changes in the concentration of plasma electrolytes on the concentration of electrolytes in the red blood cells of dogs, monkeys, and rabbits, J. Biol. Chem. 112: 477, 1936. McCance, R. A.: The changes in the plasma and cells during experimental human salt deficiency, Biochem. J. 31: 278, 1937. Kim, J., Borges, W. H., and Holliday, M. A.: Correlation between RBC osmotic fragility and serum sodium, Am. J. Dis. Child. 104: t05, 1962. Hellerstein, S., Varavithya, W., and Graddy, D.: Plasma and red blood cell water and solute, Am. J. Dis. Child. I12: 298, 1966. Yannet, H.: Changes in the brain resulting from depletion of extracellular electrolytes, Am. J. Physiol. 128: 683, 1940. Finberg, L., Luttrell, C., and Redd, H.: Pathogenesis of lesions in the nervous system in hypernatremic states. II. Experimental studies of gross anatomic changes and alterations of chemical composition of the tissues, Pediatrics 23: 46, 1959. Sotos, J. F., Dodge, P. R., Meara, P., and Talbot, N. B.: Studies in experimental hypertonicity. I. Pathogenesis of the clinical syndrome, biochemical abnormalities and cause of death, Pediatrics 26: 925, 1960. Van Harreveld, A., Collewijn, H., and Malhotra, S. K.: Water, electrolytes, and extracellular space in hydrated and dehydrated brains, Am. J. Physiol. 210: 251, 1966. Holliday, M. A., Chan, H., and Harrah, J. Hypotonicity--its effect upon muscles, brain, and red cells as a function of time, Proceedings of the American Pediatric Society 76th Annual Meeting, Atlantic City, N. J., April, 1966. Pitcavage, J., Borges, W. H., and Holliday, M. A.: A relation between cell water and serum sodium, Am. J. Dis. Child. 104: 276, 1962. Darrow, D. C., and Hellerstein, S.: Interpretation of certain changes in body water and electrolytes, Psysiol. Rev. 38: 141, 1958.

63. 64. 65.

66. 67.

68. 69.

70. 71. 72.

73.

74.

75.

76.

77.

283