Fluid and Electrolyte Therapy

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Hypernatremia

Susan B. Conley, MD*

Under normal conditions, serum sodium concentration is tightly regulated between 135 and 145 mEq per liter. Hypernatremia is present when the serum sodium concentration exceeds 150 mEq per liter. Clinical consequences are often severe when the sodium concentration increases above 160 mEq per liter.23 Hypernatremia reflects a deficiency of water relative to total body sodium content and is usually a disorder of water balance rather than of sodium balance. Because water moves freely across cell membranes in response to osmotic gradients to maintain osmotic equilibrium, hypernatremia reflects the increased concentration of solutes throughout body fluids. Hypernatremia does not indicate total body sodium content, which can be high, low, or normal depending on the cause of the hypernatremia and total body water content. Hypertonicity, the increased concentration of osmotically active solutes in body fluids, results from hypernatremia and stimulates the secretion of antidiuretic hormone (ADH) followed by the sensation of thirst, which is stimulated at a slightly higher level of serum osmolality than is ADH secretion?5.29 ADH modulates water reabsorption in the cortical-collecting duct, increasing urine concentration and decreasing urine volume. ADH is released from the posterior pituitary gland in response to stimulation of the osmoreceptors of the anterior hypothalamus or in response to a decrease in blood volume, which has been sensed by left atrial volume receptors. The nonosmotic (volume) receptors over-ride osmoreceptors to cause ADH release even when volume contraction is accompanied by hypotonicity. They are slow to respond compared with osmoreceptors. Hypertonicity is not quite the same as hyperosmolality. Hypertonicity results from an increase in the concentration of solutes that do not cross cell membranes to enter the cell. Hypernatremia is the most frequent cause of hypertonicity. Mannitol, which crosses cell membranes slowly, is a less frequent cause of hypertonicity. Hyperosmolality, which may be present without hypertonicity, can be caused by an increased concentration in body fluids of solutes such as urea or alcohol, which freely cross cell membranes, or by an increased concentration of solutes such as sodium, which do not. Hyperosmolality without hypertonicity is a weak stimulus of ADH secretion and thirst?9 Hypertonicity causes a shift of water from the intracellular to the extracellular compartment, resulting in cellular dehydration. In hyperosmolarity without hyper-

*Associate Professor of Pediatrics,

Director, Division of Pediatric Nephrology, The University of Texas Medical School at Houston, Houston, Texas

Pediatric Clinics of North America-Vol. 37, No.2, April 1990

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tonicity, intracellular and extracellular compartments remain proportionate. In hypernatremic dehydration, the extracellular fluid volume and plasma volume are relatively preserved, and the typical signs of dehydration such as decreased skin turgor, tachycardia, and hypotension are less pronounced than would be seen in the patient with a similar degree of hyponatremic or isonatremic dehydration. Thirst is more important as a defense against hypernatremia and hypertonicity than is the secretion of ADH. ADH release begins when plasma osmolality rises above 280 mOsm per kg and is the first line of defense against hypernatremia and hypertonicity. If plasma tonicity remains high despite ADH secretion, the awake, alert patient will be thirsty and increase water intake to compensate for the lack of ADH effect and to maintain normal tonicity. 25, 29 Patients with inability to secrete ADH or who have intrinsic renal disease preventing renal response to ADH do not usually develop hypernatremia provided they have free access to water. Infants who cannot obtain water for themselves, comatose patients, and patients with a central nervous system (CNS) lesion affecting the thirst center are most prone to hypernatremia. 1 Hypernatremia can be the result of pure sodium excess (rare), of water deficit or of water deficit coupled with a lesser degree of sodium deficit such as occurs with abnormal hypotonic fluid losses (e.g., diarrhea).

SODIUM EXCESS Pure sodium excess, or salt poisoning, is unusual but has been reported as a result of feeding improperly mixed high-sodium rehydration solutions or formulas to infants' or to older patients who cannot access water for some reason (e.g., coma or paralysis) or as a result of the excessive administration of sodium bicarbonate during resuscitative efforts. The newborn infant, whose ability to excrete a sodium load is less than that of the older infant or child, is particularly at risk from the administration of large quantities of sodium. Excess sodium administration causes fluid to move from the intracellular to the extracellular space so that severe sodium overdoses can result in pulmonary edema, One infant with end-stage renal disease seen by the author received an improperly mixed nasogastric tube feeding formula containing 190 mEq per liter sodium, and developed hypernatremia, hypervolemia, pulmonary edema, and seizures. Table 1. Causes of Hypernatremia Sodium excess Improperly mixed formula or rehydration solution Excessive sodium bicarbonate administration during resuscitation Ingestion of sea water (480 mEq/L) Water deficit Central diabetes insipidus (see Table 2) Nephrogenic diabetes insipidus (see Table 3) Diabetes mellitus Excessive sweating Increased insensible water loss (e.g., newborn on a radiant warmer) Inadequate access to water Lack of thirst (adipsia) Water deficit in excess of sodium deficit Diarrhea Osmotic diuretics Diabetes mellitus Obstructive uropathy Renal dysplasia

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Table 2. Causes of Central Diabetes Insipidus Idiopathic Head trauma Suprasellar or infrasellar tumors (e.g., craniopharyngioma, pinealoma) Granulomatous disease Sarcoid Tuberculosis Wegener's granulomatosis

Histiocytosis Sickle cell disease Cerebral hemorrhage Infection Meningitis Encephalitis Associated with cleft lip and palate

WATER DEFICIT Pure renal water losses can occur secondary to central diabetes insipidus (DI) or to nephrogenic diabetes insipidus (NDI). In central DI the posterior pituitary fails to secrete ADH, and in NDI the collecting duct is resistant to the effect of ADH. Causes of DI and NDI are given in Tables 2 and 3. In both DI and NDI, hypernatremia does not usually occur unless access to water is restricted. In both DI and NDI the urine is dilute; urine sodium is variable, dependent on intake and whether extracellular fluid (ECF) volume depletion is also present. With isolated increased water losses, such as can occur with excessive sweating, fever, sustained hyperventilation, or increased environmental temperature, urine is concentrated and the urine sodium concentration generally low. Inadequate water intake, secondary to lack of availability or to inappropriately absent thirst, presents the same clinical picture as does the excessive, unreplaced extrarenal loss of water. Water deprivation has been reported as a form of child abuse. 24 Multiple examples of patients with adipsia can be found in the literature!6 some of whom have demonstrable hypothalamic lesions such as an ectopic pinealoma or histiocytosis. 18, 19 At least five young children have been reported with primary adipsia. 5, 6, 8, 15, 27 Adipsia has also been reported with hydrocephalus 16 and after head trauma. 14 A child with congenital dysplasia of midline brain structures also had defective osmoregulation of ADH secretion, such that ADH was not released until plasma osmolality rose above 310 mOsm per kg.28

HYPOTONIC FLUID LOSSES The excessive loss of hypotonic fluid without adequate water intake is the most common cause of hypernatremia and hypernatremic dehydration in the pediatric patient, In this situation total body sodium content is decreased, but total body water content is decreased even further. Diarrhea (average diarrheal fluid sodium Table 3. Secondary Causes of Nephrogenic Diabetes Insipidus Congenital (familial) Renal disease Obstructive uropathy Renal dysplasia Medullary cystic disease Reflux nephropathy Polycystic disease Systemic disease with renal involvement Sickle cell disease Sarcoidosis Amyloidosis

Drugs Amphotericin Phenytoin Lithium Aminoglycosides Methoxyflurane

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content 30 to 65 mEq per liter, higher in cholera) is the most common cause of hypotonic fluid losses in children.23 Diarrhea most often results in isonatremic or hyponatremic dehydration, but if fluid intake is low or if vomiting occurs at the same time, hypernatremic dehydration may result. Because infants have high maintenance water requirements related to their large surface area for size, hypernatremic dehydration develops during episodes of diarrhea more frequently in infants than in older children. The administration of orallactulose, which is used in hepatic failure and for constipation and which induces watery diarrhea, has been associated with hypernatremic dehydration. 22 The patient with hypernatremic dehydration secondary to hypotonic fluid losses has concentrated urine with a low urine sodium content (concentration less than 10 mEq per liter). Infants and children with congenital renal disease, such as obstructive uropathy or renal dysplasia, have tubular dysfunction and are unable to concentrate the urine. Their urine osmolality may be fixed between 200 and 300 mOsm per kg with urine sodium concentration between 60 and 100 mEq per liter. These children when faced with diarrhea or vomiting, especially when coupled with lack of access to water, may also develop hypernatremic dehydration. A few have secondary nephrogenic diabetes insipidus with dilute urine and are at risk of developing hypernatremia whenever they lack free access to water. Osmotic diuretics such as mannitol or glycerol can also induce hypernatremia secondary to excessive hypotonic urine flow, as can the glucose-driven osmotic diuresis of diabetes mellitus. In this situation, urine tends to be isosthenuric, and urine sodium concentration is high (greater than 20 mEq per liter), but is less than serum sodium concentration.

CLINICAL SIGNS OF HYPERNATREMIC DEHYDRATION Because sodium does not freely penetrate cell membranes, ECF and plasma volume tend to be maintained in hypernatremic dehydration until dehydration is severe (greater than 10 per cent loss of body weight). Shock is an infrequent occurrence. When the severity of dehydration results in loss of 10 per cent of body weight the skin turgor becomes reduced, and a characteristic "doughy" feel can be appreciated when the skin of the abdomen is pinched between the fingers. The child becomes irritable and may have a high-pitched cry or wail. Periods of lethargy may be interspersed with periods of irritability. As dehydration and hypernatremia become even more severe, coma, increased muscle tone, and eventually seizures may be noted. Fever can both be a contributing cause and a result ofhypernatremic dehydration. 10

CNS EFFECTS OF HYPERNATREMIA Hypernatremia can cause acute CNS dysfunction and even leave permanent CNS sequelae. Acute symptomatology is seen in most children with a serum sodium concentration of over 158 mEq liter. 23 Careful observations have been made of adult rabbits given intravenous hypertonic saline. Restlessness and irritability occur when serum osmolality increases to between 350 and 375 mOsm per kg secondary to hypernatremia. Ataxia and tremulousness occur when osmolality is between 375 and 400 mOsm per kg, and asynchronous jerks and tonic spasms occur when osmolality is above 400 mOsm per kg. Death usually occurs at an osmolality above 430 mOsm per kg. 7, 31 This progression is similar to that noted in children with hypernatremia. Acute CNS symptomatology correlates with the height of serum

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sodium concentration. Experience in human infants indicates, however, that the serum sodium concentration and the severity of the acute neurologic signs may not correlate with the degree of neurologic recovery. 20, 23 Permanent sequelae are not uncommon in children when serum sodium concentration reaches 160 mEq per liter. I~ one study, 16 of 100 children with hypernatremia who did not have preexisting CNS disease developed chronic neurologic deficits as a consequence of the hypernatremia. 20 In 8 of these 16 the neurologic deficits were contributing causes of death. The overall mortality of hypernatremia is about 10 per cent. Hypocalcemia is also frequently seen in hypernatremia and may contribute to CNS symptomatology. The mechanism of the hypocalcemia is unclear. Brain hemorrhage, either massive hemorrhage or multiple small hemorrhages and thromboses, may occur when hypernatremia causes cellular dehydration with resultant brain shrinkage and tearing of cerebral vessels. 2.11,13 This has been observed in neonates from the administration of an acute sodium load. 30 During the last 15 years pediatricians have become aware that they must limit the amount of sodium bicarbonate administered to acidotic infants. When hypernatremia is persistent, brain cellular dehydration may resolve, and brain water content may return to normal or near-normal levels. '7 This is believed to be due to the accumulation in brain cells of "idiogenic osmoles," which are amino acids, particularly taurine. Their formation increases intracellular osmolality, attracts water back into brain cells, and restores cellular volume. 33, 34 When hypertonicity develops gradually, this protective mechanism may prevent severe cell shrinkage and brain hemorrhage. In one study, Trachtman and colleagues 34 depleted kittens of taurine by restricting their diets and then gradually made them hypernatremic. They found that taurine depletion increased both the incidence of seizures and the mortality from hypernatremia. Brain cell water content was lower in taurinedepleted hypernatremic kittens than in taurine-replete hypernatremic kittens. They concluded that taurine is an important osmoprotective molecule, and that it constitutes 50 per cent of the adaptable intracellular osmolal pool ("idiogenic osmoles") that responds to increases in ECF tonicity. This protective response has significant implications for therapy and the speed with which hypernatremia should be corrected.

THERAPY When dehydration is severe and shock is present or imminent, then regardless of serum sodium concentration plasma volume should first be repleted with plasmaexpanding fluids such as normal saline, lactated Ringer's solution, 5 per cent albumin, or plasma, until blood pressure rises. Once perfusion is re-established, fluid containing 75 to 80 mEq per liter sodium should be given until the child has urine output. When the urine output is established, hypotonic fluids should be given with the aim of bringing serum sodium concentration down to normal and restoring normal hydration in no less than 48 hours. A rate of reduction of serum sodium concentration, 10 to 15 mEq per liter daily, is recommended. The degree of hypotonicity of the fluids is less important than the rate of correction. In determining what fluid to give at this point, Finberg12 recommends first calculating fluid deficit from the estimate of percentage dehydration or from acute weight loss. The fluid volume to be administered during 48 hours is fluid deficit plus maintenance needs, calculated by the usual rules. If the child has significant ongoing losses, these must also be included. Sodium to be given can be calculated as 80 to 100 mEq per liter of estimated fluid deficit. Maintenance sodium needs can be disregarded. Sodium is given primarily as chloride, depending on the degree of accompanying acidosis. Because of the predilection of children with hypernatremia

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to develop hyperglycemia, glucose may be given as a 2.5 per cent dextrose solution. Calcium gluconate may also be added, depending on serum calcium content. Once the child is urinating, 40 mEq per liter potassium chloride should be added to fluids. Potassium aids water entry into cells. Example: A l-year-old child whose usual weight is 10 kg presents with diarrhea, vomiting, and dehydration. The child now weighs 9 kg (10 per cent dehydration). He is alert and blood pressure is 85 over 50. Serum sodium concentration is 160 mEq per liter. His fluid deficit is therefore 1000 m!. During 48 hours, he should receive 3000 ml (1000 ml deficit plus about 2000 ml maintenance fluid) containing a total of 100 mEq of sodium (100 mEq per 1000 ml deficit). One hundred milliequivalents of sodium in 3000 ml means that he should receive fluid containing 30 to 35 mEq per liter sodium, in 2.5 per cent dextrose, administered at a rate of approximately 60 ml per hour. When urine output is observed, if serum potassium is normal 40 mEq per liter potassium should be added.

Unless the hypernatremia is of short duration, idiogenic osmoles are presumably present in brain cells and too rapid rehydration and lowering of serum sodium concentration will cause brain cells to swell, resulting in cerebral edema and increasing the likelihood of death or permanent neurologic sequelae. Serum electrolyte levels should be monitored frequently to ensure that the appropriate rate of decline of serum sodium concentration occurs. In the case of acute hypernatremia, correction of serum sodium concentration can be achieved rapidly because idiogenic osmoles will not yet be present in brain cells. Rapid fluid administration, however, in the patient with acute pure sodium excess (e.g., excessive sodium administration) may result in hypervolemia and pulmonary edema. In the child with severe sodium excess (i. e., massive salt poisoning) and a serum sodium concentration of more than 200 mEq per liter, peritoneal dialysis using a high-glucose (7.5 per cent), low-sodium dialysate may be life saving,21 but must be done with frequent monitoring of serum electrolyte levels. Whenever the duration of the hypernatremia is unclear, slow correction is recommended. Hypocalcemia is a common, unexplained finding in hypernatremia, and the addition of calcium gluconate to rehydration fluids is often indicated. Hyperglycemia may also accompany hypernatremia. 32 Insulin treatment is not recommended because it may increase brain "idiogenic osmole" content. 3 In the case of central diabetes insipidus, administration of vasopressin or 1deamino-(8-D-arginine)-vasopressin must be undertaken carefully and fluid intake regulated based on response so that the serum sodium concentration does not drop too rapidly.

SUMMARY Hypernatremia results when the water content of body fluids is deficient compared with sodium content. Hypernatremia can be the result of pure sodium excess but is usually associated with dehydration, secondary to excess losses of water or hypotonic fluids. Hypernatremic dehydration is less common than hyponatremic or isonatremic dehydration, but is associated with the highest morbidity and mortality rate, primarily related to CNS dysfunction. Except when hypernatremia has developed rapidly, the serum sodium concentration should be corrected slowly with frequent monitoring of serum electrolytes. Even then CNS damage can result, either as a consequence of the hypernatremia itself or of rapid lowering of the serum sodium concentration.

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REFERENCES 1. Arieff AI: Osmotic failure: Physiology and strategies for treatment. Hosp Pract ;173-194, 1988 2. Arieff AI, Guisado R: Effects on the central nervous system of hypernatremic and hyponatremic states. Kidney Int 10:104-116, 1976 3. Arieff AI, Kleeman CR: Studies on mechanisms of cerebral e~ema in diabetic comas: Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. J Clin Invest 52:571-583, 1973 4. Arneil GC, Chin KC: Lower-solute milks and reduction of hypernatremia in young Glasgow infants. Lancet 2:840--842, 1979 5. Blank MS, Farnsworth PB: Idiopathic symptomatic hypernatremia in a 9 year old boy: A clinical and physiological evaluation. J Pediatr 85:215-219, 1974 6. Conley SB, Brocklebank JT, Taylor IT, et al: Recurrent hypernatremia: A proposed mechanism in a patient with absence of thirst and abnormal excretion of water. J Pediatr 89:898-903, 1976 7. Dodge PR, Sotos JF, Gamstorp I, et al: Neurophysiologic disturbances in hypertonic dehydration. Trans Am Neurol Assoc 87:33-36, 1962 8. Dunger DB, Leonard JV, Wolf OH, et al: Effect of naloxone in a preViously undescribed hypothalamic syndrome. Lancet 1:1277-1279, 1980 9. Feig PD: Hypernatremia and hypertonic syndromes. Med Clin North Am 65:271-290, 1981 10. Finberg L: Hypernatremic dehydration. In Finberg L, Kravath RE, Fleischman AR (eds): Water and Electrolytes in Pediatrics. Philadelphia, WB Saunders, 1982, pp 78-89 11. Finberg L: Pathogenesis of lesions in the nervous system in hypernatremic states: I. Clinical observations of infants. Pediatrics 23:40-45, 1959 12. Finberg L: Therapeutic management ofhypernatremic dehydration. In Finberg L, Kravath PE, Fleischman AR (eds): Water and Electrolytes in Pediatrics. Philadelphia, WB Saunders, 1982, pp 129-135 13. Finberg L, Lutrell C, Redd H: Pathogenesis of the lesion in the central nervous system in hypernatremic stress: II. Experimental studies of gross anatomic changes and alterations of chemical composition of tissues. Pediatrics 23:46-53, 1959 14. Golonka JE, Richardson JA: Postconcussive hyperosmolality and deficient thirst. Am J Med 48:261-267, 1970 15. Hayek A, Peake GT: Hypothalamic adipsia without demonstrable structural lesion. Pediatrics 70:275-278, 1982 16. Hays RM, McHugh PR, Williams HE: Absence of thirst in association with hydrocephalus. N Engl J Med 269:227-231, 1963 17. Holliday MA, Kalayci MN, Harrah J: Factors that limit brain volume changes in response to acute and sustained hyper- and hyponatremia. J Clin Invest 47:1916-1928, 1968 18. Khomani-Asadi F, Norman ME, Parks JS, et al: Hypernatremia associated with pineal tumor. J Pediatr 90:605-606, 1977 19. Lascelles PT, Lewis PD: Hypodipsia and hypernatremia associated with hypothalamic and suprasellar lesions. Brain 95:249-264, 1972 20. Macaulay D, Watson M: Hypernatremia in infants as a cause of brain damage. Arch Dis Child 42:485--491, 1967 21. Miller NL, Finberg L: Peritoneal dialysis for salt poisoning. N Engl J Med 263:1347, 1960 22. Nelson DC, McGraw WRG, Hoyumpa AM: Hypernatremia and lactulose therapy. JAM A 249:1295-1298, 1983 23. Paneth N: Hypernatremic dehydration of infancy: An epidemiologic review. Am J Dis Child 134:785-792, 1980 24. Pickel S, Anderson C, Holliday MA: Thirsting and hypernatremic dehydration: A form of child abuse. Pediatrics 45:54-56, 1970 25. Robertson GL: Abnormalities of thirst regulation. Kidney Int 25:460-469, 1984 26. Robertson GL, Aycinena P, Zerbe RL: Neurogenic disorders of osmoregulation. Am J Med 72:339-353, 1982 27. Schaad D, Vassella F, Zuppinger K, et al: Hypodipsia-hypernatremia syndrome. Helv Paediatr Acta 34:63-76, 1974

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28. Schaff-Blass E, Robertson GL, Rosenfield RL: Chronic hypernatremia from a congenital defect in osmoregulation of thirst and vasopressin. J Pediatr 102:703-708, 1983 29. Schrier RW, Berl J, Anderson RJ: Osmotic and nonosmotic control of vasopressin release. Am J Physiol 236:F321-F332, 1979 30. Simmons MA, Adcock EW, Bard H, et al: Hypernatremia and intracranial hemorrhage in neonates. N Engl J Med 291:6-10, 1974 31. Sotos JF, Dodge PR, Meara P, et al: Studies in experimental hypertonicity: I. Pathogenesis of the clinical syndrome, biochemical abnormalities and cause of death. Pediatrics 26:925-937, 1960 32. Stevenson RE, Bowyer FP: Hyperglycemia with hyperosmolal dehydration in nondiabetic infants. J Pediatr 77:818-823, 1970 33. Thurston JH, Hauhart RE, Dirgo JA: Taurine: A role in osmotic regulation of mammalian brain and possible clinical significance. Life Sci 26:1561-1568, 1980 34. Trachtman H, Barbour R, Sturman JA, et al: Taurine and osmoregulation: Taurine is a cerebral osmoprotective molecule in chronic hypernatremic dehydration. Pediatr Res 23:35-39, 1988

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