Serum Sodium Abnormalities in Children

Symposium on Pediatric Nephrology

Serum Sodium Abnormalities in Children Alan B. Gruskin, M.D.,* H. jorge Baluarte, M.D.,t james W. Prebis, M.D.,+ Martin S. Polinsky, M.D.§ Bruce Z. Morgenstern, M.D.,II and Sharon A. Perlman, M.D.~

Even though multiple mechanisms operate to maintain the serum sodium concentration within a narrow range, serum sodium concentration is frequently abnorm1;1l in hospitalized children. Nine combinations define the relationship between the serum sodium concentration and total body water (Fig. 1): One is normal; six have an altered sodium to water ratio; and two reflect iso-osmotic gains or losses. This review will initially focus on defining terms clinically useful in categorizing such disorders and on providing an overview of the physiology of sodium and water homeostasis. Subsequently, the recognition and treatment of disorders associated with an abnormal serum sodium will be considered. Definitions of the terms to be used follow: Sodium concentration: The ratio of the number of ions of sodium to 1000 ml of serum, mEq/L. Isonatremia, Hypernatremia, and Hyponatremia: A serum sodium concentration between 131 and 149 mEq/L, greater than 150 mEq/L, or less than 130 mEq/L, respectively. From the Section of Pediatric Nephrology, St. Christopher's Hospital for Children, and the Deparhnent of Pediatrics, Temple University School of Medicine, Philadelphia, Pennsylvania *Professor of Pediatrics, Temple; Chief, Section of Nephrology, St. Christopher's tAssociate Professor of Pediatrics, Temple; Director, Dialysis Unit and Transplant Room, St. Christopher's tAssistant Professor of Pediatrics, Temple; Attending Physician in Nephrology, St. Christopher's §Assistant Professor of Pediatrics, Temple; Staff Pediatric Nephrologist, St. Christopher's IIFellow, Pediatric Nephrology, St. Christopher's ~Fellow, Pediatric Nephrology, St. Christopher's Supported in part by NIH Grants RR-75 and HL 23511

Pediatric Clinics of North America-Vol. 29, No. 4, August 1982

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Sodium excess and deficiency: An increase or decrease in the total number of sodium ions in the body independent of the serum sodium concentration. Hyper, iso, and hypotonicity: An increase, equivalence, or decrease in the extracellular fluid concentration of sodium and/or other solutes which can exert an osmotic force across cell membranes. Total Body Water: A quantity of water which in normal children approximates a volume equal to 60 per cent of normal body weight. Total body water is greater than 60 per cent of body weight in children less than one year of age. Extracellular Fluid Compartment: A body compartment the volume of which appro~mates 20 per cent of normal body weight. Extracellular fluid is composed of plasma volume and interstitial volume (volumes equal to 5 and 15 per cent of normal body weight, respectively). Intracellular Fluid Compartment: A body compartment the volume of which is approximately 40 per cent of normal body weight. · Hypervolemia and Hypovolemia: Clinical states in which total body water is increased or decreased, respectively. Euvolemia: A clinical state in which total body water may be unchanged or increased to a degree which does not result in clinically apparent edema. Pseudohyponatremia: A falsely low serum sodium concentration occurring because of the replacement of serum water by lipid and/or protein. Factitious Hyponatremia: A lowering of the serum sodium concentration resulting from the movement of intracellular fluid into extracellular fluid because of the addition of nonpermeant solutes to the .extracellular compartment. Milli-Osmolality: The ratio of the number of particles in serum to 1000 gm of water, mOsm/kg H 20. "Effective" Osmolality: The concentration of osmotically active particles which exerts an osmotic force between extracellular fluid and intracellular fluid. "Effective" Volume: An unmeasured quantity of volume located somewhere within the extracellular compartment which has the capacity to alter the usual quantities of sodium and water reabsorbed within the proximal tubule of the kidney. Free Water: That component of urinary water from which all solute has been removed.

PHYSIOLOGY OF SERUM SODIUM REGULATION The body critically limits the total quantities of sodium and water as well as their ratio by two mutually supportive systems operating in parallel. Regulation of the serum

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sodium concentration occurs primarily through regulation of body water-osmoregulation. Regulation of total body volume occurs primarily through regulation of sodium balance. Central to the control of the serum sodium concentration is the participation of the pituitary gland in regulating release of antidiuretic hormone (ADH).'7 Changes in serum osmolality of 3 to 4 per cent are recognized by osmoreceptors,54 alter thirst perception, and influence production and release of ADH. A number of nonosmotic stimuli also result in release of ADH centrally, or potentiate the renal effects of ADH. Most important is the stimulatory effect of hypovolemia on release of ADH. The principal volume receptors are located in the left atrium. ADH release is more responsive to small increases in osmolality when mild to moderate volume depletion occurs. But iso-osmotic dehydration exceeding 10 per cent has a stimulatory effect on ADH release similar in magnitude to that of significant hyperosmolalityP !so-osmotic sodium and extracellular fluid volume regulation occurs primarily in the kidney, which can respond to subtle changes in "effective" volume by altering the quantity of glomerular filtrate reabsorbed in the proximal tubule. Additional adjustments occur in the distal tubule and collecting ducts. The clinical pathophysiology of an abnormal serum sodium concentration may be viewed as occurring in two separate yet related stages: generation and persistence. The mechanisms involved in these two phases often differ and reflect the nature of the underlying disorders and the segment or segments of the diluting and!or concentrating mechanisms involved. Extrarenal losses or gains involving both salt and water as well as alterations in renal function play a substantial role. Diluting Mechanismf1· 54 The attempt of the kidney to correct hyponatremia by elaborating a dilute urine may be viewed as a five-step process: (1) formation of glomerular filtrate; (2) reabsorption of glomerular filtrate in the proximal tubule; (3) chloride and sodium reabsorption in the water-impermeable segment of the ascending limb of Henle; (4) sodium reabsorption in the distal tubule leading to a maximally hypotonic urine; and (5) failure of water reabsorption in the ADH-sensitive segment of the collecting duct. The quantity of filtrate formed and delivered from the proximal tubule determines the quantity of, and the rate at which, solute free water can eventually be excreted, thereby enabling a depressed serum sodium level to rise toward normal. Solute is separated from filtrate at two sites beyond the proximal tubule: the ascending limb of Henle where chloride is actively transported in a segment impermeable to water and the distal convoluted tubule where a maximally diluted urine is formed. The osmolality of the urine finally excreted depends upon the magnitude of ADH effect on the collecting duct. By influencing production of cyclic adenosine monophosphate (cAMP), ADH enables water to be passively reabsorbed in the collecting duct because the osmolality of fluid within the tubular lumen is less than that of the surrounding interstitium in the hypertonic medulla. Concentrating Mechanism. 38 The kidney's mechanism of protecting against volume depletion and hyperosmolality involving the formation of hypertonic urine may also be viewed as a five-step process: (1) formation of glomerular filtrate; (2) degree of reabsorption of glomerular filtrate in the proximal tubule; (3) degree of water removal from the loop of Henle as a reflection of the magnitude of countercurrent multiplication and exchange in the medulla; (4) degree of chloride, sodium, and urea reabsorption in the water-impermeable ascending limb of Henle; and (5) degree of ADH effect on the water-permeable segment of the collecting duct together with the magnitude of passive urea movement out of the collecting duct into the medullary interstitium. The amount of glomerular filtrate formed combined with the volume of iso-osmotic filtrate reabsorbed in the proximal tubule determines the quantity of water and solute presented to the descending limb of Henle. The amount of water absorbed in the descending limb of Henle and the maximal osmolality achieved at the hairpin turn of the loop of Henle reflect three processes: (1) the osmolality generated in the medullary interstitium as a reflection of active chloride and passive sodium movement in the thick ascending limb of Henle; (2) passive movement of urea from the collecting duct into the medullary interstitium; (3) a slow rate of blood flow through the capillaries permeating the inner regions of the medulla and the loop of Henle. As filtrate moves through the waterimpermeable ascending limb of Henle, solute is removed and the intratubular osmolality falls. By the time filtrate reaches the early segments of the distal tubule, the

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intraluminal fluid is maximally diluted. Subsequently, water is abstracted in the more distal segments of the distal tubule and especially in the collecting duct by the combination of the ADH effect and a high interstitial osmolality. The final result is a urine of high osmolality and small volume.

CLINICAL PATHOPHYSIOLOGY Abnormalities in serum sodium concentration occur in conjunction with normovolemia, hypovolemia, or hypervolemia. The greater the deviation from normal, and the faster its development, the more severe the clinical manifestations which are profoundly influenced not only by the total quantity of extracellular fluid, but also by its distribution between intravascular and interstitial spaces. 2 • 13 In general, th~ younger the child, the more rapid the development of the serum sodium abnormalities. Measurement of the urinary sodium concentration is often helpful in identifying the nature of the underlying disorder in children with serum sodium abnormalities, and can be used to estimate extracellular fluid. A urinary sodium concentration of less than 5 to 10 mEq/L usually indicates contraction of either the actual or the "effective" extracellular fluid (Table I). When the urinary sodium concentration exceeds 20 mEq/L in either a dehydrated or a hyponatremic child, a defect in some aspect of the concentrating or diluting mechanism should be suspect. While some disorders are characterized by a urinary sodium concentration which is always high or low, others are associated with a variable urinary sodium concentration. This variability reflects the secondary effects of sodium and water gains or losses on renal function associated with the underlying disease process. The clinical manifestations of both hyponatremia and hypernatremia primarily reflect functional changes in one or more of four organ systems: cardiovascular system, central nervous system, musculoskeletal system, voluntary and involuntary, and the genitourinary system. The many signs and symptoms associated with an abnormal serum sodium are compiled in Table

2. Cardiovascular System. Water movement between extracellular and intracellular fluid is the only way by which osmotic equilibration occurs when changes in serum osmolality occur quickly. When iso-osmotic gains or losses occur, changes in water balance are distributed in accordance with the normal proportion of total body water occupied by extracellular fluid (one third) and intracellular fluid (two thirds). Plasma volume, the principal determinant of blood volume and comprising one fourth the extracellular fluid, shares l/4 X l/3 or 1112 of the total change of the salt and water involved in iso-osmotic disorders. In a volume-depleted child, the development of hyponatremia further compromises extracellular and intravascular volume because of the simultaneous movement of water into intracellular fluid. Since depletion of plasma volume determines the development of hypovolemic shock, hypo-osmotic states are associated with the onset of shock at lesser levels of total body water depletion. Most importantly, a child with hypo-osmolality may become shocky even when total body water is normal. In contrast, vascular collapse is unusual in hypernatremic children because hyperosmolality causes water to move into the extracellular com-

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Table l. Relationship of Urinary Sodium Concentration to Serum Sodium Abnormality HYPERNATREMIA

HYPONATREMIA

Urinary Sodium Concentration <10-15 mEq/L

Urinary Sodium Concentration >20 mEq/L

Urinary Sodium Concentration <10-15 mEq/L

Urinary Sodium Concentration >20 mEq/L

Diabetes inspidus (central and nephrogenic) Diarrhea Hyperventilation- inadequate humidification, ventilator use, 1' skin losses, sweat, cystic fibrosis, fever, thyrotoxicosis Increase<' breast milk sodium concentration Cushing syndrome Inadequate replacement of salt and H 2 0 losses Vomiting

Osmotic diuresis: glucose, urea, mannitol Hypertonic dialysis Nephrogenic diabetes insipidus

Gastrointestinal losses: diarrhea, fistula, postoperative tube drainage, vomiting Third space losses: burn, muscle trauma, pancreatitis, peritonitis

Diuretic excess Metabolic alkalosis with bicarbonaturia Mineralocorticoid excess Osmotic diuresis: glucose, glycerol, mannitol, urea Postobstructive diuresis Renal tubular acidosis with bicarbonaturia Sodium-losing nephropathies

Expanded

Over-correction of hyponatremic dehydration with hypertonic sodium infusions Heart failure Cirrhosis Nephrosis

Hypertonic sodium loads (IV, PO, rectally), salt poisoning Advanced renal failure Therapeutic hypertonic saline abortions

Cardiac failure Cirrhosis Hepatic failure, acute Nephrotic syndrome

Acute tubular necrosis Progressive renal failure

Euvolemic

Essential hypernatremia Sea water drowning?

Hyperaldosteronism Hypertonic sodium loads

Iatrogenic water loading? Psychogenic water loading? SIADH (low-sodium diet)

SIADH, drugs, emotion, pain Glucocorticoid deficiency Hypothyroidism

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Table 2. Symptoms and Signs Associated with an Abnormal Serum Sodium SYMPTOMS

Hypematremia Anorexia Apathy Diarrhea Irritability Polyuria Restlessness Thirst Vomiting

Hyponatremia Apathy Anorexia Diarrhea Muscle cramps Nausea Polyuria Vomiting Weakness

SIGNS

Ataxia Circulatory insufficiency-shock-death CNS death Coma Doughy skin Exaggerated deep tendon reflexes Fever High-pitched cry Lethargy Memory alterations Rigidity Seizures Stupor Tachypnea Tetany Tonic spasm Tremulousness Agitation Altered consciousness Coma Cheyne-Stokes respirations Circulatory insufficiency-shock-death CNS death Depressed deep tendon reflexes Disordered thinking Disorientation Hypotension Pathologic reflexes Pseudobulbar palsy Seizures

partment from intracellular compartment; therefore, when it occurs it should be viewed as a potentially pre-agonal event. The concentration of serum albumin controls the oncotic pressure within the intravascular compartment and determines the distribution of water between intravascular and interstitial compartments. Any alterations in the size of body fluid compartments occurring in response to changes in serum osmolality will be further modified if the affected child also has an abnormal serum albumin concentration. Central Nervous System. Neurologic dysfunction caused by abnormalities in the serum sodium concentration is a major cause of morbidity and mortality in affected children. 2 When serum sodium concentration is increased and the serum osmolality exceeds 335 mOsm/kg in the experimental animal, central nervous system symptoms become progressively more severe. 6 Death from respiratory failure occurs when serum osmolality reaches 430 mOsm!kg. Electroencephalographic changes include decreased voltage, and bursts of high voltage waves. 35 When hyperosmolality has developed rapidly in children, postmortem studies have shown congested capillaries and veins, venous thrombosis, and subarachnoid and parenchymal bleeding. The immediate effect of acute hypematremia is a dehydrated brain

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reflecting an acute reduction in intracellular water. After several days of persistent hypernatremia, the amount of intracellular water returns toward normal because of the production of new intracellularly located "idiogenic" osmols. 2 • 13 The generation of idiogenic osmols appears to be limited to the central nervous system. These "new" particles are amino acids (glutamine, aspartic acid, alanine) which derive from minimally osmotically active high molecular weight intracellular proteins. Once formed, they exert an osmotic effect and return the quantity of intracellular water to near normal. The presence of idiogenic osmols also explains why it is necessary to lower extracellular fluid osmolality slowly during the treatment phase of hypernatremia; otherwise rebound water intoxication may occur. The disappearance of idiogenic osmols, as with their development, takes hours to a few days. When the serum sodium is lowered over a few hours to levels less than 125 mEq/L in experimental studies, cerebral edema occurs and is often accompanied by seizures. 2 • 36 Most children whose serum sodium exceeds 120 mEq/L or who develop hyponatremia slowly are asymptomatic unless they are dehydrated. Symptoms increase progressively as the serum sodium concentration is lowered further. Nonspecific changes in the electroencephalogram occur in hyponatremic children. Such changes which disappear after correction of the hyponatremia include irregular bursts of slow (4 to 7 Hz) wave activity and loss of alpha wave activity. 51 Limited postmortem studies in patients dying of hyponatremia have revealed generalized swelling of the brain with obstruction of the subarachnoid space, sulci, and cerebral gyri. The astrocytes appear to be the cells primarily involved. 66 When hyponatremia persists for a few days, the sodium, potassium, and chloride content of the brain remains low and the brain water content remains elevated, yet the degree of brain edema which occurs with chronic hyponatremia is less than that expected and less than that which occurs in other organs. 36 The reduced swelling of the brain is due to the loss of intracellular sodium and potassium and a lowering of intracellular brain osmolality. 25 This sequence of events reduces the osmotic gradient caused by the initial lowering of the extracellular osmolality. Thus, although the symptoms of acute hyponatremia can be explained on the basis of rapidly developing cerebral edema and increased intracranial pressure, the symptoms of chronic hyponatremia probably reflect other mechanisms. Evidence exists supporting the concept that hyponatremia inhibits neurotransmitter release 43 and energy metabolism.25 Mortality data related to hyponatremia are unavailable for pediatric populations. Mortality in hyponatremic adults is related to the rapidity with which it develops. 3 In one series, including 66 adult patients, a 50 per cent mortality was observed in the acutely hyponatremic patients, all of whom were symptomatic. In the chronically hyponatremic group, 50 per cent were symptomatic and 12 per cent of this group died. In this series the nature of the underlying disorder may have also contributed to the observed mortality. Hyperosmolality. Although hypernatremia is reflected as hyperosmolality, hyperosmolality can affect central nervous sytem function independently of hypernatremia. 19 Solutes which increase serum osmolality include urea, glucose, glycerol, galactose, mannitol, and various alcohols including

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ethanol and methanol. Increases in blood urea or alcohols which distribute equally throughout most of the body water (permeant solutes) lead to hyperosmolality without internal rearrangement of water, whereas the addition of nonpermeant solutes such as sugars to the extracellular fluid does influence the distribution of water between extracellular fluid and intracellular fluid and may cause hyperosmolar factitious hyponatremia. Musculoskeletal System. Although most patients with hypernatremia have normal muscle tone, some will have muscular tWitching or hyperactive deep tendon reflexes. Rhabdomyolysis has been described in hypernatremic children. 50 Hyponatremia may be associated with muscular cramps, irritability, weakness, paresis, and ataxia. Genitourinary System. Renal function is altered in children with abnormalities of their serum sodium concentration primarily because of changes occurring in the concentrating and/or diluting mechanisms. These manifestations include more or less frequent voidings and alterations in the quantity of urine excretion and the color of urine. Also, hyperosmolality in the experimental animal lowers the glomerular filtration rate. 57

HYPERNATREMIC DISORDERS (Table 3) Euvolemic Hypernatremia The generation phase of most disorders associated with euvolemic hypernatremia is due to the input of excessive amounts of sodium. Sources include the inadvertent use of salt rather than sugar in preparing formula, 24 the administration of intravenous solutions containing large quantities of sodium (for example, "push" infusions of hypertonic sodium bicarbonate to treat acidosis 30 or cardiac arrest<8 ), the use of hypertonic saline for purposes of therapeutic abortions, 15 or the improper preparation of solutions for hemodialysis 46 or peritoneal dialysis. 62 Sea water aspiration may also be associated with hypernatremia. 29 However, most children surviving neardrowning have reasonably normal levels of serum sodium because of the presumed development of spasm within the airways in response to the introduction of water and the small quantity of fluid which is actually aspirated. Hypernatremia may also develop as a consequence of the overzealous oral ingestion of compounds containing sodium being given therapeutically especially in children with a low glomerular filtration rate (GFR) related to either disease or young age. Exchange transfusion in neonates weighing less than 1500 gm has been associated with the development of hypernatremia, 16 the source of sodium being the anticoagulant added to the blood. A few patients have been described as having hypernatremia with either euvolemia and/or hypovolemia in association with an elevated osmostat. 28 The maintenance of the hypernatremic state in such patients is a reflection of the ongoing input of the offending agent. The role of the kidney in enabling hypernatremia to persist is complex. Multiple mechanisms, some of which involve retention of sodium while others tend to reduce the serum sodium concentration, are functioning simultaneously. The reabsorption in the proximal tubule of a glomerular filtrate whose sodium concentration is high may

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Table 3. Etiology of Hypernatremia EUVOLEMIC HYPERNATREMIA

Dialysis related, peritoneal or hemodialysis Essential hypernatremia Exchange transfusion in infants < 1500 gm Formula errors Iatrogenic: intravenous solutions, medications HYPOVOLEMIC IIYPERNATREMIA

Absence of thirst Asymptomatic hypovolemic essential hypernatremia Ingestion of boiled milk Breast milk with elevated sodium concentration Child abuse Diabetes insipidus central or nephrogenic Diabetes mellitus, hyperosmolality Formula errors: measuring errors, use of incorrect solute, failure to follow directions Gastroenteritis Hypertonic sodium-containing emetics or enemas Increased insensible water loss Lungs: increased respiratory rate, fever Salicylism Increased skin losses: burn, phototherapy, preterm (<36 wks gestation), seborrheic dermatitis, sweating (cystic fibrosis) HYPERVOLEMIC HYPERNATREMIA

Administration of hypertonic salt solutions (formula, dialysate, intravenous fluids, saline abortions) Steroid excess Water loss (acute) by edematous patients

help sustain hypernatremia. Also, any drop in GFR will help maintain an already elevated serum sodium. This maintenance mechanism is simultaneously offset by the increase in serum sodium, which, by increasing extracellular fluid, and presumably" effective" volume, ought to increase the excretion of sodium. 7 Alterations in ADH occurring in response to changes in volume and/or osmolality influence water balance simultaneously.

Hypovolemic Hypernatremia Hypotonic Fluid Loss. Hypovolemic hypernatremia can be generated by either the loss of water alone or by the loss of hypotonic fluid. The more common mechanism in children is the loss of hypotonic fluids, usually from gastroenteritis. 8 • 21 Such losses are often aggravated by increases in insensible water loss through the lung' and/or skin or, most importantly, the simultaneous ingestion or administration of relatively hypertonic diets and/or solutions. 10 The inadequate preparation of infants' formula may lead to hypernatremia.24 Errors have occurred when preparing either "normal" formula for well infants or "special" formula for ill infants. Prolonged boiling of milk leads to the loss of water and an increase in the sodium concentration of the milk. The substitution of tablespoon or teaspoon quantities for pinches of salt,' 4 or the inadvertent substitution of sodium salts for other solutes will result in infants being offered a high solute load. Occasionally breast milk contains a high concentration of sodium. 1· 6" Although the ingestion of such formula might

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be expected to result in either euvolemic or hypervolemic hypernatremia, the administration of such formulas is often associated with vomiting and the loss of extracellular fluid, or they are given to dehydrated infants. Thirsty, irritable infants are then given more of the same formula without any free water being offered. The past few years have seen the widespread application of the World Health Organization oral rehydration solutions to treat infantile gastroenteritis. Their improper preparation and/or the failure to interspace solutions containing solute with those not containing solute has resulted in hypernatremia because of the net ingestion of a high solute load. 23 • 65 Excessive losses of hypotonic sweat may lead to hypernatremia (normal sweat has a sodium concentration of 15 to 46 mEq/L)."" Low humidity environment, such as that which exists when nonhumidified heating systems are used, may also help contribute to excessive skin losses. Another major cause of hypotonic fluid loss is that which occurs during an osmotic diuresis. In such patients the urine is generally iso-osmotic or hyperosmotic to plasma but the urinary sodium concentration is low. The osmols in the urine reflect the osmotically active solute-urea, glucose, mannitol. Clinical examples include high protein diets, uncontrolled diabetes mellitus, repetitive attempts to lower intracranial pressure with infusions of mannitol, administration of glycerol, and the intravenous infusion of solutions with high concentrations of glucose, such as total parenteral nutrition. Maintenance of the hypernatremic state in patients with a sustained osmotic diuresis occurs because of the persistence of the initiating factors as well as the inhibitory effect of an osmotic diuresis on the concentrating mechanism. The true value of the serum sodium is often not appreciated in children with diabetes mellitus and very high blood sugar levels. Unrecognized hypernatremia may contribute to the hyperosmolality of diabetes mellitus:56 The addition to the extracellular compartment of each 100 mg/dl of sugar above normal should lower the measured serum sodium concentration by 1.6 mEq/LY Thus, a child with a blood sugar of 1100 mg/dl and a serum sodium of 143 mEq/L should be viewed as potentially having a serum sodium of 160 mEq/L, were his blood sugar to be "instantaneously" corrected. Hypertonic peritoneal or hemodialysis can lead to hypovolemic hypernatremia by removing extra "pure" water as well as iso-osmotic fluid. Hypernatremia has also been reported as part of the spectrum of child abuse. The etiology of the water loss includes enforced thirst, malnutrition, lack of feeding, and voluntary withholding of fluids. 52 Thus, the generation of hypovolemic hypernatremia owing to a net loss of hypotonic fluid is variable and often multifactorial. Maintenance of the hypernatremic state in hypovolemic hypernatremia is also complex and is due to a combination of the continued ongoing loss of hypotonic fluids, the reabsorption of a greater fraction of the glomerular filtrate which has a high sodium concentration, and the input of hypertonic solutions. Pure Water Loss. A number of disorders may be viewed as being generated by "pure" water loss. Net pure water loss occurs in two ways: (1) disorders affecting any of the steps of the concentrating mechanism can lead to the urinary loss of solute free water, and (2) losses of both water and solute which are replaced by hypertonic solutions. An increase in insensible water loss is one cause of pure water loss

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leading to hypovolemic hypernatremia. Increases in insensible water loss through the lung can occur in many conditions associated with an increased rate and/or depth of breathing. Cutaneous water loss is increased in preterm infants because of thin skin, 18 in patients with excessive sweating and in disorders involving widespread destruction of the protective outer layers of cornium. 39 Hypernatremia in these disorders most often occurs because the increase in insensible water loss is not appreciated. A few patients have been described as having developed hypernatremia because of the absence of thirst. 11 The genesis of the hypernatremia in these patients is the ongoing losses of water by insensible and renal routes. Maintenance of the hypernatremia ensues as a result of the patient's failure to perceive and respond to thirst. Even fewer patients have been reported as having an elevated osmostat, i.e., having hypernatremia with the ability to dilute and concentrate urine about an elevated serum osmolality. Most affected patients have had impaired central nervous system function. Diabetes insipidus, central or nephrogenic in nature (Table 4), is a generic term applied to a large number of disorders having the potential for hypovolemic hypernatremia and having similar clinical features. 6 Polyuria in the absence of an osmotic diuresis, polydipsia, volume depletion, and hypernatremia are the hallmarks of these disorders. Polyuria should be suspected when the age-related maintenance rate of urine excretion is increased by a factor exceeding 2.5. The polyuria associated with central diabetes insipidus may approach rates of 13 to 15 times maintenance, depending on the magnitude of the defect in ADH release. A fluid deprivation test is the currently preferred method for diagnosing central diabetes insipidus. It is necessary when performing water deprivation tests that weight and vital signs be monitored frequently throughout the

Table 4. Etiology of Diabetes Insipidus CENTRAL DIABETES INSIPIDUS

Anoxic encephalopathy Guillain-Barre Histiocytosis X Mass lesions: suprasellar and intrasellar in location, cysts, tumors Postinfectious: encephalitis, meningitis, tuberculosis, lues Primary or idiopathic: familial, sporadic Sarcoidosis Trauma: accidental or surgical damage to pituitary gland, basal skull fracture Vascular lesions: aneurysm, thrombosis, Sheehan's syndrome NEPHROGENIC DIABETES INSIPIDUS

Congenital: familial, sporadic Electrolyte disturbance: hypokalemia, hypercalciuria, hypercalcemia (e.g., adrenal insufficiency, hyperaldosteronism, sarcoidosis) ?Hereditary insensitivity of renal adenylcyclase to ADH Osmotic diuresis: glucose, glycerol, mannitol, urea Pharmacologic agents: diuretics Renal disease: acute tubular necrosis-recovery phase, amyloidosis, cystic disorders (medullary cystic, polycystic), myeloma, pyelonephritis, obstructive uropathy and postobstructive diuresis, radiation nephritis, renal insufficiency (GFR <50 per cent normal), sickle cell anemia, Sjogren's syndrome, tubular transport defects.

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duration of the test so as to avoid severe dehydration with its attendant consequences. The test is performed by measuring urine output continuously and measuring urine osmolality in each urine specimen while restricing fluid intake up to 12 to 18 hours or until the child loses 4 to 5 per cent of body weight and/or the urine osmolality fails to continue to rise. If the urine osmolality spontaneously increases to more than 800 mOsm/kg the concentrating mechanism can be viewed as functioning normally. Otherwise, an intravenous injection of 0.1 units of aqueous pitressin can be given and further changes in urinary osmolality sought. Another way to demonstrate ADH responsiveness is to give a continuous intravenous infusion of aqueous pitressin beginning at a rate of 50 ~J.U/kglhour (if no response occurs, the rate may be sequentially increased to 150 to 300 ILU/kg/hour) and to measure changes in urine osmolality and volume or, even more physiologically, free water clearance. 53 If the urinary osmolality increases to values greater than that of serum, central diabetes insipidus is suspected; otherwise a diagnosis of nephrogenic diabetes insipidus should be entertained. A major advantage of the fluid deprivation test is its value in being able to recognize partial defects in ADH effect, i.e., patients whose urine osmolality increases to 450 to 650 mOsm/kg after fluid deprivation and after pitressin to values exceeding 750 to 800 mOsm/kg. The term nephrogenic diabetes insipidus refers to a vasopressin-resistant defect in the concentrating mechanism and may be either congenital or acquired. Congenital nephrogenic diabetes insipidus has its onset in infancy and is manifested by episodes of fever, vomiting, dehydration, the continued excretion of a hypotonic urine, and unresponsiveness to ADH infusions. Although almost all affected infants are males, it has been reported in females. Also, females may have a mild form of this disorder demonstrable only by a fluid deprivation test. Acquired nephrogenic diabetes insipidus occurs in conjunction with a large number of pathologic, pharmacologic, and physiologic conditions. These disorders are clinically manifested by a moderate degree of polyuria, the ability of affected patients if clinically dehydrated to elaborate a urine with an osmolality which exceeds that of plasma, and euvolemic or hypovolemic hypernatremia depending upon the nature of replacement fluids. Circulating levels of ADH are often elevated in these disorders. The most common cause of nephrogenic diabetes insipidus in children is some form of intrinsic renal disease (Table 4). Renal disease associated with greater than 50 per cent reduction in GFR often is accompanied by nephrogenic diabetes insipidus. Conditions affecting the medullary and interstitial segments of the kidney often are associated with nephrogenic diabetes insipidus despite a normal GFR. The factors involved in generating a concentrating disorder include: (1) distortion of the normal spatial relationship involved in countercurrent multiplication and exchange; (2) changes in serum electrolytes and their effect on tubular transport mechanisms; (3) the influence of "effective" volume on proximal tubule function; (4) an osmotic diuresis related to changes in blood urea levels; and (5) altered medullary blood flow. The maintenance phase is a reflection of a permanent defect in the concentrating mechanism. A number of pharmacologic agents which are not often used in pediatric

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SERUM SODIUM ABNORMALITIES IN CHILDREN

Table 5. Pharmacologic Agents Causing Nephrogenic Diabetes Insipidus 61 CAUSE OF NEPHROGENIC DIABETES INSPIDUS

Colchicine Glybenclamide (glyburide) Isophosphamide Lithium Methoxyflurane Propoxyphene Tetracycline (demeclocycline)

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probably increases yes yes yes yes yes

? ? yes no no no no

yes ? ? yes

*1. Reduced ADH effect on nephron H 20 movement t2. Reduced salt transport in ascending limb of Henle :J:3. Reduced cyclic AMP production

medicine can cause nephrogenic diabetes insipidus by interfering with various components of the concentrating mechanism. 61 The sites at which the concentrating mechanism is affected by each of these agents are summarized in Table 5. Nephrogenic diabetes insipidus associated with transplacental transfer of lithium in a neonate has been reported. 49 The generation and maintenance phases of these disorders result from the continued administration of these agents. Treatment should be aimed at modifying drug usage or providing adequate amounts of solute free water. Nephrogenic diabetes insipidus occurs in some patients as a consequence of a physiologic alteration which has a secondary influence on the concentrating mechanism. Starvation and/or continuous massive protein losses may generate nephrogenic diabetes insipidus by altering the available urea which accounts for 50 per cent of the osmols in the inner medulla. Also, nephrogenic diabetes insipidus may occur in disorders associated with hypokalemia or hypercalciuria. Hypokalemia generates nephrogenic diabetes insipidus by preventing osmotic equilibrium between the tubular fluid and medullary interstitium or by impairing the response to ADH. Hypercalciuria can lead to nephrocalcinosis and an altered spatial relationship of the multiple structures involved in the concentrating mechanism. Also, the effect of ADH on water reabsorption may be altered.

Hypervolemic Hypernatremia Hypervolemic hypernatremia occurs infrequently and most often is generated accidentally or iatrogenically either by the administration of sodium-containing tablets or the intravenous infusion of hypertonic solutions in volume expanded patients. Another cause is dialysis against a high sodiumcontaining solution. Occasionally, patients with conditions associated with mineralocorticoid excess such as primary hyperaldosteronism or Cushing's syndrome develop hypervolemic hypernatremia. 42

Treatment Guidelines for Hypernatremia Answers should be formulated to the following four questions prior to initiating therapy for hypernatremia: (1) Can the underlying disease be treated? (2) Is it necessary to rapidly lower the serum sodium concentration? (3) How rapidly should the serum sodium concentration be lowered? (4) To what extent should total body water be altered? When possible, therapy

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should be directed toward correcting the basic disease process which leads to hypernatremia. Examples include the use of vasopressin analogues to treat central diabetes insipidus, diuretics and/or low salt diet for nephrogenic diabetes insipidus, and the immediate discontinuation of any oral and/or parenteral excesses of sodium. Since persistent high levels of serum sodium can have permanent sequelae, the rapid lowering of the serum sodium to levels of 165 to 170 mEq/L should be considered in patients whose serum sodium exceeds 175 to 180 mEq/L. This may be attempted by the infusion of hypotonic solutions. Sodium may be removed by administering loop diuretics such as furosemide. Since such agents remove more water than sodium, it is necessary to simultaneously administer enough hypotonic solution to prevent worsening of the hypertonicity. Peritoneal dialysis using 4.25 per cent glucose solutions and hemodialysis also have been successfully used to acutely lower the serum sodium concentration. The following imprecise formulas can be used to estimate how much salt has been gained and how much water is theoretically required to lower the serum sodium concentration. 19 This quantity of water should be viewed as that amount which will only lower the serum sodium concentration and as a value independent of any water required to correct any concurrent deficit of total body water. Thus, these formulas are in error to the extent that total body water and its distribution have been altered by disease. Liters of TBW = approximately 0.6 x body wt in kg. Sodium excess in mEq = 0.6 x body wt in kg x (current [Na+] - 140)

and , ., m . 1tters . water "deuctt

=

. kg 0 .6 wt m

X

[1

-

(current serum [Na+] 140

J

The third formula states that the addition of 4 ml of H 2 0/kg of body weight will lower serum sodium by 1.0 mEq/L assuming no ongoing losses or input. Thus, an individual with a serum sodium concentration of 180 mEq/L, weight of 10 kg and having 6 liters of total body water would require 4 X 10 x 10 or 400 ml of water to lower the serum to 170 mEq/L. These formulas are most useful in two clinical settings: (1) when it is clear that the problem is very acute, and (2) when the patient is oligoanuric. In the latter case sodium should not be given in order to avoid the possibility of iatrogenic pulmonary edema. Such patients may require dialysis. The rate at which the serum sodium can safely be lowered depends upon the duration of the hypernatremia. Therapy using minimal concentrations of sodium or, on occasion, 5 per cent dextrose alone can safely be initiated if it can be unequivocally documented that the duration of the hypernatremia has been less than a few hours. In most clinical settings involving children, however, the duration of the hypernatremia is much longer, intracellular idiogenic osmols have probably formed, and the serum sodium concentration should be lowered slowly. The approach which we have used to treat most children with hypernatremia, especially when volume depletion is also present, consists of two parts.4· 22 • 55 First, if intravascular depletion had compromised cardiovascular hemodynamics, a rapid infusion (15 to 45 minutes) of a glucose-free electrolyte

SERUM SODIUM ABNORMALITIES IN CHILDREN

921

solution similar in composition to extracellular fluid is given. Plasmanate, albumin solutions, or, in the presence of blood loss or severe anemia, whole blood is used to treat shock. If the patient has been oliguric but not shocky, an infusion of 5 per cent dextrose containing 60 to 90 mEq/L of sodium without any potassium at a rate of 15 to 20 ml/kg per hour may be given until urine output occurs. It is helpful to measure the urinary sodium concentration and specific gravity of the first urine passed to obtain data supportive of the fact that the etiology of the oliguria is most likely volume depletion. Once intravascular repletion has been accomplished, a computation of maintenance volume and requirements for correction of the remaining deficit should be made. Replacement for any ongoing losses will need to be added to this quantity. Most commonly used solutions have a sodium concentration in the range of 20 to 35 mEq/L and a glucose concentration of 2.5 to 5 per cent. If it is felt that an intracellular deficit of potassium also exists, potassium is added to the infusion in concentrations of 30 to 40 mEq/L, once urine formation is assured. The addition of potassium serves two purposes. It corrects intracellular deficits and it helps to increase the extracellular fluid osmolality. This quantity of solution is best given in equal increments over the next 48 hours if the serum sodium is less than 170 mEq/L or over 72 hours if the serum sodium exceeds 170 mEq/L. Also, the anionic composition of the infusate needs to be determined. Anions may be given as all chloride, or one fourth bicarbonate and three fourths chloride. When significant metabolic acidosis exists, the concentration of bicarbonate can be increased. Solutions containing the above mixture of solutes and infused at the suggested rate generally results in the serum sodium falling by 1 to 1.5 mEq/hour. Serum sodium levels should be monitored every 4 to 6 hours to ensure that the rate of drop in the serum sodium concentration is satisfactory. Should central nervous system symptoms worsen because of isotonic water intoxication caused by a rapidly falling serum osmolality, the rate of infusion ml}st be slowed and/or additional osmols added to the infusate. Because of the unpredictability of the absorption of any fluids given by any means other than the intravenous route, the initial correction for hypernatremia is best accomplished by providing solute and water intravenously. Once the serum sodium has fallen to 150 mEq/L further needs can be met by providing appropriate solutions orally. The initial oral fluids should contain electrolytes as well as dextrose so that the serum sodium will continue to fall slowly. Also, the total quantity and rate of administration of water should be carefully controlled until the serum sodium is in the range of normal (140 ± 5 mEq/ L) for 8 to 12 hours. The treatment in diabetic children of hypertonic hyperglycemic nonketotic coma which may be associated with an elevated serum sodium concentration can be approached by initially withholding insulin and infusing physiologic saline to treat extracellular fluid volume contraction and to prevent further loss of extracellular fluid as serum glucose falls. 19 Small doses of insulin may be added sequentially. Also, potassium and possibly phosphate may be needed. Therapy for diabetes insipidus depends on the nature of the defect. Chronic therapy for central diabetes insipidus can be accomplished by the nasal insufflation of the vasopressin analog 1-deamino, 8-D-arginine vaso-

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pressin (DDAVP). Doses in the range of0.05 to 0.1 ml (1 ml = 400 IU) twice a day usually results in adequate control of urine output for periods of 8 to 24 hours. The maximum dose should not exceed 0.2 ml twice a day. When using DDAVP, the family should be advised to limit fluid intake somewhat and perhaps to be sure that urine volume has begun to increase before the next dose so as to avoid problems such as hyponatremia resulting from excessive administration of ADH. Therapy for nephrogenic diabetes insipidus consists of the chronic use of thiazide diuretics and/or a low salt diet. Both treatments cause volume contraction, enhance proximal reabsorption of iso-osmotic filtrate, and, by virtue of diminished delivery of filtrate to more distal sites involved in the concentrating mechanism, result in the formation of a smaller volume of more concentrated urine. When nephrogenic diabetes insipidus is due to intrinsic renal disease, therapy should consist of the provision of solute free water in amounts sufficient to prevent hypovolemic hypernatremia, as well as treatment of the basic disease process, for example, discontinuation of drugs causing an interstitial nephritis.

HYPONATREMIC DISORDERS Hyponatremic children can be evaluated in a stepwise fashion. 33 The first step is deciding whether the low serum sodium is truly low or whether pseudo or factitious hyponatremia is present. This is done by determining if the clinical history and physical examination are compatible with true hyponatremia, by inspecting the serum for hyperlipidemia, and if necessary by measuring serum osmolality. Serum osmolality is low when true hyponatremia is present, near normal with pseudohyponatremia, and usually high when factitious hyponatremia is caused by the addition of nonpermeant solutes to the extracellular fluid. Next an estimate of total body water obtained from history and physical examination, urinalysis, and routine chemistries permits the child to be classified as being euvolemic, hypovolemic, or hypervolemic. Finally, the determination, when needed, of the urinary sodium concentration provides essential information about the state of "effective" volume and the role of the kidney in sodium reabsorption or excretion.

Euvolemic Hyponatremia Factitious hyponatremia is hyponatremia generated by a redistribution of water between extracellular fluid and intracellular fluid as a consequence of the addition of nonpermeant solutes such as glucose or mannitol to the extracellular fluid. Diabetes mellitus is the leading cause of factitious hyponatremia in children. As already discussed, the true serum sodium in these patients can be estimated by adding 1.6 mEq/L of sodium to the measured serum sodium for each increase above normal of 100 mg/dl of blood sugar. Maintenance of hyponatremia is due to the continued reabsorption of glomerular filtrate having a reduced sodium concentration and the continued input of the nonpermeant solute into the extracellular fluid. Pseudohyponatremia occurs most commonly in children with the ne-

923

SERUM SODIUM ABNORMALITIES IN CHILDREN

Table 6. Etiology of Hyponatremia 12 • 33 EUVOLEMIC HYPONATREMIA

Factitious hyponatremia Glucocorticoid deficiency Hypothyroidism Iatrogenic water loading: parenteral therapy, mist tent, tap water enema Oral intake (with diminished output) Pseudohyponatremia Psychogenic water drinker Reset osmostat: (a) cerebrovascular accident, (b) infection, tuberculosis, (c) malnutrition SIADH HYPOVOLEMIC HYPONATREMIA

A. Excessive loss (often with water replacement) Gastrointestinal: diarrhea, vomiting, fistula, tube drainage, salivary losses Renal: glomerular and interstitial disorders, ATN (recovery phase), postobstructive diuresis, transport defects (adrenal insufficiency, renal tubular acidosis, mineralocorticoid excess), diuretics, SIADH?, cerebral salt wasting? Skin: excessive normal sweat, abnormal sweat (cystic fibrosis, adrenal insufficiency) Third space: burn, muscle trauma, pancreatitis, peritonitis, emphysema, thoracentesis, paracentesis B, Inadequate intake (may occur simultaneously with disorder of excessive loss): low sodium diet, parenteral therapy (low sodium content), resin therapy which may bind sodium C. Redistribution: acid base disorders, malnutrition (chronic severe), potassium deficiency, trauma IIYPERVOLEMIC HYPONATREMIA

Edema forming disorders: cardiac failure, cirrhosis, malnutrition, nephrotic syndrome, acute hepatic failure, renal failure, acute or chronic Excessive intake: oral, increased environmental humidity, i.e., incubators, mist tent, parenteral therapy

phrotic syndrome, as well as in patients with hyperproteinemia, and is easily recognized when sought. The volume of serum water occupied by serum lipid and/or protein in patients with pseudohyponatremia may be estimated by the formula: 67 water content/100 ml

=

99.1 - (1.03 x total lipids gm/dl)

(0.73 X total protein gm/dl)

Children with euvolemic hyponatremia have conditions characterized by a truly low serum sodium and an amount of total body water which ranges in size from normal to high normal. "Pure" water retention is the most common cause of euvolemic hyponatremia in children. In order for hyponatremia to develop as a consequence of pure water loading, total body water must increase by more than 7 to 8 per cent. The reasons that clinical edema, which should be apparent, is absent in such patients are twofold: (l) as hyponatremia develops there is a movement of water into cells, and (2) as "effective" volume expansion occurs in response to the addition of water, sodium will be lost through the kidney and sodium balance maintained despite hyponatremia. The most common cause of childhood euvolemic hyponatremia is the

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Table 7. Criteria for Diagnosing SIADH 1. 2. 3. 4.

Normal adrenal, pituitary* and renal function Extracellular fluid hypo-osmolality (true hyponatremia) Persistent urinary excretion of sodium despite hyponatremia Excretion of urine with a concentration (osmolality) that is inappropriately high for the level of serum sodium. The urinary osmolality is always greater than that of a maximally dilute urine and may either be less than or greater than the corresponding serum osmolality. 5. Severe water restriction corrects hyponatremia *Normal pituitary function other than that involved in ADH control.

syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Table 7). 59 The most common error in recognizing SIADH is the failure to realize that the urine osmolality need only be inappropriately elevated-not maximally dilute-and not necessarily greater than the corresponding serum osmolality. The generation of hyponatremia in SIADH is due to water retention, while its persistence reflects the combined influences of an increase in "effective" volume on sodium homeostasis as well as the continuing effect of excessive ADH activity. Many disorders alter ADH release or its metabolism (Table 8). SIADH occurs most frequently in children with infections involving the central nervous system40 and during the postoperative period. In such patients, the generation of hyponatremia is often due to the administration of routine quantities of salt and water and the modification of their excretion by excessive ADH release. Treatment of both acute 34 and chronic26 SIADH will be discussed later. The development of hyponatremia rarely occurs as a consequence of the ingestion of too much water, because the kidney with a normal GFR has the capacity to excrete 15 to 20 per cent of its filtered load as free water. When

Table 8. Disorders Associated with Excessive ADH Effect 1. CNS: infection, tumor, injury, vascular accidents, Guillain-Barre syndrome 2. Drug-related: Acetaminophen (Tylenol) Morphine Barbiturates Navane Carbamazepine (Tegretol) Nicotine Chlorpropamide Phenformin Clofibrate Polymyxin B Cyclophosphamide Thiazides Elavil Tolbutamide Indomethacin Vincristine Isoproterenol 3. Endocrine:' myxedema, cortisol deficiency, pituitary stalk section, 4. Heart: Congestive heart failure, left atrial stretching, constrictive pericarditis 5. Infections: acute childhood infectious disorders, especially viral 6. Liver: Cirrhosis, hepatic failure, portal hypertension 7. Metabolic: acute intermittent porphyria 8. Pulmonary: asthma, infections, emphysema, fibrosis, tumors, ventilation (CPAP) 9. Renal: changes in sodium handling by the kidney related to volume contraction and/or diuretics, hypoalbuminemia 10. Surgery related: anesthesia or premedication, peritoneal reflexes, intracranial manipulation, postoperative pain 11. Tumors: duodenum, pancreas, salivery gland, thymus

SERUM SODIUM ABNORMALITIES IN CHILDREN

925

an older child or an adult ingests a large quantity of water, most of it is excreted within 3 to 4 hours. Although he possesses the ability to dilute his urine (urine osmolality) to the same degree as an adult, a neonate given the same quantity of water in relation to body weight usually does not regain water balance as rapidly as an adult. The reason for such age-related differences is that children below one year of age have a lower G FR per 1. 73 M2 and consequently form relatively less glomerular filtrate and excrete less free water per unit of time. So-called psychogenic water intoxication is rare in children. Symptomatic water intoxication and asymptomatic hyponatremia have been reported in infants with altered parent-child interrelationships 47 and in older children with extreme behavioral disorders. In some infants, the parents have been unaware of their excessive use of water to respond to the irifant' s request for comforting. Once the nature of the problem has been identified and discussed, appropriate behavioral modification has resulted in a resolution of the problem in the cases with which we are familiar. Conversely, the treatment of the older child with psychogenic water drinking often requires psychiatric referral, and a successful outcome involves a slow and difficult process. Recently a group of infants, ages 2 to 5 months, have been described as having developed a symptom complex characterized by somnolence, irritability, seizures, hypothermia, and hyponatremia following the ingestion of dilute formula, water, or breast milk, supplemented with glucose-water solutions. 14 Transient elevations of plasma arginine vasopressin and/or chemical evidence for SIADH were found. The symptom complex readily resolved spontaneously or with water restriction. Its etiology remains unclear. Euvolemic hyponatremia rarely may be due to a reset osmostat27-a situation in which the control of the serum sodium concentration and the renal concentrating and diluting mechanism fluctuate about an abnormally low serum sodium concentration. Endocrinologic dysfunction has been associated with hyponatremia. 27 Glucocorticoid deficiency may lead to hyponatremia because of increased circulating levels of ADH. Thyroid deficiency may inhibit generation of solute-free water because of its association with a lower GFR and the resultant reduced delivery of glomerular filtrate to the diluting segment of the nephron. Maintenance of hyponatremia in these two. endocrinologic disorders is due to the continued absence of hormones and their secondary effects on segments of the diluting mechanism. Successful therapy requires adequate hormonal replacement and water restriction. Finally, the use of tap water enemas has been associated with symptomatic hyponatremia.

Hypovolemic Hyponatremia Hypovolemic hyponatremia occurs in three clinical settings: (1) the net loss of sodium in excess of water; (2) inadequate input of sodium; (3) movement of sodium into cells. Frequently, more than one mechanism may be operative. The most common cause of hypovolemic hyponatremia in the first clinical setting is the loss of gastrointestinal fluids as a result of vomiting and/or diarrhea, fistula formation, or tube drainage. The generation of hypovolemic hyponatremia results from net loss of salt in excess of water often associated

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with an input either orally or intravenously of hypotonic solutions. The input of hypotonic fluids in children with excessive losses of normal sweat (mean [Na +] = 28 mEq/L) or sweat containing a high concentration of sodium such as occurs in cystic fibrosis 60 (mean [N a+] = 111 mEq/L), or with conditions in which there is movement of isotonic solutions into burn tissue or pleural or peritoneal cavities can generate hypovolemic hyponatremia. Maintenance of hyponatremia is achieved by the combined effects of a reduced effective volume on proximal reabsorption of a hyponatremic glomerular filtrate, decreased delivery of filtrate to the diluting segments, increased release of ADH, and the ongoing input of hypotonic solutions. Such patients have a low urine output, low urinary sodium concentration, a high urine specific gravity or osmolality and, if significantly hypovolemic, pre renal azotemia. The increased reabsorption of glomerular filtrate, including urea by the proximal tubule, is the primary mechanism by which an increase in the blood urea nitrogen to creatinine ratio occurs in prerenal azotemia. Diabetic ketoacidosis often results in hypovolemic hyponatremia because of the combined influence of an osmotic diuresis, cation loss, serum hyperosmolality and hyperlipidemia and the ingestion of hypotonic fluids. In addition, transport defects in sodium reabsorption such as occurs in patients with adrenal insufficiency may lead to hypovolemic hyponatremia. Hypovolemic hyponatremia occurring in patients with renal disease results from the inability of the renal tubule to conserve sodium either because of a continuous osmotic diuresis or a sodium transport defect which may be inherent or reflective of a drug effect. It is the loss of both sodium and water and the failure of proper replacement, combined with the continued ingestion or infusion of hypotonic solutions which results in the generation of hyponatremia in renal patients. Such patients often have a urinary sodium concentration exceeding 20 mEq/L. Hyponatremia does not usually occur in children whose GFR exceeds 25 to 35 ml/min/1.73 m 2 , unless the child has a nephron sodium transport defect such as occurs in cystic disorders and interstitial nephropathies. The reason that hyponatremia does not develop at higher levels of GFR despite ingestion of hypotonic fluids is that the increased loss of sodium and water occurring per damaged nephron is offset by the smaller quantities filtered. But, when renal losses of sodium are not replaced, when oral intake ceases, or when the GFR falls to less than 20 ml/min/1.73 m 2 the usual intake of hypotonic solutions commonly results in hyponatremia. This occurs because the capacity of the nephron to filter and appropriately modify the chemical composition of the filtrate is exceeded. Depending upon the circumstances, the hyponatremia may be associated with either hypovolemia or hypervolemia. The second clinical setting leading to hypovolemic hyponatremia is the prolonged reduced input of sodium. One example of a diminished oral input is that which occurred with the use oflow chloride formulas, especially when associated with episodes of vomiting. Another example is the continued provision of diets or infusions containing less sodium than that being lost in hypovolemic patients especially when water intake is adequate. Hyponatremia is generated because of the combined influence of a diminished "effective" volume and the non-osmotic stimulation of ADH release. The prolonged oral administration of certain forms of exchange resins. in which calcium is

SERUM SODIUM ABNORMALITIES IN CHILDREN

927

exchanged for both sodium and potassium also has the potential to lead to sodium depletion and hyponatremia with or without volume depletion. The third setting in which hyponatremia can develop is the exchange of extracellular sodium ions for intracellular potassium and/or hydrogen ion. Although such exchanges may occur without depletion of extracelluar fluid, most disorders in which this occurs are also associated with hyponatremia. Clinical examples include malnutrition, acid-base disorders, trauma, and potassium deficiency.

Hypervolemic Hyponatremia Hypervolemic hyponatremia occurs most commonly in edema forming conditions when the net retention of water exceeds that of sodium. The mechanism(s) of persistence of the hyponatremic state include an ongoing input of hypotonic solutions, an alteration in the normal function of the diluting mechanism including a reduced GFR, increased proximal reabsorption of filtrate, reduced delivery of filtrate to the diluting segment, and/or osmotic and non-osmotic stimulation of ADH release. Two clinical settings may be associated with hypervolemic hyponatremia: (1) edema-generating disorders such as cirrhosis, 45 heart failure, 37 and nephrosis" in which the urinary concentration of sodium is often less than 10 mEq/L; and (2) advanced acute or chronic renal failure in which the urinary sodium may be variable but usually exceeds 20 mEq/L. Most patients with edema forming disorders have hypervolemic normonatremia and do not develop low sodium syndromes unless they have severe disease. Multiple mechanisms are involved. The hyponatremia of congestive heart failure in most patients is associated with elevated levels of radioimmunoassayable plasma arginine vasopressin and with concentrated urines. 63 Other patients have a dilute urine, and/or low levels of hormone indicating appropriate depression of ADH secondary to volume expansion, suggesting the presence of dysfunction of a component of the diluting mechanism other than that related to ADH. Support for a contributory role of an increased reabsorption of proximal filtrate and diminished delivery of filtrate to the diluting mechanism is provided by studies which have shown that in patients with heart failure an infusion of mannitol which depresses proximal reabsorption of filtrate increases free water excretion. 5 Less well studied is the hyponatremia seen in patients with cirrhosis and nephrosis. Elevated levels of ADH, which is primarily metabolized by the liver, as well as alterations in renal function, including a reduced GFR and diminished delivery of filtrate, have been implicated as being responsible for the hyponatremia seen in hepatic insufficiency. 45 In children with the nephrotic syndrome pseudohyponatremia should be ruled out prior to concluding that 'hypervolemic hyponatremia is present. The development of hyponatremia in patients with the nephrotic syndrome may reflect a nonosmotically generated release of ADH. Diuretic usage in both normovolemic and hypervolemic patients can lead to hyponatremia for three reasons. First, drugs which inhibit salt absorption in the ascending limb of Henle or the cortical diluting segment limit the generation of solute-free water, and hyponatremia will develop when the intake of hypotonic solutions exceeds the ability of the kidney to

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form solute-free water. Second, volume contraction results in non-osmotic stimulation of ADH and increased water retention in the collecting tubule. Third, significant potassium depletion occurring with chronic diuretic use may be associated with the exchange of extracellular sodium for intracellular potassium. 20 Treatment should be directed toward replacing the sodium and/ or potassium deficits. Depending on the distribution and quantity of total body water, water may need to be either given or withheld.

Reset Osmostat Hyponatremia occurring as a consequence of a fixed reset osmostat is a rare occurrence. 64 The few patients with this syndrome have been severely malnourished and chronically ill. In such patients the serum sodium concentration and serum osmolality fluctuates around a low value, and the renal diluting and concentrating mechanisms respond appropriately to changes in serum osmolality. Prior to concluding that such a condition is operative, it is necessary to investigate all of the known mechanisms capable of generating hyponatremia.

Treatment of Hyponatremia Specific considerations of therapies for all of the disorders associated with hyponatremia exceeds the intended scope of this review. General principles helpful in dealing with the correction of serum sodium per se will be considered here. Treatment should address four issues. (1) Can the basic disease be treated? (2) How much sodium is required if it is necessary to acutely raise serum sodium? (3) Once the serum sodium concentration is within a safe range, how much additional sodium is necessary to fully correct the serum sodium abnormality? (4) To what extent should total body water be altered? Treatment directed toward correcting or positively modifying the basic disease process should begin whenever possible. Some therapies currently available to modify the serum sodium concentration in specific disorders have already been considered. The acute treatment ofhyponatremic patients should be considered when the true serum sodium-concentration is less than 120 mEq/L or when significant symptoms are present. 31• 32 Very rapid intravenous "push infusions" of hypertonic sodium-containing solutions are best avoided in order to prevent a severe transient elevation of extracellular fluid osmolality with its attendant consequences. Rather, the serum sodium concentration should be increased to approximately 125 mEq/L by a continuous infusion over a period of 30 to 240 minutes depending on the nadir of the serum sodium concentration and the clinical status of the patient. The quantity of sodium necessary to raise the serum concentration may be approximated by the following formula: mEq/L sodium required = (desired [Na+] - present [Na+])

X

TBW in liters

Total body water may be estimated in most children by multiplying the body weight of the ill patient by 0.6 but it should be realized that the actual amount of total body water may have been altered because of disease. The error in the required number of mEq of sodium derived by estimating total

SERUM SODIUM ABNORMALITIES IN CHILDREN

929

body water in this fashion should not present any clinical problem. Repeated measurements of the serum sodium concentration are necessary to document the progress of therapy. The further correction of the serum sodium may then be planned to occur during the ensuing 18 to 36 hours. The same formula may be used to ascertain how much sodium is required to return the serum sodium concentration to normal. In hypovolemic hyponatremic patients not only should the sodium concentration be increased but also the extracellular fluid requires iso-osmotic expansion. It should be remembered that if a hypovolemic hyponatremic child were to have his abnormal serum sodium fully corrected, the child would still be hypovolemic with an iso-osmotic total body sodium and water deficit. · Once it is decided how much sodium is required, the next decision ought to address whether, and then how much, water should be added to or removed from the patient. Total body water needs to be lowered in some euvolemic hyponatremic patients. In patients with an increase in "effective" volume such as that occurring in patients with SIADH, most of the administered sodium will be excreted and the serum sodium will remain low unless extracellular fluid volume is simultaneously reduced. Effective volume may be reduced either by severe water restriction, i.e., 20 to 25 per cent of daily maintenance, or in severely symptomatic patients by the intravenous administration of loop diuretics and the replacement of a fraction of the measured urinary losses of water and sodium by sodium-containing solutions. 34 Although it is best to measure the urinary sodium and potassium losses to ascertain specific losses, the replacement of 80 per cent of the urinary output until weight has dropped by 4 to 5 per cent with a solution containing NaCl, 75 mEq/L, and potassium, 30 mEq/L, is usually sufficient. Frequent determinations of serum electrolytes should be obtained. If prolonged therapy for SIADH is required and continued water restriction is not possible, a trial of lithium or demeclocycline should be considered. 26 The administration of these agents has been successful in the chronic management of SIADH, but experience in children is limited. Treatment of the hyponatremic component of hypervolemic hyponatremia should be aimed at correction of the basic disorder if possible and at the simultanous restriction of water if ADH excess is operative. In massively edematous patients with excesses of total body water and sodium, the ultimate therapeutic plan should be to reduce both with a combination of salt and water restriction, and the judicious use of diuretics. Diuretic administration alone may worsen the hyponatremia while reducing the total amount of sodium and water. If this occurs, the simultaneous provision of sodium to increase the serum sodium concentration will be required. If the patient is symptomatic because of hyponatremia it may be necessary to increase the sodium concentration acutely. The hypervolemic hyponatremia of renal failure occurring as a result of the continued input of hypotonic solutions may be treated by water restriction and rarely by the careful administration of additional sodium, realizing that pulmonary edema may develop. Dialysis remains the most effective therapy available to correct the electrolyte imbalance when severe symptomatic hypervolemic hyponatremia exists in children with renal failure.

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