Abstract:

Dysnatremias can be a challenging diagnosis for pediatric emergency care providers because patients can present with vague symptoms but can quickly develop neurologic sequelae. It is important that emergency care physicians are knowledgeable about higher risk populations, clinical presentation, and possible etiologies to provide prompt treatment. This article will present 2 cases with sodium abnormalities and then review the epidemiology, pathophysiology, and current management practices for dysnatremias.

Keywords:
Dysnatremias; hypernatremia; hyponatremia; cerebral edema; central pontine myelinosis; water deficit

Hypernatremia and Hyponatremia: Current Understanding and Management

Catherine H. Chung, MD, MPH ,* Donald Zimmerman, MD

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*Division of Emergency Medicine, Childrens Memorial Hospital, Chicago, IL; Division of Endocrinology, Childrens Memorial Hospital, Chicago, IL. Reprint requests and correspondence: Catherine H. Chung, MD, MPH, Division of Emergency Medicine, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614. cachung@childrensmemorial.org
1522-8401/$ - see front matter 2009 Published by Elsevier Inc.

ysnatremias are a relatively common problem in the pediatric emergency department (ED). If not identified promptly or managed properly, patients can develop neurologic sequelae. Infants are at particular risk due to immature renal function, increased insensible water loss, and their inability to communicate symptoms or thirst. Hospitalized children are also at particular risk due to increased incidence of the syndrome of inappropriate antidiuretic hormone (SIADH), lack of free access to water, and improper intravenous fluid administration. To appropriately manage dysnatremias, the clinician must pay particular attention to fluid intake, fluid status (hypovolemia, euvolemia, hypervolemia), and insensible water losses.

CASE 1
A 3-week-old full-term female infant presents to the ED with a 2day history of weakness, lethargy. and worsening oral intake. The infant has been exclusively breast-fed; however, milk production has been minimal, and the patient feeds 5 minutes per breast every 3 hours. The patient has lost 15% of her birth weight and has not been urinating well today. Vitals signs on presentation include the following: temperature 37.5C; heart rate 180; respiratory rate 25; blood pressure 88/P mmHg; and weight 2.7 kg. The physical

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examination was remarkable for a depressed fontanelle, weak cry, and capillary refill time of 2 seconds. The electrolyte panel revealed the following: Na 160 mEq/L; K 4 mEq/L; Cl 130 mEq/L; HCO3 10 mEq/L; blood urea nitrogen 29 mg/dL; and creatinine 0.5 mg/dL. What is the likely cause of her hypernatremia? How should it be managed?

Defining Hypernatremia
Hypernatremia is defined by serum Na of more than 145 mEq/L and is a result of either excess total body sodium, limited free water intake, or free water loss1 (Table 1).

concentrated formula, inadequate breast-feeding, limited access to water for hospitalized patients, and iatrogenic administration of concentrated saline solutions have been reported in the literature.2-5 Moritz6 found that 60% of patients with hypernatremia developed it while they were inpatients. In the case above, the infant has breast-feeding hypernatremic dehydration. Several hypotheses for this etiology are proposed in the literature; however, it seems that in the setting of poor milk production, breast milk has higher levels of sodium with little free water.2-5

Neurologic Sequelae
Retrospective analysis of children with hypernatremic dehydration demonstrates significant neurologic sequelae, including hypertonicity, developmental delay, seizures, cerebral thrombosis, and cerebral hemorrhage despite appropriate rate of correction.3,5-7 Secondary complications such as acute renal failure and disseminated intravascular coagulation have also been reported in some patients.7 The acuity of the onset of hypernatremia, duration of uncorrected hypernatremia, and comorbidities (eg, metabolic syndromes and prematurity) result in higher morbidity and mortality. Mortality from hypernatremia is estimated at 10% to 16% despite correct rates of rehydration.5,6,8 In the setting of hypernatremia, water from the intracellular space will shift to the extracellular space via osmosis. When this occurs, the brain can acutely lose 10% to 15% of its volume and separate from the meninges, resulting in rupture of the cerebral veins.9 Cerebral hemorrhage, venous sinus thrombosis, and demyelinating disease can occur in the most severe cases. If hypernatremia slowly evolves over a long period of time, the clinical presentation and sequelae are less severe because neurons have the opportunity to adapt and reestablish intracellular volume. Osmolytes, which consist of amino acids and carbohydrates, will be produced inside neurons to provide a diffusion gradient to keep water in the intracellular space. This adaptive process is essential for neuroprotection; however, it can pose a danger if the hypernatremia is rapidly corrected such that neurons swell and result in cerebral edema.1

Clinical Manifestations
Patients can present with nonspecific signs such as weight loss, dehydration, lethargy, and weakness. If severe hypernatremia occurs acutely, the patient can be at risk for seizures and coma.1 Historical information and the physical examination can often highlight the cause of hypernatremia; however, hyperosmolality in serum (in association with hypernatremia) and dilute urine (urine osmolality b600 mOsm/kg or urine specific gravity b1.016) can help differentiate diabetes insipidus from other causes.

Epidemiology
Although diarrheal illness is the most common etiology of hypernatremia, the overall incidence of diarrhea-associated hypernatremia has been decreasing due to availability and widespread use of oral rehydration formulas. In a retrospective review of hospitalized children with hypernatremia, diarrheal illness accounted for only 20% of the cases.2 More recently, case reports of hypernatremia from

TABLE 1. Causes of hypernatremia.

Sodium excess Concentrated breast milk or formula Salt ingestion (accidental, seawater, Munchausen by proxy) Salt water enemas Hypertonic saline administration Sodium bicarbonate Free water deficit Diarrhea Increased insensible water loss (fever, tachypnea, premature infants) Diuresis (hyperosmolar states) Poor access to water or blunted sensation of thirst Diabetes insipidus

Management
How to best manage the patient's hydration status with close attention to the rate of sodium correction can be challenging. Certainly, if the patient is in hypovolemic shock or has significant hypovolemia, isotonic saline should be administered at 10 to 20 mL/kg for 1 hour to replenish the intravascular

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volume. To prevent rapid fluid shifts into neurons and cerebral edema, the remainder of the fluid deficit should be corrected during a 48- to 72-hour period, and in clinical circumstances suggesting chronicity of more than 1 day, serum sodium should be reduced at a rate no greater than 0.5 mEq/L per hour.1 There are several methodologies to estimate the affected child's water and solute deficit.1,9-12 However, the most important point to understand is that these calculations are merely rough estimations and that patients will vary in terms of the actual rate of correction. Therefore, it is imperative to closely monitor serum electrolytes every 2 to 4 hours to

ensure judicious correction. Figure 1 provides one example for the calculation of fluid and electrolyte requirements in a hypernatremic infant.

CASE 2
A 2-week-old full-term female infant with an unremarkable birth history presents with generalized tonic-clonic seizures. The mother, who is 19 years old, denies any fevers, changes in appetite, or activity. She states that the infant has been feeding well with powdered formula, in which she mixes 1 scoop of powder for every 4 oz of water. Vital signs on presentation include the following: temperature

Figure 1. Fluid and electrolyte management in hypernatremia.

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36.5C; heart rate 160; respiratory rate 24; blood pressure 89/P mmHg, and weight 3.2 kg. The infant's pre-illness weight was 3.5 kg. The physical examination was remarkable for a lethargic, mildly dehydrated neonate with a weak cry. Capillary refill was less than 2 seconds. The electrolyte panel revealed the following: Na 118 mEq/L; K 3.0 mEq/L; Cl 92; HCO3 18 mEq/L; blood urea nitrogen 17 mg/ dL; creatinine 0.3 mg/dL; and glucose 90 mg/dL. What is the likely cause of her hyponatremia? How should it be managed?

exclude hyperlipidemia and hyperproteinemia to differentiate between true hyponatremia versus pseudohyponatremia (Table 2).

Pathophysiology
When the body is in an intravascularly depleted state (ie, third spacing or dehydration), antidiuretic hormone is released; this triggers the kidneys to retain water even if hyponatremia is present. The preservation of intravascular volume supersedes the countervailing signal of hyponatremia.13 In the setting of SIADH, the body retains water from the overproduction of antidiuretic hormone despite being euvolemic. In a hyponatremic state caused by excess free water, there is an influx of water into the intracellular space, which can cause intracellular edema. In attempts to minimize cerebral edema, neurons and endothelial cells will excrete electrolytes, protein, and carbohydrates to the extracellular space. If correction with hypertonic fluid occurs too quickly, endothelial cells in proximity to neuronal processes rapidly lose water. This loss of cellular water produces endothelial cell shrinkage, which, in turn, enlarges the spaces between endothelial cells. Enlargement of spaces between endothelial cells changes the blood-brain barrier and allows myelinotoxic substances such as tumor necrosis factor and interferon- to cross. Destruction of the myelin sheath ensues this process; osmotic pontine myelinosis, also known as central pontine myelinosis, can result in mild to severe neurologic deficits.

Defining Hyponatremia
Hyponatremia is defined by serum Na less than 130 mEq/L and may be a result of excess free water intake and/or the inability of the kidneys to excrete free water, or it can be a result of inadequate total body sodium (due to insufficient intake or to excessive losses). Sodium levels are also closely linked to serum osmolality where hyperglycemia and treatment with mannitol or glycerol can cause increased osmolality in the extracellular space, which, in turn, causes efflux of water from the intracellular to the extracellular space; translocation of water produces a relative decrease of sodium compared with water. Finally, severe hyperlipidemia or hyperproteinemia can cause a substantial portion of plasma volume to restrict admixture with sodium; thus, sodium concentrations are normal in the plasma compartment, which allows sodium entry, but low in the total plasma volume. Therefore, it is important to confirm serum/urine osmolarity and to

Clinical Manifestations TABLE 2. Causes of hyponatremia. 1

Normal total body water and sodium Hyperglycemia Mannitol, glycerol therapy Increased total body water and sodium Congestive heart failure Acute renal failure Nephrosis Decreased total body water and sodium Gastrointestinal losses (diarrhea, emesis) Renal losses (diuretic, renal tubular acidosis, renal interstitial disease) Adrenal causes Third spacing Increased total body water and normal sodium SIADH Water intoxication Pseudohyponatremia Extreme hyperlipidemia or hypoproteinemia

The clinical presentation should greatly assist the ED physician in diagnosing the cause of hyponatremia. Children with hyponatremic dehydration manifest signs of dehydration such as low blood pressure, tachycardia, increased capillary refill time, dry mucus membranes, and decreased skin turgor. Children with congestive heart failure, nephrotic syndrome, or liver dysfunction manifest signs typical of these conditions, including edema. Children with hypothyroidism have typical symptoms of decreased energy, constipation, and cold intolerance and manifest signs including dry and sallow skin, bradycardia with narrow pulse pressure, and delayed relaxation phase of the deep tendon reflexes. Children with adrenal insufficiency have low energy and may have a history of prostration with intercurrent illness and hypoglycemic symptoms. Those with primary adrenal insufficiency have hyperpigmentation of the skin over bony prominences, in skin creases and of recent scars.

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Children with SIADH frequently have a history of central nervous system or pulmonary disease or a history of taking medications that can promote SIADH such as cyclophosphamide, vincristine, carbamazepine, haloperidol, or antidepressants. With the acute onset of hyponatremia, the shift of water from the extracellular to the intracellular space can cause cellular edema and may present with nonspecific signs such as anorexia, lethargy, and muscle cramps.1 If hyponatremia occurs quickly or if corrected too rapidly, cerebral edema can ensue, resulting in headache, emesis, mental status

changes, permanent neurologic damage, and death.9 Children are at greater risk for cerebral edema than are adults because they have higher brain to skull volume ratio, which means that there is less volume for cerebral expansion.9

Epidemiology
It is believed that water intoxication and gastroenteritis are the most common causes of hyponatremia in the first few years of life. A retrospective study of infants presenting with seizures and

Figure 2. Fluid and electrolyte management in hyponatremic dehydration.

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hyponatremia demonstrated that water intoxication was the primary cause in 70% of children younger than 6 months and in 56% of children younger than 2 years.12 Water intoxication is often due to dilution of powdered formula, as in the case above, usually by parents who are unaware how to properly mix formula or by those who try to extend their limited supplies. There have also been a few case reports of water intoxication as a manifestation of child abuse.13-16 The incidence of hyponatremia from gastroenteritis is unclear. Many recent studies have focused on iatrogenic hyponatremia of hospitalized children from hypotonic fluid administration.9,17-22 The incidence of iatrogenic hyponatremia has been estimated to be equivalent to 1% of hospitalized children.10 There have been 2 case reports describing the use of D5W in the ED for resuscitation, both of which resulted in mortality.23 Most of the case reports of death from iatrogenic hyponatremia have been in healthy children who received hypotonic fluid postoperatively.10 Overall, there seems to be strong evidence supporting a causal relationship; therefore, the use of hypotonic fluid in maintenance intravenous fluid therapy should be avoided.

hypothyroidism, congestive heart failure, liver failure, nephrotic syndrome, or intrinsic renal disease) or due to hyperosmolar states such as hyperglycemia or to pseudohyponatremic states such as hyperlipidemia. The sodium correction for hyperglycemia can be calculated as follows: Corrected sodium = measured sodium + 0:016 serum glucose 100: Obtaining serum and urine osmolarity will help delineate between a renal hyperconcentration state and water intoxication. In water intoxication, the urine will be appropriately dilute. In renal hyperconcentration, the urine is not diluted despite the presence of hyponatremia. In the context of SIADH, the patient will be euvolemic with high urine osmolality and sodium.9 In this case, fluid restriction will be the management of first choice unless the patient has seizures, impaired consciousness, or other severe symptoms or signs of hyponatremia. Figure 2 provides one example of calculating the deficit for the hypovolemic and hyponatremic patient described in the case above. Again, the most important point to understand is that these calculations are merely rough estimations and that patients will vary in terms of their actual rate of correction. Therefore, it is imperative to closely monitor serum electrolytes every 2 to 4 hours to ensure judicious correction.

Management
The management of seizures due to hyponatremia is the administration of 0.9% (normal) saline or 3% saline until the patient is seizure free. According to Fleisher and Ludwig, the volume of 3% saline to be administered can be calculated as follows: 10 mEq/L weight (kg) 0.6 or 10-12 mL/kg over 1 hour. There are different opinions regarding the continued use of 3% saline to obtain normal sodium levels. Moritz's recommendations also include the use of 3% saline to achieve an increase of sodium levels by 20 to 25 mEq/L or to achieve a serum sodium level of 125 to 130 mEq/L.9 Ray recommends a more judicious approach, citing successful outcomes with smaller increases in serum sodium levels.20 The overall aim is to base treatment on symptoms rather than the serum sodium level. The utilization of 3% saline to stop seizures due to hyponatremia is well accepted and should also be considered if the patient has symptoms consistent with cerebral edema. However, the rate of correction should not exceed 0.5 mEq/ h once seizures are controlled to minimize the risk of central pontine myelinosis. In less symptomatic patients, the clinician must try to determine if the hyponatremia is due to dehydration, water intoxication, renal hyperconcentration states (ie, SIADH, adrenal insufficiency,

SUMMARY
Dysnatremias can be a diagnostic challenge for pediatric emergency care providers because patients can present with vague symptoms. It is imperative that the ED physician consider the etiology to direct treatment. Correction of a dysnatremia should be judicious to avoid neurologic sequelae. This article provides management examples for both hypernatremia and hyponatremia; however, each patient will vary in the rate of his or her correction so calculations are mere estimations. Emergency department physicians should consult with a nephrologist if renal etiologies are considered.

REFERENCES
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