Hypernatremia in Emergency Medicine

Practice Essentials

Sodium levels are tightly controlled in a healthy individual by regulation of urine concentration and an intact thirst mechanism. Hypernatremia (defined as a serum sodium level >145 mEq/L) is rare in patients with preserved thirst mechanism. When hypernatremia is discovered in a patient, obtain urine osmolality and sodium levels. Check serum glucose level to ensure that osmotic diuresis has not occurred. The emergency department management of hypernatremia revolves around two tasks: restoration of normal serum tonicity and diagnosis and treatment of the underlying etiology. [1] Hypernatremia is associated with a high mortality rate (>50% in most studies). Consequently, the emergency physician must be able to recognize and treat this condition. This article discusses the patients in whom hypernatremia should be suspected and how to initiate workup and administer appropriate treatment. In general, hypernatremia can be caused by derangement of the thirst response or altered behavioral response thereto (primarily psychiatric patients, and elderly patients who are institutionalized), impaired renal concentrating mechanism (diabetes insipidus [DI]) secondary to kidney pathology (nephrogenic DI) or difficulty with the neurohormonal control of this concentrating mechanism (central DI), or by losses of free water from other sources. Assessment and treatment of a hypernatremic patient focuses on two important questions:

• What is the patient's volume status?

• Is the problem acute or chronic?

Signs and symptoms of hypernatremia Symptoms of hypernatremia tend to be nonspecific. Anorexia, restlessness, nausea, and vomiting occur early. These symptoms are followed by altered mental status, lethargy or irritability, and, eventually, stupor or coma. Musculoskeletal symptoms may include twitching, hyperreflexia, ataxia, or tremor. Neurologic symptoms are generally nonfocal (eg, mental status changes, ataxia, seizure), but focal deficits such as hemiparesis have been reported. Workup in hypernatremia When hypernatremia is discovered in a patient, obtain urine osmolality and sodium levels. Check the serum glucose level to ensure that osmotic diuresis has not occurred. Serum sodium level indications include the following:

• Serum sodium levels of more than 190 mEq/L usually indicate long-term salt ingestion

• Serum sodium levels of more than 170 mEq/L usually indicate diabetes insipidus (DI)

• Serum sodium levels of 150-170 mEq/L usually indicate dehydration

Head computed tomography (CT) scanning or magnetic resonance imaging (MRI) is suggested in all patients with severe hypernatremia. Traction on dural bridging veins and sinuses caused by movement of water from the brain and brain shrinkage can lead to intracranial hemorrhage, most often in the subdural space. Hemoconcentration from total body water loss may lead to dural sinus thrombosis. Imaging studies may indicate a central cause for hypernatremia. Emergency department management of hypernatremia The emergency department management of hypernatremia revolves around two tasks: restoration of normal serum tonicity and diagnosis and treatment of the underlying etiology. When possible, providing free water to a patient orally is preferred. Hypernatremia should not be corrected at a rate greater than 1 mEq/L per hour. Using isotonic sodium chloride solution, stabilize hypovolemic patients who have unstable vital signs before correcting free water deficits, because hypotonic fluids quickly leave the intravascular space and do not help to correct hemodynamics. Once stabilization has occurred, free water deficits can be replaced either orally or intravenously. Euvolemic patients can be treated with hypotonic fluids, either orally or intravenously (ie, dextrose 5% in water solution [D5W], quarter or half isotonic sodium chloride solution), to correct free fluid deficits. Hypervolemic patients require removal of excess sodium, which can be accomplished by a combination of diuretics and D5W infusion. Patients with acute renal failure may require dialysis. Traditionally, correction of hypernatremia begins with the following calculation of fluid deficit: Free Water Deficit = Body Weight (kg) X Percentage of Total Body Water (TBW) X ([Serum Na / 140] - 1)

Pathophysiology

Water homeostasis is maintained by a balance between water intake and the combined water loss from renal excretion, respiratory, skin, and GI sources. Under normal conditions, water intake and losses are matched. To maintain salt homeostasis, the kidneys similarly adjust urine concentration to match salt intake and loss. See the image below.

Figure A: Normal cell. Figure B: Cell initially responds to extracellular hypertonicity through passive osmosis of water extracellularly, resulting in cell shrinkage. Figure C: Cell actively responds to extracellular hypertonicity and cell shrinkage in order to limit water loss through transport of organic osmolytes across the cell membrane, as well as through intracellular production of these osmolytes. Figure D: Rapid correction of extracellular hypertonicity results in passive movement of water molecules into the relatively hypertonic intracellular space, causing cellular swelling, damage, and ultimately death. Hypernatremia results from disequilibrium of one or both of these balances. Most commonly, the disorder is caused by a relative free water loss, although it can be caused by salt loading. The various ways in which these equilibria can be disturbed are discussed in Causes. When hypernatremia (of any etiology) occurs, cells become dehydrated. Either the osmotic load of the increased sodium acts to extract water from the cells or a portion of the burden of the body's free water deficit is borne by the cell. (Sodium, primarily an extracellular ion, is actively pumped out of most cells and is the primary determinant of serum osmolarity.) Dehydrated cells shrink from water extraction. Cells immediately respond to combat this shrinkage and osmotic force by transporting electrolytes across the cell membrane, thus altering rest potentials of electrically active membranes. After an hour of hypernatremia, intracellular organic solutes are generated in an effort to restore cell volume and to avoid structural damage. This protective mechanism is important to remember when treating a patient with hypernatremia. Cerebral edema ensues if water replacement proceeds at a rate that does not allow for excretion or metabolism of accumulated solutes. The effects of cellular dehydration are seen principally in the CNS, where stretching of shrunken neurons and alteration of membrane potentials from electrolyte flux lead to ineffective functioning. If shrinkage is severe enough, stretching and rupture of bridging veins may cause intracranial hemorrhage.

Epidemiology

Frequency Pediatric patients in developing nations may be at increased risk for hypernatremia because infant feeding may be complicated by poor maternal milk production (secondary to nutritional status) and errors in reconstitution of powdered formula. An Italian study, by Giordano et al, found that hypernatremia accounted for just 4.4% of all cases of electrolyte imbalance in the study’s emergency department (compared with 44% for hyponatremia). [4] Mortality/Morbidity The mortality rate from hypernatremia is high, especially among elderly patients. Mortality rates of 42-75% have been reported for acutely evolving hypernatremia and 10-60% for chronic hypernatremia. Because patients with hypernatremia often have other serious comorbidities, precisely evaluating the degree of mortality directly due to hypernatremia is difficult. Morbidity in survivors is high, with many patients experiencing permanent neurologic deficits. Most deaths are due to an underlying disease process, rather than the hypernatremia itself. Delay in treatment (or inadequate treatment) of hypernatremia increase mortality. A study by Vedantam et al reported that in patients with severe traumatic brain injury (TBI), an independent association exists between the development of hypernatremia after hospital admission, whether mild, moderate, or severe, and an increased likelihood of early mortality. The investigators cited mortality hazard ratios for mild, moderate, and severe hypernatremia of 3.4, 4.4, and 8.4, respectively, in severe TBI. [5] A study by Huang et al indicated that in patients with chronic kidney disease, hypernatremia is associated with an increased risk for all-cause mortality and for deaths unrelated to cardiovascular problems or malignancy. Hyponatremia was found to be associated with an increased risk for the same, as well as for cardiovascular- and malignancy-related mortality. The study included 45,333 patients with stage 3 or 4 chronic kidney disease, 9.2% of whom had dysnatremia. [6] A Turkish study, by Ates et al, indicated that in patients presenting to emergency departments with severe hypernatremia, independent risk factors for mortality included low systolic blood pressure, low pH, Na+ level over 166 mmol/L, increased plasma osmolarity, a mean sodium reduction rate of -0.134 mmol/L/h or less, dehydration, and, pneumonia. The retrospective study included 256 patients. [7] A study by Castello et al indicated that in patients with sepsis, the presence of hypernatremia or moderate to severe hyponatremia, at presentation to the emergency department, is an independent risk factor for mortality. For hypernatremia, the hazard ratios for 7- and 30-day mortality were 3.52 and 2.14, while for mild to moderate hyponatremia they were 4.89 and 1.79. [8] In hospitalized patients, persistent hypernatremia and protracted hypotension have been associated with a very poor prognosis. A study by Jung et al indicated that in patients with community-acquired hypernatremia, an independent association exists between admission to the hospital from the emergency department and hospital mortality, with the same being true for oral intake restriction, mean arterial pressure, and respiratory rate. Also with regard to hospital mortality, multivariate analysis revealed a peak sodium level in the moderate or severe range to be an independent risk factor. [9] The aforementioned study by Giordano et al stated that the great majority of electrolyte imbalances encountered in the report were associated with other systemic diseases. Dividing the study population into young, middle aged, and elderly, the investigators found that in the young group, electrolyte imbalances were most commonly associated with gastrointestinal disease, while in the middle-aged group, they were most often associated with cardiovascular disease, and in the elderly group, with cardiovascular disorders and lung disease. [4] Sex Hypernatremia is diagnosed in males and females in equal numbers. Age Patients who present to the hospital with hypernatremia tend to be at the extremes of age. Breastfed infants occasionally present with hypernatremia in the first weeks of life, and elderly patients who are institutionalized are especially heavily represented. A study from Japan, by Imai et al, indicated that the prevalence of hyponatremia in the emergency department is greater in elderly patients than in adults aged 18-64 years (2.6% vs 0.7%, respectively). Moreover, moderate to severe hypernatremia had a prevalence of 1.0% in the elderly group, versus 0.1% in other adults. Although higher prevalence in the elderly occurred year round, the investigators found seasonal variation, with the prevalence of moderate to severe hypernatremia in the older cohort being greatest in winter. [10]

Clinical Presentation

History The history in the hypernatremic patient often points to the etiology of the syndrome. Search for any cause of extrarenal fluid losses (eg, burns, vomiting, diarrhea, fevers). Investigate the patient's perception of his or her fluid status and corrective measures he or she has taken. Does the patient complain of polyuria or polydipsia (ie, signs of DI or osmotic diuresis)? Does the patient have an intact thirst response? (This is often impaired in elderly persons.) A diminished thirst response is an indication to investigate the hypothalamus for a lesion in the thirst centers. For unclear reasons, patients with DI often crave ice-cold water (pagophagia). In infants, seek sources of extra-renal losses, and investigate the patient's dietary habits. Hypernatremia in infants is often caused by improper preparation of formula or poor maternal milk production. [11] In patients who are hospitalized, reviewing the medicines and the types of feedings that the patient has received is important to exclude iatrogenic excessive sodium load. Commonly identified sources include the administration of sodium bicarbonate during cardiac arrest, high-sodium tube feedings, or overaggressive infusion of 3% isotonic sodium chloride solution. Pharmaceutical causes of nephrogenic DI should also be considered (see Causes). Symptoms of hypernatremia tend to be nonspecific. Anorexia, restlessness, nausea, and vomiting occur early. These symptoms are followed by altered mental status, lethargy or irritability, and, eventually, stupor or coma. Musculoskeletal symptoms may include twitching, hyperreflexia, ataxia, or tremor. Neurologic symptoms are generally nonfocal (eg, mental status changes, ataxia, seizure), but focal deficits such as hemiparesis have been reported.

Physical Physical examination findings in hypernatremia are nonspecific. Assessment of overall fluid status is important when determining the cause of the hypernatremia. Note signs of volume status, including mucous membranes, skin turgor, orthostatic vital signs, and neck veins. Because neurologic deficits are common in hypernatremia, perform a thorough neurologic examination. Significant hypovolemia can result when hypotonic fluid losses cause hypernatremia. The physical findings are those of dehydration or even hypovolemic shock, with tachycardia, orthostasis, and hypotension.

Causes Hypernatremia is due to too little water, too much salt, or a combination thereof. The alteration can be in administration (too much salt or too little water) or output (too much dilute urine or extrarenal free water losses). [12, 13, 14] The most common cause of hypernatremia in the elderly or institutionalized patients is lack of free water intake to meet losses adequately. Thirst is the body's main defense against increased serum tonicity. The thirst drive is activated through 2 pathways, one responsive to decreased intravascular volume and the other responsive to even slight increases in serum osmolarity. Most patients with an intact thirst mechanism and access to water can prevent the development of hypernatremia. Even patients with a defective renal concentrating mechanism (eg, patients with DI who may produce up to 20 L of urine a day) generally can keep up with water losses if they have free access to water. Some patients, however, cannot respond to their thirst drive. Infants and elderly patients who are debilitated depend on caregivers to provide fluids. Similarly, institutionalized patients may have limited access to water secondary to either external or internal constraints (eg, no access to water in their room, they believe the water is poisoned and refuse to drink it). Intrinsic water losses cannot be avoided, and some urine must be produced, even if it is maximally concentrated. Without access to water, these patients encounter a free water deficit, and their serum sodium level increases. In some instances, the difficulty stems from an inability of the kidneys to concentrate the urine. This is known as diabetes insipidus (DI). DI can be due to a lack of a central stimulus to concentrate the urine (ie, lack of antidiuretic hormone [ADH] production [central DI]) or to a lack of renal response to such stimulus (ie, nephrogenic DI). The kidneys can fail to respond secondary to resistance to vasopressin or due to loss of the medullary-concentrating gradient for urine. The differential diagnosis is most easily managed if the physician considers the patient's volume status. Hypovolemic hypernatremia (ie, water deficit >sodium deficit) Adipsic hypernatremia is secondary to decreased thirst. This can be behavioral or, rarely, secondary to damage to the hypothalamic thirst centers.

• Extrarenal losses - Diarrhea, vomiting, fistulas, significant burns

• Renal losses - Osmotic diuretics, diuretics, postobstructive diuresis, intrinsic renal disease

Hypervolemic hypernatremia (ie, sodium gains >water gains) See the list below:

• Hypertonic saline

• Sodium bicarbonate administration

• Accidental salt ingestion (eg, error in preparation of infant formula)

• Mineralocorticoid excess (Cushing syndrome)

Euvolemic hypernatremia See the list below:

• Extrarenal losses - Increased insensible loss (eg, hyperventilation)

• Renal losses - Central DI, nephrogenic DI

These patients appear euvolemic because most of the free water loss is from intracellular and interstitial spaces, with less than 10% occurring from the intravascular space. Typically, symptoms result if serum sodium level is more than 160-170 mEq/L. Central DI differential diagnosis See the list below:

• Head trauma

• Suprasellar or intrasellar tumors

• Granulomas (sarcoidosis, Wegener granulomatosis, tuberculosis, syphilis)

• Histocytosis (eosinophilic granuloma)

• Infectious (encephalitis, meningitis, Guillain-Barré syndrome)

• Vascular (cerebral aneurysm, thrombosis, hemorrhage, Sheehan syndrome)

• Congenital

• Transient DI of pregnancy

Nephrogenic DI (deficient renal response to ADH) differential diagnosis See the list below:

• Advanced renal disease (interstitial disease)

• Electrolyte disturbances - Hypokalemia, hypercalcemia

• Systemic diseases - Sickle cell disease, Sjögren syndrome, amyloidosis, Fanconi syndrome, sarcoidosis, renal tubular acidosis, light-chain nephropathy

• Dietary disturbances - Excessive water intake, decreased salt intake, decreased protein intake

• Drugs - Lithium, demeclocycline, colchicine, vinblastine, amphotericin B, gentamicin, furosemide, angiographic dyes, osmotic diuretics

• Miscellaneous - Postobstructive diuresis, diuretic phase of acute renal failure, osmotic diuresis, paroxysmal hypertension

Differential Diagnoses

• Hyperosmolar Hyperglycemic Nonketotic Coma

Workup

Laboratory Studies When hypernatremia is discovered in a patient, obtain urine osmolality and sodium levels. Check serum glucose level to ensure that osmotic diuresis has not occurred. The kidneys' normal response to hypernatremia is excretion of a minimal amount of maximally concentrated urine. If urine osmolarity is high, suspect extrarenal hypotonic fluid losses (eg, vomiting, low sodium diarrhea, sweat, evaporation from burns, low sodium ostomy output). The urine also is concentrated in salt overload states, although the total volume should increase. Isotonic urine osmolality can be observed with diuretics, osmotic diuresis (mannitol, glucose, urea), or salt wasting. Hypotonic urine and polyuria are characteristic of DI. Note, however, that partial DI can occur in which some concentrating ability remains, especially in the absence of a water load. Serum sodium level indications include the following:

• Serum sodium levels of more than 190 mEq/L usually indicate long-term salt ingestion

• Serum sodium levels of more than 170 mEq/L usually indicate DI

• Serum sodium levels of 150-170 mEq/L usually indicate dehydration

A study by Solak indicated that results from blood gas analyzers (BGAs), which may be used in the emergency department to measure sodium pending results from biochemistry laboratory autoanalyzers (BLAs), tend to significantly differ from BLA values. It was found that BLA serum sodium values tended to be higher than BGA results for hyponatremia, eunatremia, and hypernatremia, with an absolute mean difference of over 4 mmol/L for the three groups. [15]

Imaging Studies Head CT scan or MRI is suggested in all patients with severe hypernatremia. Traction on dural bridging veins and sinuses caused by movement of water from the brain and brain shrinkage can lead to intracranial hemorrhage, most often in the subdural space. Hemoconcentration from total body water loss may lead to dural sinus thrombosis. Imaging studies may indicate a central cause for hypernatremia.

Other Tests Water deprivation test With DI, water deprivation induces serum hyperosmolality and hypernatremia, but urine osmolality does not increase appropriately. ADH stimulation With nephrogenic DI, urine osmolality does not increase after ADH or desmopressin acetate administration.

Treatment & Management

Prehospital Care Standard supportive attention to the ABCs is appropriate. Hypovolemic patients with signs of hemodynamic compromise (eg, tachycardia, hypotension) should receive volume resuscitation with isotonic sodium chloride solution. If a thirsty patient's mental status allows, he or she does not need to be kept in a nothing-by-mouth status. In the debilitated nursing home patient, hypodermoclysis (subcutaneous fluid administration) may be considered as an alternative to transport to a hospital.

Emergency Department Care The emergency department management of hypernatremia revolves around two tasks: restoration of normal serum tonicity and diagnosis and treatment of the underlying etiology. When possible, providing free water to a patient orally is preferred. Hypernatremia should not be corrected at a rate greater than 1 mEq/L per hour. Carefully monitor all patients' inputs and outputs during treatment. Consider CNS imaging to exclude a central cause or to identify CNS bleeding from stretching of veins. Using isotonic sodium chloride solution, stabilize hypovolemic patients who have unstable vital signs before correcting free water deficits, because hypotonic fluids quickly leave the intravascular space and do not help to correct hemodynamics. Once stabilization has occurred, free water deficits can be replaced either orally or intravenously. Euvolemic patients can be treated with hypotonic fluids, either orally or intravenously (ie, dextrose 5% in water solution [D5W], quarter or half isotonic sodium chloride solution), to correct free fluid deficits. Hypervolemic patients require removal of excess sodium, which can be accomplished by a combination of diuretics and D5W infusion. Patients with acute renal failure may require dialysis. Traditionally, correction of hypernatremia begins with a calculation of the fluid deficit as shown below. Predicted insensible and other ongoing losses are added to this number and the total is administered over 48 hours. Recheck serum electrolyte levels frequently during therapy. To avoid cerebral edema and associated complications, the serum sodium level should be lowered by no more than 1 mEq/L every hour. In patients with chronic hypernatremia, an even more gradual rate is preferred. An alternative method to plan the correction of sodium imbalances has been proposed by Adrogue and Madias. They have devised a formula that can be used to calculate the change in serum sodium level after the administration of 1 L of a given infusate. This formula has the advantages of taking into consideration the tonicity of the infusate and encouraging reassessment of the treatment plan with each liter of solution or new set of electrolytes. Free Water Deficit = Body Weight (kg) X Percentage of Total Body Water (TBW) X ([Serum Na / 140] - 1) The percentage of TBW should be as follows:

• Young men - 0.6%

• Young women and elderly men - 0.5%

• Elderly women - 0.4%

An example is as follows: A serum sodium level of 155 in a 60-kg young man represents a fluid deficit of 60 X 0.6 X ([155 / 140] - 1) or 3.9 L. With another 900 mL of insensible losses, the patient requires 4.8 L of fluid in the next 48 hours, resulting in an infusion rate of 100 mL/h. The Adrogue and Madias formula is as follows: Change in Serum Sodium = ([Na] Infused - [Na] serum) / (TBW + 1) The "1" in the denominator represents the extra liter of infusate added to TBW. When TBW is calculated as above, TBW = Body Weight (kg) X Percent Water An example is as follows: For the patient above, the expected change can be calculated with D5W or D5 half isotonic sodium chloride solution. For D5W, Change = (0 - 155) / ([60 X 0.6] + 1) = -4.18 mEq/L For half isotonic sodium chloride solution, Change = (77 - 155) / ([60 X 0.6] + 1) = -2.1 mEq/L If D5W is chosen to avoid fluid overload, an infusion rate of 250 mL/h results in a correction just over 1 mEq/h. (Note: This assumes the patient has no other losses during this time. Intrinsic losses make the correction slower [more conservative] than calculated.)

Consultations Patients with renal failure may require dialysis to help correct sodium and fluid balance.

Medication

Medication Summary Maintenance of adequate fluid intake is the most important therapy for all causes of DI that can result in hypernatremia. Hormonal and pharmacologic therapies must be tailored for the specific causes of DI (eg, central, nephrogenic). Central DI is treated with replacement therapy of ADH. The therapy for nephrogenic DI depends on reducing urine volume with combinations of salt restriction, thiazide diuretics, and prostaglandin synthetase inhibitors. The other causes of hyponatremia do not require medications beyond hypotonic fluid for correction.

ADH replacement therapy Class Summary This therapy reduces free water loss and concentrates the urine. Vasopressin (Pitressin) Has vasopressor and ADH activity. Increases water resorption at the distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction also is increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Decreases portal pressure in patients with portal hypertension. A notable undesirable effect is coronary artery constriction, which may dispose patients with coronary artery disease to cardiac ischemia. This can be prevented with concurrent use of nitrates. Duration of action is approximately 3-6 h. Short half-life lessens the risk of acute water intoxication and makes it the ideal treatment of central DI in emergent situations. Desmopressin acetate (DDAVP)

Increases cellular permeability of collecting ducts, resulting in reabsorption of water by the kidneys. Duration of action is approximately 12-24 h. Has become the long-term treatment of choice for central DI.

Follow-up

Further Inpatient Care Perform frequent reexaminations, especially neurologic examinations. Monitor electrolytes frequently (every 1-2 h during initial resuscitation, then every 4 h). Ensure adequate energy intake. Assess daily weights, intakes, and outputs.

Transfer Patients with hypernatremia who are fluid overloaded may require hemodialysis. If necessary, transfer these patients to a center with hemodialysis capabilities.

Deterrence/Prevention Prevention is directed at the underlying cause. Hypernatremia in infants is largely due to inappropriately reconstituted infant bottle formula. Avoid preparing homemade infant formulas, and never add salt to any commercial infant formula.

Complications Acute hypernatremia often results in significant brain shrinkage, thus causing mechanical traction of cerebral vasculature. Stretching of bridging veins can result in subdural hemorrhages. Venous congestion can lead to thrombosis of the intracranial venous sinuses. Arterial stretching can result in subcortical hemorrhages and cerebral infarctions. Seizures are possible. Hypernatremia of more than 2 days' duration is considered chronic hypernatremia and is associated with an increased mortality rate. Patients whose serum sodium level exceeds 180 mEq/L often have residual CNS damage. If hypernatremia is corrected too rapidly, brain edema and associated neurologic sequelae can occur. Patients with chronic hypernatremia are especially prone to this complication.

Prognosis Most patients survive, but residual neurologic deficits are common. Permanent neurologic sequelae have been reported in up to 30% of patients with acute hypernatremia.

Patient Education Because elderly patients often are affected, educating caretakers about dehydration avoidance measures is important. Patients with nephrogenic DI must be trained to avoid salt and to drink large amounts of water.

References

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