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Hospital-acquired hyponatremia: Why are patients still dying?

From the February ACP Hospitalist, copyright © 2009 by the American College of Physicians

By Michael L. Moritz, MD, and Juan Carlos Ayus, FACP

A healthy 32-year-old woman with a history of migraine headaches was admitted for an elective abdominal hysterectomy. She bled profusely during surgery and was given postoperative D5 1/4 NS with 10 mEq/L KCl at 125 mL per hour. Meperidine (Demerol) and promethazine (Phenergan) were administered for pain and nausea. Sixteen hours postoperatively she was awake and alert, but reported nausea and vomited once. Twenty-four hours postoperatively, she reported severe prefrontal headache with continued nausea and vomiting, which was treated with additional doses of meperidine and promethazine. Thirty-six hours postoperatively she had a brief apneic spell. She was found to be confused and combative with anisocoria, a serum sodium level of 119 mEq/L and osmolarity of 250 mOsm/kg, with a corresponding urine osmolality of 625 mOsm/kg. Her hemoglobin level was 8.2 g/L, and her hematocrit was 25%. Hypoxia was present on an arterial blood gas with a pH of 7.34, Po2 of 57 mm Hg, and Pco2 of 48 mm Hg. A chest X-ray revealed evidence of pulmonary edema.

The patient was transferred to the intensive care unit, where the pulmonary capillary wedge pressure was normal at 8 mm/Hg. She was evaluated by an intensivist and a neurologist. The intensivist thought she had a pulmonary embolism, the neurologist a subarachnoid bleed due to recurrent migraines; neither considered hyponatremic encephalopathy. The patient was sent for a CT scan. En route to radiology she had a seizure and a respiratory arrest. Her pupils were fixed and dilated. Six hours later the urine output increased to 300 mL/hour, and the urine osmolality fell to 60 mOsm/L. The serum sodium level rose to 164 mEq/L. Twenty-four hours later, the patient died. An autopsy showed uncal herniation, intact basilar artery, massive cerebral edema and patent pulmonary arteries.

Why was the diagnosis of hyponatremic encephalopathy missed?

Most physicians are unfamiliar with acute symptomatic hyponatremia as a complication of elective surgery. In 1986, Arieff reported on 15 healthy women undergoing elective surgery who died or developed permanent brain damage from hyponatremic encephalopathy (N Engl J Med. 1986;314:1529-35). The disorder was suspected in only one-third of patients at the time of respiratory arrest, despite the involvement of 42 consultants and the performance of multiple neuroimaging studies. Neurogenic pulmonary edema is an often-overlooked clinical presentation of hyponatremic encephalopathy; this is now referred to as Ayus-Arieff syndrome (Nat Clin Pract Nephrol. 2006;2:283-8, quiz 9; Clin J Am Soc Nephrol. 2008;3:1852-6), after these authors’ initial report of its occurrence in 30 postoperative patients (Chest. 1995;107:517-21). (Hyponatremic encephalopathy has similarly been underdiagnosed in the exercise community, resulting in the death of many marathon runners who present to the medical tent with neurogenic pulmonary edema [Clin J Sport Med. 2008;18:379-81]. Ayus and Arieff were the first to report the successful treatment of this presentation with hypertonic saline [Ann Intern Med. 2000;132:711-4]).

The patient in the current case developed brain herniation and death from untreated hyponatremic encephalopathy. She had two generally underappreciated features of hyponatremic encephalopathy with herniation: anisocoria and central diabetes insipidus. Cerebral herniation results in compression of the third cranial nerve (occulomotor nerve), resulting in anisocoria, and also leads to infarction of the pituitary and hypothalamus, resulting in central diabetes insipidus and mellitus (Ann Intern Med. 1990;112:113-9).

Why did this patient develop hyponatremia?

Hospital-acquired hyponatremia (Na <135 mEq/L) affects approximately 30% of hospitalized patients (Nat Clin Pract Nephrol. 2007;3:374-82). It primarily results from an impaired ability to excrete free water due to arginine vasopressin (AVP) excess and administration of hypotonic fluids (Nephrol Dial Transplant. 2003;18:2486-91). Postoperative patients are at the highest risk for developing hyponatremia because they have multiple stimuli for AVP production. The patient in the current case had multiple hemodynamic stimuli, including volume depletion from profuse blood loss and the vasodilatory affect of narcotic administration. She also had nonhemodynamic stimuli for AVP production: nausea, vomiting and severe pain. Nausea and vomiting are among the most potent stimuli for AVP production. The combination of these factors put her at significant risk for hyponatremia. The AVP excess seen in the postoperative setting usually lasts for two to three days, but can persist for as long as five days (Ann Intern Med. 1992;117:891-7).

For hyponatremia to develop, there also must be a source of free water. This patient received a significant amount of free water postoperatively in the form of 1/4 NS. Hyponatremia developed not only from free water retention, but also from the renal generation of free water as the patient was excreting a hypertonic urine (625 mOs/kg). If 0.9% NS had been administered, serum sodium levels would probably not have decreased (Pediatrics. 2003;111:227-30).

Are women more susceptible to developing hyponatremic encephalopathy?

Menstruant females are at the highest risk for hyponatremic encephalopathy, and most of the reported deaths and neurologic dysfunction from hyponatremic encephalopathy in adults have occurred in women (Neurology. 1996;46:323-8). It is not uncommon to encounter severe hyponatremic encephalopathy in menstruant females with a serum sodium level as high as 128 mEq/L, whereas an elderly man can have a serum sodium of 110 mEq/L with minimal symptoms. Epidemiologic studies have shown that the relative risk of death or permanent neurologic dysfunction from hyponatremic encephalopathy is approximately 30 times greater for women than for men and about 25 times greater for menstruant women than for postmenopausal women (Ann Intern Med. 1992;117:891-7). Estrogens appear to impair brain cell volume regulation by reducing Na+-K+-ATPase pump activity and thereby inhibiting sodium extrusion from brain astrocytes. Androgens, on the other hand, appear to enhance Na+-K+-ATPase pump activity and confer a protective role in men (Am J Physiol Renal Physiol. 2008;295:F619-24). Women are also more susceptible to hyponatremic encephalopathy because the vasoconstrictive effects of AVP are more pronounced in the female brain than in that of the male. AVP excess leads to cerebral vasoconstriction with corresponding decreased oxygen delivery (Am J Physiol Renal Physiol. 2008;295:F619-24).

How common is postoperative hyponatremic encephalopathy?

The incidence of significant postoperative hyponatremia (Na < 130 mEq/L) is between 1% and 5%, and symptomatic hyponatremia occurs in approximately 20% of these patients (Neurology. 1996;46:323-8). The morbidity and mortality of postoperative hyponatremic encephalopathy is approximately 50%. The U.S., then, could see at least 20,000 cases of postoperative hyponatremic encephalopathy per year with a morbidity and mortality of 10,000 cases per year, assuming 25 million surgeries per year with at least a 1% incidence of postoperative hyponatremia, a 10% incidence of hyponatremic encephalopathy and a 50% incidence of morbidity and mortality (Neurology. 1996;46:323-8).

Are hypoxia and pulmonary edema common features of hyponatremic encephalopathy?

Many clinical studies have found that hypoxia is a common presenting feature of hyponatremic encephalopathy and a major comorbidity factor (Chest. 1995;107:517-21). In a study of 65 adults with hyponatremic encephalopathy, 33 patients who died or suffered brain damage had hypoxia (Ann Intern Med. 1992;117:891-7). In a study of 53 adult women with chronic symptomatic hyponatremia, approximately 25% presented with hypoxia before therapy was started or respiratory arrest occurred (JAMA. 1999;281:2299-304). Hyponatremic encephalopathy can lead to hypoxia by neurogenic pulmonary edema or hypercapnic respiratory failure (Chest. 1995;107:517-21). In a variety of conditions, increased intracranial pressure can result in pulmonary edema via either a centrally mediated increase in pulmonary vascular permeability to proteins or increased sympathetic neuronal activity with catecholamine release, resulting in pulmonary vasoconstriction with increased capillary hydrostatic pressure and capillary wall injury (Clin J Sport Med. 2008;18:379-81). Hypercapnic respiratory failure appears to be a sign of central respiratory depression and impending herniation. Hypoxia is particularly dangerous in hyponatremic patients because the combination of these two factors leads to a decrease in cerebral perfusion and cerebral oxygen delivery, impairing the brain volume regulatory response (Kidney Int. 2006;69:1319-25).

How can this condition be prevented?

We believe 0.9% sodium chloride should be used in maintenance parenteral fluids to prevent hyponatremia (Nat Clin Pract Nephrol. 2007;3:374-82, Pediatrics. 2003;111:227-30). Several prospective studies in children and adults have shown that the administration of 0.9% sodium chloride is effective prophylaxis and that hypotonic fluids result in a consistent fall in serum sodium level (Pediatr Nephrol. 2005;20:1687-700). Even in patients with syndrome of inappropriate antidiuretic hormone (SIADH), the administration of normal saline does not aggravate hyponatremia. There can be no justification for administering hypotonic fluids in postoperative patients who have multiple stimuli for AVP production with impaired free water excretion.

What is the best treatment?

Hyponatremic encephalopathy is a medical emergency that requires early recognition and treatment. Headache with nausea and vomiting are the most common presenting symptoms. Hyponatremic encephalopathy should be considered in any hyponatremic patients with headache, nausea, vomiting or confusion. Multiple studies have shown that poor neurological outcome in hyponatremic encephalopathy is the result of inadequate therapy rather than overcorrection (N Engl J Med. 1986; 314:1529-35, JAMA. 1999;281:2299-304). Treatment should be based on neurological symptoms, not on the absolute serum sodium concentration.

Patients with symptomatic hyponatremia should be treated promptly with 3% sodium chloride. Unfortunately, perceived risk of cerebral demyelination from overcorrection of hyponatremia has been a significant barrier to hypertonic saline use. Cerebral demyelination, a rare condition, has been reported in patients with chronic hyponatremia (>48 hours) who had an additional risk factor of liver disease or alcoholism, hypoxia, or correction in serum sodium level of more than 25 mEq/L in the first 24 to 48 hours of therapy (N Engl J Med. 1987;317:1190-5). We advocate a new approach to using 3% sodium chloride for hyponatremic encephalopathy to facilitate early and aggressive therapy and prevent any inadvertent overcorrection of hyponatremia. Any patient with suspected hyponatremic encephalopathy should receive a 100-mL bolus of 3% sodium chloride (Clin J Sport Med. 2008;18:379-81, Nat Clin Pract Nephrol. 2007;3:374-82, N Engl J Med. 2005;353:427-8), which would result in at most a 2 mEq/L acute rise in serum sodium level that would quickly reduce brain edema. The bolus could be repeated two to three times if symptoms persist. A patient who does not show some clinical improvement after two to three boluses of 3% sodium chloride probably does not have hyponatremic encephalopathy. Our approach is superior to a continuous infusion of 3% sodium chloride because it facilitates a controlled, immediate rise in serum sodium level and presents little or no risk of overcorrection if the infusion runs too long.

The authors thank Karen Branstetter for editorial assistance.

Dr. Moritz is associate professor of pediatrics at the Children’s Hospital of Pittsburgh of UPMC and University of Pittsburgh School of Medicine. Dr. Ayus is the director of clinical research at Renal Consultants of Houston in Texas. This article is based in part on Dr. Ayus’s presentation at Internal Medicine 2008 in Washington, D.C.

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Atypical features of hyponatremic encephalopathy

  • Neurogenic pulmonary edema, usually postoperatively
  • Collapse in marathon runners or other high-endurance athletes
  • Gait disturbances with fall and orthopedic injury as the initial presentation of chronic hyponatremia; most common in elderly patients taking thiazide diuretics
  • Central diabetes insipidus following untreated hyponatremic encephalopathy with cerebral herniation

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Related reading

Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. 1986;314:1529-35.
Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol. 2008;295:F619-24.
Ayus JC, Arieff A, Moritz ML. Hyponatremia in marathon runners. N Engl J Med. 2005;353:427-8.
Ayus JC, Arieff AI. Brain damage and postoperative hyponatremia: the role of gender. Neurology. 1996;46:323-8.
Ayus JC, Arieff AI. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA. 1999;281:2299-304.
Ayus JC, Arieff AI. Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure. Chest. 1995;107:517-21.
Ayus JC, Armstrong D, Arieff AI. Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents. Kidney Int. 2006;69:1319-25.
Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med. 1987;317:1190-5.
Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med. 2000;132:711-4.
Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med. 1992;117:891-7.
Campbell GA, Rosner MH. The agony of ecstasy: MDMA (3,4-methylenedioxymethamphetamine) and the kidney. Clin J Am Soc Nephrol. 2008;3:1852-60.
Fraser CL, Arieff AI. Fatal central diabetes mellitus and insipidus resulting from untreated hyponatremia: a new syndrome. Ann Intern Med. 1990;112:113-9.
Kalantar-Zadeh K, Nguyen MK, Chang R, Kurtz I. Fatal hyponatremia in a young woman after ecstasy ingestion. Nat Clin Pract Nephrol. 2006;2:283-8, quiz 9.
Moritz ML, Carlos Ayus J. Hospital-acquired hyponatremia—why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol. 2007;3:374-82.
Moritz ML, Ayus JC. Exercise-associated hyponatremia: why are athletes still dying? Clin J Sport Med. 2008;18:379-81.
Moritz ML, Ayus JC. The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant. 2003;18:2486-91.
Moritz ML, Ayus JC. Preventing neurological complications from dysnatremias in children. Pediatr Nephrol. 2005;20:1687-700.
Moritz ML, Ayus JC. Prevention of hospital-acquired hyponatremia: a case for using isotonic saline. Pediatrics. 2003;111:227-30.

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Key points

  • Postoperative patients are at high risk for hyponatremia due to multiple hemodynamic and nonhemodynamic stimuli for arginine vasopressin production
  • Administration of hypotonic fluids is the main contributing factor to developing postoperative hyponatremia
  • 0.9% sodium chloride in maintenance fluids perioperatively is the most effective therapy to prevent postoperative hyponatremia
  • Headache, nausea and vomiting are universal presenting features of hyponatremic encephalopathy
  • A 100-mL bolus of 3% NaCl should be administered if hyponatremic encephalopathy is suspected

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