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Exercise-Associated Hyponatremia Masquerading as Acute Mountain Sickness: Are We Missing the Diagnosis?

Ayus, Juan Carlos MD*; Moritz, Michael L MD

Clinical Journal of Sport Medicine: September 2008 - Volume 18 - Issue 5 - p 383-386
doi: 10.1097/JSM.0b013e3181883d2d
Editorial

From the *Renal Consultants of Houston, Houston, Texas; and †Division of Nephrology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Submitted for publication July 9, 2008; accepted July 28, 2008.

The authors state that they have no financial interest in the products mentioned within this article.

Reprints: Juan Carlos Ayus, MD, Director of Clinical Research, Renal Consultants of Houston, 2412 Westgate St, Houston, TX 77019 (e-mail: carlosayus@yahoo.com).

We have recently observed that the symptom complex of exercise-associated hyponatremia (EAH) has significant overlap with features of acute mountain sickness (AMS). Given the life-threatening nature of both conditions, it is imperative that physicians recognize these entities and rapidly institute appropriate treatment.

The evolution of this connection began in 1995 when our group first reported on 30 patients with postoperative hyponatremic encephalopathy and hypoxia who developed pulmonary edema.1 This was recognized to be non-cardiogenic pulmonary edema as a result of increased intracranial pressure. In 2000, our group further reported on 7 patients with EAH after marathon participation who presented to local emergency rooms with hyponatremic encephalopathy and non-cardiogenic pulmonary edema.2 Since the initial report, this has been found to be an important complication of high endurance events.3 More recently, one of the authors (JCA) has personally witnessed the same phenomena occurring in a hiker presenting with hyponatremic encephalopathy and non-cardiogenic pulmonary edema, but with the diagnosis being confused as AMS with high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE). The similar clinical manifestations of these 2 conditions prompt us to wonder how often cases labeled as AMS are really EAH or are complicated by EAH. In this report, we will discuss the similarities, pathogenesis, and the implications for treatment.

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SIMILARITIES BETWEEN EAH AND AMS

In the absence of laboratory measurement of serum sodium (NA+), EAH and AMS are indistinguishable. Both occur in otherwise healthy individuals. The clinical features are essentially the same, a headache in combination with any or all of the following: nausea, vomiting, lethargy, confusion, and gait disturbances (Table 1).3,4 Both conditions can progress to cerebral edema with non-cardiogenic pulmonary edema.2 In fact, both conditions are associated with intense physical exertion: exercise is a risk factor for the development of both AMS and HACE.5 The main distinguishing feature between these 2 conditions is the altitude at which each occurs. These are 2 distinct clinical entities with different pathophysiological mechanisms, but which present with the same clinical features (Figure 1).

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

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PATHOGENESIS OF EAH AND AMS

In athletes affected by EAH, heavy exercise seems to produce AVP excess, impairing the ability to excrete free water.3 When these athletes then ingest excessive amounts of free water, the results are weight gain and hyponatremia.3 Hyponatremia leads to a cytotoxic cerebral edema with intracranial hypertension.6 This intracranial hypertension causes non-cardiogenic or neurogenic pulmonary edema with a low or normal pulmonary capillary wedge pressure.1,2,7 This leads to hypoxia, which impairs brain adaptation and leads to a vicious cycle of worsening cerebral and pulmonary edema that can ultimately lead to death unless rapidly reversed with hypertonic saline.8

In AMS, the primary inciting event is hypoxia, induced by decreased oxygen tension at high altitudes, which can lead to both HAPE and HACE. Hypoxia appears to cause pulmonary vasoconstriction and pulmonary hypertension with an elevated pulmonary capillary wedge pressure, which causes pulmonary capillary leak and results in pulmonary edema.9 Hypoxia also induces a poorly understood neurohormonal and hemodynamic response that can lead to HACE due to a disruption in the blood-brain barrier and increasing cerebral perfusion.4 AMS with vasogenic cerebral edema can be produced experimentally by exposing subjects to isobaric hypoxia in the absence of exertion.10 The cornerstone of therapy is descent to a lower altitude and the provision of additional therapies, including oxygen supplementation, dexamethasone, acetazolamide, and calcium channel blockers.4

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HYPONATREMIA IN AMS

These 2 conditions are not mutually exclusive, and it is very likely that individuals who suffer from AMS in the context of high-altitude exertion, such as hikers and skiers, also have some component of EAH. Exertion is a major risk factor for developing AMS.5 Experimental models of AMS in humans reveal that individuals who develop AMS have significantly elevated AVP levels and have fluid retention with weight gain.11,12 This is likely compounded by the fear of dehydration at altitude, which may promote the same overconsumption of fluids seen in endurance sports.3 Individuals who develop AMS have been reported to develop an acute fall in serum sodium.11 In 1 study of 5 skiers who developed HAPE, the average serum sodium was 135 mEq, significantly lower than a similar control group, 144 mEq/l.13

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THE EFFECTS OF HYPOXIA AND HYPONATREMIA ON BRAIN CELL VOLUME REGULATION

Hypoxia may place athletes exercising at high altitude at increased risk for developing hyponatremic encephalopathy. Brain cell ion concentrations are maintained within a narrow range via energy-dependent exchange pumps such as the Na+-K+-ATPase pump and sodium calcium exchangers.6 Hypoxia will decrease brain energy metabolism, which will result in membrane depolarization, a disruption of the Na+-K+-ATPase pump and an influx in sodium and calcium, which will in turn lead to cytotoxic cerebral edema (ie, an increase in intracellular volume).6 The adaptive response to hypoxia is to increase cerebral perfusion to deliver more oxygen.6 Our group has shown that the combination of hyponatremia and hypoxia actually leads to decreased cerebral perfusion, which further decreases cerebral oxygen delivery and decreases energy-dependent exchange pump activity.14 Hyponatremia also results in cytotoxic cerebral edema, with an influx of water into the intracellular space down a concentration gradient, resulting in brain parenchymal swelling.6 One mechanism for the brain's adaptation is the extrusion of sodium via the Na+-K+-ATPase pump. Our group has demonstrated in the animal model that the combination of hypoxia and hyponatremia impairs the brain cell volume regulatory response.14,15 Animals with both hypoxia and hyponatremia have significantly more cerebral edema, with both a higher brain water and sodium content than either controls, or hypoxic or hyponatremic animals alone (Figure 2).14,15

FIGURE 2

FIGURE 2

Individuals exercising at high altitude may be at risk for both hypoxia and hyponatremia, which will severely impair brain cell volume regulation and place them at risk for cerebral edema. In humans with hyponatremic encephalopathy, hypoxia is one of the main risk factors for a poor neurological outcome.16 A decrease in serum sodium in an individual with AMS will add a component of cytotoxic cerebral edema to the preexisting cerebral edema. The combination of these 2 conditions can be deadly. A similar observation has been made in children with viral encephalitis, where those with a poor neurologic outcome are found to have mild hyponatremia (Na 132 mEq/L) with a serum sodium approximately 2 mEq/L lower than those with a favorable outcome.17 It seems clear that hyponatremia could be a lethal factor in individuals exercising at altitude.

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RISKS OF OVERHYDRATION IN ATHLETES

It is now well accepted that the long-held recommendation of pushing oral fluids in marathon runners is dangerous and is a major contributing factor to the development of EAH.3 EAH with encephalopathy was an unrecognized phenomenon until our group reported this condition in 2000.2 It has now been appreciated that this is a relatively common event.3 It is our belief that this same syndrome is likely affecting individuals who exercise at high altitudes and is going unrecognized. Vigorous hydration is an unproven yet widely favored maneuver to prevent AMS. Hikers are known to drink copious amounts of fluids until they produce “gin clear” urine. This is both an unphysiologic and unsafe practice for individuals who may be at risk for AVP excess, fluid retention, and vasogenic cerebral edema. In all likelihood, a significant number of hikers and skiers are developing encephalopathy at high altitude with EAH, yet the hyponatremic encephalopathy component of their condition is going unrecognized.

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3% SODIUM CHLORIDE IN THE TREATMENT OF EAH AND AMS

Whenever possible, the serum sodium should be determined in the field when treating any individual with suspected AMS in the context of physical exertion, such as hiking or skiing, in order to rule out EAH. Serum sodium below 136 mEq/L should be viewed as abnormal and as a contributing factor to AMS. EAH should be considered the primary cause of encephalopathy if the serum sodium is less than 130 or if symptoms are not improving with conventional therapy. Initial experience in using hypertonic saline to treat EAH with non-cardiogenic pulmonary edema produced excellent results and has now become the accepted treatment for this condition.23 We have proposed the prompt, initial administration of a 100-cc bolus of 3% NaCl to any individual suspected of having symptomatic hyponatremia, before transferring them to a medical center or pursuing radiologic investigations.18 In exercise-induced hyponatremia, there is no risk for developing cerebral demyelination, as this is an acute form of hyponatremia. In prolonged periods of exertion at high altitude, chronic hyponatremia (longer than 48 hours) could develop. A 100-cc bolus of 3% NaCl would not result in the theoretical complication of cerebral demyelination as it would produce at most a 2 mEq/L rise in serum sodium, which is well below the limits for this condition to develop.19 We hypothesize that hypertonic saline could play a similar role in the management of HACE. A bolus of 100-cc of 3% NaCl could acutely decrease brain edema and stabilize a patient until they can be transported to a lower altitude where other therapies can be initiated.

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FUTURE DIRECTIONS

In summary, athletes such as hikers and skiers who exercise at high altitudes should be considered at risk for developing EAH; hyponatremia should be considered as an additional risk factor complicating AMS. A consensus conference should be held to discuss gaps of knowledge in these 2 conditions and future directions for research. The incidence of hyponatremia should be evaluated in individuals engaged in intense physical exertion at high altitudes. Recommendations for hydration in hikers and skiers should be readdressed; overhydration is likely harmful and may produce hyponatremia in susceptible individuals. Those who exercise at high altitude are exposed to multiple stimuli for AVP production, which makes vigorous hydration a potentially dangerous practice. Although the administration of 3% NaCl in individuals with AMS and HACE needs to be further evaluated, it is important to recognize for the present that measurement of serum sodium and the prompt administration of 3% NaCl may play a critically important role in the successful management of these patients.

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ACKNOWLEDGEMENT

We thank Karen Branstetter for her editorial assistance.

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REFERENCES

1. Ayus JC, Arieff AI. Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure. Chest. 1995;107:517-21.
2. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med. 2000;132:711-714.
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13. Cosby RL, Sophocles AM, Durr JA, et al. Elevated plasma atrial natriuretic factor and vasopressin in high-altitude pulmonary edema. Ann Intern Med. 1988;109:796-799.
14. Ayus JC, Armstrong D, Arieff AI. Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents. Kidney Int. 2006;69:1319-1325.
15. Vexler ZS, Ayus JC, Roberts TP, et al. Hypoxic and ischemic hypoxia exacerbate brain injury associated with metabolic encephalopathy in laboratory animals. J Clin Invest. 1994;93:256-264.
16. Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med. 1992;117:891-897.
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Keywords:

acute mountain sickness; exercise; hyponatremia; cerebral edema; pulmonary edema; altitude; saline; fluid therapy

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