Exercise-Associated Hyponatremia: Why Are Athletes Still Dying?

In 2000, we were the first to report on the successful use of hypertonic saline in the treatment of a large series of patients with symptomatic exercise-associated hyponatremia (EAH).1 Although others have adopted our therapeutic approach, successfully reproducing our results,2 our view is that the failure to ensure the universal application of this life-saving treatment has led to multiple unnecessary deaths.3 We initially described 7 patients with EAH after marathon participation.1 These patients presented to local emergency rooms in Texas, California, and Canada with nausea, vomiting, pink frothy sputum, pulmonary edema, and serum sodiums (SNa) ranging from 117 to 127 mEq/L. All were found to have low pulmonary capillary wedge pressures, indicating a non-cardiogenic cause of their pulmonary edema. We recognized this as hyponatremic encephalopathy, which can cause non-cardiogenic pulmonary edema. Cerebral edema leads to increased intracranial pressure, which can result in pulmonary edema via 2 mechanisms: (1) centrally mediated increase in pulmonary vascular permeability to proteins, leading to increased alveolar and interstitial fluid,4 and (2) increased sympathetic neuronal activity with catecholamine release, resulting in pulmonary vasoconstriction with increase capillary hydrostatic pressure and capillary wall injury (Figure 1).5 We were familiar with this condition because we first reported on this syndrome in 1995 in 30 patients with postoperative hyponatremia.6 This syndrome, now referred to as the Ayus-Arieff syndrome,7is particularly dangerous because the pulmonary edema produces hypoxia, which in turn worsens brain edema by impairing brain-cell volume regulation (Figure 2).8 It is crucial that cerebral edema be treated rapidly with hypertonic saline, as this will also reverse pulmonary edema. Other novel factors known to play a role in the development of this syndrome are elevated vasopressin levels and female sex steroids; both impair brain cell volume regulation and increase the risk for hyponatremic encephalopathy at higher serum sodium levels.9 Six of the patients under our care were treated with 3% sodium chloride (NaCl), which produced an increase in serum sodium of 10 mEq in 12 hours and made a complete recovery. The one patient not managed by us died with massive cerebral edema, never having received hypertonic saline. At the time of our initial report, treating patients with pulmonary edema and hyponatremia with 3% NaCl was considered a novel therapy and struck many as counterintuitive.FIGURE 1: Mechanism of non-cardiogenic pulmonary edema in exercise-associated hyponatremia.FIGURE 2: A depiction of the Ayus-Arieff syndrome. Hyponatremia produces cytotoxic cerebral edema which in turn leads to a neurogenic pulmonary edema. Pulmonary edema leads to hypoxia, which impairs brain cell volume regulation, resulting in a vicious cycle of worsening cerebral edema and pulmonary edema. This syndrome can be reversed by the prompt administration of 3% NaCl.Soon after our initial report, Davis reported similar findings after a San Diego marathon.2 At that time in 1998 (reported in 2001), 5 marathon participants presented to an emergency department with symptomatic hyponatremia that worsened after treatment with 0.9% NaCl, requiring intubation or admission. The University of California San Diego Medical Center subsequently changed its policy regarding the treatment of EAH to ensure the use of 3% NaCl. In 1999, 4 marathon participants with symptomatic hyponatremia were treated with 3% NaCl, experienced prompt improvement, and were discharged from the emergency department. After these reports, we had hoped that 3% NaCl would be embraced as the accepted treatment for EAH. This has not been the case. Some in the exercise community challenged our treatment approach (Arthur Siegel, Boston Marathon).3 It was argued that these patients had “exercise-related hypovolemic hyponatremia, as shown by low pulmonary wedge pressures,” and that this “might be more appropriately treated with intravenous isotonic sodium chloride to enhance extracellular fluid volume while more gradually correcting plasma tonicity in the high-risk setting of rapid-onset osmotic dysequilibrium.”3 This contrary view has persisted despite the recognition of this condition. Unnecessary deaths have continued. Two women died in the 2002 Boston and Marine Corps marathons.10 These women presented with Ayus-Arieff syndrome with severe hyponatremia (Na < 125), were treated with 0.9% NaCl, and died of cerebral herniation without ever receiving treatment with hypertonic saline. It was not until 2004 that the Boston and Marine Corps marathons adopted our approach of using 3% NaCl for the treatment of EAH; there have been no further deaths from EAH in those races.10 In the 2003 London Marathon, 14 participants presented to an emergency department with symptomatic hyponatremia and were treated with 0.9% NaCl; 8 of them had a further decrease in SNa.11 Those who failed to improve or worsened were treated with 1.8% NaCl and not 3% NaCl. In another report from London, a marathon participant with a SNa of 133 mEq/L was administered 1 L of 5% dextrose in water and developed midbrain herniation; his SNa dropped to 130 mEq/L.12 The patient had an extraventricular device placed and eventually died without receiving hypertonic saline. It must be emphasized that any NaCl solution with a concentration less than 3% NaCl is inappropriate for the treatment of hyponatremic encephalopathy due to AVP excess, as it is not sufficiently hypertonic to induce the necessary reduction in cerebral edema central to the management of this condition. In the presence of elevated AVP levels, there will be an impaired ability to excrete free water with the urine osmolality exceeding that of the plasma. This is a saline-resistant state, where urinary excretion of electrolytes can be hypertonic to that of the plasma. The only consistent way of acutely increasing the plasma sodium is to administer a hypertonic solution with a sodium concentration that exceeds the maximum achievable urinary sodium concentration. 3% NaCl has a sodium concentration of 513 mEq/L, which exceeds the kidney's ability to generate free water. Four years after our initial report, a consensus conference was convened in South Africa to address the issue of EAH.13 An unequivocal statement emerged, asserting that the administration 0.9% NaCl is contraindicated in EAH because it could worsen the degree of hyponatremia and that 3% sodium chloride is the treatment of choice for symptomatic EAH.13 Now that there was general agreement that hypertonic saline was the treatment of choice for symptomatic EAH, the next important step was to establish the safest and most effective way to administer 3% NaCl. A significant barrier to the use of 3% NaCl has been the recognition that overcorrection of hyponatremic encephalopathy has been associated with brain injury.14 Cerebral demyelination is a rare condition that has been reported in some patients after the correction of severe chronic hyponatremia (>48 hours). The principal risk factors for this condition are liver disease, alcoholism, thiazide diuretic use, hypoxia, and a SNa correction of at least 25 mEq/L within the first 24 to 48 hours.14 As a consequence of these issues, some have proposed even more conservative paramenters for the treatment of symptomatic hyponatremia.15 Fortunately, the aforementioned risk factors do not play a role in EAH, an acute form of hyponatremia, where the dangers of not treating with hypertonic saline far outweigh any risk of rare complications from therapy. Our group introduced a novel approach to the treatment of EAH that was derived from our considerable experience in treating other cases of hyponatremic encephalopathy.14,16,17 We proposed that patients with symptomatic EAH be treated with a 100-cc bolus of hypertonic NaCl over 10 minutes.18,19 This would raise the serum sodium by approximately 2 mEq/L and quickly reduce brain cell volume to get the patient out of harm's way. This approach was first used in the field by JC Ayus at the Two Oceans Marathon in Cape Town, South Africa, in 2005 while serving on the 1st International EAH Consensus Panel.20 A male athlete presented to the medical tent with symptomatic hyponatremia: SNa of 128, comatose, with pulmonary edema. The on-site medical staff was planning to transfer him to a medical center for further treatment, but it was recognized that urgent treatment was necessary. The patient was treated with a 100-cc bolus of 3% NaCl, and he showed an immediate and dramatic clinical improvement. This therapeutic approach was adopted as the preferred therapy by the Second International EAH Consensus Panel in New Zealand in 2007,20 and it has been validated by others in the field.21 Up to 2 repeated boluses can be administered if symptoms persist. The advantage of this approach is that brain swelling is reduced immediately and there is no potential for inadvertent overcorrection, as can result from a prolonged infusion of 3% NaCl. This approach is simple and straightforward, it does not require an infusion pump, and it can be used in the medical tent or at the bedside in the ER. It also avoids any possibility of overcorrection because it limits SNa correction to 3 to 4 mEq/L acutely. We believe that there is adequate evidence in the literature to demonstrate that EAH is a lethal condition, one that can occur in any athlete in an endurance event, even in those with mild levels of hyponatremia. Symptomatic EAH can be safely treated with hypertonic saline. We are concerned that unproven therapies such as V2-receptor antagonists have been suggested for the treatment of symptomatic EAH.10 V2-receptor antagonists are a new class of drug known as vaptans, which block the binding of AVP to its V2-receptor located in the renal collecting duct.22 These drugs are primarily indicated for the treatment of euvolemic hyponatremia from symptom of inappropriate antidiuretic hormone secretion and hypervolemic hyponatremia in congestive heart failure. There are no data to suggest that V2-receptor antagonists will cause either a sufficiently rapid or consistent increase in SNa for it to be used in the treatment of symptomatic hyponatremia. Current data indicates that V2-receptor antagonists do not exert affect for 1 to 2 hours, which would make it an inappropriate agent for symptomatic hyponatremia.22 It is also known that there are a subset of patients who will not respond to V2-receptor antagonists; these are patients with the nephrogenic syndrome of inappropriate antidiuresis who have a gain-of-function mutation of AVP receptor 2.23 We feel strongly that 3% NaCl is the only therapy proven to be safe and effective in treating this condition.1 It is imperative in our view that marathon organizers equip their medical staff to appropriately manage this potentially lethal condition. Marathon medical officials must be able to: (1) recognize the symptoms and sign of EAH; (2) measure serum Na on site; (3) treat symptomatic patients immediately with a 100-mL bolus of 3% NaCl before transfer to a medical center. To do otherwise is to put lives at risk. Now that the sports medicine community is aware of the dangers of this condition and there is agreement on its treatment, let the races begin.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.