Treatment of EAH-induced encephalopathy with hypertonic (3%) saline: new paradigm, new therapy.
Exercise-associated hyponatremia (EAH) is a water-to-salt imbalance with a blood sodium concentration [Na+] less than 135 mmol/L during or after endurance sports, which may lead to fatal pulmonary and cerebral edema. Mechanisms leading to this predominantly dilutional effect include avid fluid intake and a concurrent decrease in urine formation. Cases of life-threatening hypotonic encephalopathy and fatal cerebral edema demonstrated euvolemia with non-osmotic secretion of arginine vasopressin (AVP), fulfilling the essential diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Intravenous hypertonic (3%) saline as a well validated treatment based on this paradigm results in rapid clinical improvement without adverse effects. AVP receptor antagonists as novel aquaretic agents also deserve study as adjunctive therapy for EAH given their recent approval for similar clinical conditions.
Since the index cases of water intoxication reported in ultradistance runners in 1985 (1), exercise-associated hyponatremia (EAH) as identified in 13% of recent Boston marathon runners may result in fatal pulmonary and cerebral edema (2,3). While a recent evidence-based consensus statement concluded that this condition is dilutional in nature (4), the relative pathogenetic contributions from avid fluid consumption and a concurrent decrease in urine formation were not resolved therein. Subsequent studies in marathon runners with EAH-induced encephalopathy including two cases of fatal cerebral edema demonstrated euvolemia with non-osmotic secretion of arginine vasopressin (AVP). These findings satisfy the essential diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) first described in 1957 (5,6). The mechanism for non-osmotic stimulation of AVP secretion may in part be due to the release of muscle-derived interleukin (IL)-6, linking exertional rhabdomyolysis to the pathogenesis of EAH (7). Understanding EAH as a variant of SIADH accounts for otherwise inexplicable clinical aspects of this condition including cases with moderate levels of fluid intake and the delayed onset after races in runners who continue to drink hypotonic fluids before resuming urination. Most importantly, the SIADH paradigm points to treatment with intravenous hypertonic (3%) saline for hypotonic encephalopathy as a well-established and validated intervention (8). This therapeutic approach improves clinical outcomes without adverse effects as observed at multiple races. Arginine vasopressin V2 receptor antagonists deserve study as adjunctive therapy, as these pure aquaretic agents rapidly normalize serum [Na+] safely in similar clinical conditions (9). The top ten take-away messages regarding the pathogenesis, prevention, and treatment of EAH based on this paradigm shift take into account the basic science and clinical insights articulated in "Hypontaremia: New Understandings, New Therapy" (10).
1. EAH is characterized by an imbalance in the water-to-salt ratio in extracellular fluid, which is usually the result of another underlying condition. Symptomatic cases are generally associated with positive fluid balance as assessed by changes in body weight and euvolemia as determined by serum blood urea nitrogen, which corroborates water intoxication as a dilutional effect. Marathon runners with EAH-induced encephalopathy including two cases with fatal cerebral edema showed measurable levels of arginine vasopressin (AVP), fulfilling the essential diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (5,6). Exertional rhabdomyolysis may be linked to the pathogenesis of EAH with release of muscle-derived interleukin(IL)-6 leading in part to a decrease in urine formation.
2. While runners with EAH showed inappropriate secretion of AVP consistent with SIADH, the two fatal cases fulfilled all of the essential diagnostic criteria for this condition. Urine osmolalities were less than maximally dilute (> 100 mOsm/L) with measurable levels of AVP, indicating antidiuresis as the proximate cause of the dilutional hyponatremia. These findings are pathognomonic for SIADH rather than primary polydipsia, which circumstance would result in maximally dilute urine with physiological suppression of AVP. While avid fluid consumption is a major predisposing factor for EAH, this behavior alone would not result in fluid retention sufficient to induce symptomatic EAH in most cases without a concomitant decrease in urine production. Antidiuresis as the inside job might therefore be viewed as the proximate cause of EAH while avid fluid consumption as the outside job might be seen as a precondition.
3. Additionally, urine [Na+] in the two fatal cases was greater than 30 mEq/L, which natriuretic effect is consistent with the decrease in free water clearance under conditions of SIADH rather than representing renal salt wasting. Natriuresis excludes dehydration from salt loss during sweating as a primary mechanism, which circumstance would result in low urine [Na+] due in part to increased renal sodium reabsorption from activation of the reninangiotensin-aldosterone system. This finding establishes that water retention rather than salt loss is the essential mechanism leading to EAH.
4. The SIADH paradigm also accounts for occurrences of EAH at moderate levels of fluid intake, as water retention before the onset of an escape from antidiuresis leads to weight increase with an expanded extracellular fluid volume. An increase in body weight by 2-3% as occurs in the acute phase of SIADH without invoking polydipsia or salt loss and may be associated with a fall in serum [Na+] to the range of 130 mmol/L where symptoms follow.
5. The SIADH formulation has a bearing upon optimal strategies for prevention of EAH. Beyond advice to drink moderately according to thirst, monitoring changes in body weight during races would provide an objective measure for early detection of positive fluid balance especially among slower runners at greatest risk. Any weight gain would be an indication for stopping fluid intake until the onset of spontaneous urination to preempt progression of early symptoms such as nausea, vomiting and headache. Continued consumption of hypotonic fluids such as sports drinks adds to the total fluid load under conditions of SIADH.
6. The SIADH paradigm accounts for clinical presentations of EAH that would otherwise be inexplicable such as the delayed onset in runners after races who sometimes continue to force fluids under the mistaken assumption that absence of spontaneous urination must be a symptom of dehydration. Additionally, SIADH accounts for the observation that use of nonsteroidal anti-inflammatory drugs (NSAIDS) may promote clinical severity. While not an independent risk factor for EAH, these prostacycline synthase inhibitors enhance the action of AVP and should be avoided the day before and during races.
7. Beyond nonspecific symptoms, mental status changes including disorientation and delirium should raise the index of suspicion for EAH as early symptoms of hypotonic encephalopathy. These neurotoxic effects result from an influx of water into brain cells in response to the acute onset of hypo-osmolality. While fluid restriction until the onset of urination may be sufficient for managing mild cases, an added clinical benefit has been observed by administering concentrated oral salt solutions such as broth to reverse the flow of water in the central nervous system. In contrast, hypotonic fluids should be withheld until the onset of urination to avoid adding to the total fluid load.
8. Life-threatening symptoms of hypotonic encephalopathy including hallucinations, psychomotor agitation, convulsions, unconsciousness and coma are an indication for emergent treatment with intravenous hypertonic solutions such as 3% saline or mannitol. Infusion of hypertonic (3%) saline at a suggested rate of 1 ml/Kg/h should be continued until improvement in neurological symptoms is observed by establishing an osmotic gradient to shift water out of brain cells. After initially increasing the serum [Na+] by 4-6 mmol/L over the first few hours, treatment may subsequently be adjusted according to clinical status and changes in serum [Na+] to satisfy established guidelines for safe maximal rates of correction of hyponatremia over the first 12 to 24 hours. In contrast, infusion of isotonic 0.9% saline may fail to raise the serum [Na+] under conditions of STADH and has been observed to promote seizures. In cases where isotonic (0.9%) saline has been started before the diagnosis of EAH is known, hypertonic (3%) saline should be substituted for the reasons discussed above. Loop diuretics are indicated for clinical signs of volume overload such as pulmonary edema.
9. A 100 ml bolus of 3% saline may be advisable in cases with seizures or coma to prevent progression of cerebral edema to respiratory depression from brainstem compression. Such an intervention reduces cerebral edema without risk for osmotic demyelination syndrome as may occur during the rapid correction of chronic hyponatremia, as the prerequisite compensatory adaptation of brain cells to hypo-osmolality has not yet taken place. Based on these sequential adaptive responses, hypertonic (3%) saline would be the treatment of choice for all cases of EAH-induced encephalopathy even in ultra-endurance athletes in whom sodium depletion may be a contributing mechanism.
10.The efficacy of arginine vasopressin receptor antagonists as adjunctive treatment for EAH-induced encephalopathy deserves study as they become available. These rapid-onset agents promote an aquaresis with normalization of serum [Na+] in a controlled manner without neurological injury in clinical conditions similar to EAH.
The paradigm shift to an understanding of EAH as a variant of SIADH provides a unifying explanation for its pathogenesis and accounts for otherwise inexplicable clinical aspects including cases after moderate fluid intake and the delayed onset after races. The major benefit of this formulation is the application of intravenous hypertonic (3%) saline for treatment of hypotonic encephalopathy as a well-established and validated strategy leading to improved clinical outcomes.
1. Noakes TD, Goodwin N, Rayner BL, Branken T, Taylor RKN. Water intoxication: a possible complication during endurance exercise. Med Sci Sporls Exerc 1985;17:370-375.
2. Almond CSD, Shin AY, Fortescue EB, et al. Hyponatremia among runners in the Boston Marathon. N Engl J Med 2005;352:1550-1556.
3. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med 2000; 132:711-714.
4. Hew-Butler T, Almond C, Ayus JC, et al. Consensus statement of the 1st international exercise-associated hyponatremia consensus development conference, Cape Town, South Africa 2005. Clin J Sport Med 2005;15:208-213.
5. Siegel AJ, Verbalis JG, Clement S, et al. Exertional hyponatremia is associated with inappropriate secretion of arginine vasopressin. Am J Med 2006, accepted for publication.
6. Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. J Am Soc Nephrol 2001;12:2860-2870. Reprinted from: Am JMed 1957;23:529-542.
7. Siegel AJ. Exercise-associated hyponatremia: role of cytokines. Am J Med 2006; 119(7A): S87-S92.
8.Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab 2003;17:471-503.
9. Palm C, Pistrosch F, Herbrig K, Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med 2006; 119(7A):S87-S92.
10. Verbalis JG. Ed Hyponatremia: new understanding, new therapy. Am J Med 2006;119(7A): S1-S3.
By Arthur J. Siegel, MD; McLean Hospital, Belmont, MA; Harvard Medical School, Boston, MA
Requests for reprints should be addressed to:
Arthur J. Siegel, MD
Director, Internal Medicine
115 Mill Street
Belmont, MA 02478
RELATED ARTICLE: Researchers Solve Mystery of 2002 Marathoner's Death
Reprinted from the Boston Globe, May 7, 2007.
When Cynthia Lucero died while running the 2002 Boston Marathon, apparently from drinking too much water, doctors didn't really understand the disorder they called exercise-associated hyponatremia, or EAH. Now, a new study, helped by research from more recent Boston Marathons, suggests that the problem was hormonal. The stress of running the marathon apparently can disrupt the hormone that governs water balance, basically causing cells, including brain cells, to swell with water. "This is a major paradigm shift for those who think that EAH is due primarily to salt loss or over consumption of fluids," said Arthur J. Siegel, the lead researcher. "Although anyone can experience hyponatremia, slower, inexperienced runners appear to be at greater risk, since they lose less water through perspiration than those in better shape." Knowing the cause has important implications for treatment of hyponatremia. "At this year's Boston and Marine Corps marathons, the research team found that giving runners concentrated bouillon or delivering a 3-percent intravenous saline solution can help reverse symptoms of hyponatremia by pulling fluid out of cells," Siegel said.
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|Author:||Siegel, Arthur J.|
|Article Type:||Disease/Disorder overview|
|Date:||Sep 22, 2007|
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