Exercise-associated hyponatremia (EAH) is a well-recognized potential complication of endurance runners. It is a syndrome of hypervolemic hyponatremia and occurs secondary to a relative increase in total body water primarily caused by water intake exceeding urinary and sweat losses. Symptomatic EAH has been found in up to 23% to 38% in those seeking medical care in triathalons, marathons, and ultramarathons (1,2). Mild EAH is likely underdiagnosed, as symptoms of nausea, vomiting, headache, and dizziness are often ascribed to dehydration or heat-related illness (3–5). Severe EAH symptoms are mainly neurologic due to the osmotic gradient between plasma and brain cells that induces cerebral edema. Symptoms are related to both rapidity and amount of change in plasma sodium, not necessarily the absolute level (6,7). EAH can be fatal, (8–12) and has led to a dozen confirmed deaths (13).
Consensus guidelines recommend immediate testing with a point-of-care device when severe EAH is suspected, and when diagnosed, to treat with 100-mL boluses of 3% sodium chloride (hypertonic saline, HTS) until neurologic symptoms resolve (5,14). Small volume HTS (200 mL) has been given empirically in the field for severe EAH with rapid improvement, (15) and volumes as large as 0.95 L given over 7 h have successfully treated severe EAH in a hospital setting (16). However, in the absence of on-site sodium testing some consensus guidelines recommend small amounts of HTS that may be clinically insufficient, or algorithms that direct fluid avoidance until confirmatory serum testing is available (5). Because ultramarathons are often held in wilderness environments where testing is usually unavailable, (17) medical providers need to have an empiric treatment protocol for suspected severe EAH (18).
In June 2016, a previously healthy 31-yr-old female with no medical problems, drug use, or issues with prior endurance running participated in an 80-km (50 miles) ultramarathon foot race with the hottest ambient temperatures ranging from 46°C to 50°C (115°F to 122°F). Competitors had 2 L of water provided at a checkpoint every 10 km (6 miles). The runner had been performing well and consumed one electrolyte tablet every other liter of water, with an additional salt tablet every 2 h throughout the day. At the fifth checkpoint at 50 km (30 miles), the racer was nauseous and vomited once. She was given ondansetron 4-mg oral dissolving tablet (ODT), observed for 1 h while tolerating fluids, and continued racing. She finished the next 10 km (6 miles) in 2 to 3 h while ingesting 3 to 4 L more water and arrived at approximately 10 p.m. the ambient temperature was 32°C (90°F). The runner consumed 1 L of electrolyte mix and then vomited. Over the next hour, she was unable to tolerate fluids or food, so ondansetron 4 mg ODT was given. She consumed a 250-mL soda and a salt tablet and was feeling well. She ambulated without difficulty to the optional sleeping area of the checkpoint and slept for 2 h when she had a generalized tonic-clonic seizure that resolved spontaneously after 2 min.
The patient was obtunded, withdrawing from pain, eyes opening spontaneously, and normal vital signs. Intravenous access was rapidly obtained and given the recent caloric ingestion and several hours of rest preceding the seizure, it was unlikely hypoglycemia or heat stroke; 100 mL of HTS was given within minutes of seizure cessation for presumed severe EAH. Evacuation was initiated via an off-road truck. Ten minutes after the first HTS bolus, there was no neurologic improvement, and a second bolus was given, which was repeated every 10 to 15 min. During this evacuation, a total of 600 mL of HTS was given with no change in the patient's mental status. The patient was transferred to an ambulance and transported 3 h to the nearest hospital with critical care facilities. En route, local paramedics repeatedly attempted to start a 0.9% sodium chloride (normal saline [NS]) intravenous drip, but were dissuaded by the race physician coordinating care.
Upon arrival in the emergency department at approximately 6 a.m. (4 h postseizure), the patient had normal vital signs, was afebrile, and continued her postictal state (Glasgow Coma Scale of 10). A noncontrast head computed tomography (CT) scan was negative for acute intracranial process, and she had a serum sodium of 121 mmol·L−1, chloride of 79 mmol·L−1, and potassium of 2.8 mmol·L−1. The patient was admitted to the intensive care unit ICU at 8 a.m. on a HTS drip at 30 mL·h−1 for 11 h until 7 p.m. at which time the serum sodium was 128 mmol·L−1, and the drip was discontinued. The next morning, the patient was found awake, without complaints, and mentating normally. Repeat serum electrolyte testing revealed normal values. Within 6 h, she was discharged from the hospital. The patient was monitored for the following 36 h without any neurologic events and remained asymptomatic. She reported no neurologic sequelae at 6, 12, and 18 months after the event.
This case is the largest known volume of HTS given for severe EAH in the absence of confirmatory serum testing. Treatment of severe EAH with HTS (513 mEq·L−1) is known to result in typically rapid correction of sodium levels, (16) and highly efficacious and more rapid than that of NS (154 mEq·L−1) (7). NS should be avoided in severe EAH, (5,14) and there have been numerous grievous examples of worsened morbidity and mortality when given isotonic fluids (8,12,19). This is due to the urinary excretion of all the sodium in isotonic fluids with a proportion of water to equal the high urine osmolality, leaving a net positive of serum-free water which can worsen the osmotic gradient and cerebral edema. There have been no reported cases of central pontine myelinolysis (osmotic demyelination) with the rapid correction of severe EAH. The successful outcome of this case highlights the safety of this intervention. The patient's prolonged encephalopathy while unusual in severe EAH, is not unprecedented (8,20). Nor was a negative head CT, which was seen in a runner with severe EAH who received 650 mL of HTS for persistent altered mental status (16). Although the lack of information regarding weight changes, urinary output, sand race sodium, and dietary intake limit pathophysiologic insight. This case clearly illustrates the potential need for larger volumes of HTS for event medical management than the often recommended three 100-mL boluses, (5,14) and supports the sideline medical provider to pursue treatment until “neurologic symptoms subside” (14). Delay of empiric treatment can lead to worsened hyponatremia (21).
The etiology of EAH is likely multifactorial, thought to be due to several proposed mechanisms. A combination of overhydration from excessive hypotonic fluid intake (i.e., water or sports drinks); (22,23) impaired excretion of water due to inadequate suppression of arginine vasopressin (AVP), (14,22) and sodium and/or fluid losses through sweating to form a hypovolemic stimulus of ADH. These mechanisms have been proposed to coexist and present as a “continuum” that can range from pure overhydration to excessive sweat sodium losses and overhydration (24). Increased consumption of hypotonic solutions can lead to a dilutional hyponatremia, and intake overwhelms the rate of renal water excretion. In the setting of hypervolemia and/or hyponatremia, plasma AVP that presents at “normal levels” is actually abnormal, as AVP should be maximally suppressed (22,25) resulting in a syndrome of inappropriate antidiuretic hormone secretion. Also, hypovolemia from insensible losses, such as sweating, will stimulate ADH secretion and contribute to the hyponatremia (24). While the symptoms of EAH may be acute, delay of symptomatic EAH may occur several hours after the end of exercise (26,27). During heavy exercise, blood flow is diverted from the gastrointestinal tract to skeletal muscle, and ingested water is sequestered in the gut (28). When exercise ceases, partial redistribution of blood to the mesentery may lead to abrupt absorption of water into the bloodstream and resultant symptomatic EAH.
Upon arrival in the emergency room, the diagnosis of EAH was confirmed with the serum sodium level of 121 mmol·L−1. This is consistent with severe EAH, as 121 mmol·L−1 was the average sodium level in seven cases of marathon runners intubated with severe EAH (8). It is unknown what the initial sodium level in this patient was, but reasonable to assume it was less than 110 mmol·L−1 when she seized, as 100 mL of 3% sodium chloride is estimated to increase the serum sodium concentration 2 to 5 mmol·L−1 (6,29). The patient's nausea and vomiting earlier were likely insidious symptoms of mild EAH, and nausea is known as a potent trigger for ADH secretion. As gastrointestinal distress is very common in ultramarathoners (30), holding a participant until symptom cessation and able to tolerate fluids and food by mouth is a reasonable safety measure. The nausea likely contributed to poor food ingestion which could have contributed to inadequate dietary sodium intake.
The 3-L to 4-L water ingested during the 10 km (6 miles) preceding the runner's final stop with minimal sodium supplementation was a recipe for hypervolemic hyponatremia, as excess water ingestion and weight gain are well-recognized independent risk factors for EAH (22,31,32). The high ambient temperatures during the 60-km (37 miles) run and vomiting likely contributed to hypovolemia and a mixed mechanism. It is unknown the exact amount of sodium ingested by the runner during the race, but the reported rates in the setting of aggressive hydration were likely inadequate to maintain isotonicity. Exercise in hot environments has been shown to increase the need for hydration as well as medical consults in endurance runners (31,33,34). While challenging in hot conditions, avoidance of overhydration has been found to be more protective of EAH than sodium supplementation (35). Event planners and medical providers at endurance race events should be aware of severe heat as a potential risk factor for EAH, and although empiric large volume HTS has not been rigorously tested, it should be considered a safe and effective treatment modality for severe EAH.
Medical support staff of endurance activities particularly in hot environments should be aware of the risks of overhydration, symptom recognition of severe EAH, and preparedness to deliver large volumes of HTS. The rapid treatment of severe EAH is essential to prevent fatal outcomes. This case highlights the potential need for larger volumes of HTS than often recommended, and neurologic presentation should dictate treatment rather than a set amount of fluid. An empiric treatment algorithm that is based on presenting symptoms rather than serum blood testing can enhance survival and outcomes of endurance runners.
1. Speedy DB, Noakes TD, Rogers IR. Hyponatremia in ultradistance triathletes. Med. Sci. Sports Exerc
. 1999; 31:809–15.
2. Lee JK, Nio AQ, Ang WH, et al. First reported cases of exercise-associated hyponatremia in Asia. Int. J. Sports Med
. 2011; 32:297–302.
3. Lipman GS, Eifling KP, Ellis MA, et al. Wilderness Medical Society practice guidelines for the prevention and treatment of heat-related illness: 2014 update. Wilderness Environ. Med
. 2014; 25(Suppl. 4):S55–65.
4. Backer HD, Shopes E, Collins SL, Barkan H. Exertional heat illness and hyponatremia in hikers. Am. J. Emerg. Med
. 1999; 17:532–9.
5. Bennett BL, Hew-Butler T, Hoffman MD, et al. Wilderness Medical Society practice guidelines for treatment of exercise-associated hyponatremia: 2014 update. Wilderness Environ. Med
. 2014; 25(Suppl. 4):S30–42.
6. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur. J. Endocrinol
. 2014; 170:G1–47.
7. Hew-Butler TD, Boulter J, Bhorat R, Noakes TD. Avoid adding insult to injury—correct management of sick female endurance athletes. S. Afr. Med. J
. 2012; 102:927–30.
8. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann. Intern. Med
. 2000; 132:711–4.
9. Gardner JW. Death by water intoxication. Mil. Med
. 2002; 167:432–4.
10. Siegel AJ. Hypertonic (3%) sodium chloride for emergent treatment of exercise-associated hypotonic encephalopathy. Sports Med
. 2007; 37:459–62.
11. Loyola Medicne Newswire. Drinking too much water can be fatal for athletes. 2014. [cited 2015 March 1]. Available from: http://www.loyolamedicine.org/newswire/news/drinking-too-much-water-can-be-fatal-athletes
12. Thompson J, Wolff AJ. Hyponatremic encephlaopathy in a marathon runner. Chest
. 2003; 124:313S.
13. Noakes T. Waterlogged: The Serious Problem of Overhydration in Endurance Sports
. Champaign, IL: Human Kinetics; 2012.
14. Hew-Butler T, Rosner MH, Fowkes-Godek S, et al. Statement of the 3rd International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, 2015. Clin. J. Sport Med
. 2015; 25:303–20.
15. Hoffman MD, Stuempfle KJ, Sullivan K, Weiss RH. Exercise-associated hyponatremia with exertional rhabdomyolysis: importance of proper treatment. Clin. Nephrol
. 2015; 83:235–42.
16. Elsaesser TF, Pang PS, Malik S, Chiampas GT. Large-volume hypertonic saline therapy in endurance athlete with exercise-associated hyponatremic encephalopathy. J. Emerg. Med
. 2013; 44:1132–5.
17. Hoffman MD, Pasternak A, Rogers IR, et al. Medical services at ultra-endurance foot races in remote environments: medical issues and consensus guidelines. Sports Med
. 2014; 44:1055–69.
18. Lipman GS. Clinical practice guidelines for treatment of exercise-associated hyponatremia. Wilderness Environ. Med
. 2013; 24:466–8.
19. Petzold A, Keir G, Appleby I. Marathon related death due to brainstem herniation in rehydration-related hyponatraemia: a case report. J. Med. Case. Reports
. 2007; 1:186.
20. Davis DP, Videen JS, Marino A, et al. Exercise-associated hyponatremia in marathon runners: a two-year experience. J. Emerg. Med
. 2001; 21:47–57.
21. Rothwell SP, Rosengren DJ. Severe exercise-associated hyponatremia on the Kokoda Trail, Papua New Guinea. Wilderness Environ. Med
. 2008; 19:42–4.
22. Noakes TD, Sharwood K, Speedy D, et al. Three independent biological mechanisms cause exercise-associated hyponatremia: evidence from 2,135 weighed competitive athletic performances. Proc. Natl. Acad. Sci. USA
23. Noakes TD, Speedy DB. Case proven: exercise associated hyponatraemia is due to overdrinking. So why did it take 20 years before the original evidence was accepted? Brit. J. Sports Med
. 2006; 40:567–72.
24. Lewis D, Blow A, Tye J, Hew-Butler T. Considering exercise-associated hyponatraemia as a continuum. BMJ Case Rep
. 2018; 2018. pii: bcr-2017-222916.
25. Hew-Butler T. Arginine vasopressin, fluid balance and exercise: is exercise-associated hyponatraemia a disorder of arginine vasopressin secretion? Sports Med
. 2010; 40:459–79.
26. Zelingher J, Putterman C, Ilan Y, et al. Case series: hyponatremia associated with moderate exercise. Am. J. Med. Sci
. 1996; 311:86–91.
27. Noakes TD, Norman RJ, Buck RH, et al. The incidence of hypoantremia during prolonged endurance exercise. Med. Sci. Sports Exerc
. 1990; 22:165–70.
28. Irving RA, Noakes TD, Buck R, et al. Evaluation of renal function and fluid homeostasis during recovery from exercise-induced hyponatremia. J. Appl. Physiol. (1985)
. 1991; 70:342–8.
29. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am. J. Med
. 2007; 120(11 Suppl. 1):S1–21.
30. Hoffman MD, Fogard K. Factors related to successful completion of a 161-km ultramarathon. Int. J. Sports Physiol. Perform
. 2011; 6:25–37.
31. Almond CS, Shin AY, Fortescue EB, et al. Hyponatremia among runners in the Boston Marathon. N. Engl. J. Med
. 2005; 352:1550–6.
32. Krabak BJ, Lipman GS, Waite BL, Rundell SD. Exercise-associated hyponatremia, hypernatremia, and hydration status in multistage ultramarathons. Wilderness Environ. Med
. 2017; 28:291–8.
33. Roberts WO. Heat and cold: what does the environment do to marathon injury? Sports Med
. 2007; 37:400–3.
34. McGowan V, Hoffman MD. Characterization of medical care at the 161-km Western States Endurance Run. Wilderness Environ. Med
. 2015; 26:29–35.
35. Hoffman MD, Stuempfle KJ. Sodium supplementation and exercise-associated hyponatremia during prolonged exercise. Med. Sci. Sports Exerc
. 2015; 47:1781–7.