Advertisement

Wilderness Medical Society Practice Guidelines for Treatment of Exercise-Associated Hyponatremia

Published:April 15, 2013DOI:https://doi.org/10.1016/j.wem.2013.01.011
      Exercise-associated hyponatremia (EAH) typically occurs during or up to 24 hours after prolonged physical activity, and is defined by a serum or plasma sodium concentration below the normal reference range of 135 mEq/L. It is also reported to occur in individual physical activities or during organized endurance events conducted in austere environments in which medical care is limited or often not available, and patient evacuation to definitive care is often greatly delayed. Rapid recognition and appropriate treatment are essential in the severe form to ensure a positive outcome. Failure in this regard is a recognized cause of event-related fatality. In an effort to produce best practice guidelines for EAH in the austere environment, the Wilderness Medical Society convened an expert panel. The panel was charged with the development of evidence-based guidelines for management of EAH. Recommendations are made regarding the situations when sodium concentration can be assessed in the field and when these values are not known. These recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians.

      Key words

      Introduction

      Nearly 3 decades after the first report of exercise-associated hyponatremia (EAH),
      • Noakes T.D.
      • Goodwin N.
      • Rayner B.L.
      • Branken T.
      • Taylor R.K.
      Water intoxication: a possible complication during endurance exercise.
      great strides are taking place in an effort to prevent what is now recognized as a leading cause of preventable morbidity and mortality in endurance activities throughout the world. To date, review articles and international consensus statements have documented risk factors, pathophysiology, signs and symptoms, prevention, and patient management strategies.
      • Montain S.J.
      • Sawka M.N.
      • Wenger C.B.
      Hyponatremia associated with exercise: risk factors and pathogenesis.
      • Speedy D.B.
      • Noakes T.D.
      • Schneider C.
      Exercise-associated hyponatremia: a review.
      • Rosner M.H.
      • Kirven J.
      Exercise-associated hyponatremia.
      • Rosner M.H.
      Exercise-associated hyponatremia.
      • Rosner M.H.
      • Bennett B.
      • Hew-Butler T.
      • Hoffman M.D.
      Exercise induced hyponatremia.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Hew-Butler T.D.
      • Almond C.S.
      • Ayus J.C.
      • et al.
      Consensus Statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005.
      These reports have primarily focused on incidences of EAH in organized endurance events that are conducted in the front country where medical tents and local emergency medical services are available on site to assist these participants and to transport as needed to a local hospital for appropriate management. Beyond front country triathlons and marathons, many prolonged individual activities, ultramarathons, and multiday endurance events take place in the backcountry.
      To date in the backcountry, EAH has been documented in hikers, trekkers, climbers, and cold climate endurance athletes.
      • Backer H.D.
      • Shopes E.
      • Collins S.L.
      Hyponatremia in recreational hikers in Grand Canyon National Park.
      • Basnyat B.
      • Sleggs J.
      • Spinger M.
      Seizures and delirium in a trekker: the consequences of excessive water drinking?.
      • Rothwell S.P.
      • Rosengren D.J.
      Severe exercise-associated hyponatremia on the Kokoda Trail, Papua New Guinea.
      • Zafren K.
      Hyponatremia in a cold environment.
      • Stuempfle K.J.
      • Lehmann D.R.
      • Case H.S.
      • et al.
      Hyponatremia in a cold weather ultraendurance race.
      • Coler C.
      • Hoffman M.D.
      • Towle G.
      • Hew-Butler T.
      Hyponatremia in an 85-year-old hiker: when depletion plus dilution produces delirium.
      Furthermore, it is likely that many individuals with symptomatic or asymptomatic EAH go underreported in the literature.
      • Rogers I.R.
      • Hew-Butler T.
      Exercise-associated hyponatremia: overzealous fluid consumption.
      The lessons learned from current evidence-based EAH guidelines can be extended to those providing care in the backcountry in a limited-resource environment. Thus, it was the intent of this panel to develop evidence-based practice guidelines for EAH for use in austere environments, during transport by emergency medical services, and for immediate care by the receiving hospital.

      Methods

      The expert panel was convened at the Wilderness Medical Society annual meeting in Whistler, British Columbia, Canada, July 2012. Members were selected based on clinical interest or research experience. Relevant articles were identified by a search of MEDLINE as the primary database, US National Library of Medicine, National Institutes of Health (http://www.ncbi.nlm.nih.gov/pubmed/). Key search terms used were hyponatremia, exercise-associated hyponatremia, arginine vasopressin, syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremic encephalopathy, and 3% hypertonic saline. Peer-reviewed studies related to EAH including randomized controlled trials, observational studies, and case series were reviewed, and the level of evidence supporting the conclusions was assessed. Abstract-only studies were not included. Conclusions from review articles were not considered in the formulation of recommendations but are cited below in an effort to provide context. When no relevant studies were identified, the expert panel recommendation was based on risk vs benefit perceptions derived from patient-care experience. The panel used a consensus approach to develop recommendations regarding management of EAH in the wilderness. These recommendations have been graded based on clinical strength as outlined by the American College of Chest Physicians (ACCP; Table 1).
      • Guyatt G.
      • Gutterman D.
      • Baumann M.H.
      • et al.
      Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
      Table 1American College of Chest Physicians classification scheme for grading evidence and recommendations in clinical practice
      • Guyatt G.
      • Gutterman D.
      • Baumann M.H.
      • et al.
      Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
      GradeDescriptionBenefits vs risks and burdensMethodological quality of supporting evidence
      1AStrong recommendation, high-quality evidenceBenefits clearly outweigh risks and burdens or vice versaRCTs without important limitations or overwhelming evidence from observational studies
      1BStrong recommendation, moderate-quality evidenceBenefits clearly outweigh risks and burdens or vice versaRCTs with important limitations or exceptionally strong evidence from observational studies
      1CStrong recommendation, low-quality or very low quality evidenceBenefits clearly outweigh risks and burdens or vice versaObservational studies or case series
      2AWeak recommendation, high-quality evidenceBenefits closely balanced with risks and burdensRCTs without important limitations or overwhelming evidence from observational studies
      2BWeak recommendation, moderate-quality evidenceBenefits closely balanced with risks and burdensRCTs with important limitations or exceptionally strong evidence from observational studies
      2CWeak recommendation, low-quality or very low quality evidenceUncertainty in the estimates of benefits, risks and burden; benefits, risk and burden may be closely balancedObservational studies or case series
      ACCP, American College of Chest Physicians; RCT, randomized controlled trial.

      Scope of the Problem

      EAH typically occurs during or up to 24 hours after prolonged physical activity, and is defined by a serum or plasma sodium concentration below the normal reference range of 135 mEq/L.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      The reported incidence of EAH varies widely, in part because the diagnosis is based solely on an abnormal biochemical result in an appropriate clinical setting. Many cases of EAH may be asymptomatic and are largely detected from blood samples taken from consenting athletes participating in research screening protocols with reported incidence ranges from 0% to 51%. The highest reported incidence of “asymptomatic” hyponatremia has been noted in ultramarathon races covering 161 km (100 miles) in North America, in which the incidence of EAH has ranged between 30% and 51%.
      • Stuempfle K.J.
      • Lehmann D.R.
      • Case H.S.
      • et al.
      Hyponatremia in a cold weather ultraendurance race.
      • Lebus D.K.
      • Casazza G.A.
      • Hoffman M.D.
      • Van Loan M.D.
      Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?.
      • Hoffman M.D.
      • Stuempfle K.J.
      • Rogers I.R.
      • Weschler L.B.
      • Hew-Butler T.
      Hyponatremia in the 2009 161-km Western States Endurance Run.
      • Hoffman M.D.
      • Hew-Butler T.
      • Stuempfle K.J.
      Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners.
      The incidence of asymptomatic EAH is greater than the incidence of “symptomatic” EAH, which refers to a biochemical diagnosis of EAH combined with clinical symptoms and signs. Severe EAH manifests as significant mental status changes resulting from cerebral edema (termed exercise-associated hyponatremic encephalopathy [EAHE]), at times associated with noncardiogenic pulmonary edema.
      • Rosner M.H.
      Exercise-associated hyponatremia.
      • Rosner M.H.
      • Bennett B.
      • Hew-Butler T.
      • Hoffman M.D.
      Exercise induced hyponatremia.
      Twelve confirmed deaths of public record have been directly attributed to complications associated with EAHE.
      • Noakes T.
      Waterlogged: The Serious Problem of Overhydration in Endurance Sports.
      • Kipps C.
      • Sharma S.
      • Tunstall Pedoe D.
      The incidence of exercise-associated hyponatraemia in the London marathon.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Hew T.D.
      • Chorley J.N.
      • Cianca J.C.
      • Divine J.G.
      The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners.
      The overall incidence of symptomatic EAH in all marathon participants is generally less than 1%,
      • Hew T.D.
      • Chorley J.N.
      • Cianca J.C.
      • Divine J.G.
      The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      but the percentage of EAH seen in all symptomatic athletes seeking medical care has been reported to be as high as 23% in an Ironman Triathlon
      • Speedy D.B.
      • Noakes T.D.
      • Rogers I.R.
      • et al.
      Hyponatremia in ultradistance triathletes.
      and 38% in runners participating in a marathon and ultramarathon in Asia.
      • Lee J.K.
      • Nio A.Q.
      • Ang W.H.
      • et al.
      First reported cases of exercise-associated hyponatremia in Asia.
      An increasing trend is that symptomatic EAH is now being reported in much shorter distance events, such as a half marathon
      • Glace B.
      • Murphy C.
      Severe hyponatremia develops in a runner following a half-marathon.
      and sprint triathlon taking approximately 90 minutes to complete.
      • Shapiro S.A.
      • Ejaz A.A.
      • Osborne M.D.
      • Taylor W.C.
      Moderate exercise-induced hyponatremia.
      Symptomatic cases of EAH have been reported with increased frequency in both hikers and military infantry personnel. The reported incidence of hyponatremia in Grand Canyon hikers seeking medical care from exercise-associated collapse or exhaustion from May 31, 1993, through September 31, 1993, was 16% with an estimated incidence rate between 2.0 and 4.0 per 100,000 persons.
      • Backer H.D.
      • Shopes E.
      • Collins S.L.
      Hyponatremia in recreational hikers in Grand Canyon National Park.
      • Backer H.D.
      • Shopes E.
      • Collins S.L.
      • Barkan H.
      Exertional heat illness and hyponatremia in hikers.
      US military services have reported an increased trend of EAH cases primarily in marine corps and army infantry personnel with 4 reported deaths from EAH.
      • Gardiner J.W.
      Death by water intoxication.
      • Garigan T.P.
      • Ristedt D.E.
      Death from hyponatremia as a result of acute water intoxication in an Army basic trainee.
      Between 1999 and 2011, there were 1329 incident diagnoses of EAH (incidence of 12.6 per 100,000 person-years) among active-duty members.
      This incidence represents an increase from the previous military surveillance taken between 1997 and 2005,
      • Kolka M.A.
      • Latzka W.A.
      • Montain S.J.
      • Sawka M.N.
      Current U.S. Military Fluid Replacement Guidelines.
      which documented an incidence of 1.0 to 3.0 per 100,000 person-years across all military. The US Marine Corps had the highest incident rate in 2011 at 20.9 per 100,000 person-years despite the fact that EAH preventive measures aimed at reducing excessive forced fluid intake were adopted in 1998 by services for all infantry and other personnel. Thus, these data on military personnel reveal that their reported modest hiking and marching activities in young and healthy individuals
      • Zelingher J.
      • Putterman C.
      • Ilan Y.
      • et al.
      Case series: hyponatremia associated with moderate exercise.
      have led to documented EAHE morbidity and mortality.

      Pathogenesis of EAH

      Two major pathologic mechanisms largely account for the development of EAH: 1) excessive fluid intake, and 2) impaired urinary water excretion, largely as a result of persistent secretion of arginine vasopressin (AVP), also referred to as antidiuretic hormone or ADH.
      • Rosner M.H.
      • Kirven J.
      Exercise-associated hyponatremia.
      • Rosner M.H.
      Exercise-associated hyponatremia.

      Excessive Fluid Intake

      Overhydration appears to be the primary risk factor for the development of EAH. This is reflected in the weight gains seen in the majority of, but not all, athletes who become hyponatremic. Individuals with normal renal function, ingesting a regular diet, can excrete between 500 and 1000 mL/h of water.
      • Rose B.D.
      • Post T.W.
      Clinical Physiology of Acid-Base and Electrolyte Disorders.
      With the additional, non-renal losses of water due to sweat and insensible fluid losses, athletes should be able to consume as much as 1000 to 1500 ml/h before developing water retention and dilutional hyponatremia. Thus, although fluid ingestion is necessary to develop EAH, it is likely not sufficient except in those circumstances in which water intake is very excessive (<1500 mL/h).

      Inappropriate AVP Secretion

      Failure to suppress AVP can markedly reduce the ability of the kidneys to excrete a water load. For instance, in normal circumstances, ingestion of excessive water should suppress AVP, leading to production of dilute, high-volume urine (urine osmolality as low as 50 mOsm/kg and a volume of 500 to 1000 mL/h). If AVP is not suppressed appropriately with water loading, then the ability to produce dilute urine is markedly impaired (for instance, a low-level persistence of AVP can result in a fixed urine osmolality of 150 mOsm/kg and a decrease in the rate of water excretion by two thirds as compared with a urine osmolality of 50 mOsm/kg). In fact, the available data support the concept that many athletes who experience EAH have submaximal suppression of AVP and an inappropriately high urine osmolality.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      This is similar to SIADH. There are a number of nonosmotic stimuli that lead to secretion of AVP that may be operable in endurance athletes: intense exercise itself, nausea or vomiting, hypoglycemia, and nonspecific stresses such as pain and emotion.
      • Hew-Butler T.
      • Dugas J.P.
      • Noakes T.D.
      • Verbalis J.G.
      Changes in plasma vasopressin concentrations in cyclists participating in a 109-km cycle race.
      • Rowe J.W.
      • Shelton R.L.
      • Helderman J.H.
      • Vestal R.E.
      • Robertson G.L.
      Influence of the emetic reflex on vasopressin release in man.
      • Baylis P.H.
      • Zerbe R.L.
      • Robertson G.L.
      Arginine vasopressin response to insulin-induced hypoglycemia in man.
      Not all AVP release in athletes may be inappropriate as excessive sweat losses may induce volume depletion and appropriate secretion of AVP. This appropriate AVP secretion may be important in those athletes who experience EAH along with net weight loss (Figure 1).
      Figure thumbnail gr1
      Figure 1Exercise-associated hyponatremia pathogenesis. ANP, atrial natriuretic peptide; AVP, arginine vasopressin; BNP, brain natriuretic peptide; GI, gastrointestinal.

      Other Factors

      Although the combination of excessive water intake and inappropriate AVP secretion will clearly lead to hyponatremia, other factors may be operable in endurance athletes. In a study of endurance athletes running for a mean of 6 hours with ad libitum fluid intake, it was noted that even with a mean 3.8-kg mass loss, serum sodium was maintained at normal levels.
      • Hew-Butler T.
      • Jordaan E.
      • Stuempfle K.J.
      • et al.
      Osmotic and nonosmotic regulation of arginine vasopressin during prolonged endurance exercise.
      Despite the loss in plasma volume in these subjects, there were elevations in the levels of brain natriuretic peptide (NT-BNP).
      • Hew-Butler T.
      • Jordaan E.
      • Stuempfle K.J.
      • et al.
      Osmotic and nonosmotic regulation of arginine vasopressin during prolonged endurance exercise.
      The elevations in NT-BNP may lead to excessive losses of urine sodium and raise the risk of hyponatremia.
      A possible mechanism for maintenance of a normal serum sodium level despite weight gain is the release of sodium from internal stores.
      • Noakes T.D.
      • Sharwood K.
      • Speedy D.
      • et al.
      Three independent biological mechanisms cause exercise-associated hyponatremia: evidence from 2,135 weighed competitive athletic performances.
      Up to 25% of body sodium is bound in bone (to negatively charged proteoglycan matrix) and, although not osmotically active, is potentially recruitable into an osmotically active form.
      • Edelman I.S.
      • James A.H.
      • Brooks L.
      • Moore F.D.
      Body sodium and potassium IV. The normal total exchangeable sodium; its measurement and magnitude.
      • Edelman I.S.
      • James A.H.
      • Baden H.
      • Moore F.D.
      Electrolyte composition of bone and the penetration of radiosodium and deuterium oxide into dog and human bone.
      Thus, this pool could minimize the fall in serum sodium induced by overhydration or exacerbate hyponatremia if not mobilized.
      The absorption of water retained in the gastrointestinal tract at the end of a race has been suggested as a cause for an acute drop in serum sodium concentration.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      This may account for a transient lucid period after finishing a race followed by the acute development of clinical signs of EAHE within about 30 minutes after a competition. The breakdown of glycogen into smaller, more osmotically active molecules, such as lactate, during exercise initially increases cellular osmolality and shifts water into cells, leading to a rise in serum sodium. This may then reverse within 5 minutes after the cessation of exercise and transiently lower the serum sodium.
      • Halperin M.L.
      • Kamel K.S.
      • Sterns R.
      Hyponatremia in marathon runners.
      • Lindinger M.I.
      • Heigenhauser G.J.
      • McKelvie R.S.
      • Jones N.L.
      Blood ion regulation during repeated maximal exercise and recovery in humans.
      Changes in potassium balances that serve as effective osmoles may also affect the serum sodium such that hypokalemia will lead to or exacerbate hyponatremia.
      The issue of whether sweat sodium loss contributes to the development of EAH remains controversial. There is a highly variable degree of sodium loss from sweat (ranging from 15 to 65 mEq/L), and as compared with the general population, endurance athletes generally have lower sweat sodium levels.
      • Buono M.J.
      • Ball K.D.
      • Kolkhorst F.W.
      Sodium ion concentration vs. sweat rate relationship in humans.
      • Buono M.J.
      • Sjoholm N.T.
      Effect of physical training on peripheral sweat production.
      The direct effect of losing hypotonic sweat would be to raise the serum sodium. However, sweat loss could contribute to the development of hyponatremia if the degree of fluid loss were sufficient to produce significant volume depletion and provide a stimulus to AVP release and, thereby, impair urine excretion of water. In this case, there would also have to be ingestion of hypotonic fluids. This scenario may explain the finding of EAH developing in some athletes with net weight loss.
      • Lebus D.K.
      • Casazza G.A.
      • Hoffman M.D.
      • Van Loan M.D.
      Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?.
      • Hoffman M.D.
      • Stuempfle K.J.
      • Rogers I.R.
      • Weschler L.B.
      • Hew-Butler T.
      Hyponatremia in the 2009 161-km Western States Endurance Run.
      • Hoffman M.D.
      • Hew-Butler T.
      • Stuempfle K.J.
      Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners.

      Risk Factors

      As stated above, the major risk factor for developing EAH is excessive water intake beyond the capacity for renal water excretion.
      • Speedy D.B.
      • Noakes T.D.
      • Boswell T.
      • Thompson J.M.
      • Rehrer N.
      • Boswell D.R.
      Response to a fluid load in athletes with a history of exercise induced hyponatremia.
      • Noakes T.D.
      • Wilson G.
      • Gray D.A.
      • Lambert M.I.
      • Dennis S.C.
      Peak rates of diuresis in healthy humans during oral fluid overload.
      Other independent risk factors include longer race times (continuous endurance exercise lasting <4 hours)
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Almond C.S.
      • Shin A.Y.
      • Fortescue E.B.
      • et al.
      Hyponatremia among runners in the Boston Marathon.
      and a low
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Almond C.S.
      • Shin A.Y.
      • Fortescue E.B.
      • et al.
      Hyponatremia among runners in the Boston Marathon.
      or high
      • Almond C.S.
      • Shin A.Y.
      • Fortescue E.B.
      • et al.
      Hyponatremia among runners in the Boston Marathon.
      body mass index (BMI). Practically speaking, smaller athletes (low BMI) who are following fluid intake guidelines designed for larger individuals and slower, unfit athletes (high BMI) drinking generous amounts of fluids because they are exercising at a lower intensity are at increased risk for experiencing hyponatremia during exercise. Although the incidence of women experiencing symptomatic hyponatremia appears to be greater than that of men in some environments,
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Hew T.D.
      • Chorley J.N.
      • Cianca J.C.
      • Divine J.G.
      The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners.
      • Speedy D.B.
      • Noakes T.D.
      • Rogers I.R.
      • et al.
      Hyponatremia in ultradistance triathletes.
      • Almond C.S.
      • Shin A.Y.
      • Fortescue E.B.
      • et al.
      Hyponatremia among runners in the Boston Marathon.
      when adjusted for BMI and racing time, the apparent sex difference has not been shown to be statistically significant.
      • Almond C.S.
      • Shin A.Y.
      • Fortescue E.B.
      • et al.
      Hyponatremia among runners in the Boston Marathon.
      Along with other nonosmotic stimuli to AVP secretion,
      • Noakes T.D.
      • Sharwood K.
      • Speedy D.
      • et al.
      Three independent biological mechanisms cause exercise-associated hyponatremia: evidence from 2,135 weighed competitive athletic performances.
      • Hew-Butler T.
      • Hoffman M.D.
      • Stuempfle K.J.
      • Rogers I.R.
      • Morgenthaler N.G.
      • Verbalis J.G.
      Changes in copeptin and bioactive vasopressin in runners with and without hyponatremia.
      • Schmidt W.
      • Rojas J.
      • Böning D.
      • Bernal H.
      • Garcia S.
      • Garcia O.
      Plasma-electrolytes in natives to hypoxia after marathon races at different altitudes.
      • Hellmann K.
      • Weiner J.S.
      Antidiuretic substance in urine following exposure to high temperatures.
      • Grant S.M.
      • Green H.J.
      • Phillips S.M.
      • Enns D.L.
      • Sutton J.R.
      Fluid and electrolyte hormonal responses to exercise and acute plasma volume expansion.
      • Stebbins C.L.
      • Symons J.D.
      • McKirnan M.D.
      • Hwang F.F.
      Factors associated with vasopressin release in exercising swine.
      • Siegel A.J.
      Exercise-associated hyponatremia: role of cytokines.
      nonsteroidal anti-inflammatory drugs (NSAIDs) have been implicated as a risk factor in the development of EAH
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Wharam P.C.
      • Speedy D.B.
      • Noakes T.D.
      • Thompson J.M.
      • Reid S.A.
      • Holtzhausen L.M.
      NSAID use increases the risk of developing hyponatremia during an Ironman triathlon.
      by potentiating the water retention effects of AVP at the kidney.
      • Baker J.
      • Cotter J.D.
      • Gerrard D.F.
      • Bell M.L.
      • Walker R.J.
      Effects of indomethacin and celecoxib on renal function in athletes.
      • Walker R.J.
      • Fawcett J.P.
      • Flannery E.M.
      • Gerrard D.F.
      Indomethacin potentiates exercise-induced reduction in renal hemodynamics in athletes.
      However, data are still conflicting,
      • Hew T.D.
      • Chorley J.N.
      • Cianca J.C.
      • Divine J.G.
      The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners.
      • Almond C.S.
      • Shin A.Y.
      • Fortescue E.B.
      • et al.
      Hyponatremia among runners in the Boston Marathon.
      and further investigation is necessary to determine whether NSAID usage—with respect to both classification and dosages—is a clear risk factor for the development of EAH. Other medications associated with SIADH such as selective serotonin reuptake inhibitors may also increase the risk for EAH, but data are not conclusive.

      Prevention

      Avoid Overhydration

      The primary strategy to prevent EAH is to avoid overdrinking during exercise. Because fluid losses through sweat and urine are highly dynamic and variable across individuals participating in a variety of outdoor activities, recommending “fixed ranges” of fluid intake are not appropriate. Using the sensation of thirst as a real-time guide to fluid ingestion during exercise appears safe and effective and eliminates both of the detrimental extremes of fluid balance (dehydration and overhydration).
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Walker R.J.
      • Fawcett J.P.
      • Flannery E.M.
      • Gerrard D.F.
      Indomethacin potentiates exercise-induced reduction in renal hemodynamics in athletes.
      • Hew-Butler T.
      • Verbalis J.G.
      • Noakes T.D.
      International Marathon Medical Directors Association
      Updated fluid recommendation: position statement from the International Marathon Medical Directors Association (IMMDA).
      • Cheuvront S.N.
      • Haymes E.M.
      Ad libitum fluid intakes and thermoregulatory responses of female distance runners in three environments.
      • Armstrong L.E.
      • Maresh C.M.
      • Gabaree C.V.
      • et al.
      Thermal and circulatory responses during exercise: effects of hypohydration, dehydration, and water intake.
      Therefore, participant education on this approach to hydration during exercise is an important prevention strategy. Another strategy that has been shown to reduce the incidence of hyponatremia during endurance events is to reduce the availability of fluids along the routes of exercise.
      • Speedy D.B.
      • Rogers I.R.
      • Noakes T.D.
      • et al.
      Diagnosis and prevention of hyponatremia at an ultradistance triathlon.
      Recommendation: Participants should focus on decreasing overdrinking during exercise by drinking according to thirst, and race organizers might consider reducing the overavailability of fluids (<3 km apart) along routes of exercise. Recommendation Grade: 1C.

      Avoid Excessive Sodium Supplementation

      Sodium supplementation during exercise has not been shown to prevent the development of hyponatremia during physical activity lasting less than 18 hours.
      • Speedy D.B.
      • Thompson J.M.
      • Rodgers I.
      • Collins M.
      • Sharwood K.
      • Noakes T.D.
      Oral salt supplementation during ultradistance exercise.
      • Hew-Butler T.D.
      • Sharwood K.
      • Collins M.
      • Speedy D.
      • Noakes T.
      Sodium supplementation is not required to maintain serum sodium concentrations during an Ironman triathlon.
      • Twerenbold R.
      • Knechtle B.
      • Kakebeeke T.H.
      • et al.
      Effects of different sodium concentrations in replacement fluids during prolonged exercise in women.
      • Barr S.I.
      • Costill D.L.
      • Fink W.J.
      Fluid replacement during prolonged exercise: effects of water, saline, or no fluid.
      In athletes who drink beyond thirst or fully replace 100% of body weight losses during exercise, supplemental sodium may attenuate the decline in blood sodium concentration
      • Barr S.I.
      • Costill D.L.
      • Fink W.J.
      Fluid replacement during prolonged exercise: effects of water, saline, or no fluid.
      • Vrijens D.M.
      • Rehrer N.J.
      Sodium-free fluid ingestion decreases plasma sodium during exercise in the heat.
      but will not prevent the development of hyponatremia if overdrinking were to continue.
      • Hew-Butler T.D.
      • Sharwood K.
      • Collins M.
      • Speedy D.
      • Noakes T.
      Sodium supplementation is not required to maintain serum sodium concentrations during an Ironman triathlon.
      Supplemental sodium has no effect on blood sodium concentration when athletes drink according to thirst.
      • Speedy D.B.
      • Thompson J.M.
      • Rodgers I.
      • Collins M.
      • Sharwood K.
      • Noakes T.D.
      Oral salt supplementation during ultradistance exercise.
      • Hew-Butler T.D.
      • Sharwood K.
      • Collins M.
      • Speedy D.
      • Noakes T.
      Sodium supplementation is not required to maintain serum sodium concentrations during an Ironman triathlon.
      • Twerenbold R.
      • Knechtle B.
      • Kakebeeke T.H.
      • et al.
      Effects of different sodium concentrations in replacement fluids during prolonged exercise in women.
      However, exercisers who drink insufficient amounts of fluid during exercise will often finish races with elevated blood sodium concentrations.
      • Röcker L.
      • Kirsch K.A.
      • Heyduck B.
      • Altenkirch H.U.
      Influence of prolonged physical exercise on plasma volume, plasma proteins, electrolytes, and fluid-regulating hormones.
      • Beckner G.L.
      • Winsor T.
      Cardiovascular adaptations to prolonged physical effort.
      • Riley W.J.
      • Pyke F.S.
      • Roberts A.D.
      • England J.F.
      The effect of long-distance running on some biochemical variables.
      • Åstrand P.O.
      • Saltin B.
      Plasma and cell volume alterations after prolonged severe exercise.
      Collectively, these results demonstrate that it is the amount of fluid ingested rather than the amount of sodium ingested during exercise that has a more pronounced effect on blood sodium concentrations as mathematically predicted elsewhere.
      • Weschler L.B.
      Exercise-associated hyponatraemia: a mathematical review.
      Adverse effects associated with abnormal water retention from excessive sodium intake have been reported.
      • Luks A.M.
      • Robertson H.T.
      • Swenson E.R.
      An ultracyclist with pulmonary edema during the Bicycle Race Across America.
      Recommendation: Excessive sodium supplementation is not recommended during physical activity lasting less than 18 hours. Recommendation Grade: 2B.

      Monitoring Body Weight

      Because overconsumption of hypotonic fluids beyond the capacity to excrete any fluid excess is often key in the pathophysiology of EAH, the monitoring of body weight change is one strategy commonly used in 161-km ultramarathons to help prevent overhydration. As a result of the combination of substrate losses and the liberation of glycogen-bound water during exercise, some weight loss is appropriate during exercise. Furthermore, EAH has been reported with substantial weight loss in some environments,
      • Lebus D.K.
      • Casazza G.A.
      • Hoffman M.D.
      • Van Loan M.D.
      Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?.
      • Hoffman M.D.
      • Stuempfle K.J.
      • Rogers I.R.
      • Weschler L.B.
      • Hew-Butler T.
      Hyponatremia in the 2009 161-km Western States Endurance Run.
      • Hoffman M.D.
      • Hew-Butler T.
      • Stuempfle K.J.
      Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners.
      so weight loss is not a reliable approach for excluding the diagnosis of EAH. On the other hand, in the presence of weight gain during exercise, fluid intake should be reduced, and if sodium supplementation has been taking place, this should also be curtailed until body weight returns to an appropriate level. If feasible, weight scales can be made available at organized athletic events for this purpose, but care should be taken to assure proper scale calibration and placement on solid level surfaces, and participants should be educated in proper use of body weight information.
      Recommendation: Body weight can be monitored in organized events, and in the presence of weight gain during exercise, fluid and sodium intake should be reduced until weight returns to 2% to 4% of body weight loss from baseline level. Recommendation Grade: 1B.

      Educate Event Support and Medical Personnel

      Event support staff should have a basic understanding of EAH to avoid the provision of improper hydration advice to participants because it has been previously shown that runners have a poor understanding of the relationship between drinking habits and hyponatremia.
      • Williams J.
      • Tzortziou Brown V.
      • Malliaras P.
      • Perry M.
      • Kipps C.
      Hydration strategies of runners in the London Marathon.
      • Winger J.M.
      • Dugas J.P.
      • Dugas L.R.
      Beliefs about hydration and physiology drive drinking behaviours in runners.
      On-site medical personnel should be aware of proper treatment of EAH. This should include the recognition that hypotonic fluid replacement (intravenous or oral) should be avoided when the diagnosis of EAH is under consideration to prevent further declines in blood sodium concentration. Such education can be provided by event medical directors via prerace briefings and the use of suggested reading material or educational videotapes.
      Recommendation: Event support staff should be educated so they can provide proper hydration advice, and on-site medical and emergency medical service (EMS) personnel should be educated about proper recognition and treatment of EAH. Recommendation Grade: 1C.

      Field Treatment

      Appropriate management of EAH depends first on correctly diagnosing the condition. A requisite for correctly diagnosing EAH is that it must be routinely considered in the differential diagnosis of an individual presenting for medical attention during or shortly after exercise or strenuous activity. In fact, EAH can easily be mistaken for dehydration, heat illness, or acute altitude illnesses
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Ayus J.C.
      • Moritz M.L.
      Exercise-associated hyponatremia masquerading as acute mountain sickness: are we missing the diagnosis?.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      • Sucholeiki R.
      Heatstroke.
      because of overlapping signs and symptoms if the diagnosis is not considered (Table 2). Differentiation between dehydration and EAH is critical as provision of isotonic or hypotonic fluids is appropriate for the dehydrated athlete,
      • Patel D.R.
      • Gyamfi R.
      • Torres A.
      Exertional rhabdomyolysis and acute kidney injury.
      whereas such treatment could be disastrous for an athlete with EAH, in whom the administration of these hypotonic or isotonic fluids may worsen hyponatremia.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      Table 2Signs and symptoms of exercise-associated hyponatremia and heat illness or altitude illness
      GeneralEAHHeat illnessAMS, HACE, or HAPE
      Fatigue/weaknessPossiblePossibleLikely
      Increased thirstPossibleLikelyPossible
      Temperature
       ElevatedPossiblePresentNot present
      Cardiovascular
       TachycardiaPossibleLikelyPossible
       OrthostasisPossibleLikelyPossible
      Gastrointestinal
       Nausea/vomitingPossiblePossiblePossible
      Neurological
       Headache/dizzinessPossiblePossiblePresent
       Blurred visionPossiblePossiblePossible
       Confusion/disorientationPossiblePossiblePossible
       ObtundationPossiblePossiblePossible
       SeizurePossiblePossiblePossible
       ComaPossiblePossiblePossible
      Respiratory distressPossibleNot presentPossible
      Urine output
       OliguriaPossibleLikelyPossible
       DiuresisPossibleNot presentPossible
      AMS, acute mountain sickness; EAH, exercise-associated hyponatremia; HACE, high altitude cerebral edema; HAPE, high altitude pulmonary edema.
      A conclusion of the Second International Exercise-Associated Hyponatremia Consensus Development Conference was that “medical directors should ensure the availability of onsite serum sodium concentration analysis.”
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      When EAH is routinely considered in the differential diagnosis of a collapsed athlete and point-of-care serum sodium concentration analysis is available, the field diagnosis of EAH becomes straightforward. However, the reality is that on-site analysis of serum sodium concentration is not widely available at organized endurance competitions nor is it currently feasible to implement. Even relatively large and established events often have no capacity for on-site blood analysis. This is also the case with most wilderness activities.
      Therefore, we provide strategies for the following 2 scenarios (Figure 2) .
      • Scenario 1: An EAH diagnosis has been made by point-of-care sodium analysis.
      • Scenario 2: Point-of-care sodium analysis is not available, and the diagnosis of EAH is presumed.
      Figure thumbnail gr2
      Figure 2Algorithm for exercise-associated hyponatremia (EAH) field management.

      Therapeutic Options for Both Scenarios

      Fluids

      An important element in the treatment of EAH is to avoid exacerbating the condition with improper fluid management. If EAH is clinically suspected, an assessment of volume status should be considered before treatment with IV fluids is rendered. It must be made clear that inappropriate IV fluid administration risks worsening hyponatremia with potentially devastating consequences.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      Thus, clear indications (such as unstable blood pressure) should be present to support administration of IV fluids. The use of hypotonic IV fluids should be avoided. If the patient does not have clear indications for IV fluids and EAH is suspected, then fluid restriction while the patient is being transported to a medical center should be instituted.
      Recommendation: Hypotonic or isotonic fluid intake should be restricted in known or suspected EAH until urination begins. Recommendation Grade: 1A.

      Supplemental oxygen

      Hypoxemia from pulmonary edema has been reported in EAH.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      As a supportive intervention, supplemental oxygen (flow rate 2–4 L/min nasal) should be provided to treat any respiratory distress if available.
      Recommendation: Respiratory symptoms should be supported with supplemental oxygen if available. Recommendation Grade: 1C.

      Appropriate transfer of care

      The intent of field management is to stabilize the patient until their care can be transferred to a definitive care medical facility. Unfortunately, EAH recognition is challenging,
      • Hoffman M.D.
      • Fogard K.
      • Winger J.
      • Hew-Butler T.
      • Stuempfle K.J.
      Characteristics of 161-km ultramarathon finishers developing exercise-associated hyponatremia.
      and appropriate management is not universally understood. Therefore, when transferring care, it is critical to relay the potential diagnosis of EAH and to caution the transport team about the dangers of aggressive IV hydration with isotonic or hypotonic fluids. Ideally, an IV saline lock should be placed for EMS transport, and the provision of IV fluids should be based on clear indications of marked hypovolemia such as sustained hypotension. However, if the transport team insists on provision of isotonic or hypotonic fluids, they should be cautioned that a patient with EAH could experience worsening symptoms with this intervention. If symptoms worsen in this scenario, IV fluids should be stopped, and consideration of immediate hypertonic (3%) saline administration should occur.
      Recommendation: When transferring care, alert receiving caregivers of the diagnosis of EAH and appropriate management. Recommendation Grade: 1C.

      Specific Recommendations—Scenario 1 (Blood Sodium Estimation is Available)

      Clinical assessment

      The portability of point-of-care testing devices means that they may be available to confirm a diagnosis of EAH (for instance at a mass-participation wilderness sporting event or on a well-equipped expedition).
      • Backer H.D.
      • Shopes E.
      • Collins S.L.
      • Barkan H.
      Exertional heat illness and hyponatremia in hikers.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      In general, a sodium level of 130 mmol/L or higher will be minimally symptomatic or asymptomatic, whereas levels below this are increasingly likely to be symptomatic.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Speedy D.B.
      • Noakes T.D.
      • Rogers I.R.
      • et al.
      Hyponatremia in ultradistance triathletes.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      Symptoms and signs of EAHE (ranging from headache and nausea or vomiting to confusion and obtundation) are a key element in making the diagnosis of severe or clinically significant findings. Although the early symptoms of EAH may be nonspecific, the presence of altered mental state, coma, seizures, or respiratory distress (suggesting pulmonary edema) indicates EAHE
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      and should be promptly recognized.
      Recommendation: A rapid assessment for signs and symptoms of cerebral edema or noncardiogenic pulmonary edema should be made in all patients with possible EAH. Recommendation Grade: 1B.
      Developing signs of cerebral or pulmonary edema (noncardiogenic) signify an urgent medical condition requiring emergent care. In such situations, urgent blood sodium measurement is invaluable in guiding initial therapy.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Recommendation: When point-of-care sodium analysis is available in the field and EAH is suspected, blood sodium measurement should be obtained as rapidly as possible. Recommendation Grade: 1B.

      Hypertonic saline

      It is possible to commence and indeed even complete treatment for EAH in the field.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Individuals with EAH who are neurologically stable can be advised to limit fluid intake and consume salty snacks, soups or bouillon, or a small volume of hypertonic fluid until the onset of urination. They should be observed for at least 60 minutes during the initial postexercise period because water remaining in the gastrointestinal tract can be quickly absorbed at the cessation of exercise and result in rapid development of symptoms from EAH.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      More urgent medical attention, including planning for transfer to definitive care, is required if signs or symptoms of EAH develop. Once any neurological symptoms more serious than headache develop, regardless of the degree of hyponatremia, treatment with hypertonic saline is indicated. When able to tolerate oral intake, a hypertonic (∼9% saline) solution of concentrated broth (3–4 bouillon cubes in 125 mL [½ cup] of water) would be an appropriate initial treatment.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Recommendation: Oral hypertonic saline solutions are an appropriate intervention in the field for cases of EAH when oral intake is possible. Recommendation Grade: 1C.
      If the individual is unable to tolerate oral intake, or when there is no improvement or symptoms worsen with oral hypertonic saline, the recommended treatment is a 100-mL bolus of 3% hypertonic saline infused through a peripheral vein in less than 60 seconds. This can be repeated 2 additional times at 10-minute intervals if there is no clinical improvement.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Experience has proven this treatment to be without untoward symptoms at the infusion site (no burning, phlebitis, or residual discomfort) and no risk of osmotic demyelination or central pontine myelinolysis.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      Recommendation: Symptomatic biochemically confirmed EAH can be treated in the field with a 100-mL bolus of 3% hypertonic saline, which can be repeated twice at 10-minute intervals (3 doses in total) with the aim of acutely increasing serum sodium concentration by about 4 to 5 mmol/L and reversing cerebral edema in the setting of acute hyponatremia. Recommendation Grade: 1B.

      Specific Recommendations—Scenario 2 (Blood Sodium Estimation is Not Available)

      When the capacity for onsite serum sodium measurement is not available, the decision-making process becomes challenging. Unfortunately, the possible signs and symptoms that can be present with EAH are quite similar to those present with heat illness, dehydration, or acute mountain sickness (Table 2). Furthermore, there were no differences between those experiencing mild EAH and those not experiencing EAH after a 161-km ultramarathon in terms of various individual characteristics, signs, and symptoms.
      • Hoffman M.D.
      • Fogard K.
      • Winger J.
      • Hew-Butler T.
      • Stuempfle K.J.
      Characteristics of 161-km ultramarathon finishers developing exercise-associated hyponatremia.
      Even oliguria, which would be typical of the dehydrated state, is also commonly seen with EAH when AVP secretion is part of the pathophysiological mechanism leading to a highly concentrated, low-volume urine output.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      In some environments in which overhydration is a key feature in the underlying etiology of EAH, those experiencing EAH have been shown to be more likely to lose less weight or to gain weight during the exercise compared with those not experiencing EAH.
      • Noakes T.D.
      • Sharwood K.
      • Speedy D.
      • et al.
      Three independent biological mechanisms cause exercise-associated hyponatremia: evidence from 2,135 weighed competitive athletic performances.
      However, in other environments, it is not at all uncommon for those with EAH to have considerable weight loss, suggesting other mechanisms in the development of EAH.
      • Lebus D.K.
      • Casazza G.A.
      • Hoffman M.D.
      • Van Loan M.D.
      Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?.
      • Hoffman M.D.
      • Stuempfle K.J.
      • Rogers I.R.
      • Weschler L.B.
      • Hew-Butler T.
      Hyponatremia in the 2009 161-km Western States Endurance Run.
      • Hoffman M.D.
      • Hew-Butler T.
      • Stuempfle K.J.
      Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners.
      Therefore, changes in body weight are not universally helpful in making the diagnosis of EAH. This unfortunately means that the only reliable method of diagnosing EAH at present is through measurement of serum sodium concentration.

      Fluid restriction

      A high clinical suspicion of EAH necessitates fluid restriction and salt supplementation. Certainly in environments such as long ultramarathon races in which the incidence of EAH may be high (30%–51%),
      • Stuempfle K.J.
      • Lehmann D.R.
      • Case H.S.
      • et al.
      Hyponatremia in a cold weather ultraendurance race.
      • Lebus D.K.
      • Casazza G.A.
      • Hoffman M.D.
      • Van Loan M.D.
      Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?.
      • Hoffman M.D.
      • Stuempfle K.J.
      • Rogers I.R.
      • Weschler L.B.
      • Hew-Butler T.
      Hyponatremia in the 2009 161-km Western States Endurance Run.
      • Hoffman M.D.
      • Hew-Butler T.
      • Stuempfle K.J.
      Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      one should resist treating athletes with IV hypotonic or isotonic saline without certainty that they do not have EAH.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      However, fluid restriction is contraindicated in the case of dehydration and rhabdomyolysis with impending acute kidney injury.
      • Patel D.R.
      • Gyamfi R.
      • Torres A.
      Exertional rhabdomyolysis and acute kidney injury.
      Therefore, in the situation in which the diagnosis of EAH is uncertain, the potential benefits of fluid restriction if the individual has EAH must be weighed against the potential harm that could result when the individual might have dehydration, rhabdomyolysis, and impending acute renal failure.
      Recommendation: Hypotonic or isotonic fluids should be restricted in suspected EAH with consideration toward the potential harm that could result from fluid restriction if the diagnosis is incorrect. Recommendation Grade: 2C.

      Hypertonic saline

      In the event of neurological deterioration without access to rapid determination of serum sodium concentration, the use of IV hypertonic saline, if available, is a consideration for presumed EAH. Such an intervention carries potential risks, yet the benefit that could be derived from a bolus of hypertonic saline of approximately 51 mmol of sodium for fluid volume expansion and the limited effect it would have on increasing blood sodium concentration suggest that the risk is low, even under conditions of dehydration and hypernatremia. When the patient is neurologically stable, oral sodium with limited fluid has been demonstrated to be an appropriate treatment.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      In the field, this could be prepared by dissolving 3 to 4 bouillon cubes in 125 mL (½ cup) of water (∼9% saline).
      Recommendation: IV hypertonic saline (100 mL bolus of 3% hypertonic saline, which can be repeated twice at 10-minute intervals) is an appropriate consideration in suspected EAH with neurological deterioration, whereas an oral hypertonic saline solution would be an appropriate consideration in suspected mild EAH. Recommendation Grade: 2C.

      Emergency transport

      When point-of-care serum sodium concentration cannot be determined and any attempted field treatment has been insufficiently successful, emergency transport to a definitive care facility should be expedited. Organized endurance exercise events that do not have the on-site capacity for measurement of serum sodium concentration and treatment with hypertonic saline should prearrange an appropriate emergency transport system. Local emergency department physicians and transport personnel should also be educated about EAH in advance of the event.
      Recommendation: The assurance that an emergency transport system is in place is critical when point-of-care serum sodium measurement will not be available or treatment with hypertonic saline will not be feasible. Recommendation Grade: 1C.

      Immediate Medical Care in Hospital—Assessment

      The medical care of suspected EAH in hospital is assumed to occur in a facility that has the capacity to measure an urgent sodium level either by point-of-care testing or in a hospital laboratory. The sodium level and a clinical assessment for signs of cerebral edema are the key factors that will determine urgent treatment. The primary intervention (when indicated) is the use of IV hypertonic saline (HTS), usually as a 3% solution, to acutely increase serum sodium and reduce cerebral edema, whereas the role of other therapeutic agents such as vasopressin receptor antagonists (“vaptans”), urea, oral saline solutions, and diuretics in the treatment of acute symptomatic cases of EAH has not been firmly established.
      • Hew-Butler T.D.
      • Almond C.S.
      • Ayus J.C.
      • et al.
      Consensus Statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005.
      See Table 3 for a summary of critical steps for immediate medical care in a receiving hospital.
      Table 3Summary of acute hospital assessment and management of EAH
      Assessment
       Urgent measurement of blood sodium by the most rapidly available means
       Assess for clinical signs suggestive of developing cerebral edema
       Obtain and store specimens if possible for later analysis of blood serum osmolality and urine sodium and osmolality
      Management
       Supplemental oxygen to maintain oxygen saturation above 95%
       Restrict fluids (both IV and oral) until onset of urination
       Avoid IV normal saline until sodium correction is initiated
      Thereafter normal saline may be required for hypovolemic shock or in renal protection therapy for rhabdomyolysis
       In severe EAH (signs of cerebral edema or serum sodium <125 mmol/L) administer IV 3% hypertonic saline as a 100-mL bolus repeated twice at 10-minute intervals aiming to reverse cerebral edema
       Aim to increase serum sodium by approximately 4 to 5 mmol/L or until neurological symptoms are reversed by active treatment, then allow the remaining correction to occur spontaneously via urinary free water excretion

      Urgent sodium estimation

      The in-hospital diagnosis of EAH is made in an appropriate clinical context, whether or not signs or symptoms are present, by the determination of a sodium level below the normal reference range. In general a sodium level of 130 mmol/L or higher will be minimally symptomatic or asymptomatic,
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Hew-Butler T.D.
      • Almond C.S.
      • Ayus J.C.
      • et al.
      Consensus Statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      whereas levels below this are increasingly likely to be symptomatic.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Developing signs of cerebral edema signify an urgent medical condition requiring emergent care.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Recommendation: With suspected EAH, and especially those with altered mental state, sodium estimation should be obtained as rapidly as possible after hospital arrival. Recommendation Grade: 1B.

      Assessment for cerebral and pulmonary edema

      Symptoms and signs of cerebral edema are a key element in making the diagnosis of severe or clinically significant EAH. Although the early symptoms of EAH may be nonspecific, the presence of altered mental state, coma, seizures, or respiratory distress (suggesting pulmonary edema) indicates severe EAH.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      Such an assessment is made clinically at the bedside. It does not require imaging or scans and should never delay the use of IV HTS when indicated (see following sections).
      Recommendation: A rapid assessment for signs and symptoms of cerebral edema and/or non-cardiogenic pulmonary edema should be made in all patients with possible EAH. Recommendation Grade: 1B.

      Other laboratory testing

      Although not essential to guide initial therapy, there are other laboratory tests that can help to better delineate the pathophysiology of EAH in an individual patient and help guide subsequent treatment if more prolonged in-hospital care is required.
      • Rosner M.H.
      • Kirven J.
      Exercise-associated hyponatremia.
      These tests may help to differentiate euvolemic from hypovolemic EAH and the role of AVP in its pathogenesis.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Hew-Butler T.D.
      • Almond C.S.
      • Ayus J.C.
      • et al.
      Consensus Statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Verbalis J.G.
      • Goldsmith S.R.
      • Greenburg A.
      • Schrier R.W.
      • Sterns R.H.
      Hyponatremia treatment guidelines 2007: expert panel recommendations.
      Such tests are best taken before therapy is commenced even if they are only stored for subsequent analysis. However, such testing should never delay the use of IV HTS when indicated (see following sections).
      Recommendation: When possible, urine for sodium and osmolality and blood for osmolality should be obtained before commencement of treatment. Recommendation Grade: 2C.

      Fluid restriction

      Mild or asymptomatic EAH (essentially a biochemical-only diagnosis) will usually resolve without treatment during a period of observation. Hypotonic fluids, whether taken orally or given IV, will generally worsen the situation, especially before the onset of urination. IV normal saline will worsen EAH acutely in the presence of osmotically inappropriate (nonosmotic) AVP secretion (SIADH),
      • Kipps C.
      • Sharma S.
      • Tunstall Pedoe D.
      The incidence of exercise-associated hyponatraemia in the London marathon.
      • Siegel A.J.
      • Verbalis J.G.
      • Clement S.
      • et al.
      Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      but may be required later in specific clinical contexts such as the prevention of renal injury in rhabdomyolysis or the treatment of hypovolemic shock.
      Recommendation: Oral and IV hypotonic or isotonic hydration should be avoided early in the management of EAH although it may be appropriate in certain clinical contexts once sodium correction has been initiated or hypovolemia is biochemically confirmed (by elevated blood urea nitrogen and urine sodium less than 30 mmol/L). Recommendation Grade: 1B.

      Hypertonic saline

      The most commonly available form of IV HTS is a 3% solution.
      • Rosner M.H.
      • Kirven J.
      Exercise-associated hyponatremia.
      • Davis D.P.
      • Videen J.S.
      • Marino A.
      • et al.
      Exercise-associated hyponatremia in marathon runners: a two-year experience.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Hypertonic saline will acutely raise the serum sodium, resulting in a fluid shift that will decrease cerebral edema. A 100-mL solution of 3% HTS contains 51 mmol of sodium and in the average adult would be expected to increase the serum sodium by 1 to 2 mmol/L. It is used whenever there are signs of significant cerebral edema in EAH.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Frizzell R.T.
      • Lang G.H.
      • Lowance D.C.
      • Lathan S.R.
      Hyponatremia and ultramarathon running.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      It may also be indicated in severe biochemical hyponatremia (<125 mmol/L) when initially presenting as asymptomatic or mildly symptomatic, as these cases have been known to progress to EAHE. When using IV HTS, the aim is not to normalize the serum sodium concentration but rather to reverse cerebral edema while preventing or treating the life-threatening consequences of EAHE.
      • Rosner M.H.
      • Kirven J.
      Exercise-associated hyponatremia.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Siegel A.J.
      • d'Hemecourt P.
      • Adner M.M.
      • Shirey T.
      • Brown J.L.
      • Lewandrowski K.B.
      Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
      Generally this will require an increase in the sodium level of about 4 to 5 mmol/L. Thereafter, further normalization of sodium is not urgent and may be best allowed to occur spontaneously through suppression of nonosmotic AVP secretion and resultant urinary free water excretion. The use of IV HTS in EAH appears to be safe,
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      • Rogers I.R.
      • Hook G.
      • Stuempfle K.J.
      • Hoffman M.D.
      • Hew-Butler T.
      An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
      with no recorded cases of osmotic demyelination known to have occurred as opposed to the situation with rapid correction of chronic hyponatremia.
      • Backer H.D.
      • Shopes E.
      • Collins S.L.
      Hyponatremia in recreational hikers in Grand Canyon National Park.
      Recommendation: In hospital, severe biochemically confirmed or symptomatic EAH should be treated with a 100-mL bolus of 3% hypertonic saline, which can be repeated twice at 10-minute intervals (3 doses in total), with the aim of acutely increasing serum sodium concentration by about 4 to 5 mmol/L and reversing cerebral edema. Recommendation Grade: 1A.

      Supplemental oxygen

      Although the major manifestation of EAH is cerebral, pulmonary manifestations can occur.
      • Hew-Butler T.
      • Ayus J.C.
      • Kipps C.
      • et al.
      Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
      Hypoxemia, which may worsen cerebral injury, should be avoided, but hyperoxia may possibly have detrimental effects.
      • Iscoe S.
      • Beasley R.
      • Fisher J.A.
      Supplementary oxygen for nonhypoxemic patients: O2 much of a good thing?.
      Recommendation: Supplemental oxygen to maintain an oxygenation saturation of 95% should be provided to treat hypoxemia from pulmonary edema when evident. Recommendation Grade: 1C.

      Conclusions

      Exercise-associated hyponatremia has a complex pathogenesis and multifactorial etiology. It can result in devastating outcomes to participants in both organized or individual endurance activities in communities or in remote backcountry environments.
      Preventing EAH is the key factor in protecting participants in endurance events and other wilderness activities. Currently, there is no one recommendation that fits all individuals for fluid and salt consumption during endurance events, although prudent general guidelines include drinking to thirst and specifically avoiding excessively high fluid intake. There is an ongoing need for education to ensure that participants understand the risk of overhydration. Furthermore, a knowledge gap persists internationally among practitioners and prehospital EMS personnel about the assessment and treatment of EAH, which is compounded by the nonspecific nature of many of the signs and symptoms of EAH. The typical field response is to administer rapid isotonic IV fluids to endurance activity participants in the suspicion they are dehydrated. However, such universal treatment may result in increased morbidity and mortality in the asymptomatic and symptomatic EAH patient.

      Acknowledgments

      The authors thank the Wilderness Medical Society for the assistance provided for two Exercise-Associated Hyponatremia panel presentations at the Desert Medicine conference, Tucson, Arizona, November 2011, and at the 6th World Congress on Wilderness Medicine, Whistler, British Columbia, July 2012. This material is the result of work supported with resources and the use of facilities at the VA Northern California Health Care System. The contents reported here do not represent the views of the Department of Veterans Affairs or the United States Government.

      References

        • Noakes T.D.
        • Goodwin N.
        • Rayner B.L.
        • Branken T.
        • Taylor R.K.
        Water intoxication: a possible complication during endurance exercise.
        Med Sci Sports Exerc. 1985; 17: 370-375
        • Montain S.J.
        • Sawka M.N.
        • Wenger C.B.
        Hyponatremia associated with exercise: risk factors and pathogenesis.
        Exerc Sport Sci Rev. 2001; 29: 113-117
        • Speedy D.B.
        • Noakes T.D.
        • Schneider C.
        Exercise-associated hyponatremia: a review.
        Emerg Med (Fremantle). 2001; 13: 17-27
        • Rosner M.H.
        • Kirven J.
        Exercise-associated hyponatremia.
        Clin J Am Soc Nephrol. 2007; 2: 151-161
        • Rosner M.H.
        Exercise-associated hyponatremia.
        Semin Nephrol. 2009; 29: 271-281
        • Rosner M.H.
        • Bennett B.
        • Hew-Butler T.
        • Hoffman M.D.
        Exercise induced hyponatremia.
        in: Simon E.E. Hyponatremia: Evaluation and Treatment. Springer, New York, NY2013 (In press)
        • Hew-Butler T.
        • Ayus J.C.
        • Kipps C.
        • et al.
        Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.
        Clin J Sport Med. 2008; 18: 111-121
        • Hew-Butler T.D.
        • Almond C.S.
        • Ayus J.C.
        • 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
        • Backer H.D.
        • Shopes E.
        • Collins S.L.
        Hyponatremia in recreational hikers in Grand Canyon National Park.
        J Wilderness Med. 1993; 4: 391-406
        • Basnyat B.
        • Sleggs J.
        • Spinger M.
        Seizures and delirium in a trekker: the consequences of excessive water drinking?.
        Wilderness Environ Med. 2000; 11: 69-70
        • Rothwell S.P.
        • Rosengren D.J.
        Severe exercise-associated hyponatremia on the Kokoda Trail, Papua New Guinea.
        Wilderness Environ Med. 2008; 19: 42-44
        • Zafren K.
        Hyponatremia in a cold environment.
        Wilderness Environ Med. 1998; 9: 54-55
        • Stuempfle K.J.
        • Lehmann D.R.
        • Case H.S.
        • et al.
        Hyponatremia in a cold weather ultraendurance race.
        Alaska Med. 2002; 44: 51-55
        • Coler C.
        • Hoffman M.D.
        • Towle G.
        • Hew-Butler T.
        Hyponatremia in an 85-year-old hiker: when depletion plus dilution produces delirium.
        Wilderness Environ Med. 2012; 23: 153-157
        • Rogers I.R.
        • Hew-Butler T.
        Exercise-associated hyponatremia: overzealous fluid consumption.
        Wilderness Environ Med. 2009; 20: 139-143
        • Guyatt G.
        • Gutterman D.
        • Baumann M.H.
        • et al.
        Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
        Chest. 2006; 129: 174-181
        • Lebus D.K.
        • Casazza G.A.
        • Hoffman M.D.
        • Van Loan M.D.
        Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?.
        Clin J Sport Med. 2010; 20: 193-199
        • Hoffman M.D.
        • Stuempfle K.J.
        • Rogers I.R.
        • Weschler L.B.
        • Hew-Butler T.
        Hyponatremia in the 2009 161-km Western States Endurance Run.
        Int J Sports Physiol Perform. 2012; 7: 6-10
        • Hoffman M.D.
        • Hew-Butler T.
        • Stuempfle K.J.
        Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners.
        Med Sci Sports Exerc. 2013; 45: 784-791
        • Noakes T.
        Waterlogged: The Serious Problem of Overhydration in Endurance Sports.
        Human Kinetics, Champaign, IL2012
        • Kipps C.
        • Sharma S.
        • Tunstall Pedoe D.
        The incidence of exercise-associated hyponatraemia in the London marathon.
        Br J Sports Med. 2011; 45: 14-19
        • Ayus J.C.
        • Varon J.
        • Arieff A.I.
        Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
        Ann Intern Med. 2000; 132: 711-714
        • Siegel A.J.
        • Verbalis J.G.
        • Clement S.
        • et al.
        Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion.
        Am J Med. 2007; 120: 461.e11-461.e17
        • Hew T.D.
        • Chorley J.N.
        • Cianca J.C.
        • Divine J.G.
        The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners.
        Clin J Sport Med. 2003; 13: 41-47
        • Davis D.P.
        • Videen J.S.
        • Marino A.
        • et al.
        Exercise-associated hyponatremia in marathon runners: a two-year experience.
        J Emerg Med. 2001; 21: 47-57
        • Speedy D.B.
        • Noakes T.D.
        • Rogers I.R.
        • et al.
        Hyponatremia in ultradistance triathletes.
        Med Sci Sports Exerc. 1999; 31: 809-815
        • Lee J.K.
        • Nio A.Q.
        • Ang W.H.
        • et al.
        First reported cases of exercise-associated hyponatremia in Asia.
        Int J Sports Med. 2011; 32: 297-302
        • Glace B.
        • Murphy C.
        Severe hyponatremia develops in a runner following a half-marathon.
        JAAPA. 2008; 21: 27-29
        • Shapiro S.A.
        • Ejaz A.A.
        • Osborne M.D.
        • Taylor W.C.
        Moderate exercise-induced hyponatremia.
        Clin J Sport Med. 2006; 16: 72-73
        • Backer H.D.
        • Shopes E.
        • Collins S.L.
        • Barkan H.
        Exertional heat illness and hyponatremia in hikers.
        Am J Emerg Med. 1999; 17: 532-539
        • Gardiner J.W.
        Death by water intoxication.
        Mil Med. 2002; 167: 432-434
        • Garigan T.P.
        • Ristedt D.E.
        Death from hyponatremia as a result of acute water intoxication in an Army basic trainee.
        Mil Med. 1999; 164: 234-238
      1. Medical Surveillance Monthly Report. 2012; 19: 20-23
        • Kolka M.A.
        • Latzka W.A.
        • Montain S.J.
        • Sawka M.N.
        Current U.S. Military Fluid Replacement Guidelines.
        RTO-MP-HFM-086, 6-1–6-6. 2003;
        • Zelingher J.
        • Putterman C.
        • Ilan Y.
        • et al.
        Case series: hyponatremia associated with moderate exercise.
        Am J Med Sci. 1996; 311: 86-91
        • Rose B.D.
        • Post T.W.
        Clinical Physiology of Acid-Base and Electrolyte Disorders.
        5th ed. McGraw Hill, New York, NY2001
        • Hew-Butler T.
        • Dugas J.P.
        • Noakes T.D.
        • Verbalis J.G.
        Changes in plasma vasopressin concentrations in cyclists participating in a 109-km cycle race.
        Br J Sports Med. 2010; 44: 594-597
        • Rowe J.W.
        • Shelton R.L.
        • Helderman J.H.
        • Vestal R.E.
        • Robertson G.L.
        Influence of the emetic reflex on vasopressin release in man.
        Kidney Int. 1979; 16: 729-735
        • Baylis P.H.
        • Zerbe R.L.
        • Robertson G.L.
        Arginine vasopressin response to insulin-induced hypoglycemia in man.
        J Clin Endocrinol Metab. 1981; 53: 935-940
        • Hew-Butler T.
        • Jordaan E.
        • Stuempfle K.J.
        • et al.
        Osmotic and nonosmotic regulation of arginine vasopressin during prolonged endurance exercise.
        J Clin Endocrinol Metab. 2008; 93: 2072-2078
        • Noakes T.D.
        • 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 U S A. 2005; 102: 18550-18555
        • Edelman I.S.
        • James A.H.
        • Brooks L.
        • Moore F.D.
        Body sodium and potassium.
        Metabolism. 1954; 3: 530-538
        • Edelman I.S.
        • James A.H.
        • Baden H.
        • Moore F.D.
        Electrolyte composition of bone and the penetration of radiosodium and deuterium oxide into dog and human bone.
        J Clin Invest. 1954; 33: 122-131
        • Halperin M.L.
        • Kamel K.S.
        • Sterns R.
        Hyponatremia in marathon runners.
        N Engl J Med. 2005; 353: 427-428
        • Lindinger M.I.
        • Heigenhauser G.J.
        • McKelvie R.S.
        • Jones N.L.
        Blood ion regulation during repeated maximal exercise and recovery in humans.
        Am J Physiol. 1992; 262: R126-R136
        • Buono M.J.
        • Ball K.D.
        • Kolkhorst F.W.
        Sodium ion concentration vs. sweat rate relationship in humans.
        J Appl Physiol. 2007; 103: 990-994
        • Buono M.J.
        • Sjoholm N.T.
        Effect of physical training on peripheral sweat production.
        J Appl Physiol. 1988; 65: 811-814
        • Speedy D.B.
        • Noakes T.D.
        • Boswell T.
        • Thompson J.M.
        • Rehrer N.
        • Boswell D.R.
        Response to a fluid load in athletes with a history of exercise induced hyponatremia.
        Med Sci Sports Exerc. 2001; 33: 1434-1442
        • Noakes T.D.
        • Wilson G.
        • Gray D.A.
        • Lambert M.I.
        • Dennis S.C.
        Peak rates of diuresis in healthy humans during oral fluid overload.
        S Afr Med J. 2001; 91: 852-857
        • Almond C.S.
        • Shin A.Y.
        • Fortescue E.B.
        • et al.
        Hyponatremia among runners in the Boston Marathon.
        N Engl J Med. 2005; 352: 1550-1556
        • Hew-Butler T.
        • Hoffman M.D.
        • Stuempfle K.J.
        • Rogers I.R.
        • Morgenthaler N.G.
        • Verbalis J.G.
        Changes in copeptin and bioactive vasopressin in runners with and without hyponatremia.
        Clin J Sport Med. 2011; 21: 211-217
        • Schmidt W.
        • Rojas J.
        • Böning D.
        • Bernal H.
        • Garcia S.
        • Garcia O.
        Plasma-electrolytes in natives to hypoxia after marathon races at different altitudes.
        Med Sci Sports Exerc. 1999; 31: 1406-1413
        • Hellmann K.
        • Weiner J.S.
        Antidiuretic substance in urine following exposure to high temperatures.
        J Appl Physiol. 1953; 6: 194-198
        • Grant S.M.
        • Green H.J.
        • Phillips S.M.
        • Enns D.L.
        • Sutton J.R.
        Fluid and electrolyte hormonal responses to exercise and acute plasma volume expansion.
        J Appl Physiol. 1996; 81: 2386-2392
        • Stebbins C.L.
        • Symons J.D.
        • McKirnan M.D.
        • Hwang F.F.
        Factors associated with vasopressin release in exercising swine.
        Am J Physiol. 1994; 266: R118-R124
        • Siegel A.J.
        Exercise-associated hyponatremia: role of cytokines.
        Am J Med. 2006; 119: S74-S78
        • Wharam P.C.
        • Speedy D.B.
        • Noakes T.D.
        • Thompson J.M.
        • Reid S.A.
        • Holtzhausen L.M.
        NSAID use increases the risk of developing hyponatremia during an Ironman triathlon.
        Med Sci Sports Exerc. 2006; 38: 618-622
        • Baker J.
        • Cotter J.D.
        • Gerrard D.F.
        • Bell M.L.
        • Walker R.J.
        Effects of indomethacin and celecoxib on renal function in athletes.
        Med Sci Sports Exerc. 2005; 37: 712-717
        • Walker R.J.
        • Fawcett J.P.
        • Flannery E.M.
        • Gerrard D.F.
        Indomethacin potentiates exercise-induced reduction in renal hemodynamics in athletes.
        Med Sci Sports Exerc. 1994; 26: 1302-1306
        • Hew-Butler T.
        • Verbalis J.G.
        • Noakes T.D.
        • International Marathon Medical Directors Association
        Updated fluid recommendation: position statement from the International Marathon Medical Directors Association (IMMDA).
        Clin J Sport Med. 2006; 16: 283-292
        • Cheuvront S.N.
        • Haymes E.M.
        Ad libitum fluid intakes and thermoregulatory responses of female distance runners in three environments.
        J Sports Sci. 2001; 19: 845-854
        • Armstrong L.E.
        • Maresh C.M.
        • Gabaree C.V.
        • et al.
        Thermal and circulatory responses during exercise: effects of hypohydration, dehydration, and water intake.
        J Appl Physiol. 1997; 82: 2028-2035
        • Speedy D.B.
        • Rogers I.R.
        • Noakes T.D.
        • et al.
        Diagnosis and prevention of hyponatremia at an ultradistance triathlon.
        Clin J Sport Med. 2000; 10: 52-58
        • Speedy D.B.
        • Thompson J.M.
        • Rodgers I.
        • Collins M.
        • Sharwood K.
        • Noakes T.D.
        Oral salt supplementation during ultradistance exercise.
        Clin J Sport Med. 2002; 12: 279-284
        • Hew-Butler T.D.
        • Sharwood K.
        • Collins M.
        • Speedy D.
        • Noakes T.
        Sodium supplementation is not required to maintain serum sodium concentrations during an Ironman triathlon.
        Br J Sports Med. 2006; 40: 255-259
        • Twerenbold R.
        • Knechtle B.
        • Kakebeeke T.H.
        • et al.
        Effects of different sodium concentrations in replacement fluids during prolonged exercise in women.
        Br J Sports Med. 2003; 37: 300-303
        • Barr S.I.
        • Costill D.L.
        • Fink W.J.
        Fluid replacement during prolonged exercise: effects of water, saline, or no fluid.
        Med Sci Sports Exerc. 1991; 23: 811-817
        • Vrijens D.M.
        • Rehrer N.J.
        Sodium-free fluid ingestion decreases plasma sodium during exercise in the heat.
        J Appl Physiol. 1999; 86: 1847-1851
        • Röcker L.
        • Kirsch K.A.
        • Heyduck B.
        • Altenkirch H.U.
        Influence of prolonged physical exercise on plasma volume, plasma proteins, electrolytes, and fluid-regulating hormones.
        Int J Sports Med. 1989; 10: 270-274
        • Beckner G.L.
        • Winsor T.
        Cardiovascular adaptations to prolonged physical effort.
        Circulation. 1954; 9: 835-846
        • Riley W.J.
        • Pyke F.S.
        • Roberts A.D.
        • England J.F.
        The effect of long-distance running on some biochemical variables.
        Clin Chim Acta. 1975; 65: 83-89
        • Åstrand P.O.
        • Saltin B.
        Plasma and cell volume alterations after prolonged severe exercise.
        J Appl Physiol. 1964; 19: 829-832
        • Weschler L.B.
        Exercise-associated hyponatraemia: a mathematical review.
        Sports Med. 2005; 35: 899-922
        • Luks A.M.
        • Robertson H.T.
        • Swenson E.R.
        An ultracyclist with pulmonary edema during the Bicycle Race Across America.
        Med Sci Sports Exerc. 2007; 39: 8-12
        • Williams J.
        • Tzortziou Brown V.
        • Malliaras P.
        • Perry M.
        • Kipps C.
        Hydration strategies of runners in the London Marathon.
        Clin J Sport Med. 2012; 22: 152-156
        • Winger J.M.
        • Dugas J.P.
        • Dugas L.R.
        Beliefs about hydration and physiology drive drinking behaviours in runners.
        Br J Sports Med. 2011; 45: 646-649
        • Ayus J.C.
        • Moritz M.L.
        Exercise-associated hyponatremia masquerading as acute mountain sickness: are we missing the diagnosis?.
        Clin J Sport Med. 2008; 18: 383-386
        • Frizzell R.T.
        • Lang G.H.
        • Lowance D.C.
        • Lathan S.R.
        Hyponatremia and ultramarathon running.
        JAMA. 1986; 255: 772-774
        • Sucholeiki R.
        Heatstroke.
        Semin Neurol. 2005; 25: 307-314
        • Patel D.R.
        • Gyamfi R.
        • Torres A.
        Exertional rhabdomyolysis and acute kidney injury.
        Phys Sportsmed. 2009; 37: 71-79
        • Hoffman M.D.
        • Fogard K.
        • Winger J.
        • Hew-Butler T.
        • Stuempfle K.J.
        Characteristics of 161-km ultramarathon finishers developing exercise-associated hyponatremia.
        Res Sports Med. 2013; 21: 164-175
        • Rogers I.R.
        • Hook G.
        • Stuempfle K.J.
        • Hoffman M.D.
        • Hew-Butler T.
        An intervention study of oral versus intravenous hypertonic saline administration in ultramarathon runners with exercise-associated hyponatremia: a preliminary randomized trial.
        Clin J Sport Med. 2011; 21: 200-203
        • Siegel A.J.
        • d'Hemecourt P.
        • Adner M.M.
        • Shirey T.
        • Brown J.L.
        • Lewandrowski K.B.
        Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy.
        Am J Clin Pathol. 2009; 132: 336-340
        • Verbalis J.G.
        • Goldsmith S.R.
        • Greenburg A.
        • Schrier R.W.
        • Sterns R.H.
        Hyponatremia treatment guidelines 2007: expert panel recommendations.
        Am J Med. 2007; 120: S1-S21
        • Iscoe S.
        • Beasley R.
        • Fisher J.A.
        Supplementary oxygen for nonhypoxemic patients: O2 much of a good thing?.
        Crit Care. 2011; 15: 305

      Linked Article

      • Erratum
        Wilderness & Environmental MedicineVol. 25Issue 1
        • Preview
          It has come to the editors’ attention (personal communication with Scott Montain PhD, Research Physiologist, United States Army Research Institute of Environmental Medicine) that a few statements in Bennett, Hew-Butler, Hoffman et al, paper “Wilderness Medical Society Practice Guidelines for Treatment of Exercise-Associated Hyponatremia”1 warrant correction. While one previously published paper entitled “Death by Water Intoxication” details four fatal cases of dilutional hyponatremia in military personnel,2 whether or not all four of these fatalities were primarily associated with exercise-associated hyponatremia (EAH) has been called into question.
        • Full-Text
        • PDF
      • Clinical Practice Guidelines for Treatment of Exercise-Associated Hyponatremia
        Wilderness & Environmental MedicineVol. 24Issue 4
        • Preview
          The incidence of exercise-associated hyponatremia (EAH) is common in endurance and ultraendurance events, in which both athletes and medical providers need to be aware of risk factors, symptom presentation, and management. The recently published Wilderness Medical Society (WMS) practice guidelines for EAH1 present a thorough review of the pathophysiology: a combination of excessive water intake and an endocrine-axis–focused dilutional state characteristic of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
        • Full-Text
        • PDF
      • Is Drinking to Thirst a Prudent Guideline to Avoid Hyponatremia?
        Wilderness & Environmental MedicineVol. 25Issue 4
        • Preview
          I would like to address a statement made in the recent article on treatment of exercise-associated hyponatremia by Bennett et al.1 The statement “…prudent guidelines include drinking to thirst..” is a questionable and perhaps dangerous suggestion.
        • Full-Text
        • PDF