Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007

INTRODUCTION The Second International Exercise-Associated Hyponatremia (EAH) Consensus Development Conference convened in Queenstown, New Zealand (November 2007) with a panel of eighteen international experts. This conference utilized the United States National Institute of Health (NIH) Consensus Conference protocol and was deliberately free from commercial sponsorship. The delegates represented seven countries and eight medical and scientific sub-specialties pertaining to exercise physiology, sports medicine, water metabolism, and body fluid homeostasis. The primary goal of the panel was to review the existing data on EAH and update the 2005 Consensus Statement.1 This document serves to replace the 1st International EAH Consensus Development Conference Statement. The purpose of this update is to summarize the most current information on the prevalence, nature and treatment of EAH for medical personnel, athletes, and the greater public and to curtail the morbidity and mortality associated with the disorder. The panel strived to clearly articulate what we agreed upon, debate issues that we did not agree upon, and describe in detail what we did and did not know, including minority viewpoints that were supported by clinical and experimental data. The following statement is a concise summary of the data synthesized by the 2007 EAH Consensus Panel and represents an evolution of the most current knowledge on EAH. Further updates will be required as the understanding of EAH advances. METHODS The International Exercise-Associated Hyponatremia Consensus Development Conference followed the guidelines set forth by the National Institutes of Health (NIH).2 The basic principles governing the conduct of a consensus development conference are summarized below: A broad based non-government, non-advocacy panel was assembled to give balanced, objective and knowledgeable attention to the topic. Panel members included researchers in endocrinology (JGV), epidemiology (WHM), nephrology (JCA, MHR), emergency medicine (IRR), family medicine (WOR), internal medicine (AJS), sports medicine (CK, AJP, SAR, DBS, PW) and exercise physiology (TH, RJM, SM, NJR, KJS, LBW). These experts presented data in a public session, followed by inquiry and discussion. The panel then met in a closed session to prepare the consensus statement. A number of specific questions were prepared and posed in advance to define the scope and guide the direction of the conference. The principle task of the panel was to elucidate responses to these questions and incorporate these answers in the updated document. A systematic literature review was prepared and circulated in advance for use by the panel in addressing the conference questions. The consensus statement is intended to serve as the scientific record of the conference. The consensus statement will be widely disseminated to achieve maximum impact on both current health care practice and future medical research. The panel chairperson (WHM) did not identify with any advocacy position or present data on EAH.2 The chairperson was responsible for directing the plenary session and guiding the panel's deliberations. The strict criterion for invitation to the EAH Consensus Panel in 20051 was waived for the 2007 Conference, as an independent decision by the conference organizer (TH) to encourage a wider range of expertise. An open call for abstracts was placed in the July 2007 issue of the Clinical Journal of Sport Medicine and formal invitations were sent to clinicians and scientists who had published papers pertaining to EAH. This necessary deviation from the NIH guidelines served to enhance the scope of our deliberations and include researchers (WOR, CK, SM) who had data, yet unpublished, that might significantly contribute to our existing knowledge. Hence, the “no exclusion” criteria served to ameliorate previous concerns raised by those who felt that the previous “inclusion” criteria were too stringent to allow for a well-balanced consensus. Several invitees declined the invitation to participate. The following focus questions were identified by the panel to be of significant priority for the 2007 closed panel deliberations. The answer to these updated focus questions formed the basis for the discussion and were incorporated into the revised 2007 EAH Consensus Statement: What is the role of sodium supplementation in the prevention of EAH? What is the evidence supporting sodium loss in EAH? What are the potential benefits and dangers of excess sodium supplementation before, during and after exercise? Should on-site rapid sodium measurement be required for all marathons? What are the current evidenced-based options for treating EAH in the field and in the hospital settings (ie, hypertonic saline, urea, mannitol, arginine vasopressin (AVP) receptor antagonists, and fluid restriction)? What is the role of concomitant medication use in the pathogenesis of EAH (ie, selective serotonin reuptake inhibitors or non-steroidal anti-inflammatory medications)? Does EAH only occur in the presence of the syndrome of inappropriate anti-diuretic hormone secretion (SIADH), and what is the role of non-osmotic AVP secretion in the development of dilutional EAH during exercise? What role do ambient temperature, training and/or gender play in the incidence, evolution and treatment of EAH? Is full replacement of body weight losses a physiologically appropriate prevention strategy during prolonged endurance exercise? How can we best disseminate educational information to reduce the increasing incidence and morbidity of exercise-associated hyponatremia? RESULTS AND DISCUSSION Definition of Exercise Associated Hyponatremia (EAH) EAH is the occurrence of hyponatremia during or up to 24 hours after prolonged physical activity3-38 and is defined by a serum or plasma sodium concentration ([Na+]) below the normal reference range of the laboratory performing the test. For most laboratories, this is a [Na+] less than 135 mmol/L.39 Classification of EAH by Clinical and Laboratory Criteria EAH should be classified using the same clinical criteria as any acute or rapid onset hyponatremia.40 In any acute onset hyponatremia, the most important factor is determining the presence or absence of clinical signs and symptoms: specifically neurological manifestations. In general, the lower the [Na+] the more severe the neurological signs and symptoms41 However, individual variability is great and the numerical value of [Na+] is not a reliable predictive index of the clinical severity of hyponatremia, including EAH.40,42 Early signs and symptoms of EAH can include: bloating, “puffiness”, nausea, vomiting, and headache.4,5,7,11,14,21,34,43 However, many of these signs and symptoms are non-specific and can be present following prolonged exercise in the absence of EAH.44 As the severity of EAH progresses, more serious signs and symptoms of hyponatremic encephalopathy can develop as a result of cerebral edema (brain swelling), including alteration of mental status (eg, confusion, disorientation, agitation, delirium), seizures, respiratory distress (pulmonary edema), obtundation, coma and death.6,7,9-11,17,18,21,31,33,34,43,45-49 The presence of any of these signs and symptoms represents an absolute indication to measure [Na+]. Signs and symptoms of EAH can develop when the [Na+] falls below 135 mmol/L.14,15,22,25,28,30 However, in general, hyponatremia ([Na+] between 130-134 mmol/L) is relatively asymptomatic,3,15,22,25,26,28,30,32,50 although exceptions have been reported.42 Symptomatic hyponatremia can occur if the rate of fall of Na approaches a 7-10% decrease within a 24 hour period.51 For example, a pre-exercise [Na+] value of 142 mmol/L - that decreases to a post-exercise [Na+] value of 132 mmol/L - can be associated with significant morbidity from the increased osmotic pressure gradient of change even though the absolute [Na+] may appear relatively benign. Etiology and Pathophysiology of EAH EAH is predominantly a dilutional hyponatremia caused by an increase in total body water relative to the amount of total body exchangeable [Na+].3-6,10-13,13,14,17,19-21,26,34,43,46,48,52-54 The primary etiologic factor in cases that have been adequately studied appears to be consumption of fluids (water or sports drinks) in excess of total body fluid losses: insensible (transcutaneous, respiratory and gastrointestinal),55,56 sweat and renal (urine) fluid losses.3-6,10-13,13,14,17,19-21,26,34,43,48 In most reported cases of symptomatic EAH, there is body weight gain suggestive of an absolute increase in total body water.3,4,6,8,13,19,20,24,26,28,43,48,50,53,54,57 However, it should be recognized that some loss of body weight is expected with prolonged physical activity due to substrate oxidation without a net loss of total body water.56,58,59 For example, during a typical 42 km marathon a 1-2% decrease in body weight typically occurs without a change in total body water as inferred by the maintenance of plasma osmolality from pre to post race.60 A dilutional hyponatremia may therefore occur despite no change or even a fall in body weight.53,61 A positive fluid balance during exercise can occur because of overconsumption of fluid and/or impaired renal water clearance. Hyponatremia caused solely by the overconsumption of fluids has been demonstrated at rest in athletes with and without a history of EAH.13,57,62 Weight gain in these athletes occurred despite an increase in free water excretion and what appeared to be maximally suppressed AVP levels (as reflected by mean urine osmolalities <100 mOsm/kg H2O). This is consistent with known maximal urine excretory rates of 800-1,000 ml/h in normal adults under resting conditions.63 Thus, in these cases water intake simply overwhelms the renal water excretion rate. Although some cases of EAH may be due to pure water intoxication from overconsumption of fluids, recent data indicate that AVP secretion is an exacerbating factor in most cases. During exercise, plasma AVP levels are not maximally suppressed implicating non-osmotically stimulated AVP secretion.5,13,49 In the presence of hyponatremia and/or hypervolemia, plasma AVP levels within “normal ranges” are physiologically inappropriate because AVP should be maximally suppressed under these two conditions. This pathophysiology characterizes the syndrome of inappropriate anti-diuretic hormone secretion (SIADH).26-28,49 Small increases in circulating AVP markedly reduce maximal kidney excretory capacity,40 thus increasing the propensity to retain ingested fluids even if rates of drinking do not exceed 800-1,000 mL/h. Thus, the risk of developing fluid overload with previously “normal” or excessive fluid intakes is enhanced when AVP is secreted inappropriately during prolonged exercise, resulting in increased urine osmolality and decreased urine volume. High urine osmolalities have been measured in athletes hospitalized with critical hyponatremia, and inappropriate plasma AVP levels have been documented in EAH.5,6,12,19,34,64 A lower rate of urine production correlates significantly with a higher rate of [Na+] decrease in athletes drinking excessively during exercise.65 The higher the plasma AVP level, the more reduced will be the maximum urine excretory capacity. This effect can potentially account for the marked inter-individual variability in the development of EAH, as well as individual variability in outcome across different events, despite similar fluid intakes. Multiple potential stimuli to AVP secretion, such as nausea/vomiting, hypoglycemia, hypotension or hypovolemia40 can exacerbate fluid retention at any time during prolonged exercise.4,66 Given the short half life (6-8 minutes)66 of AVP, measurement of suppressed AVP levels at time points after the cessation of physical activity do not eliminate the possibility of inappropriate AVP secretion as a contributory factor to the development of EAH. Excessive [Na+] loss has not been demonstrated to be a primary causative factor in the pathogenesis of EAH. Sodium loss is no greater in individuals who develop EAH than in individuals who do not.4,17,27,28 However, there may be several potential mechanisms whereby sodium losses play a role in the pathogenesis of EAH: 1) hypovolemia produced by sodium losses can act as a stimulus to AVP secretion, producing a secondary retention of water, as is seen medically in some cases of diuretic-induced hyponatremia67 and/or 2) sodium losses themselves can worsen the degree of hyponatremia, although in most cases not nearly as much as water retention68 when summed up over time. While mathematical models suggest that EAH may occur from excessive sodium depletion during ultraendurance exercise,69 this phenomenon has not been documented in any laboratory or field investigation to date. Therefore, further (direct measurement) studies are necessary to fully investigate the role of sodium losses on this small cohort of athletes who develop EAH, particularly those with a weight loss in excess of 3% or with a large volume of sweat over time, in warmer climates and in events lasting over 12 hours. Risk Factors The presence of a risk factor implies a correlation with higher rates of EAH, but not necessarily causation. It is likely that these risk factors interact with each other and, in some cases, may not have an independent association with EAH. Recognized risk factors include: • Athlete-related ▪ excessive drinking behavior3,7,10,14,19,23 ▪ weight gain during exercise3,4,6,8,13,19,20,24,26,28,43,48,50,53,54,57 ▪ low body weight3,27,30,35 ▪ female sex3,5,7,14,26,30,45 ▪ slow running or performance pace3,7,14,19 ▪ event inexperience14,33,38 ▪ nonsteroidal anti-inflammatory agents6,7,31,45,54,70-72 • Event-related ▪ high availability of drinking fluids14,29,54 ▪ >4 hours exercise duration3,4,6,8-10,13-15,17-20,22,24-32,48,73 ▪ unusually hot environmental conditions4,5,9,10,12,16,23,37,38,74 ▪ extreme cold temperature30 There are known medical risk factors for the development of hyponatremia in the general population that also may play a role in EAH. These include altered renal water excretory capacity potentially impaired by drugs (eg, selective serotonin re-uptake inhibitors, thiazide diuretics, etc.),75 intrinsic renal disease,76 low solute diets,77-79 or SIADH.80 Published data on the cystic fibrosis genotype (either homozygous or heterozygous) is inconclusive.81-84,85,86 Further studies will need to be made before excluding these variables as potential risk factors for EAH. Prevention EAH is caused primarily by the consumption of fluid in excess of urinary and sweat losses. Therefore, it follows that any individual participating in endurance exercise, and particularly those at increased risk for EAH, should avoid over consumption of fluids before, during and after exercise.29,87,88 Blanket universal guidelines are neither possible nor appropriate because there is a wide variability in sweat rates11,89 and renal water excretory capacity65,90 during exercise, both among individuals and in the same individual depending on ambient environmental conditions during the time of exercise. The primary means of preventing EAH is to avoid excess fluid retention, as manifested by weight gain, during or after exercise. It should be recognized that even maintenance of body weight has been associated with the development of EAH.61 Therefore the goal should be to expect to lose up to two percent of body weight and never to gain weight during exercise.56,58 There are at least two ways to reduce the risk of excess fluid retention: 1) drink only according to thirst (ie, ad libitum)44,60 and 2) monitor body weight so as to avoid weight gain during exercise.91 Moreover, athletes should be encouraged to weigh themselves pre- and post-training in a variety of conditions to estimate their fluid requirements during competition. Athletes should recognize the potential limitations of this method, however. In situations where AVP is not appropriately suppressed, a drinking schedule that worked well in identical training conditions may lead to weight gain and EAH in competition. Ingestion of electrolyte-containing sports drinks cannot prevent the development of EAH in athletes who drink to excess.3,5,16,32,68,92 This is due to two factors: 1) all such drinks have [Na+] < 135 mmol/L and therefore will cause dilution of [Na+] if excess water is retained in the body during exercise and 2) it is well known that even administration of isotonic saline will not increase [Na+] in hyponatremic patients with SIADH because in a euvolemic or hypervolemic state the infused sodium will be excreted in the urine rather than retained.80 There is evidence as to the effect of sodium by or on the incidence of EAH and the rate of change of [Na+] with However, some of excessive sodium supplementation in with have been An athletes on the of with fluid availability at a are factors associated with a in the incidence of EAH without for an and km are In a marathon of km is associated with an absence of However, of appropriate drinking has to the incidence of EAH in a km despite fluid placed km for EAH at endurance events should include of signs or symptoms of acute hyponatremia should be for EAH by [Na+]. on this the following treatment are EAH hyponatremia is not an has for some other In athletes with this fluid intake should be the onset of Athletes should also be to medical attention if any signs or symptoms of EAH EAH is a for the administration of normal saline or fluids, can worsen the degree of hyponatremia and fluid overload in some cases. The emergency treatment of EAH encephalopathy (as is administration of hypertonic saline because of the known rapid of encephalopathy and This treatment was in In that all the patients who hypertonic saline and the only occurred in the who was with normal The reported in the literature were patients who to hypertonic be and should be with EAH encephalopathy should be with a of of 3% to reduce to two 3% should be at if there is no clinical This should not any to the There have been no reported cases of osmotic or in association with the rapid of an acute hyponatremia hour Therefore, osmotic should not be an to hyponatremia in symptomatic The of hypertonic 3% as the treatment for EAH encephalopathy has been documented in the hospital and was in the field at the under a protocol by the and the The use of a of hypertonic saline was documented by in the 2005 and by in the 2005 and by This to the to hospital without producing The should be to a medical care the should be with knowledgeable to the same of care The of EAH and be to the emergency of be to avoid the administration of isotonic or fluids to prevent the degree of hyponatremia and fluid overload the of cases where there is evidence of where hospital Athletes primarily to the hospital or medical with signs or symptoms of hyponatremia should have their serum measured and be as without if EAH is Athletes from the medical both clinical and laboratory with care to avoid treatment such as of or isotonic fluids during this is because of the potential to exacerbate hyponatremia and fluid symptomatic EAH or current treatment guidelines for acute symptomatic hyponatremia should be followed in an or critical care including appropriate with a with this of for Prevention and of EAH Athletes and at and athletes to fluid to avoid the over consumption of fluids (water or sports to recognize the signs and symptoms of EAH, and to the critical need to medical attention be attention should be to athletes with any of the risk factors and medical should be in all for These include number and of of drinking to athletes and training of the to by should be and not the information by the medical weight should be (eg, on a or on the so that it is for medical should it be required for to post should the availability of [Na+] and hypertonic A record of EAH cases should be including up and to in for future medical be on the and treatment of EAH. of all to the medical is saline should be in the medical and to the or the medical should a with the emergency and medical and emergency This may include specific at all of these for and clinical on fluid replacement during exercise should be both in the laboratory and in the The following were identified by the panel as for further for EAH including hypertonic and vasopressin receptor the maintenance of despite and weight gain the possible of sodium or from other factors if cases occur where sodium depletion with significant weight loss play a role in the pathogenesis of EAH the role of different of sodium supplementation (eg, or in the of EAH the for inappropriate (ie, plasma AVP during endurance exercise the potential role of water production or during endurance exercise, in water to and in the pathogenesis of EAH cases of EAH should be and (ie, scope of treatment and on the International EAH in EAH are to the EAH serve is a of the EAH Consensus but not the for The 2007 EAH Consensus Panel to and of for their and this