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Practise-Associated Hyponatremia

CJASN January 2007, ii (1) 151-161; DOI: https://doi.org/x.2215/CJN.02730806

Abstract

Exercise-associated hyponatremia has been described after sustained physical exertion during marathons, triathlons, and other endurance athletic events. Equally these events take go more popular, the incidence of serious hyponatremia has increased and associated fatalities take occurred. The pathogenesis of this condition remains incompletely understood but largely depends on excessive water intake. Furthermore, hormonal (peculiarly abnormalities in arginine vasopressin secretion) and renal abnormalities in water handling that predispose individuals to the evolution of severe, life-threatening hyponatremia may be present. This review focuses on the epidemiology, pathogenesis, and therapy of exercise-associated hyponatremia.

Severe and potentially life-threatening hyponatremia tin can occur during exercise, specially in athletes who participate in endurance events such as marathons (42.2 km), triathlons (3.viii km of swim, 180 km of cycling, and 42.2 km of running), and ultradistance (100 km) races. In fact, hyponatremia has been stated to exist one of the well-nigh mutual medical complications of long-distance racing and is an of import cause of race-related fatalities (1). On the basis of recent studies of the incidence and adventure factors of hyponatremia in endurance athletes, along with well-publicized reports of fatalities every bit a result of hyponatremia, medical directors and marathon organizations have begun to warn participants of the dangers of hyponatremia and excessive fluid intake (2).

Exercise-associated hyponatremia (EAH) commencement was described in Durban, South Africa, in 1981; subsequently, Noakes et al. (3) in 1985 described the occurrence of severe hyponatremia in four athletes who participated in endurance events that were longer than 7 h. This written report was followed by a similar paper past Frizzel et al. (4) that described the development of EAH in two of the authors. Chiefly, before 1981, athletes were brash to avert drinking during practice, leading to the development of hypernatremia and aridity in some athletes (5). Since that time, it generally has been advised that athletes consume equally much fluid as possible during exercise, and rates of fluid intake during running races vary widely from 400 to 1500 ml/h or greater (6–viii). In fact, most race organizers currently provide copious supplies of water and "sports beverages" throughout the race course to fend off dehydration. Concomitant with these recommendations, the incidence of hyponatremia in athletes seems to be increasing, especially in the United states of america (one,ix–xiii). As the popularity of marathon races and other endurance events increase, more athletes are probable to exist at risk for the development of EAH.

EAH tin take ii forms, depending on whether specific symptoms that are attributable to hyponatremia are present (14). Athletes may nowadays with symptoms such as confusion, seizures, and altered mental status in association with serum sodium levels <135 mmol/Fifty and are considered to have exercise-associated hyponatremic encephalopathy (EAHE). Alternatively, athletes may nowadays with isolated serum sodium levels <135 mmol/L without easily discernible symptoms and accept EAH.

This review focuses on of import historic, epidemiologic, and pathophysiologic aspects of this status, highlighting contempo manufactures that bear witness the importance of excessive water intake in the genesis of EAH. Important handling-related bug also are discussed.

Incidence

Until recently, the incidence of hyponatremia during endurance exercise was unknown and thought to be relatively uncommon. However, contempo studies have shown that endurance athletes not uncommonly develop hyponatremia at the terminate of the race, unremarkably in the absenteeism of clear central nervous system symptoms (9,10,12,15–25). For example, in the 2002 Boston Marathon, Almond et al. (15) found that thirteen% of 488 runners studied had hyponatremia (defined equally a serum sodium concentration of 135 mmol/L or less) and 0.6% had critical hyponatremia (serum sodium concentration of 120 mmol/50 or less). Speedy et al. (21) investigated 330 athletes who finished an ultramarathon race. In this study, 58 (eighteen%) were hyponatremic (defined as a serum sodium <135 mmol/L) and 11 had severe hyponatremia (serum sodium <130 mmol/L). Studies of other endurance events take reported the incidence of hyponatremia to exist upwardly to 29% (9,10,12,15–25). These incidence rates may be overestimations every bit a issue of sampling biases. For example, in the 2002 Boston Marathon report, of 766 runners enrolled in the study, only 488 runners had serum sodium values assayed (15). Some of these runners did not terminate the race, and others had fourth dimension constraints that did not let them to have blood samples obtained. As is discussed later, the majority of these athletes are asymptomatic or mildly symptomatic (nausea, lethargy). However, severe manifestations such as cognitive edema, noncardiogenic pulmonary edema, and death tin occur (11–fourteen).

There have been at least 8 reported deaths from EAH (5,ten,xi,26–29). Many of these reports chronicle to a series of fatalities in the military between 1989 and 1996 (27–29). During this menses, military recruits were encouraged to ingest 1.8 Fifty of fluid for every hr they were exposed to temperatures above xxx°C (thirty). At least four other deaths have been attributed to EAH in the United States (5,10,11,26,31). It is interesting that two of these deaths occurred in doctors (31). The exact incidence of mortality related to EAH is non known but is likely to exist low.

Risk Factors

Several risk factors take been linked with the development of EAH (Table 1). The major risk factor seems to be overhydration or excessive fluid consumption during activity (reviewed in reference [31]). This first was suggested by Noakes et al. in their original publication in 1985 and confirmed in this group's later studies (three,5,21). The chronological history of the incidence of EAH likewise points to the primary part of overhydration in the pathogenesis. Earlier 1981, athletes were encouraged to drink heavily during exertion to avoid dehydration (7,31). With the clarification of EAH in South Africa and New Zealand in 1985, new fluid consumption guidelines that restricted overzealous fluid intake for endurance events in these countries were promoted (32,33). Concomitant with these recommendations, the incidence of EAH fell in both of these regions (19,xx). Similar observations were fabricated afterwards the US military revised its guidelines for fluid consumption during training activities after the incidence of EAH increased (31). With an upper limit of fluid consumption prepare at 1.0 to ane.5 L/h, the incidence of EAH in the US armed forces fell (31).

Table one.

Risk factors for the development of EAH^a

In a study of runners in the Boston Marathon, Almond et al. (15) institute pregnant correlations betwixt fluid intake and the incidence of hyponatremia. Specifically, a fluid intake of >three Fifty, a postrace weight greater than prerace weight, self-reported water loading (increased fluid consumption in a higher place baseline in preparation for the marathon), and self-reported fluid intake during the race all were constitute to be meaning predictors for the development of hyponatremia (P < 0.05) (xv). Substantial weight proceeds during the elapsing of the activity seemed to be the most important predictor of hyponatremia and correlated well with increased fluid intake. Speedy et al. (21) besides found correlations between intrarace weight gain and hyponatremia; 73% of patients who were found to be severely hyponatremic had either gained or maintained weight during the race. Noakes et al. (34) in the largest study to engagement investigated the changes in serum sodium concentration associated with changes in body weight in 2135 endurance athletes. The mean ± SD serum sodium was 136.ane ± half dozen.4 mmol/L for athletes who gained weight during the race, 140.5 ± 3/7 mmol/Fifty for those with minimal weight gain, and 141.1 ± 3.7 mmol/L for those who lost weight during the race. The authors estimated that athletes who gained >4% body weight during exercise had a 45% probability of developing hyponatremia. Importantly, 70% of individuals who gained weight during do did not develop hyponatremia, pointing to other of import factors in the pathogenesis, every bit discussed next (34).

Almond et al. (15) were not able to find a correlation in the type of fluids consumed (water versus electrolyte-containing solutions) and the subsequent development of hyponatremia. Other studies also have shown that the consumption of a carbohydrate/electrolyte-containing sports drinkable does not protect confronting the evolution of hyponatremia (35–38). This likely reflects the relative hypotonicity of near of the commercial sports drinks in which the sodium concentration typically is 18 mmol/Fifty (39).

Gender likely plays a function in the risk for development of EAH, with female person athletes more than likely than male athletes to develop hyponatremia during endurance events (10–12,15,21,xl). Of 26 cases of EAH reported after the San Diego Marathon, 23 occurred in women (12). Hyponatremia was three times more common in women than in men in the 1997 New Zealand Ironman triathlon (21). Almond et al. (xv) too found that hyponatremia developed more unremarkably in women in the Boston Marathon. Still, in this written report, when these results were corrected for body mass alphabetize, racing fourth dimension, and weight change, the difference did not reach statistical significance, suggesting that body size and elapsing of exercise may explicate the gender differences. Furthermore, the incidence of hyponatremia in Usa armed services recruits reflects the gender distribution of this cohort and is non skewed to women (41). Some investigators also have suggested that women attach more than stringently to hydration recommendations during exercise and therefore eat more fluids (42). The finding of a gender association for the risk for symptomatic hyponatremia as well has been seen in the postoperative state. Ayus et al. (43) noted that despite equal incidences of postoperative hyponatremia in men and women, 97% of those with permanent brain damage were women and 75% of them were menstruant. This predisposition likely is explained by the effects of sexual practice hormones on the Na⁺-K⁺-ATPase (44). Both estrogen and progesterone inhibit the function of the Na⁺-K⁺-ATPase, which normally has an important part in the extrusion of sodium from cells during the development of hyponatremia. Ultimately, this inhibition may issue in a higher chance for cerebral edema and increased intracranial pressure in women who are exposed to acute hyponatremia.

The development of hyponatremia also has been correlated with the number of marathons run, the preparation step, and the race duration (10,12,15,45). Those who have run fewer marathons (less experienced runners), take slower training paces, and accept longer race times (especially >4 h) each were shown independently to have a significantly higher risk for developing hyponatremia (10,12,15,45). Longer race times likely correlate with increased water consumption and increased sodium losses (x,12,46). For example, participants who developed hyponatremia in the 1998 and 1999 San Diego Marathons had an average finishing time of five h and 38 min, and many of these individuals admitted to drinking as much fluid as possible during and afterward the event (12). A low body mass alphabetize also was shown to be a pregnant risk cistron, possibly as a result of the ingestion of larger amounts of fluid in proportion to size and total body water (TBW) (15).

Medications also may play a significant role in the hyponatremia that is constitute in endurance athletes, but this largely is unproved. Nonsteroidal anti-inflammatory drug (NSAID) use is common among marathon runners, existence used in 50 to 60% of men and women, respectively (10,22,47). NSAID are known to potentiate the effects of arginine vasopressin (AVP) by inhibiting renal prostaglandin synthesis via the COX-ii isoform of cyclo-oxygenase (48–fifty). Furthermore, NSAID decrease the GFR when given to those with constructive book depletion, such as exercising endurance athletes (51). These effects may impair the urine-diluting capacity of the kidney (51). Despite these theoretical considerations, Almond et al. (xv) were unable to associate the employ of NSAID with the development of hyponatremia in the runners who were studied in the 2002 Boston Marathon. Other studies likewise accept not been able to ascribe conclusively to NSAID utilize the evolution of hyponatremia, although several of these studies were underpowered to practice and then (10,22). Notwithstanding, a recent written report in 330 triathletes demonstrated a significant clan of NSAID use and the evolution of hyponatremia (23). In this study, the incidence of NSAID apply in athletes was xxx%, and NSAID utilise was highly associated with the development of hyponatremia (P = 0.0002), as well equally higher plasma potassium and creatinine levels. Several other, smaller studies and case reports besides have suggested a potentiating role for NSAID employ (eleven,12,52). Therefore, the role of NSAID in the development of EAH remains controversial but in some runners likely is a potentiating gene. Whether other medications, such as selective serotonin reuptake inhibitors or thiazide diuretics, that are associated with hyponatremia in nonathletes can potentiate the evolution of EAH is not known. Information technology is important to recognize that these chance factors do not suggest causation or even an independent clan with the evolution of hyponatremia. Yet, they exercise offer of import clues to the pathogenesis of the condition.

Pathophysiology

Usually, renal and hormonal systems maintain the plasma osmolality within tight limits with variability of no more than i to 2% (reviewed in reference [53]). These tight limits reflect the physiologic importance of osmolality regulation on cell volume and role (54). The development of hyponatremia (ordinarily, in the setting of hypo-osmolality) reflects either defects in these hormonal and renal control mechanisms or h2o ingestion that overwhelms them. In the specific example of EAH, defects in renal diluting mechanisms, hormonal command of water excretion, excessive sodium losses, and excessive water intake all contribute to the development of hypo-osmolality (summarized in Effigy 1).

Current evidence strongly supports that EAH is, in big part, dilutional in nature. In the majority of athletes who develop hyponatremia, there is an increase in TBW relative to that of total body exchangeable sodium (34). Every bit described previously, this seems to occur by the ingestion of hypotonic fluids (h2o or sports drinks) in excess of sweat, urine, and insensible (mainly respiratory and gastrointestinal) losses. In a seminal written report, Noakes et al. (34) described a linear relationship with a negative slope between the serum sodium after racing and the caste of weight change in 2135 athletes (Figure 2). The main cause of this weight gain during exercise must be the consumption of fluids during do. This consumption of fluids during exercise can be driven by thirst or through conditioned behavior. Some take hypothesized that in some athletes, the thirst drive may be excessive, simply, more than likely, the excessive fluid intake during practice reflects conditioned beliefs that is based on recommendations to potable fluid during practice to avert aridity as well equally the wide availability of fluids along the race form (31,55). This hypothesis is supported by data, previously described, that the incidence of EAH was rare or nonexistent before 1981, when recommendations for fluid intake during practise were bourgeois. EAH was seen merely after recommendations for more ambitious hydration were promulgated (31). Occasionally, some athletes may beverage up to 3 L/h in an attempt to produce dilute urine to escape detection of banned drugs in the urine (56). Finally, some athletes may drink large volumes of fluid in the days leading up to a marathon in an attempt to ward off dehydration. This was the example for one female person runner who drank 10 L of fluid on the evening before a marathon and then experienced postrace hyponatremia (57).

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Figure 2.

Human relationship betwixt serum sodium after racing and the weight alter (in %) during exercise in 2135 athletes who competed in endurance events. •, asymptomatic athletes; ○, athletes with symptoms compatible with EAH encephalopathy (EAHE). The bulk of athletes who develop clinically significant hyponatremia accept positive weight changes. Reprinted from reference (34), with permission. Copyright 2005 National Academy of Sciences.

Withal, excessive fluid consumption is not the sole caption for the development of EAH. In the written report of Noakes et al. (34), hyponatremia did not develop in 70% of the athletes who overconsumed fluids and had an increment in TBW. This indicates that other important factors must be operational in the pathogenesis of EAH. The importance of other factors besides is highlighted past the fact that the maximum water excretory chapters of the kidneys is between 750 and 1500 ml/h (53). In combination with fluid losses from sweating and insensible losses (which may exist in excess of 500 ml/h), most athletes should exist able to consume fluids in excess of 1500 ml/h earlier retaining weight and increasing TBW. This amount of fluid consumption is at the upper limit of what most athletes would swallow during an action (31). Therefore, either defects in renal water excretion and/or significant sodium losses or failure to mobilize exchangeable sodium stores may occur in athletes who develop EAH. Furthermore, some athletes develop hyponatremia without appreciable gains in full body weight (34). As discussed adjacent, these athletes may accept significant sodium losses or also may accept gained cyberspace body free water as a result of the metabolism of glycogen and triglycerides and non as a result of ingestion. Nevertheless, the contribution of fuel metabolism or metabolic water production to TBW likely is small. During treadmill running at 74% of maximal oxygen consumption, metabolic water product averages 144 thousand/h (in dissimilarity, sweat loss during this fourth dimension was 1200 g/h) (58). In that location is a possibility that water that is stored with glycogen can be released with glycogen breakdown. This may be an important component in the cause of hyponatremia that occurs without weight gain because each kilogram of glycogen tin incorporate upward of 3 kg of associated water (59,lx).

Data on the levels of AVP during exercise are alien. Unfortunately, systematic measurement of AVP levels or free water clearances in athletes who present with hyponatremia has not been washed except in isolated cases. There are several potential pathways for stimulation of AVP release in exercising athletes. Controlled laboratory studies have demonstrated that every bit exercise intensity increases above 60% of maximal oxygen consumption, there are concomitant increases in AVP levels (61). Nonspecific stresses that are experienced past athletes and caused by factors such equally pain, emotion, or concrete practice have been idea to cause nonosmotic release of AVP (62). Nevertheless, it is difficult to determine whether this effect is mediated by a specific pathway or is due to a secondary stimulus, such as hypotension or nausea, that may occur in exercising athletes. AVP product also may be stimulated appropriately in athletes who develop volume depletion. All the same, the level of volume depletion that is required to stimulate AVP product in the absence of hyperosmolality is in excess of 7 to 8% of body volume. These levels of volume depletion typically are not seen in athletes (due east.m., in the 2001 South African Ironman Triathlon, just 7% of finishers had a cyberspace body weight loss >5% [20]). Furthermore, the majority of athletes with EAH cease events with an increase in body weight and possibly an expanded plasma volume (34). Exposure to heat likewise can lead to the secretion of AVP (63). Even so, this effect of temperature may be influenced secondarily by changes in constructive arterial volume that occur with heat-induced vasodilation. Despite these considerations, in some athletes during prolonged exercise, plasma AVP levels may non be suppressed maximally despite maintenance or even excess of plasma volume. This has been described in studies of hikers who developed hyponatremia in the Grand Canyon and in an ground forces recruit during a prolonged field march (40,64). Speedy et al. (46) also described median AVP levels that were significantly college in athletes who developed hyponatremia in the 1997 New Zealand Ironman Triathlon.

An intriguing link between exercise and the nonosmotic stimulation of AVP release may be related to the release of inflammatory cytokines by the exercising and injured skeletal musculus as postulated by Siegel (65). As glycogen stores are depleted, rhabdomyolysis or lesser degrees of muscle injury can occur with the release of inflammatory cytokines such as IL-6. Independent of rhabdomyolysis, studies accept shown that exercise primes an array of pro- and anti-inflammatory and growth factor expressions inside circulating leukocytes (66,67). Mastorakos et al. (68) demonstrated that IL-6 tin can act every bit an AVP secretagogue. This issue of IL-6 on hypothalamic AVP secretion also was seen in children after head trauma (69). Information technology is interesting that women respond to practice-induced stress with the production of higher levels of IL-6, perhaps explaining, in part, the increased risk for EAH in women (66). Along these lines, unmarried-nucleotide polymorphisms in the promoter region of inflammatory cytokines are of import in determining the levels of cytokine production (seventy). A particular athlete may be predisposed to EAH on the basis of the single-nucleotide polymorphism profile and specific inflammatory response to exercise. Conversely, IL-6 in a rat sepsis model has been shown to reduce the expression of aquaporin-two, the downstream target of AVP and ultimate regulator of water diuresis (71). How these factors interact to cause EAH is not known merely should be an avenue of research.

Consistent with the probable part of AVP in EAH, athletes who have finished races with hyponatremia have likewise been demonstrated, in some cases, to accept inappropriately elevated urine osmolality (72). In this setting, even small increases in plasma AVP levels can crusade pregnant water retentiveness and hyponatremia, particularly in combination with excessive water intake. Furthermore, gastrointestinal blood flow and water absorption from the breadbasket and intestine may be impaired during exercise (73). When the athlete stops activity, water absorption may increase apace and significantly (73). In the setting of elevated AVP levels, this rapid assimilation of large quantities of h2o or hypotonic fluids can atomic number 82 to significant falls in serum sodium.

Whether AVP levels are increased inappropriately in all athletes who develop EAH is not known. Speedy et al. (74) measured normal (suppressed) AVP levels in 2 triathletes who adult hyponatremia during an Ironman result and demonstrated that other causes for renal damage of complimentary h2o backlog must be present in some athletes. A possible cause of EAH is that during exercise, the diluting adequacy of the kidney is likely to be diminished (75). In both the thick ascending limb of Henle and the distal tubule, reabsorption of sodium chloride in the absence of h2o (and thus dilution of the urine) depends on the delivery of filtrate to these segments and is afflicted past the renin-angiotensin-aldosterone system, the sympathetic nervous system, renal blood flow, and proximal tubular reabsorption of sodium. During exercise, there is a release of catecholamines and angiotensin II that leads to an increase in sodium and water reabsorption in the proximal tubule, thereby decreasing the amount of filtrate that is delivered to the distal diluting segments of the kidney (75). Furthermore, renal claret flow and GFR are decreased in the setting of endurance exercise and further limit the commitment of filtrate to the diluting segments of the kidney (75). These effects on the diluting capacity of the kidney may be significant in leading to impairments of free h2o excretion.

Although overdrinking conspicuously is the most important causative factor in the development of EAH, there is a variable and of import contribution of sodium loss from sweating (38). The concentration of sodium in sweat varies widely merely is usually xv to 65 mEq/50, with highly fit athletes by and large excreting sweat with sodium concentrations <40 mEq/50 (38,76). The book of sweat during exercise also varies widely, from approximately 250 ml/h to >2 L/h, once more being less in more fit athletes (77,78). This loss of a substantial corporeality of hypotonic fluid may seem to protect against the evolution of hyponatremia. Notwithstanding, these losses are replaced past the ingestion of more hypotonic fluids (water or sports drinks), and the extracellular volume loss in sweat may serve every bit a stimulus for antidiuretic hormone (ADH) secretion. In fact, mathematical models demonstrate that the magnitude of sweat sodium loss is insufficient to produce EAH (38,79). For example (as discussed in reference [38]), in a xc-km ultramarathon race, an athlete may lose approximately 8.vi L of sweat. Assuming sweat sodium concentrations of either 25 or l mmol/L and that all fluid losses were replaced by water, the resulting sodium deficits would be 215 and 430 mmol, respectively. For a 70-kg athlete, the resulting serum sodium concentration would be either 135 or 130 mmol/L, respectively. However, for longer elapsing events and for those with high sweat sodium concentrations (>75 mmol/L), a sufficient sweat sodium arrears tin occur for athletes to finish the race both dehydrated and hyponatremic. This is supported by the finding that some athletes finish races with net weight loss and hyponatremia (34). Furthermore, one case study of a patient who had cystic fibrosis (patients with cystic fibrosis excrete large amounts of sodium in their sweat) and developed EAH points to the possibility that some people may be genetically predisposed to EAH as a result of loftier sweat sodium losses (eighty).

Equally mentioned previously, in the written report past Noakes et al. (34) seventy% of athletes who were overhydrated did not develop EAH. Why is information technology that just a percentage of athletes develop EAH? What are the factors that protect these athletes from developing EAH? An intriguing possibility discussed by Noakes et al. (34) is that some athletes are able to mobilize sodium from internal stores that otherwise are osmotically inactive. This exchangeable sodium store has been described past Edelman and colleagues, Titze and colleagues, and Heer and colleagues (81–86). For example, in the study by Heer et al. (86) participants were fed a diet of varying sodium amounts with a fixed amount of water ingestion. Despite these weather, serum sodium levels remained constant without a concomitant increase in TBW. These studies indicated that up to one fourth of the total body sodium may exist in os and cartilage stores that are not osmotically agile (i.east., in an insoluble crystal compound) merely potentially recruitable into an osmotically active grade (81–83). In rats, this nonosmotically agile sodium may reside bound to peel proteoglycans (87,88). This dynamic pool of exchangeable sodium too can lead to the osmotic inactivation of sodium if sodium moves into this compartment. This concept was explored indirectly in early on studies of syndrome of inappropriate ADH secretion (SIADH) (89,90). In these studies, the balance of sodium loss and h2o gain could not explain adequately the extent to which serum sodium was reduced. Therefore, information technology was hypothesized that hyponatremia was related to the osmotic inactivation (sequestration) of previously osmotically active sodium. It should be pointed out that the presence of this exchangeable sodium store is not supported by all investigators. Seelinger et al. (91) showed in sodium balance studies in dogs that the changes in TBW and electrolyte levels can be accounted for without invoking an osmotically inactive sodium pool. Furthermore, most of the experimental data supporting an exchangeable osmotically inactive sodium pool are derived from studies on sodium loading that occurs over a more extended period and may not be applicative to the situation that is encountered by athletes. However, the data presented past Noakes et al. (34) do support that an exchangeable sodium puddle may serve as a buffer for losses of sodium that occur through sweat or urine and also can buffer changes in serum sodium levels that occur with changes in TBW. Therefore, athletes who gain TBW and maintain a normal serum sodium concentration are able to mobilize this store of exchangeable sodium, whereas athletes who develop EAH either cannot mobilize the exchangeable pool or sodium or may osmotically inactivate sodium (34). The factors that govern the exchange of sodium between these compartments is unknown just may involve hormonal factors such equally angiotensin Ii or aldosterone (81–86). The magnitude of this effect in athletes is large with up to 700 mmol of sodium being mobilized from the osmotically inactive pool in the calculations past Noakes et al. (34).

Another possibility that may explain the discrepancy between weight proceeds and the development of hyponatremia is the contribution of h2o that remains in the lumen of the alimentary canal. This is peculiarly of import in athletes who may have consumed a big corporeality of fluid toward the end of a race and in those with elevated AVP levels. In this setting, rapid absorption of this hypotonic fluid coupled with dumb gratis water excretion would pb to a rapid fall in serum (especially arterial) sodium levels.

Clinical Features

The clinical manifestations of EAH range from no or minimal symptoms to severe encephalopathy, seizures, respiratory distress, and decease. In general, the degree of clinical symptoms is related not to the accented measured level of serum sodium but to both the charge per unit and the extent of the drop in extracellular tonicity. However, private variability in the clinical manifestations of hyponatremia is swell. It seems that the bulk of runners with EAH have mild (weakness, dizziness, headache, nausea/vomiting) or no symptoms (usually associated with serum sodium values ranging from 134 to 128 mmol/L) (ane,9–13,15). In athletes with serum sodium values <126 mmol/L, at that place is a higher likelihood of severe clinical manifestations such every bit cerebral edema, contradistinct mental status, seizures, pulmonary edema, coma, and death (11,17,19,xx,24). Notwithstanding, a systematic survey of symptoms that are associated with hyponatremia in athletes has not been performed.

Hew et al. (ten) examined the clinical manifestations of 21 hyponatremic runners who finished the Houston Marathon in 2000. These clinical manifestations were compared with those of runners who did not accept hyponatremia and presented to the medical tent at the conclusion of the race. The only symptom that was more common (P = 0.03) in the hyponatremic grouping was airsickness. Other symptoms such as headache, nausea, dizziness, and lightheadedness could non distinguish hyponatremia from other causes, attesting to the nonspecific nature of signs and symptoms that are associated with hyponatremia.

A mutual scenario for medical personnel who staff endurance athletic events is the intendance of the "collapsed athlete." Several studies have examined the incidence of hyponatremia in this cohort, and a range of 6 to 30% of these athletes had serum sodium values beneath normal (9,10,12,15–25). The wide range of incidence probable reflects differences in fluid replacement guidelines that were prevalent at the time and identify of the study.

Given the difficulty in using clinical symptoms to place athletes with hyponatremia and the potential for life-threatening consequences, recommendations have been fabricated that medical facilities at endurance events have the capability for onsite analysis of serum or plasma sodium (14). Whatsoever athlete who presents with signs or symptoms that are compatible with hyponatremia should be screened for EAH by directly measurement of serum or plasma sodium.

It is critically important to realize that a postrace venous serum sodium measurement may underestimate significantly the severity of hyponatremia (92). This occurs for three reasons: (1) Water may be retained in the gastrointestinal tract during the able-bodied outcome simply to be absorbed rapidly in the postrace flow. If AVP levels are elevated, this retained water tin lower quickly the serum sodium when reabsorbed into the apportionment. (2) Shafiee et al. (93) demonstrated that the arterial sodium concentration can be significantly lower than the venous sodium concentration, with this difference being accentuated with more rapid absorption of water (there may be every bit much equally a 4-mM difference between arterial and venous sodium concentrations when water is ingested quickly). Because it is the arterial sodium concentration that determines the risks for acute key nervous system symptoms, runners with a large amount of retained water in the gastrointestinal tract may exist at college risk for cognitive edema than their venous serum sodium concentration would bespeak. Therefore, in athletes with low trunk mass, mildly depressed venous sodium concentrations, and recent large water intakes, the risk for deterioration secondary to worsening hyponatremia may go unrecognized. (three) There may be transient rises in venous sodium concentration at the end of a race (particularly if sprinting) as muscle lactic acid accumulates and leads to a shift of water intracellularly (94). This transient rise in serum sodium tin exist every bit high as 10 mM and may mask significant hyponatremia.

Prevention of EAH

Considering EAH primarily develops by consumption of fluid in excess of urinary and sweat losses, well-nigh efforts at prevention have been focused on instruction about the risks of the overconsumption of fluids (14,95). In many respects, EAH can be viewed as an iatrogenic condition because of the prevailing view that exercising athletes should beverage as much fluid every bit tolerable during a race. Given that at that place is a broad variation of sweat production and renal water excretory capacity both between individual athletes and in the aforementioned private depending on ambience conditions during the race, universal guidelines for prevention are not viable. However, several full general recommendations for the prevention of EAH take been made (xiv,95–98). The outset is to drinkable merely co-ordinate to thirst and no more than 400 to 800 ml/h (95). The higher rates of fluid intake would exist recommended for runners with higher rates of exertion (e.thousand., heavier runners, warmer weather, longer times of exertion). This rate of fluid intake is well below the levels of intake that are seen in athletes who develop EAH (up to 1.v L/h water) only above the level that would be associated with aridity. The second recommendation is to utilise the USA Runway and Field guidelines or other methods to estimate hourly sweat losses during exercise and avert consuming amounts that are greater than this amount during endurance events (96,97). This is facilitated by serial measurements of weights during and after exercise with the goal to maintain weight or even end practice with a slighter lower weight. However, this is difficult, fourth dimension-consuming, and less probable to be followed by casual athletes. That these recommendations can exist effective was demonstrated by Speedy et al. (99), who were able to show that prerace didactics and limiting fluid availability at a race were able to reduce the incidence of hyponatremia without deleterious effects.

Currently, in that location is insufficient evidence to support the proffer that ingestion of sodium prevents or decreases the risk for EAH; neither is there any evidence that consumption of sports drinks (electrolyte-containing hypotonic fluids) can prevent the development of EAH (1,35–38,42,100,101). Over again, near commercial sports drinks are hypotonic with a sodium content of 10 to 20 mmol/L (230 to 460 mg/L). Overconsumption of such fluids may decrease the rate of serum sodium decline but is unlikely to prevent EAH (35–38,42,100–102). Currently, the American College of Sports Medicine recommends an intake of 0.5 to 0.7 thousand sodium/L of water as the appropriate level of sodium intake to replace the sodium that is lost in sweat during endurance events (6).

Therapy of EAH

Ideally, medical facilities at endurance events should be able to measure serum or plasma sodium concentrations in any athlete who manifests symptoms that are uniform with EAH or EAHE. Nevertheless, this may non be universally viable, and caregivers may take to deed empirically on the suspicion of EAH or EAHE equally the crusade of symptoms. It is crucial for on-site caregivers to exist vigilant for the possibility of EAH and not diagnose incorrectly volume depletion and implement a reflex therapy of normal saline infusion.

In 2005, a consensus panel made specific recommendations for the treatment of EAH and EAHE (14). The specific treatment recommended depends on the level of symptoms that the athlete is exhibiting at the time of presentation. Nigh forms of balmy hyponatremia (serum [Na] 130 to 135 mmol/L) will be asymptomatic and constitute but past laboratory testing. Most athletes with mild, asymptomatic hyponatremia will require only fluid brake and observation until spontaneous diuresis occurs. It is important that hydration with intravenous 0.nine% sodium chloride (NS) be used with utmost caution because this therapy runs the potential risk for farther decreasing the serum sodium if AVP levels remain elevated in some athletes (103). Furthermore, the absorption of big amounts of retained hypotonic fluids in the alimentary canal may continue to lower the serum sodium for some time afterward the event is finished. Therefore, intravenous hydration with NS should be reserved for athletes who manifest clear clinical signs of book depletion and used cautiously with mandatory monitoring of serum sodium levels (20). Furthermore, cases of pulmonary edema have been described in individuals who received aggressive hydration with 0.ix% NS (21). Monitoring of urinary sodium and potassium concentrations and calculation of the urinary free h2o excretion charge per unit can exist helpful in this situation. Athletes who are excreting gratuitous water tin can be monitored safely without need for intravenous fluids, whereas athletes with a negative gratis water clearance should not receive 0.9% NS because this may worsen the hyponatremia.

The treatment of astringent (serum [Na] <120 mmol/L) or symptomatic EAH requires the administration of hypertonic saline (xi,104–106). At that place are some important considerations when deciding to treat EAH with hypertonic saline. Get-go is the supposition that all EAH is acute (<48 h). This allows the correction of the hyponatremia to be done quickly and safely (107,108). The second consideration is that no cases of osmotic demyelination syndrome take been reported with the treatment of EAH (14). In the case series by Ayus et al. (xi), half-dozen of seven marathon runners were treated with hypertonic saline for hyponatremia, cerebral edema, and noncardiogenic pulmonary edema. All six of the athletes who received hypertonic saline made a total recovery. Of the five athletes who had follow-upward magnetic resonance imaging scans obtained 1 yr later on treatment, all were normal. The one athlete who was non treated with hypertonic saline died.

There is no general consensus on the corporeality of hypertonic saline to exist given in athletes with EAH. In the field, information technology has been suggested that experienced medical staff may give 100 ml of 3% saline over 10 min (xiv,106). This has been suggested to be safe, raising the serum sodium concentration 2 to 3 mmol/L in a short period of time, and should be used in athletes who showroom symptoms of severe hyponatremia (confusion, airsickness, respiratory insufficiency) (11,106). The use of hypertonic saline has been shown to induce a greater-than-expected increase in the serum sodium, likely as a result of a decrease in AVP, and the restoration of a dilute urine; therefore, information technology is imperative that all athletes who receive therapy for EAH or EAHE exist transported to a medical middle where the serum sodium can be monitored closely (eleven,14,106,107). Apply of hypertonic saline should exist continued in the hospital to right the hyponatremia using standard protocols. In general, three% hypertonic saline can be given at 1 to two ml/kg per h with close monitoring of both serum electrolytes and urinary sodium and potassium excretion. In cases of severe antidiuresis, the charge per unit of infusion may need to be increased to 3 to 4 ml/kg per h. Once pregnant water diuresis begins, the charge per unit of infusion can be decreased or stopped. Special mention should exist made of the patient who presents with astringent EAHE and pulmonary edema. It is imperative that these patients receive emergent therapy with iii% hypertonic saline despite evidence of volume overload. As described past Ayus et al. (21), patients who do non receive hypertonic saline have poor outcomes. The addition of a loop diuretic can exist considered in ii circumstances: (1) Significant volume overload and (two) significant antidiuresis with a very elevated urinary osmolality, sodium, and/or potassium level.

Recently, selective vasopressin receptor antagonists (VRA) have been developed for the therapy of hyponatremia that is associated with SIADH, cirrhosis, and congestive middle failure (109). These agents include 2 oral preparations (lixivaptan and tolvaptan) and an intravenous agent (conivaptan). In the phase 2 trial with lixivaptan, patients with SIADH had an increment in serum sodium from 126 ± 5 to 133 ± 5.half-dozen mmol/L after 48 h with concomitant increases in urine menstruation rate and falls in urine osmolality (110). Conivaptan has the advantage that correction of serum sodium is faster than with the oral agents, likely owing to enhanced bioavailability. In one written report with conivaptan, the median fourth dimension to a 4-mmol/L increase in serum sodium was 23.7 h (111). Nonetheless, in the handling of EAH and other forms of acute hyponatremia, the role of these agents is unclear. It is non known whether VRA alone will achieve sufficiently rapid correction of astute, severe hyponatremia without the use of hypertonic saline. As detailed by Greenberg and Verbalis (111), both VRA and hypertonic saline could be used initially. Once there is a small correction in the serum sodium, the hypertonic saline could exist stopped and the VRA continued to facilitate water diuresis. One fear of the use of VRA in the treatment of EAH is that athletes could take an extremely rapid water diuresis with the gamble for resultant hypernatremia; therefore, these agents are not likely to be useful for the therapy of EAH. Overall, in the therapy of EAH, hypertonic saline remains the therapy of choice.

Hypokalemia can develop during athletic events especially subsequently the effect is completed (112). It is of import that the potential for hypokalemia exist appreciated because information technology can have important implications for treatment. First, hypokalemia is a take a chance factor for the development of osmotic demyelination that is associated with correction of chronic hyponatremia (113). Whether hypokalemia is a hazard cistron for poor neurologic outcomes that are associated with therapy for acute hyponatremia is not known. Second, replacement of potassium deficits will increase the serum sodium as sodium shifts out of cells. With concomitant potassium repletion, the serum sodium may rise faster than anticipated, and correction of hyponatremia should be less ambitious (108).

Conclusion

EAH and EAHE are potentially devastating complications of endurance events that occur in otherwise healthy, active, and immature individuals. The pathophysiology of this condition includes multiple intersecting pathways that include both ecology (overabundance of fluids and recommendations for overdrinking) and innate physiologic command systems. When appropriately recognized, EAH and EAHE can exist treated finer with a low rate of morbidity and bloodshed. Nevertheless, when not recognized, this condition tin be fatal. Fortunately, preventive measures that stress judicious use of fluid replacement during exercise are effective and should exist widely publicized and implemented.

Footnotes

• Published online alee of print. Publication appointment available at www.cjasn.org.

• Copyright © 2007 by the American Society of Nephrology

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