Exercise-Associated Hyponatremia in Endurance and Ultra-Endurance Performance–Aspects of Sex, Race Location, Ambient Temperature, Sports Discipline, and Length of Performance: A Narrative Review

rcise-associated hyponatremia (EAH) is de ned as a plasma sodium concentration of <135 mmol/L during or after endurance and ultra-endurance performance and was rst described by Timothy Noakes when observed in ultra-marathoners competing in the Comrades Marathon in South Africa in the mid-1980s. It is well-established that a decrease in plasma sodium concentration <135 mmol/L occurs with excessive uid intake. Clinically, a mild hyponatremia will lead to no or very unspeci c symptoms. A pronounced hyponatremia (<120 mmol/L) will lead to central nervous symptoms due to cerebral edema, and respiratory failure can lead to death when plasma sodium concentration reaches values of<110–115 mmol/L. The objective of this narrative review is to present new ndings about the aspects of sex, race location, sports discipline, and length of performance. The prevalence of EAH depends on the duration of an endurance performance (i.e., low in marathon running, high to very high in ultra-marathon running), the sports discipline (i.e., rather rare in cycling, more frequent in running and triathlon, and very frequent in swimming), sex (i.e., increased in women with several reported deaths), the ambient temperature (i.e., very high in hot temperatures) and the country where competition takes place (i.e., very common in the USA, very little in

high to very high in ultra-marathon running), the sports discipline (i.e., rather rare in cycling, more frequent in running and triathlon, and very frequent in swimming), sex (i.e., increased in women with several reported deaths), the ambient temperature (i.e., very high in hot temperatures) and the country where competition takes place (i.e., very common in the USA, very little in Europe, practically never in Africa, Asia, and Oceania). A possible explanation for the increased prevalence of EAH in women could be the so-called Varon–Ayus syndrome with severe hyponatremia, lung and cerebral edema, which was rst observed in marathon runners. Regarding the race location, races in Europe seemed to be held under rather moderate conditions whereas races held in the USA were often performed under thermally stressing conditions (i.e., greater heat or greater cold). Keywords:cold; heat; cerebral edema; prolonged exercise; swimming; cycling; running 1. Introduction For years, exercise-associated hyponatremia (EAH) has been well-known among endurance and ultra-endurance athletes. Unfortunately, the occurrence of EAH continues to spread into a wider variety of sports and cause deaths in otherwise healthy individuals [1]. Athletes continue to Medicina2019,55, 537; doi:10.3390 /medicina55090537 /journal/medicina

Medicina2019,55, 537 2 of 23 die from complications associated with hyponatremic encephalopathy. In 2007, a 22-year-old male tness instructor nished the London Marathon, where upon arrival, he collapsed and died due to EAH [2]. In 2015, a 30-year-old age group triathlete died after the Ironman Frankfurt due to EAH with hyponatremic encephalopathy [3]. The most likely reason for developing EAH is uid overload [4,5] with the possibility of developing lung or brain edema [5,6] with fatal outcome [7]. Considering the increased number of endurance and ultra-endurance races, and of nishers in these races during the last years, comprehensive knowledge about EAH would be of great practical importance for athletes and professionals (e.g., coaches, nutritionists, practitioners, exercise physiologists) working with them. It should be highlighted that endurance and ultra-endurance athletes might compete in races di ering for distance (e.g., marathon versusultra-marathon) and under a wide range of environmental conditions (e.g., hotversuscold). Especially, it would be of interest to examine the variation of EAH by parameters such as sex, sport discipline, race distance and environmental conditions. The purpose of this review was to present new aspects regarding sex, race location, discipline and length of performance as risk factors in developing EAH. EAH has been described in both prolonged and non-prolonged exercise activities (e.g., yoga classes), yet it is more likely to develop in prolonged exercise [1,8]. A further aspect was to present data on the prevalence and severity of EAH regarding the discipline, environmental conditions, and length of the performance. 2. First Description and De nition of Exercise-Associated Hyponatremia EAH describes the occurrence of hyponatremia in individuals during prolonged exercise (i.e., usually longer than six hours) and is de ned when plasma or serum concentration of sodium is <135 mmol/L [9]. Apart from the de nition of hyponatraemia based on biochemical severity [10], it can be also diagnosed based on symptomatology, as symptoms have been reported even at concentrations close to 130 mmol/L [11]. This can occur during or after prolonged physical exertion for 4–6 h or longer [12] and can be detected up to 24 h after the end of the

from the de nition of hyponatraemia based on biochemical severity [10], it can be also diagnosed based on symptomatology, as symptoms have been reported even at concentrations close to 130 mmol/L [11]. This can occur during or after prolonged physical exertion for 4–6 h or longer [12] and can be detected up to 24 h after the end of the exercise [13,14]. In the mid-1980s, Tim Noakes was the rst to report severe symptomatic hyponatremia at the Comrades Marathon held in Durban, South Africa [15]. The Comrades Marathon is a 90-km long road-running race that has been held since 1921 between the South African cities of Durban and Pietermaritzburg. This race is the most traditional and participant-strong ultramarathon worldwide [16]. Hyponatremia was detected in four runners in 1981 and 1985 [17]. Prior to 1981, endurance athletes were advised not to drink during exercise [17,18], which in some cases led to hypernatremia [19]. Due to this knowledge, the American College of Sports Medicine (ACSM) recommended to drink as much as possible during exercise to prevent hypernatremia [17,18,20–22]. This advice led to an increased number of cases of EAH, especially in the USA. One major reason for this development was the US beverage industry and their funding of sports research with the aim of drinking as much as possible in order to avoid dehydration, which was measured by a loss in body mass during exercise [23]. 3. The Pathogenesis of Exercise-Associated Hyponatremia This is a condition as a common complication of especially endurance exercise due to a combination of over drinking beyond thirst and non-osmotic arginine vasopressin release [1]. Two factors determine the nature and the severity of the symptoms of hyponatremia: the speed of development and the level of plasma sodium. Rapidly developing hyponatremia tends to lead to central nervous symptoms (e.g., seizures) in the context of encephalopathy [24,25], as the cerebral adaptation mechanisms take e ect only after a certain delay and therefore brain edema can develop [1]. It is important to know that the sodium concentration in the plasma rises only after prolonged exposure [26–28]. For example, Ironman triathletes

Rapidly developing hyponatremia tends to lead to central nervous symptoms (e.g., seizures) in the context of encephalopathy [24,25], as the cerebral adaptation mechanisms take e ect only after a certain delay and therefore brain edema can develop [1]. It is important to know that the sodium concentration in the plasma rises only after prolonged exposure [26–28]. For example, Ironman triathletes who lost body mass had an increased sodium concentration, with the highest sodium concentration in athletes who had the highest body mass loss [29]. Two di erent mechanisms can lead to EAH [30]: on the one hand, increased sodium loss and on the other hand, increased water

Medicina2019,55, 537 3 of 23 intake [31]. Athletes with symptomatic hyponatremia have an increased extracellular volume due to water retention [32,33]. Hyponatremia results from a dilution of a normal or slightly reduced total extracellular sodium concentration due to a loss of sodium via sweat and urine [34]. During exercise, there may be a large loss of sodium and uid through urine and sweat, rarely vomiting [35]. When uid is replenished with a sodium-free solution or hypotonic uid, such as water, so that the extracellular uid volume either remains the same or increases, hyponatremia will result from dilution [36–38]. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been identi ed as a common cause of hyponatremia in clinical practice, though the diagnosis of SIADH and EAH should be di erentiated with each other [39]. The failure of suppressing ADH has been identi ed in cyclists and marathon runners, and leads to water retention and hyponatremia, in conjunction with excessive uid intake [1,40,41]. The body's normal response to an uncorrected loss of sodium during exercise is a decrease in extracellular volume as a function of the sodium de cit [42,43], with long-distance athletes expected to develop normonatremia or even hypernatremia [44]. EAH is generally due to a relative uid overload of the extracellular space [45]. EAH due to excessive sweat loss is likely very rare [46]. People have di ering levels of sodium in their sweat; therefore, EAH due to high sodium loss could not be detected [35]. A case of a triathlon athlete and a cystic brosis patient have been described who had developed hypovolaemic EAH due to increased sweat loss and overconsumption of uids relative to immediately available exchangeable sodium [46]. A case of a patient with cystic brosis has been described who has developed dilutional hyponatremia due to increased sweat loss during endurance exercise [46]. Three di erent mechanisms can lead to EAH, according to Noakes and colleagues [31]: excessive uid drinking during exercise, retention of excess uid because of inadequate suppression of antidiuretic hormone secretion, and osmotic inactivation of circulating sodium or failure to mobilize osmotically inactive

has been described who has developed dilutional hyponatremia due to increased sweat loss during endurance exercise [46]. Three di erent mechanisms can lead to EAH, according to Noakes and colleagues [31]: excessive uid drinking during exercise, retention of excess uid because of inadequate suppression of antidiuretic hormone secretion, and osmotic inactivation of circulating sodium or failure to mobilize osmotically inactive sodium from internal stores. The current state of knowledge is that uid overload with consecutive hyponatremia is the causative mechanism for EAH [31,32,47–49]. This dilutional hyponatremia is due to an increase in total body water relative to the total amount of exchangeable sodium in the body [12]. Although this increase may only be relative, in most cases of EAH there is an increase in body mass due to an increase in total body water [12,31]. On the basis of existing knowledge, it must be assumed that hyponatremia in the case of endurance exercise is due to excessive intake of predominantly sodium-poor or sodium-free liquids such as water [50]. This is the case when more uid is consumed than sweated [51–53]. The large uid intake leads to uid retention in the body with dilutional hyponatremia [50,54]. It is important to mention also the existence of hypovolemic EAH, which would be predicted to develop in athletes exercising for more than 20 h and/or in hotter environment [55–57] and/or with higher sweat sodium losses [58]. There is a clear correlation between sodium concentration after a race and hydration during the race [59]. For example, EAH has been shown to occur when 3 L of water are drunk within 2 h of performance [60] or when 3 L are consumed overall, or when some uid is consumed every mile [61]. It can happen that a triathlete consumes 16 L of uid during an Ironman, gaining 2.5 kg of body mass and developing EAH [32,52]. Generally, uid overload leads to an increase in body mass during endurance performance [31,62] and a decrease in plasma sodium [63]. The change in body weight correlates linearly to the plasma sodium concentration after exercise [31,64], and the relationship between

a triathlete consumes 16 L of uid during an Ironman, gaining 2.5 kg of body mass and developing EAH [32,52]. Generally, uid overload leads to an increase in body mass during endurance performance [31,62] and a decrease in plasma sodium [63]. The change in body weight correlates linearly to the plasma sodium concentration after exercise [31,64], and the relationship between the change in plasma concentration of sodium before and after exercise is inversely related to the change in body mass [65]. Often, athletes gain body mass and develop EAH [31,66]. Conversely, in long-distance competitions, it can also be seen that athletes lose body mass and have a high plasma sodium concentration [52]. The exception is hypovolemic EAH with a reduced body mass [56,57,67] indicating volume depletion. Consumption of electrolyte-free water during endurance exercise in the heat leads to a decrease of plasma sodium concentration [38]. It has been shown that body mass often remains unchanged and there is no uid loss, but rather an excess in athletes with EAH [15,36]. The water remains in the intestine

Medicina2019,55, 537 4 of 23 tract and does not move to the plasma [36]. Prolonged endurance performance with prolonged uid intake leads to chronic intra- and extracellular hyperhydration with an increase in plasma volume [68]. However, many parameters remain the same (e.g., change in plasma sodium concentration, plasma osmolality, or body mass) for both mechanisms (i.e., sodium loss through sweating versus dilution due to uid overload) [45]. In addition to uid overload, inadequate suppression of secretion of the antidiuretic hormone (i.e., ADH, vasopressin) by a non-osmotic stimulation must also be considered for the development of EAH [1,31,48]. The increase in N-terminal pro-brain natriuretic peptide (NT-proBNP) shows that uid overload is the cause of EAH [69]. SIADH is one of the mechanisms that lead to EAH [31]. Di erent stimuli have been recognised. In fact, an association between Interleukin-6 and arginine vasopressin has been observed, considering interleukin-6 to be the principal stimulator of arginine vasopressin in marathon runners with hyponatremia [55]. The authors highlight that SIADH is a pre-existing condition, in contrast to EAH due to uid overconsumption, while also noting that NSAIDs play a role on anti-diuresis, and should be avoided before the race. In addition, it has been noted that-similarly to SIADH-athletes with EAH have submaximal suppression of ADH and high urine osmolality [9]. The suboptimal ADH according to the authors could be due to intense exercise, nausea or vomiting, hypoglycemia, pain, and emotion, as well as heat [1,9]. Furthermore, rhabdomyolysis associated acute renal failure could explain EAH [70,71], as does the increase in N-terminal pro-brain natriuretic peptide (NT-proBNP) [69]. Furthermore, Noakes and colleagues [31] also list the inactivation of osmotic sodium as one of the mechanisms of EAH development. The osmotically inactive exchangeable sodium stores were rst identi ed by Edelman and colleagues [72]. These stores seem to be located in the bone, dense connective tissue, or cartilage [73]. In fact, bone loss has been associated with chronic hyponatremia in patients with SIADH [74]. The authors described sodium signalling mechanisms in osteoclasts, in order to mobilize sodium from bone stores during chronic hyponatremia, resulting in resorptive osteoporosis. Some

ed by Edelman and colleagues [72]. These stores seem to be located in the bone, dense connective tissue, or cartilage [73]. In fact, bone loss has been associated with chronic hyponatremia in patients with SIADH [74]. The authors described sodium signalling mechanisms in osteoclasts, in order to mobilize sodium from bone stores during chronic hyponatremia, resulting in resorptive osteoporosis. Some athletes seem to mobilize sodium from internal osmotically inactive exchangeable sodium stores, while others may not be able to prevent the inactivation [31,75]. The improper inactivation of osmotically-active sodium might in uence EAH development [76]. In fact, this has been speculated to be the case in athletes who developed EAH, but whose sodium de cit was similar to the one measured in other athletes that did not develop hyponatremia [28,54]. In these subjects, the predicted serum sodium concentration post-race exceeded the measured concentrations, indicating that osmotically active sodium was lost possibly due to the inactivation of osmotically active sodium. Data showed that those who osmotically activated sodium during recovery nished the race with higher serum sodium than did those who osmotically inactivated sodium during recovery. However, the hypothesis of these stores was not supported in an animal study [77]. The exact underlying mechanisms for the retention of excess uid because of inadequate suppression of antidiuretic hormone secretion, and inactivation of circulating osmotically active sodium or failure to mobilize osmotically inactive sodium from internal stores, are not completely understood [31]. Water remaining in the gut has been identi ed as a factor a ecting the risk for EAH. During high water intake, water remains in the intestinal tract which leads to sodium being transferred from the blood into the gut [32,66,78]. Considering these e ects, studies show that water alone is absorbed into the bloodstream slower than beverages with carbohydrates [79]. Water absorption is in uenced by osmolality and solute absorption, while di erent types of carbohydrates in a sports drink with carbohydrates and electrolytes can help absorption and decrease of osmolality in the intestinal track [80]. This e ect can explain the lower rate of water or hypotonic uid absorption

absorbed into the bloodstream slower than beverages with carbohydrates [79]. Water absorption is in uenced by osmolality and solute absorption, while di erent types of carbohydrates in a sports drink with carbohydrates and electrolytes can help absorption and decrease of osmolality in the intestinal track [80]. This e ect can explain the lower rate of water or hypotonic uid absorption into the bloodstream, which can lead to sodium being absorbed into the intestinal lumen. During exercise optimal water absorption from the gut is important, hence sports drinks are formulated in a way that both electrolytes, carbohydrates for fuel and water are absorbed fast [81].

Medicina2019,55, 537 5 of 23 4. The Clinical Presentation of Exercise-Associated Hyponatremia Hyponatremia is de ned biochemically when a plasma sodium concentration of<135 mmol/L is measured [53,82]. A mild and slow onset of EAH does not cause long-term symptoms, and the condition of EAH may also be asymptomatic [45,83] because in many cases EAH remains clinically unremarkable [53,83] and performance is not impaired [84]. Performance is limited in only rare cases of EAH [38]. A manifest clinical symptomatology of EAH is generally to be expected with a plasma sodium concentration of<120 mmol/L in plasma [85]. Chronic EAH up to a concentration of about 115 mmol/L will remain asymptomatic [86]. In endurance athletes, a severe clinical manifestation with a plasma sodium concentration of<130 mmol/L is present in only ~1.5% of all cases [53]. A rapid decrease in plasma osmolality leads to a water in ux across the blood-brain barrier and results in a cerebral edema. During prolonged endurance performance (e.g., longer than 10 h), symptoms of hyponatremia may be di erent after ve to six hours, since hyponatremia can develop fast or slow [12,13,87]. Table summarizes the possible symptoms of hyponatremia: malaise, mild headache, vomiting, and fatigue appear in the early stages of EAH [9,12,53]. These symptoms are very non-speci c and can also occur with other problems such as fatigue, indigestion, dehydration, or overheating. The clinical appearance of hyponatremia may look like heat stroke, hypoglycemia, stress-related collapse, muscle cramps [88], or even altitude sickness [89]. The plasma sodium concentration should then have fallen to values <125 mmol/L. Symptoms at a plasma sodium concentration>125 mmol/L are rare. In some cases, vomiting is the only clinical sign that distinguishes hyponatremia from exercise-induced collapse [90]. Table 1.Symptoms of hyponatremia. Fast Development (Brain Edema) Headache Nausea Vomiting Dizziness Weakness Adynamia Fatigue Tremor Epileptic seizures Muscle cramps Increase in body weight Swelling of hands and feet Somnolence Coma Slow to chronic development Fatigue Disorientation Lethargy Confusion Inappetence Change of personality Gait disturbance Attention de cit disorder Hyponatremia symptoms are non-speci c, vary between patients, and may be confused for other conditions. Symptomatic EAH can occur

This narrative review presents findings on EAH related to various factors in endurance sports.