Exercise-Associated Hyponatremia in Marathon Runners

ise-associated hyponatremia (EAH) was rst described as water intoxication by Noakes et al. in 1985 and has become an important topic linked to several pathological conditions. However, despite progressive research, neurological disorders and even deaths due to hyponatremic encephalopathy continue to occur. Therefore, and due to the growing popularity of exercise-associated hyponatremia, this topic is of great importance for marathon runners and all professionals involved in runners' training (e.g., coaches, medical staff, nutritionists, and trainers). The present narrative review sought to evaluate the prevalence of EAH among marathon runners and to identify associated etiological and risk factors. Furthermore, the aim was to derive preventive and therapeutic action plans for marathon runners based on current evidence. The search was conducted on PubMed, Scopus and Google Scholar using a prede ned search algorithm by aggregating multiple terms (marathon run; exercise; sport; EAH; electrolyte disorder; uid balance; dehydration;

EAH among marathon runners and to identify associated etiological and risk factors. Furthermore, the aim was to derive preventive and therapeutic action plans for marathon runners based on current evidence. The search was conducted on PubMed, Scopus and Google Scholar using a prede ned search algorithm by aggregating multiple terms (marathon run; exercise; sport; EAH; electrolyte disorder; uid balance; dehydration; sodium concentration; hyponatremia). By this criterion, 135 articles were considered for the present study. Our results revealed that a complex interaction of different factors could cause EAH, which can be differentiated into event-related (high temperatures) and person-related (female sex) risk factors. There is variation in the reported prevalence of EAH, and two major studies indicated an incidence ranging from 7 to 15% for symptomatic and asymptomatic EAH. Athletes and coaches must be aware of EAH and its related problems and take appropriate measures for both training and competition. Coaches need to educate their athletes about the early symptoms of EAH to intervene at the earliest possible stage. In addition, individual hydration strategies need to be developed for the daily training routine, ideally in regard to sweat rate and salt losses via sweat. Future studies need to investigate the correlation between the risk factors of EAH and speci c subgroups of marathon runners. Keywords: marathon; runners; hyponatremia; sports medicine; exercise; risk factors; epidemiology; review 1. Introduction Exercise-associated hyponatremia (EAH) was rst described as water intoxication by Noakes et al. in 1985, who observed that athletes attending endurance events longer than seven hours developed hyponatremia. Since then, EAH has become an important topic in the eld of endurance sports [1,2]. However, despite progressive research, neurological disorders and even death, hyponatremic encephalopathy continues to occur [3,4]. Hyponatremia occurs when the blood sodium concentration drops below 135 mmol/L (129–134.9 mmol/L) and a severe degree of EAH is typically < 125 mmol/L, which are both associated with signs and symptoms [5,6] Causes of EAH are usually individual sweat loss [7], excessive intake of (low-sodium or hypotonic) uids [8], and possible hormonal J. Clin. Med.2022,11, 6775.

drops below 135 mmol/L (129–134.9 mmol/L) and a severe degree of EAH is typically < 125 mmol/L, which are both associated with signs and symptoms [5,6] Causes of EAH are usually individual sweat loss [7], excessive intake of (low-sodium or hypotonic) uids [8], and possible hormonal J. Clin. Med.2022,11, 6775.

J. Clin. Med.2022,11, 6775 2 of 22 imbalances [9,10], which occur more frequently at longer competitive distances [11]. How- ever, cases of hyponatremia can also be found outside extreme sports, for example, in team sports and rowing, shorter races, and yoga [12]. Causes of EAH are usually individual sweat loss, excessive uid intake, and possible hormonal imbalances, which occur more frequently over longer distances [13]. Among long-distance events, the marathon is one of the most symbolic races globally and has increased participation of all age groups and both sexes [14,15]. For instance, The TCS New York City Marathon, named after the major sponsor Tata Consultancy Services, is the premier event of New York Road Runners (NYRR) and the largest marathon in the world. More than 1.2 million people have nished the race since its rst occurrence in 1970 [15]. Although runners competing in marathon events are also vulnerable to EAH, the aetiology of electrolyte imbalances in marathon runners is not well-researched [16]. Recently, this topic gained the attention of different research groups. McCubbin et al. con- cluded from their recent study about modeling sodium requirements that targeted sodium replacements may be unnecessary in elite marathoners [17]. Moreover, Fitzpatrick et al. discovered in a 9-year retrospective study an association between a collapse and serum creatinine and electrolyte concentrations in marathon runners [18]. Furthermore, evidence synthesis regarding the risk factors for EAH is warranted. The recommended sodium intake for young adults is 1.5 g per day to cover sodium sweat loss in non-acclimated individuals [19]. As described above, there is recent evidence that sodium replacement in marathon runners may not have any effect [17]. However, an intake of excess sodium can lead to methemoglobinemia and hypotension; thus, supplementation should be ad- justed individually. Besides limited evidence regarding EAH for endurance athletes that has been exten- sively reviewed by Rosner et al. [9], little information is available on marathoners. The present narrative review sought to evaluate the available evidence, and prevalence of EAH among marathon runners and to identify associated etiological and risk factors. Fur- thermore, based on current evidence, the aim was

individually. Besides limited evidence regarding EAH for endurance athletes that has been exten- sively reviewed by Rosner et al. [9], little information is available on marathoners. The present narrative review sought to evaluate the available evidence, and prevalence of EAH among marathon runners and to identify associated etiological and risk factors. Fur- thermore, based on current evidence, the aim was to derive preventive and therapeutic action plans for marathon runners. This topic is also important for marathon runners and stakeholders (athletes, coaches, medical staff, and event organizations) to better delineate training habits and uid consumption during long-distance events. 2. Materials and Methods The study was designed as a narrative review. The relevant literature was searched using a prede ned search algorithm [20,21]. The selected articles were related to EAH in marathon runners and were published until June 2022. The search was conducted for sources of high-quality scienti c information using three of the most widely used information databases in the area of health and sports sciences—PubMed, Scopus, and Google Scholar [22]. A combination of medical subject headings (MeSH) and free-text words was employed in the search [23]. The keywords used in the search were: (“marathon run” OR “exercise” OR “sport”) AND (“EAH” OR “electrolyte disorder” OR “ uid balance” OR “dehydration” OR “sodium concentration” OR “hyponatremia”). We found an overall number of 432 articles in the database of PubMed (Clinical Trials and Randomized Clinical Trials), 220 papers on SCOPUS (title search), and 1070 sources within Google Scholar (title search). In the end, a total of 135 articles were considered. Animal studies,in vitrostudies, articles not published in German or English, and articles not related to the topic were excluded after the rst screening of the search results (title and abstract screening). 3. Results 3.1. The Role of Sodium in Exercise-Associated Hyponatremia In addition to making up the major cation of extracellular uid, sodium also serves as an osmotic determinant in determining the extracellular uid volume and plasma volume [24]. It is estimated that 95% of the total sodium in the human body is found in the extracellular uid [25]. Additionally, sodium

3. Results 3.1. The Role of Sodium in Exercise-Associated Hyponatremia In addition to making up the major cation of extracellular uid, sodium also serves as an osmotic determinant in determining the extracellular uid volume and plasma volume [24]. It is estimated that 95% of the total sodium in the human body is found in the extracellular uid [25]. Additionally, sodium plays an essential role in cell membrane

J. Clin. Med.2022,11, 6775 3 of 22 potential and the active transport of molecules across the cell membrane [26]. An active, energy-dependent process is required to maintain such a concentration gradient within the cell since sodium concentration inside the cell is typically less than 10% of that outside the cell membrane [27]. Clinically, dysnatremia is one of the most prevalent electrolyte disorders [28]. In the largest prospective study of dysnatremia conducted on athletes completing a marathon in Asia, no case of symptomatic dysnatremia was found. Runners with hypernatremia performed better, drank less water after the race and were better- prepared for the race [29]. In addition, Lüning et al. reported no case of hyponatremia, although the incidence of severe exercise-associated collapses was 1.53 per 1000 starting runners [30]. Dysnatremia can be divided into hypernatremia, meaning too much sodium in the extracellular space (>145 mmol/L), which results in water ef ux from the cell and leads to cell shrinkage, and hyponatremia referring to water in ux into the cell and results in cell swelling, which can become life-threatening. The term hyponatremia refers to a serum sodium level below 135 mmol/L [6,31]. In general, hyponatremia that occurs within 48 h is considered acute hyponatremia [32], a risk especially for patients in the postoperative period, patients with polydipsia and high physical activity [3,12]. The body has several regulatory mechanisms for pathological volume uctuations or osmolarity changes [33]. Firstly, the volume regulation runs through the carotid sinus [34]. This is a vessel wall dilation in the internal carotid artery with baroreceptors, which, when the set point is exceeded, results in activation of the vagotonic via glossopharyngeal-induced stimulation of the cardioinhibitory neurons of the medulla oblongata, which initiates a reduction in blood pressure [34]. The physiological interplay of different mechanisms is critical to maintain homeostasis even under extreme conditions such as a marathon run. Moreover, cardiac dilatation releases atrial natriuretic peptide (ANP), which reduces water retention in the body by balancing the osmotic gradient in the tubular system, thus lowering water balance [35]. The juxtaglomerular apparatus of the kidney regulates the release of renin [35].

physiological interplay of different mechanisms is critical to maintain homeostasis even under extreme conditions such as a marathon run. Moreover, cardiac dilatation releases atrial natriuretic peptide (ANP), which reduces water retention in the body by balancing the osmotic gradient in the tubular system, thus lowering water balance [35]. The juxtaglomerular apparatus of the kidney regulates the release of renin [35]. When arterial blood volume decreases, renin is released, and the renin–angiotensin–aldosterone system (RAAS) is activated [36]. This causes the release of aldosterone via angiotensin I and II [36]. Aldosterone causes increased sodium reabsorption in the body and is associated with water retention, which causes the blood volume to increase again [36]. Conversely, osmoregulation runs through the hypothalamus, which releases the primary antidiuretic hormone vasopressin (AVP) in response to hypovolemia or increased serum osmolarity, which—in turn—inhibits water excretion in the kidney [37]. In the context of exercise, both the mechanisms of uid intake and the hormonal regulation of vasopressin are responsible for maintaining serum sodium levels [38]. Hyponatremia can be categorized etiologically into four forms: pseudohyponatremia, euvolemic, hypovolemic, and hypervolemic hyponatremia (Table) [ 39]. In pseudohy- ponatremia, the plasma's lipid, protein, and glucose content are increased, whereas the sodium content of plasma water is within the normal range (135–145 mmol/L) [39]. In euvolemic hyponatremia, total body volume increases, whereas total sodium is normal (135–145 mmol/L) [40]. This may be triggered by water-retentive drugs, hypercortisolism or the syndrome of inadequate AVP secretion (SIAVP) [40]. In hypovolemic hyponatremia, the volume de ciency is triggered either through the kidneys by diuretic drugs, an adreno- cortical insuf ciency, or extrarenal by vomiting, diarrhea or pancreatitis [32]. In athletes, including marathoners, hypovolemic EAH is triggered when exercising >20 h in a hot environment and/or with higher sweat sodium losses [41]. The crucial form in this work is hypervolemic hyponatremia, which can result from the overconsumption of uids, likely in combination with non-osmotic stimulation of AVP secretion [42], and damage to the heart, liver, and kidney [43]. Due to the increased extracellular uid with a decreased serum sodium concentration, macroscopic edema formation can occur [44,45].

sweat sodium losses [41]. The crucial form in this work is hypervolemic hyponatremia, which can result from the overconsumption of uids, likely in combination with non-osmotic stimulation of AVP secretion [42], and damage to the heart, liver, and kidney [43]. Due to the increased extracellular uid with a decreased serum sodium concentration, macroscopic edema formation can occur [44,45].

J. Clin. Med.2022,11, 6775 4 of 22 Table 1.De nitions of different forms of hyponatremia [46,47]. EAH Form De nition Pseudohyponatremia Plasma's lipid, protein, and glucose content are increased, whereas the sodium content of plasma water is within the normal range (135–145 mmol/L) Euvolemic hyponatremia Total body volume increased, whereas total sodium is normal (135–145 mmol/L) Hypovolemic hyponatremia Total body volume decreased and serum sodium < 135 mmol/L Hypervolemic hyponatremia Total body volume increased and serum sodium < 135 mmol/L Biochemical hyponatremia Serum sodium ranges from 129 to 134.9 mmol/L Clinically signi cant hyponatremia Serum sodium < 129 mmol/L EAH can develop symptomatically or asymptomatically, mostly during or within 24 h after exercise or competition [3,42]. EAH represents an acute form of hypervolemic or hypo- volemic hyponatremia [3]. It has been con rmed that EAH is a serious condition associated with prolonged physical activity, and the complex pathophysiology of EAH is in uenced by several factors [48,49]. When excessive water or hypertonic beverages are consumed, diluted hyponatremia occurs due to an overabundance of total body water compared to total exchangeable sodium in the body [47]. It has been proposed by Noakes et al. that EAH occurs as a result of excessive hydration during exercise, retention of excess uid as the result of inadequate suppression of antidiuretic hormone production, and inactivation of osmotically circulating sodium or inability to mobilize osmotically inactive sodium from internal reserves [47]. EAH is also linked to rhabdomyolysis, platelet activation, cardiac problems, and renal failure [50–55]. The problem is identifying athletes with an inappropriate secretion of AVP or increased body water due to increased drinking [38]. It has been observed that some athletes achieved adequate diuresis to avoid gaining weight or, if they do gain weight, to maintain their serum sodium levels by mobilizing sodium from their internal stores as needed [38]. The diuresis that occurs in other athletes is inadequate, resulting in uid retention, the release of ANP, and the expression of EAH [38,56]. Despite the fact that EAH may occur during dehydration [57], the majority of the cases of EAH that are symptomatic are those

maintain their serum sodium levels by mobilizing sodium from their internal stores as needed [38]. The diuresis that occurs in other athletes is inadequate, resulting in uid retention, the release of ANP, and the expression of EAH [38,56]. Despite the fact that EAH may occur during dehydration [57], the majority of the cases of EAH that are symptomatic are those that are associated with overhydration when weight gain has occurred or inadequate weight loss has occurred during physical activity [9,47]. It should be highlighted that dehydration refers to the loss of body water from the interstitial and intracellular compartments associated with hypertonicity. Its clinical signs include altered skin turgor, dry oral mucous membranes, sunken eyes, inability to spit, and sensation of thirst [58]. EAH may also be caused by increased sympathetic nervous system activity, speci c genotypes, and the RAAS system, as well as an increase in the splanchnic perfusion [7,59]. There is still some uncertainty regarding the role that sweating plays in the pathogen- esis of EAH, as well as the possibility that urinary sodium loss may produce increased levels of atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP) in the physiology of EAH [42]. Nonspeci c symptoms include confusion, headache, lethargy, seizures, anorexia, and even coma [12,47,60]. Marathon running is highly popular with an increase in the number of races and participants, especially the number of master marathoners and female runners [14]. Many marathon runners suffer from gastrointestinal disorders due to dehydration and electrolyte imbalance [61–65]. The reduced blood volume during exercise may reduce blood ow to the intestinal region [22]. There is a possibility that this may interfere with the digestion system's normal ability to secrete/absorb nutrients [63,66]. A runner may also experi- ence gastrointestinal symptoms when consuming non-steroidal anti-in ammatory drugs (NSAIDs) [67]. EAH in marathon runners and its associated risk factors will be more deeply explored in the next section. As con rmed by Rüst et al., EAH tends to be a complication that occurs during longer distances [68]. This is also indicated in a study by Hiller, who

when consuming non-steroidal anti-in ammatory drugs (NSAIDs) [67]. EAH in marathon runners and its associated risk factors will be more deeply explored in the next section. As con rmed by Rüst et al., EAH tends to be a complication that occurs during longer distances [68]. This is also indicated in a study by Hiller, who

The review discusses the prevalence and risk factors of exercise-associated hyponatremia in marathon runners.