- Email: [email protected]
Exercise-associated electrolyte disorders
Accepted Manuscript Exercise-associated electrolyte disorders Tamara Hew-Butler, Valerie G. Smith-Hale, Joshua Sabou PII:
S2451-9650(19)30038-9
DOI:
https://doi.org/10.1016/j.coemr.2019.06.014
Reference:
COEMR 89
To appear in:
Current Opinion in Endocrine and Metabolic Research
Received Date: 13 June 2019 Accepted Date: 25 June 2019
Please cite this article as: Hew-Butler T, Smith-Hale VG, Sabou J, Exercise-associated electrolyte disorders, Current Opinion in Endocrine and Metabolic Research, https://doi.org/10.1016/ j.coemr.2019.06.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Exercise-associated electrolyte disorders
Abstract word count: 120 Text word count: 1962
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Running head: exercise and electrolytes Keywords: hyponatremia, hypernatremia, electrolyte imbalance
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Tamara Hew-Butler, Valerie G Smith-Hale, Joshua Sabou, Kinesiology, Health and Sport Science Division, Wayne State University, Detroit, MI
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no conflicts of interest.
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Corresponding author: Tamara Hew-Butler DPM, PhD, FACSM Associate Professor, Exercise and Sport Science College of Education, Wayne State University 2152 Faculty Administration Building 656 West Kirby, Detroit, MI 48202 Tel: 313-577-8130 Email: [email protected]
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Abstract: Clinically significant derangements in plasma electrolytes rarely occur outside of excessive exercise and/or extreme dietary habits. Overzealous hydration facilitates exercise-associated disorders of sodium concentration ([Na+]), as robust overhydration may induce hyponatremia while severe fluid restriction may cause hypernatremia. Excessive exercise may facilitate plasma potassium ([K+]) disorders, as prolonged endurance exercise may induce hypokalemia (profuse sweat losses) while unaccustomed high-intensity training may cause hyperkalemia (rhabdomyolysis). Restrictive diets coupled with extensive exercise may also lead to low (hypo) plasma levels of magnesium ([Mg++]), calcium ([Ca++]), or phosphate ([P-]) whereas fanatical supplementation may trigger high (hyper) blood levels of [Mg++], [Ca++], or [P-]. Thus, most exercise-associated electrolyte disorders in healthy individuals volitionally occur from improper training and/or unhealthy dietary habits and largely preventable.
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Graphical abstract:
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1.0 Introduction: The homeostatic perturbations associated with exercise rarely result in life-threatening electrolyte derangements in otherwise healthy individuals. One notable exception, however, are exercise-associated disturbances in plasma sodium concentration ([Na+]) which are largely associated with disorders of water balance. Sodium is the main extracellular fluid (ECF) cation, which drives plasma tonicity, and associated changes in cellular size. Although rare, fatalities from both hyponatremia (plasma [Na+] < 135mmol/L) [1] and hypernatremia (plasma [Na+] >145mmol/L) [2,3] have occurred. Thus, measurement of plasma [Na+] is highly encouraged in the initial assessment of collapsed athletes particularly in those not responding favorably to conservative therapies.
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Far less common (and benign) are exercise-associated derangements in plasma potassium concentration ([K+]). Potassium is the main intracellular fluid (ICF) cation, with hypokalemia (plasma [K+] < 3.5mmol/L) most commonly seen after prolonged endurance exercise [4] while hyperkalemia (plasma [K+] >5.0mmol/L) is generally seen following high intensity exercise and skeletal muscle damage [5] . Derangements in plasma [K+] may result in muscle cramps and cardiac arrhythmias [6,7].
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Exercise-associated disorders of plasma magnesium ([Mg++]), calcium ([Ca++]), chloride ([Cl-]), and phosphorus ([P-]) mainly occur in response to other pathophysiological events (i.e. gastrointestinal losses, malnutrition, supplement abuse). Derangements in these electrolytes are rarely a direct cause of acute symptomatology in healthy individuals on a normal diet. A few case reports will be highlighted, as the exercise literature is sparse in this domain.
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This mini-review will highlight the most common exercise-associated electrolyte disorders with an emphasis on the growing incidence of dysnatremia in sport. Clinicians should be aware of the possibility for acute and chronic derangements in sodium, and to a lesser degree potassium, when dealing with patients who participate in robust physical activity. Most (if not all) exerciseassociated electrolyte disorders are preventable with proper hydration and training advice.
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2.0 Disorders of sodium balance: 2.1 Hyponatremia Exercise-associated hyponatremia (EAH) is a variant of clinical hyponatremia that is specifically induced by exercise. Hyponatremia is a biochemical diagnosis confirmed by a plasma [Na+] that is below the normal reference range for the laboratory performing the test [1]. In most cases, this biochemical threshold is <135mmol/L [1]. EAH is predominantly caused by overdrinking during exercise [1] coupled with fluid retention from exercise-induced non-osmotic arginine vasopressin (AVP) stimulation [1,8]. EAH can be asymptomatic or symptomatic, with fatal hyponatremic encephalopathy documented in marathon runners, ironman triathletes, cyclists, hikers, a canoeist, American football players and military personnel [1]. Although the role of nonosmotic AVP secretion in the pathogenesis of EAH is clear [1,8,9], the contributions of oxytocin (OT) [8] and interleukin-6 [10] in fluid retention, as well as brain natriuretic peptide (BNP)[8] in urinary sodium losses, remain unclear. Asymptomatic EAH is primarily identified through research studies, involving convenient samples of consenting athletes tested for investigative purposes [1]. The incidence of asymptomatic EAH ranges from 0% [11] to 33% of rugby players following an 80-minute competition [12], 51% of ultramarathoners tested after the race [13], 67% of ultramarathon runners tested during the race [14], and 70% of elite male rowers tested during training camp [15]. The clinical significance of asymptomatic hyponatremia is debated, especially with regards to exercise-associated bone loss [16] and rhabdomyolysis [14] and requires further study.
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In the largest sample of endurance athletes (2135 race finishers) tested post-race, only 6% of race finishers were hyponatremic while 13% of finishers were hypernatremic (Figure 1) [17]. However, EAH is associated with higher morbidity and mortality compared with hypernatremia [1]. In the clinical (non-exercise) setting, hyponatremia is the most common electrolyte abnormality seen in ~15% of older community subjects [18] and 24.6% of patients presenting to the Emergency Department [19]. The non-exercise variant of hyponatremia is also associated with an increase in morbidity and mortality as documented in intensive care units [20], critically ill patients [21] and patients undergoing major surgery [22]. This parallel between the exercise and non-exercise variants of hyponatremia underscores the critical importance of correcting low blood sodium levels in asymptomatic and symptomatic individuals.
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Symptomatic EAH is characterized by a history of overdrinking during exercise, with bloating and weight gain [1]. Nausea with or without the vomiting are common along with a severe headache. EAH becomes a medical emergency when frothy sputum, pulmonary edema, altered mental status, seizures, and coma appear [1]. Once a diagnosis of hyponatremia is confirmed by a blood test, emergent treatment with hypertonic saline is required. An intravenous (IV) bolus of 100mL of 3% saline repeated every 10 minutes until symptom resolution is recommended [1]. If tolerated, oral administration of hypertonic saline solutions (i.e. 4 bouillon cubes in 125mL water) are also effective [23,24]. No case of osmotic demyelination has occurred from this medically emergent treatment, as EAH is an acute, rather than chronic, hyponatremia and requires a rapid reversal of cerebral swelling to prevent brainstem herniation [1]. In no instance should hypotonic fluids be administered to a person with documented EAH [1].
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EAH is prevented by limiting excessive fluid intake before, during, and immediately following exercise [1]. Drinking according to thirst has been shown to prevent both the hyponatremia and hypernatremia of exercise [1]. Figure 1 summarizes the incidence, risk factors, signs and symptoms, and treatment of both exercise-associated hyponatremia and hypernatremia.
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2.2 Hypernatremia: Exercise-associated hypernatremia is biochemically defined by a plasma [Na+] >145mmol/L and characterized by cellular dehydration secondary to extracellular hypertonicity [25]. The hypernatremia of exercise is largely due to under-replaced hypotonic sweat fluid losses that can be asymptomatic [26-28], symptomatic, [29-32], or fatal [2,3]. Once diagnosed, prompt administration of hypotonic fluids reverses this electrolyte derangement.
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Asymptomatic hypernatremia may transiently appear immediately following short (<2 minutes) bouts of maximal (>95% VO2 max) exercise such as cycling [33], running [34], or swimming [35]. This phenomenon is due to plasma volume contraction [36] whereas plasma water is shifted out of the vascular space faster than solutes [33]. A return to normonatremia occurs following the cessation of maximal exercise-induced hydrostatic forces. Hypernatremia without clinical symptomatology is also commonly seen in the fastest finishers of endurance races, who rarely drink during exercise and subsequently lose the most body water/weight during competition [26,28]. Symptomatic hypernatremia is commonly seen in collapsed marathon runners [29,30,32]. Hypernatremic runners treated within the medical tent of a 90-km footrace reported significantly more vomiting than collapsed normonatremic runners in one particular study, whereas 58% of these collapsed runners were hypernatremic [30]. This association suggests that hypernatremia may be augmented by gastrointestinal water losses coupled with inadequate fluid intake (due to an inability to tolerate oral fluids) during prolonged running [30]. Dysnatremia, in general, delays
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the recovery and subsequent discharge from marathon medical tents [30], similar to the increased morbidity, mortality, complication rate, and length of stay seen in community [18] and clinical cohorts [19,37].
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Wrestlers and mixed martial artists (MMA) represent a specific athletic population at highest risk for morbidity [31] and mortality [2,3] from dehydration-induced hypernatremia due to extreme “weight-cutting” practices. Heightened clinical suspicion for severe hypernatremic dehydration include: ~10% body weight losses over a short period of time, severe food and fluid restriction, vigorous exercise in hot conditions, and use of impermeable suits to maximize sweat water loss [2,3,31]. One MMA athlete developed a plasma [Na+] of 148mmol/L (and acute kidney injury) following a 20-hour weight cutting routine which consisted of no food or fluid intake coupled with continuous cycles of sweating using nine hot-water immersion baths plus nine Egyptian Mummy towel wraps (20-minutes each) [31]. Such extreme measures underscore the exceptional difficulty necessary to induce hypernatremic dehydration popularized in combat sports with weight classifications.
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Hypernatremic dehydration during exercise can be prevented and treated with hypotonic fluids, freely available, with instructions to drink when thirsty.
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3.0 Disorders of potassium balance 3.1 Hypokalemia: Potassium is the body’s main intracellular cation, with roughly 2% of ions located within the ECF [38]. Hypokalemia is biochemically defined by a plasma [K+] below 3.5mmol/L and is often asymptomatic [5] or associated with muscular weakness [4]. One study reported a 39% incidence of hypokalemia at rest, which increased to 60% following exercise, in a cohort of 116 long-distance runners [4]. This incidence is higher than previously reported for hospitalized patients (21%) and outpatients (2-3%) [5], leading one researcher to speculate that prolonged endurance training causes a progressive hypokalemia [4] of unknown clinical significance. Under-replaced sweat K+ losses from prolonged endurance exercise coupled with an upregulation of Na+/K+-ATPase activity within skeletal muscle likely contribute to asymptomatic or transient hypokalemia following exercise [39].
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Hypokalemia-induced arrythmias are uncommon in individuals without underlying heart disease [5]. However, two 18-year-old male cyclists developed severe hypokalemia (plasma [K+] of 2.4 and 2.6mmol/L) with flattened T-waves and U-waves on the electrocardiogram (ECG) in addition to nausea, vomiting, paresthesia, and intense muscle weakness [6]. These cyclists consumed ~18 cups of caffeinated beverages daily for six days, in order to enhance performance [6]. Caffeine antagonizes adenosine-induced activation of the K+-ATP channel, which triggers intracellular K+ retention and low extracellular [K+] [6]. In healthy individuals, the prevention and treatment of exercise-associated hypokalemia is adequate replenishment with potassium-rich foods (fruits and vegetables) following long duration exercise (especially in the heat). 3.2 Hyperkalemia: A plasma [K+] above 5.0mmol/L, confirms a biochemical diagnosis of hyperkalemia. Exerciseassociated hyperkalemia, as a clinically significant isolated entity, is uncommon. The reported incidence is also low in hospitalized patients (10%) and outpatients (1%) [5]. Because 70-80% of K+ ions are located within skeletal muscle cells [38,40], maximal exercise [39,41] often elicits a significant (6-8mmol/L) increase in plasma [K+]. This transient ECF K+ efflux from contracting musculature is followed by catecholamine-induced Na+/K+-ATPase activity, which actively
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pumps K+ back into the ICF [39,41,42]. This exercise-induced stimulation of Na+/K+-ATPase subsequently induces a “rebound hypokalemia”, which is enhanced by regular training [39].
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Extreme or unaccustomed exercise, however, may induce skeletal muscle cell rupture (rhabdomyolysis). Because skeletal muscle represents ~40% of total body mass [38,40], even a 1% liberation of intramuscular K+ into the ECF may induce significant hyperkalemia [6,14]. This hyperkalemia is often exacerbated by myoglobin-induced acute renal injury, which is also a consequence of exertional rhabdomyolysis [43].
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However, hyperkalemia is often asymptomatic but may be associated with muscle weakness, paresthesias, and cardiac arrhythmias [5]. Peaked T-waves on an ECG are characteristic of hyperkalemia, due to rapid repolarization of cardiac myocytes from increased cardiac K+ conductance [6]. As such, peaked T-waves contributed to the diagnosis of hyperkalemia in a 58year-old male with a history of hypertension (on ramipril 5mg/day) who suddenly began a vigorous exercise program including use of a commercial supplement [7]. Thus, the prevention and treatment of exercise-associated hyperkalemia involves proper training and supplement use.
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4.0 Other electrolyte disorders Exercise-associated disturbances in [Mg++], [Ca++], [Cl-] and [P-] are exceptionally rare and often follow severe gastrointestinal losses, malnutrition, or overzealous supplement use. Magnesium deficiency, presenting with carpopedal cramps and reversed by magnesium supplementation, was documented in a 17-year-old military recruit who did not eat vegetables [44] and a 24-yearold female tennis player who exercised ~10 hours per day [45,46]. One case of hypercalcemia with nephrocalcinosis was documented in a 23-year-old bodybuilder who injected paraffin oil into his muscles over a 3-year period (for muscle contouring) [47]. Conversely, hypocalcemia was documented in a 51-year-old female during a 15km hike following a thyroidectomy [48]. Imbalances of chloride generally follow metabolic acidosis (hyperchloremia), alkalosis (hypochloremia), or sodium/potassium derangements [49] while hypophosphatemia may occur following severe weight loss [50]. Thus, exercise-associated derangements in in [Mg++], [Ca++], [Cl-] and [P-] can be prevented by avoiding excessive exercise, restrictive diets, and/or supplement abuse.
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In conclusion, exercise-associated electrolyte disorders are uncommon and generally result from improper hydration advice (sodium imbalance), improper training advice (potassium imbalance), profuse gastrointestinal losses (chloride imbalance), malnutrition, or supplement abuse (magnesium, calcium, and phosphorus imbalance). Plasma [Na+] and [K+] should be measured in all collapsed athletes not responding to conservative care. Prevention of electrolyte abnormalities during exercise follows proper hydration, diet and training advice.
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Figure 1: Summary of the incidence, risk factors, signs and symptoms, and treatment of hyponatremia and hypernatremia which are mainly due to overhydration and underhydration, respectively.
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This is a critical and comprehnsive review of exercise-associated hyponatremia by a panel of world experts on the topic 2. Centers for Disease Control. Hyperthermia and dehydration-related deaths associated with intentional rapid weight loss in three collegiate wrestlers--North Carolina, Wisconsin, and Michigan, November-December 1997. MMWR Morb Mortal Wkly Rep 1998; 47(6):105-108.
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3. Lee S, Kim W, Park SK, et al. A case of acute renal failure, rhabdomyolysis and disseminated intravascular coagulation associated with severe exercise-induced hypernatremic dehydration. Clin Nephrol 2004; 62(5):401-403.
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8. Hew-Butler T, Hoffman MD, Stuempfle KJ, et al. Changes in Copeptin and Bioactive Vasopressin in Runners With and Without Hyponatremia. Clin.J.Sport Med 2011; 21: 211-217.
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9. Siegel AJ, Verbalis JG, Clement S et al. Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion. Am J Med 2007; 120(5):461.e11-467.e17. 10. Siegel AJ. Exercise-associated hyponatremia: role of cytokines. Am J Med 2006; 119 (7 Suppl 1):S74-S78. 11. Reid SA, King MJ. Serum biochemistry and morbidity among runners presenting for medical care after an Australian mountain ultramarathon. Clin J Sport Med 2007; 17(4):307-310. 12. Jones BL, O'Hara JP, Till K, et al. Dehydration and hyponatremia in professional rugby union players: a cohort study observing english premiership rugby union players during match play, field, and gym training in cool environmental conditions. J Strength Cond Res 2015; 29(1):107-115.
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13. Lebus DK, Casazza GA, Hoffman MD, et al. Can changes in body mass and total body water accurately predict hyponatremia following a 161-km running race? Clin J Sport Med 2010; 20(3):193-199.
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14. Cairns RS, Hew-Butler T. Proof of concept: hypovolemic hyponatremia may precede and augment creatine kinase elevations during an ultramarathon. Eur J Appl Physiol 2016; 116(3):647-655. 15. Mayer CU, Treff G, Fenske WK, et al. High Incidence of Hyponatremia in Rowers during a Four-Week Training Camp. Am J Med 2015; 128(10):1144-51. 16. Hew-Butler T, Stuempfle KJ, Hoffman MD. Bone: an acute buffer of plasma sodium during exhaustive exercise? Horm Metab Res 2013; 45(10):697-700.
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**17. Noakes TD, Sharwood K, Speedy D et al. Three independent biological mechanisms cause exercise-associated hyponatremia: evidence from 2,135 weighed competitive athletic performances. Proc Natl Acad Sci U S A 2005; 102(51):1855018555. This paper represents the largest analyses of post-race natremia status collected from various field studies, highlighting the proportion of hyponatremia and hypernatremia in endurance athletes with an emphasis on the pathogenesis of fluid overload. 18. Liamis G, Rodenburg EM, Hofman A, et al. Electrolyte disorders in community subjects: prevalence and risk factors. Am J Med 2013; 126(3):256-263.
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19. Tazmini K, Nymo SH, Louch WE, et al. Electrolyte imbalances in an unselected population in an emergency department: A retrospective cohort study. PLoS One 2019; 14(4):e0215673. 20. Funk GC, Lindner G, Druml W et al. Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med 2010; 36(2):304-311.
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21. Darmon M, Pichon M, Schwebel C et al. Influence of early dysnatremia correction on survival of critically ill patients. Shock 2014; 41(5):394-399.
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22. Cecconi M, Hochrieser H, Chew M et al. Preoperative abnormalities in serum sodium concentrations are associated with higher in-hospital mortality in patients undergoing major surgery. Br J Anaesth 2016; 116(1):63-69. 23. Siegel AJ, d'Hemecourt P, Adner MM, et al. Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy. Am J Clin Pathol 2009; 132(3):336-340. 24. Bridges E, Altherwi T, Correa JA, et al. Is Oral Hypertonic Saline effective in Reversing MIld to Moderate Acute Hyponatremia? Clin J Sport Med 2018; [Epub ahead of print]. 25. Mange K, Matsuura D, Cizman B et al. Language guiding therapy: the case of dehydration versus volume depletion. Ann Intern Med 1997; 127(9):848-853.
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26. Hew-Butler T, Verbalis JG, Noakes TD. Updated Fluid Recommendation: Position Statement from the International Marathon Medical Directors Association (IMMDA). Clin J Sport Med 2006; 16(4):283-92.
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27. Krabak BJ, Lipman GS, Waite BL, et al. Exercise-Associated Hyponatremia, Hypernatremia, and Hydration Status in Multistage Ultramarathons. Wilderness Environ Med 2017; 28(4):291-298. 28. Au-Yeung KL, Wu WC, Yau WH, et al. A study of serum sodium level among Hong Kong runners. Clin J Sport Med 2010; 20(6):482-487. 29. Hew-Butler T, Sharwood K, Boulter J et al. Dysnatremia predicts a delayed recovery in collapsed ultramarathon runners. Clin J Sport Med 2007; 17:289-296.
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30. Hew-Butler T, Boulter J, Godlonton J, et al. Hypernatremia and Intravenous Fluid Resuscitation in Collapsed Ultramarathon Runners. Clin J Sport Med 2008; 18(3):273278.
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31. Kasper AM, Crighton B, Langan-Evans C et al. Case Study: Extreme Weight Making Causes Relative Energy Deficiency, Dehydration, and Acute Kidney Injury in a Male Mixed Martial Arts Athlete. Int J Sport Nutr Exerc Metab 2019; 29(3):331-338. 32. Siegel AJ, Januzzi J, Sluss P et al. Cardiac biomarkers, electrolytes, and other analytes in collapsed marathon runners: implications for the evaluation of runners following competition. Am J Clin Pathol 2008; 129(6):948-951.
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33. Nose H, Takamata A, Mack GW et al. Water and electrolyte balance in the vascular space during graded exercise in humans. J Appl Physiol 1991; 70(6):2757-2762. 34. Wilkerson JE, Horvath SM, Gutin B, et al. Plasma electrolyte content and concentration during treadmill exercise in humans. J Appl Physiol 1982; 53(6):1529-1539.
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37. Oude Lansink-Hartgring A, Hessels L, Weigel J et al. Long-term changes in dysnatremia incidence in the ICU: a shift from hyponatremia to hypernatremia. Ann Intensive Care 2016; 6(1):22. 38. Hoskote SS, Joshi SR, Ghosh AK. Disorders of potassium homeostasis: pathophysiology and management. J Assoc Physicians India 2008; 56:685-693. 39. Atanasovska T, Petersen AC, Rouffet DM, et al. Plasma K+ dynamics and implications during and following intense rowing exercise. J Appl Physiol (1985 ) 2014; 117(1):60-68. 40. Overgaard-Steensen C, Stodkilde-Jorgensen H, Larsson A et al. Regional differences in osmotic behavior in brain during acute hyponatremia: an in vivo MRI-study of brain and
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skeletal muscle in pigs. Am J Physiol Regul Integr Comp Physiol 2010; 299(2):R521R532. 41. Medbo JI, Sejersted OM. Plasma potassium changes with high intensity exercise. J Physiol 1990; 421:105-122.
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42. McKenna MJ, Bangsbo J, Renaud JM. Muscle K+, Na+, and Cl disturbances and Na+K+ pump inactivation: implications for fatigue. J Appl Physiol (1985 ) 2008; 104(1):288295. 43. Boulter J, Noakes TD, Hew-Butler T. Acute renal failure in four Comrades Marathon runners ingesting the same electrolyte supplement: coincidence or causation? S Afr Med J 2011; 101(12):876-878.
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45. Liu L, Borowski G, Rose LI. Hypomagnesia in a tennis player. Phys Sportsmed 1983; 11(5):79-80. *46. Bohl CH, Volpe SL. Magnesium and exercise. Crit Rev Food Sci Nutr 2002; 42(6):533563. This is the most comprehensive review of magnesium and exercise available, to date.
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47. Gyldenlove M, Rorvig S, Skov L, et al. Severe hypercalcaemia, nephrocalcinosis, and multiple paraffinomas caused by paraffin oil injections in a young bodybuilder. Lancet 2014; 383(9934):2098. 48. Perez-Ruiz M, Dominguez-Fernandez R. Risk of acute hypocalcemia in a patient after total thyroidectomy and during exercise: A case report. Semergen 2018; 44(4):285-286.
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*49. Berend K, van Hulsteijn LH, Gans RO. Chloride: the queen of electrolytes? Eur J Intern Med 2012; 23(3):203-211.
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S2451-9650(19)30038-9
DOI:
https://doi.org/10.1016/j.coemr.2019.06.014
Reference:
COEMR 89
To appear in:
Current Opinion in Endocrine and Metabolic Research
Received Date: 13 June 2019 Accepted Date: 25 June 2019
Please cite this article as: Hew-Butler T, Smith-Hale VG, Sabou J, Exercise-associated electrolyte disorders, Current Opinion in Endocrine and Metabolic Research, https://doi.org/10.1016/ j.coemr.2019.06.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Exercise-associated electrolyte disorders
Abstract word count: 120 Text word count: 1962
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Running head: exercise and electrolytes Keywords: hyponatremia, hypernatremia, electrolyte imbalance
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Tamara Hew-Butler, Valerie G Smith-Hale, Joshua Sabou, Kinesiology, Health and Sport Science Division, Wayne State University, Detroit, MI
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no conflicts of interest.
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Corresponding author: Tamara Hew-Butler DPM, PhD, FACSM Associate Professor, Exercise and Sport Science College of Education, Wayne State University 2152 Faculty Administration Building 656 West Kirby, Detroit, MI 48202 Tel: 313-577-8130 Email: [email protected]
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Abstract: Clinically significant derangements in plasma electrolytes rarely occur outside of excessive exercise and/or extreme dietary habits. Overzealous hydration facilitates exercise-associated disorders of sodium concentration ([Na+]), as robust overhydration may induce hyponatremia while severe fluid restriction may cause hypernatremia. Excessive exercise may facilitate plasma potassium ([K+]) disorders, as prolonged endurance exercise may induce hypokalemia (profuse sweat losses) while unaccustomed high-intensity training may cause hyperkalemia (rhabdomyolysis). Restrictive diets coupled with extensive exercise may also lead to low (hypo) plasma levels of magnesium ([Mg++]), calcium ([Ca++]), or phosphate ([P-]) whereas fanatical supplementation may trigger high (hyper) blood levels of [Mg++], [Ca++], or [P-]. Thus, most exercise-associated electrolyte disorders in healthy individuals volitionally occur from improper training and/or unhealthy dietary habits and largely preventable.
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Graphical abstract:
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1.0 Introduction: The homeostatic perturbations associated with exercise rarely result in life-threatening electrolyte derangements in otherwise healthy individuals. One notable exception, however, are exercise-associated disturbances in plasma sodium concentration ([Na+]) which are largely associated with disorders of water balance. Sodium is the main extracellular fluid (ECF) cation, which drives plasma tonicity, and associated changes in cellular size. Although rare, fatalities from both hyponatremia (plasma [Na+] < 135mmol/L) [1] and hypernatremia (plasma [Na+] >145mmol/L) [2,3] have occurred. Thus, measurement of plasma [Na+] is highly encouraged in the initial assessment of collapsed athletes particularly in those not responding favorably to conservative therapies.
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Far less common (and benign) are exercise-associated derangements in plasma potassium concentration ([K+]). Potassium is the main intracellular fluid (ICF) cation, with hypokalemia (plasma [K+] < 3.5mmol/L) most commonly seen after prolonged endurance exercise [4] while hyperkalemia (plasma [K+] >5.0mmol/L) is generally seen following high intensity exercise and skeletal muscle damage [5] . Derangements in plasma [K+] may result in muscle cramps and cardiac arrhythmias [6,7].
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Exercise-associated disorders of plasma magnesium ([Mg++]), calcium ([Ca++]), chloride ([Cl-]), and phosphorus ([P-]) mainly occur in response to other pathophysiological events (i.e. gastrointestinal losses, malnutrition, supplement abuse). Derangements in these electrolytes are rarely a direct cause of acute symptomatology in healthy individuals on a normal diet. A few case reports will be highlighted, as the exercise literature is sparse in this domain.
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This mini-review will highlight the most common exercise-associated electrolyte disorders with an emphasis on the growing incidence of dysnatremia in sport. Clinicians should be aware of the possibility for acute and chronic derangements in sodium, and to a lesser degree potassium, when dealing with patients who participate in robust physical activity. Most (if not all) exerciseassociated electrolyte disorders are preventable with proper hydration and training advice.
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2.0 Disorders of sodium balance: 2.1 Hyponatremia Exercise-associated hyponatremia (EAH) is a variant of clinical hyponatremia that is specifically induced by exercise. Hyponatremia is a biochemical diagnosis confirmed by a plasma [Na+] that is below the normal reference range for the laboratory performing the test [1]. In most cases, this biochemical threshold is <135mmol/L [1]. EAH is predominantly caused by overdrinking during exercise [1] coupled with fluid retention from exercise-induced non-osmotic arginine vasopressin (AVP) stimulation [1,8]. EAH can be asymptomatic or symptomatic, with fatal hyponatremic encephalopathy documented in marathon runners, ironman triathletes, cyclists, hikers, a canoeist, American football players and military personnel [1]. Although the role of nonosmotic AVP secretion in the pathogenesis of EAH is clear [1,8,9], the contributions of oxytocin (OT) [8] and interleukin-6 [10] in fluid retention, as well as brain natriuretic peptide (BNP)[8] in urinary sodium losses, remain unclear. Asymptomatic EAH is primarily identified through research studies, involving convenient samples of consenting athletes tested for investigative purposes [1]. The incidence of asymptomatic EAH ranges from 0% [11] to 33% of rugby players following an 80-minute competition [12], 51% of ultramarathoners tested after the race [13], 67% of ultramarathon runners tested during the race [14], and 70% of elite male rowers tested during training camp [15]. The clinical significance of asymptomatic hyponatremia is debated, especially with regards to exercise-associated bone loss [16] and rhabdomyolysis [14] and requires further study.
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In the largest sample of endurance athletes (2135 race finishers) tested post-race, only 6% of race finishers were hyponatremic while 13% of finishers were hypernatremic (Figure 1) [17]. However, EAH is associated with higher morbidity and mortality compared with hypernatremia [1]. In the clinical (non-exercise) setting, hyponatremia is the most common electrolyte abnormality seen in ~15% of older community subjects [18] and 24.6% of patients presenting to the Emergency Department [19]. The non-exercise variant of hyponatremia is also associated with an increase in morbidity and mortality as documented in intensive care units [20], critically ill patients [21] and patients undergoing major surgery [22]. This parallel between the exercise and non-exercise variants of hyponatremia underscores the critical importance of correcting low blood sodium levels in asymptomatic and symptomatic individuals.
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Symptomatic EAH is characterized by a history of overdrinking during exercise, with bloating and weight gain [1]. Nausea with or without the vomiting are common along with a severe headache. EAH becomes a medical emergency when frothy sputum, pulmonary edema, altered mental status, seizures, and coma appear [1]. Once a diagnosis of hyponatremia is confirmed by a blood test, emergent treatment with hypertonic saline is required. An intravenous (IV) bolus of 100mL of 3% saline repeated every 10 minutes until symptom resolution is recommended [1]. If tolerated, oral administration of hypertonic saline solutions (i.e. 4 bouillon cubes in 125mL water) are also effective [23,24]. No case of osmotic demyelination has occurred from this medically emergent treatment, as EAH is an acute, rather than chronic, hyponatremia and requires a rapid reversal of cerebral swelling to prevent brainstem herniation [1]. In no instance should hypotonic fluids be administered to a person with documented EAH [1].
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EAH is prevented by limiting excessive fluid intake before, during, and immediately following exercise [1]. Drinking according to thirst has been shown to prevent both the hyponatremia and hypernatremia of exercise [1]. Figure 1 summarizes the incidence, risk factors, signs and symptoms, and treatment of both exercise-associated hyponatremia and hypernatremia.
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2.2 Hypernatremia: Exercise-associated hypernatremia is biochemically defined by a plasma [Na+] >145mmol/L and characterized by cellular dehydration secondary to extracellular hypertonicity [25]. The hypernatremia of exercise is largely due to under-replaced hypotonic sweat fluid losses that can be asymptomatic [26-28], symptomatic, [29-32], or fatal [2,3]. Once diagnosed, prompt administration of hypotonic fluids reverses this electrolyte derangement.
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Asymptomatic hypernatremia may transiently appear immediately following short (<2 minutes) bouts of maximal (>95% VO2 max) exercise such as cycling [33], running [34], or swimming [35]. This phenomenon is due to plasma volume contraction [36] whereas plasma water is shifted out of the vascular space faster than solutes [33]. A return to normonatremia occurs following the cessation of maximal exercise-induced hydrostatic forces. Hypernatremia without clinical symptomatology is also commonly seen in the fastest finishers of endurance races, who rarely drink during exercise and subsequently lose the most body water/weight during competition [26,28]. Symptomatic hypernatremia is commonly seen in collapsed marathon runners [29,30,32]. Hypernatremic runners treated within the medical tent of a 90-km footrace reported significantly more vomiting than collapsed normonatremic runners in one particular study, whereas 58% of these collapsed runners were hypernatremic [30]. This association suggests that hypernatremia may be augmented by gastrointestinal water losses coupled with inadequate fluid intake (due to an inability to tolerate oral fluids) during prolonged running [30]. Dysnatremia, in general, delays
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the recovery and subsequent discharge from marathon medical tents [30], similar to the increased morbidity, mortality, complication rate, and length of stay seen in community [18] and clinical cohorts [19,37].
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Wrestlers and mixed martial artists (MMA) represent a specific athletic population at highest risk for morbidity [31] and mortality [2,3] from dehydration-induced hypernatremia due to extreme “weight-cutting” practices. Heightened clinical suspicion for severe hypernatremic dehydration include: ~10% body weight losses over a short period of time, severe food and fluid restriction, vigorous exercise in hot conditions, and use of impermeable suits to maximize sweat water loss [2,3,31]. One MMA athlete developed a plasma [Na+] of 148mmol/L (and acute kidney injury) following a 20-hour weight cutting routine which consisted of no food or fluid intake coupled with continuous cycles of sweating using nine hot-water immersion baths plus nine Egyptian Mummy towel wraps (20-minutes each) [31]. Such extreme measures underscore the exceptional difficulty necessary to induce hypernatremic dehydration popularized in combat sports with weight classifications.
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Hypernatremic dehydration during exercise can be prevented and treated with hypotonic fluids, freely available, with instructions to drink when thirsty.
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3.0 Disorders of potassium balance 3.1 Hypokalemia: Potassium is the body’s main intracellular cation, with roughly 2% of ions located within the ECF [38]. Hypokalemia is biochemically defined by a plasma [K+] below 3.5mmol/L and is often asymptomatic [5] or associated with muscular weakness [4]. One study reported a 39% incidence of hypokalemia at rest, which increased to 60% following exercise, in a cohort of 116 long-distance runners [4]. This incidence is higher than previously reported for hospitalized patients (21%) and outpatients (2-3%) [5], leading one researcher to speculate that prolonged endurance training causes a progressive hypokalemia [4] of unknown clinical significance. Under-replaced sweat K+ losses from prolonged endurance exercise coupled with an upregulation of Na+/K+-ATPase activity within skeletal muscle likely contribute to asymptomatic or transient hypokalemia following exercise [39].
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Hypokalemia-induced arrythmias are uncommon in individuals without underlying heart disease [5]. However, two 18-year-old male cyclists developed severe hypokalemia (plasma [K+] of 2.4 and 2.6mmol/L) with flattened T-waves and U-waves on the electrocardiogram (ECG) in addition to nausea, vomiting, paresthesia, and intense muscle weakness [6]. These cyclists consumed ~18 cups of caffeinated beverages daily for six days, in order to enhance performance [6]. Caffeine antagonizes adenosine-induced activation of the K+-ATP channel, which triggers intracellular K+ retention and low extracellular [K+] [6]. In healthy individuals, the prevention and treatment of exercise-associated hypokalemia is adequate replenishment with potassium-rich foods (fruits and vegetables) following long duration exercise (especially in the heat). 3.2 Hyperkalemia: A plasma [K+] above 5.0mmol/L, confirms a biochemical diagnosis of hyperkalemia. Exerciseassociated hyperkalemia, as a clinically significant isolated entity, is uncommon. The reported incidence is also low in hospitalized patients (10%) and outpatients (1%) [5]. Because 70-80% of K+ ions are located within skeletal muscle cells [38,40], maximal exercise [39,41] often elicits a significant (6-8mmol/L) increase in plasma [K+]. This transient ECF K+ efflux from contracting musculature is followed by catecholamine-induced Na+/K+-ATPase activity, which actively
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pumps K+ back into the ICF [39,41,42]. This exercise-induced stimulation of Na+/K+-ATPase subsequently induces a “rebound hypokalemia”, which is enhanced by regular training [39].
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Extreme or unaccustomed exercise, however, may induce skeletal muscle cell rupture (rhabdomyolysis). Because skeletal muscle represents ~40% of total body mass [38,40], even a 1% liberation of intramuscular K+ into the ECF may induce significant hyperkalemia [6,14]. This hyperkalemia is often exacerbated by myoglobin-induced acute renal injury, which is also a consequence of exertional rhabdomyolysis [43].
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However, hyperkalemia is often asymptomatic but may be associated with muscle weakness, paresthesias, and cardiac arrhythmias [5]. Peaked T-waves on an ECG are characteristic of hyperkalemia, due to rapid repolarization of cardiac myocytes from increased cardiac K+ conductance [6]. As such, peaked T-waves contributed to the diagnosis of hyperkalemia in a 58year-old male with a history of hypertension (on ramipril 5mg/day) who suddenly began a vigorous exercise program including use of a commercial supplement [7]. Thus, the prevention and treatment of exercise-associated hyperkalemia involves proper training and supplement use.
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4.0 Other electrolyte disorders Exercise-associated disturbances in [Mg++], [Ca++], [Cl-] and [P-] are exceptionally rare and often follow severe gastrointestinal losses, malnutrition, or overzealous supplement use. Magnesium deficiency, presenting with carpopedal cramps and reversed by magnesium supplementation, was documented in a 17-year-old military recruit who did not eat vegetables [44] and a 24-yearold female tennis player who exercised ~10 hours per day [45,46]. One case of hypercalcemia with nephrocalcinosis was documented in a 23-year-old bodybuilder who injected paraffin oil into his muscles over a 3-year period (for muscle contouring) [47]. Conversely, hypocalcemia was documented in a 51-year-old female during a 15km hike following a thyroidectomy [48]. Imbalances of chloride generally follow metabolic acidosis (hyperchloremia), alkalosis (hypochloremia), or sodium/potassium derangements [49] while hypophosphatemia may occur following severe weight loss [50]. Thus, exercise-associated derangements in in [Mg++], [Ca++], [Cl-] and [P-] can be prevented by avoiding excessive exercise, restrictive diets, and/or supplement abuse.
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In conclusion, exercise-associated electrolyte disorders are uncommon and generally result from improper hydration advice (sodium imbalance), improper training advice (potassium imbalance), profuse gastrointestinal losses (chloride imbalance), malnutrition, or supplement abuse (magnesium, calcium, and phosphorus imbalance). Plasma [Na+] and [K+] should be measured in all collapsed athletes not responding to conservative care. Prevention of electrolyte abnormalities during exercise follows proper hydration, diet and training advice.
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Figure 1: Summary of the incidence, risk factors, signs and symptoms, and treatment of hyponatremia and hypernatremia which are mainly due to overhydration and underhydration, respectively.
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