We are thrilled our case report (4) stimulated other investigators to reassess their exercise-associated hyponatremia (EAH) data. Hoffman et al. (6) argue that their previously reported case demonstrates identical biochemical trajectories during recovery, but claim that their patient was overhydrated because he gained 2.4% body mass after running 126 km. Furthermore, they argue that because their patient was not hypovolemic, they “cannot accept” that our cyclist demonstrates volume depletion because blood urea nitrogen (BUN) may be elevated from exercise. However, critical inspection of their highlighted case (6) provides evidence to support existence of a persistent hypovolemic stimulus in their runner (6), as argued below:
1) In the Hoffman et al. (6) case, a steady increase in serum sodium concentration ([Na+]) is demonstrated, despite exclusive and copious (20.2 L) treatment with normal (0.9%) and half-normal saline. This continued, upward trajectory of serum [Na+] strongly supports the presence of a protracted hypovolemic stimulus, according to two seminal papers (3,8):
The first seminal paper is the classic description of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion by Schwartz et al. (8) in 1957. This study demonstrates that normal saline administration to a patient with euvolemic hyponatremia does not alter serum [Na+] (8). In the absence of volume depletion (and renal sodium conservation), sustained nonosmotic arginine vasopressin (AVP) secretion would facilitate water reabsorption at the kidney while promptly excreting any sodium load (8). Only after a critical threshold of volume expansion is reached, will copious diuresis ensue (8). The absence of change in serum [Na+] with 0.9% saline administration was not demonstrated in the Hoffman et al. case. Furthermore, urinary output only surpassed fluid intake after normonatremia was achieved (6). Lastly, the Hoffman et al. patient left the hospital with a 6.6-kg weight gain (6.6 L positive fluid balance) (6). Patients with EAH from a euvolemic dilutional mechanism typically leave the hospital in negative fluid balance (weight loss), because spontaneous aquaresis of any fluid excess mediates the increase in serum [Na+] (9). Thus, the accuracy and utility of body weight as the sole surrogate measure of volemic status is questioned, while the efficacy of 0.9% saline in the treatment of hypovolemic-induced hyponatremia is supported.
The second seminal paper which suggests that the Hoffman et al. patient was hypovolemic is the 1987 study performed by Chung et al. (3). This study biochemically assessed volemic status in hyponatremic patients, originally classified as hypovolemic via clinical signs and symptoms. Hypovolemic hyponatremia was confirmed when a 0.9% saline infusion resulted in a >5 mmol·L−1 increase in blood [Na+] (“Responder”), which verified extracellular fluid (ECF) volume contraction (3). Patients, who exhibited little change in blood [Na+] after a 0.9% saline infusion (“nonresponders”), were deemed to have normal ECF volumes (euvolemia). The BUN of the hypovolemic “responders” also was significantly higher (~23 mg·dL−1) than euvolemic “nonresponders” (13 mg·dL−1) (3). Applying these biochemical criteria to the Hoffman et al. patient, both the serum [Na+] response to 0.9% saline administration (>20 mmol·L−1 increase) and initial BUN (22 mg·dL−1) would support ECF volume contraction at the time of admission. While Hoffman and Weiss argue that their patient’s elevated BUN was due to exercise-related changes, running for 26.7 h should increase BUN far in excess of the average value reported in non-exercising (hospitalized) patients (3). Hoffman and Weiss also dispute that the assessment of hypovolemia is largely a “clinical exercise” (no reference provided). However, the Chung et al. study confirms that clinical assessment of volemic status in hyponatremic patients has a 50% false-negative and 50% false-positive rate (3), minimizing the clinical utility of such assessment.
2) The Hoffman et al. runner began “regular sodium supplementation early in the race” with no mention of the actual amount. Later, it is stated that this runner finished a 161-km race, ingesting 341 mg (14 mmol) of sodium per hour. If the average sweat [Na+] in marathon runners is approximately 43 mmol·L−1 (7) and average sweat rate is approximately 1 L·h−1 (7), than the Hoffman et al. patient was under-replacing his sweat sodium losses if 14 mmol·h−1 represented “regular sodium supplementation.” If true, then the more likely explanation for being “very thirsty” resulted from physiologically appropriate hypovolemic-driven thirst stimulation, as described in salty sweaters (1). A robust nonosmotic hypovolemic stimulus to AVP would then trigger SIADH-mediated relative fluid overload with either customary or excessive hypotonic fluid intakes. This mechanistic sequence is similar to that seen with renal sodium losses in thiazide-diuretic associated hyponatremia (2). Thus, clinically significant sweat sodium loss and dilutional hyponatremia may coexist, with an under appreciation of the more subtle contributions of sweat sodium loss as a pathogenic (hypovolemic) stimulus to both fluid intake and AVP secretion.
Drs. Hoffman and Weiss “cannot accept” that our cyclist was hypovolemic because they interpreted the pathogenic stimulus differently in their own patient (with identical biochemical trajectories during recovery as our patient). EAH—like other pathophysiological variants of hyponatremia—exists as a spectrum between sodium loss with relative dilution and fluid overload with abnormal retention (5). Because evaporative sweat will always contain sodium, a variable amount of sodium loss must be acknowledged during exercise. The beauty and humility of science is that whatever paradigm we originally construct, will always evolve over time.
Tamara Hew-Butler, DPM, PhD, FACSM
School of Health Sciences
Oakland University, Rochester, MI
Exercise Science Oakland University
433 Meadow Brook Rd
Rochester, MI 48309
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