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Special Communication of a Case of Hypovolemic-Associated EAH: Lessons Learned During Recovery

Hew-Butler, Tamara DPM, PhD, FACSM1; Hamilton, Rus MBBS, M.Ed., M.Psych.Med2; Hamilton, Bridget RN, PhD3; Colesa, Zachary1

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Current Sports Medicine Reports: 7/8 2017 - Volume 16 - Issue 4 - p 289-293
doi: 10.1249/JSR.0000000000000380
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Abstract

Introduction

Almost all cases of severe exercise-associated hyponatremia (EAH) with encephalopathy have been associated with fluid overload and nonosmotic arginine vasopressin (AVP) secretion (19). Only in mathematical models (36), as well as in a handful of asymptomatic or mildly symptomatic cases demonstrating body weight loss (20,41), and/or urine sodium concentrations ([Na+]) below 30 mmol·L−1 plus elevated blood urea nitrogen (BUN) levels (8,41), has the depletional variant of EAH been documented. This may be partially attributed to conflicting definitions of dehydration (hypohydration) and volume depletion (hypovolemia) (27,31,35). While clinical dehydration refers to an overall decrease in total body water (intracellular dehydration), volume depletion refers to a loss of sodium from the extracellular space, which in turn causes a reduction in circulating plasma volume (extracellular fluid volume depletion) (27,31,35). Clinically significant decreases in extracellular sodium from the vascular space can thereby contribute to the development of EAH by causing a relative dilution of decreased circulating sodium ions (27) that is often indistinguishable from the syndrome of antidiuretic hormone secretion (SIADH) (7). The presence of hypovolemia, with either relatively modest or exuberant fluid overload, would confirm that sweat sodium losses contribute to pathogenesis of severe, symptomatic EAH. Currently, the contributions of sweat sodium losses to EAH pathophysiology remain contested (19,39) with biochemically relevant sodium losses hypothesized to result from the inappropriate inactivation of osmotically active stores during exercise (38).

The nonexercise (clinical) literature, however, supports the existence of symptomatic hyponatremia stimulated by volume depletion; mostly in patients who commence thiazide diuretic therapy in conjunction with customary modest to high fluid intakes (9,22,27,30). Modest urinary sodium losses of only 100 mmol have been shown to stimulate antidiuresis by triggering a hypovolemic stimulus to AVP secretion (14,16). A sustained reduction in plasma volume stimulates both thirst and AVP secretion (5,6), which maintains water within the vascular space (14,21,33). This baroreceptor-mediated response to volume depletion thereby induces a “hypovolemic variant” of SIADH (14,16,21,50).

We report on a case of severe symptomatic EAH, with biochemical evidence supporting volume depletion as the underlying stimulus to SIADH. Only one suspected case of depletional EAH with encephalopathy has been reported in an 85-yr-old hypertensive hiker, urged to drink beyond thirst (10). This case provides further evidence to support a volume depletion stimulus to EAH formation, which specifically targets athletes participating in unusually long events (8,20,41), held in relatively hot environments (8,20,41), and who manifest either enhanced sodium losses (i.e., diuretic use) (10) or hypothetical inactivation of circulating blood [Na+] into storage pools (38).

Case Presentation

Consent was obtained in this patient, who was a 65-yr-old man, 1.83-m tall with a body mass of 90 kg, (body mass index, 27.5 kg·m2). Medical history significant for hypertension, prostate cancer with transurethral resection of prostate (TURP), and gastroesophageal reflux disease (GERD). Medications included Tadalafil 5 mg and Telmisartan 80 mg/Amlodipine 10 mg (Twynsta 80/10™). Social history significant for moderate-heavy alcohol use (one bottle of wine per day). The patient had 20 yr of endurance cycling experience and successfully completed similar endurance rides over the previous 8 months, including a 1000-km event 3 wk prior. His training consisted of several hours of riding three times a week with long rides (200 km plus) every second weekend. All the long rides had been in mild weather, less than 25°C. He did not take salt or electrolyte supplements during training, but did eat fairly salty food (Vegemite sandwiches). The patient was participating in the Florida Sunshine 1200-km event, when he collapsed.

The patient had flown from Australia (winter) to the United States (summer), 2 d before the event. As such, he was not acclimatized to Florida’s high heat and humidity on the day of the ride (ambient temperature ranged between 25.5°C and 31.1°C, with 70% humidity). All riders started the event at 4:00 a.m. and traveled along the Florida Keys into a headwind. The patient completed the first 300 km of the event in approximately 16 h (~8 pm), consistent with previous times for that distance in similar events. Over the next 3 h and 30 min, however, the patient made little forward progress and at Fort Lauderdale (304 km from the start of the Florida event), he was found by a passing policeman suffering a tonic-clonic seizure. Emergency services transported him to the hospital where the initial serum sodium concentration was 112 mmol·L−1 (Fig. 1A) with elevated BUN (Fig. 2B). A diagnosis of EAH and dehydration was made.

Figure 1
Figure 1:
Biochemical trajectories of serum electrolytes such as [Na+], (A), [K+], (B), and [Ca++], (D) as well as serum CK (C) analyzed over the first 5 d of recovery in hospital. This patient’s biomarkers are denoted by closed circles connected by the thick line while the expected biochemical trajectories for dilutional hyponatremia (with minimal sodium loss) are denoted by a thin dotted line.
Figure 2
Figure 2:
Biochemical trajectories of individual markers of plasma volume such as serum total protein (A) and serum BUN (B), plus whole blood hemoglobin (C) and hematocrit (D) analyzed over the first 5 d of recovery in hospital. This patient’s biomarkers are denoted by closed circles connected by the thick line while the expected biochemical trajectories for dilutional hyponatremia (with minimal sodium loss) are denoted by a thin dotted line.

The patient subsequently went into respiratory arrest, which required assisted ventilation within the intensive care unit. The initial portable chest x-ray revealed a “clear chest” while a computed tomography (CT) angiogram of the chest revealed bibasilar dependent infiltrates, suggestive of atelectasis. A CT brain scan (also obtained on the day of admission, before return of normonatremia) revealed no masses, fluid collections, or hemorrhage but demonstrated cerebral edema that would explain the altered mental status, grand mal seizures, and respiratory arrest.

Once a diagnosis of hyponatremia was confirmed, the patient received 3% hypertonic saline until the return of normonatremia on day 2. He received a daily 1-L banana bag with multivitamins and 0.9% sodium chloride for rhabdomyolysis (creatine kinase peaked at day 4; Fig. 1C).

After the return of spontaneous respiration and consciousness (on day 3), the patient remained confused for several days and had no recall of the previous week. He was released from the hospital 8 d after admission, and his mental function gradually improved to normal over the ensuing 6 wk. However, he remains amnesic with regard to the events of the day and 3 d before the collapse.

Retrospective Analyses

Like many patients who develop EAH encephalopathy with retrograde amnesia, specific details regarding signs and symptoms, fluid and food intake, and urine output could only be partially reconstructed via intermittent observer reports. Thus, for a more quantifiable assessment of etiology, we chose to retrospectively plot the trajectories of select biomarkers during recovery (Figs. 1–3). This unique approach allowed us to assess the normalization of integrated body systems as a “reverse” window of insight into the pathophysiology of EAH. We categorized blood biomarkers into electrolytes (Fig. 1), plasma volume markers (Fig. 2), and indices of cellular volume (Fig. 3). We tracked the trajectories of these markers (roughly) every 24 h over 5 d, even though repeated measurements of select variables (like serum [Na+]) were obtained at shorter intervals.

Urine chemistries were only obtained on days 1 and 5. On day 1 (2 h after hyponatremia was confirmed and 3% saline was initiated), urine values were: osmolality, 583 mOsm·kg−1; sodium, 71 mmol·L−1; glucose, 300 mg·dL−1; ketones, 40 mg·dL−1; specific gravity, 1.018; blood, moderate; pH, 6.0; protein, trace; urobilinogen, <2 mg·dL−1; white blood cell, 1/hpf; and red blood cell, 10 to 25/hpf. On day 5, urine values obtained were all negative, with a urine specific gravity of 1.004 and pH of 6.5.

Figure 3
Figure 3:
Biochemical trajectories of individual markers of cellular volume found in whole blood, such as MCV (A) and MPV (B), are analyzed over the first 5 d of recovery in hospital. This patient’s biomarkers are denoted by closed circles connected by the thick line while the expected biochemical trajectories for dilutional hyponatremia (with minimal sodium loss) are denoted by a thin dotted line.

Discussion

The biochemical trajectories obtained during recovery suggest that this cyclist developed hypovolemic-induced severe hyponatremia with encephalopathy. This is in contrast with dilutional EAH due to water intoxication, which would be characterized by: 1) the dilution of all extracellular cations, which would all subsequently increase during recovery (2,18); 2) plasma volume expansion, which would subsequently contract (decrease) during recovery (2,15,23,45); and 3) increases in cellular size (4,40), which should decrease with the normalization of serum [Na+]. Additionally, serum creatine kinase (CK) levels normally peak 24 to 48 h after the initiation (8) or cessation (37) of exercise (Fig. 1C).

The presence of volume depletion was strongly supported in this patient by the downward trajectories of four clinical markers typically used to assess changes in plasma volume: total protein (Fig. 2A) (48), BUN (Fig. 2B) (33), hemoglobin, and hematocrit (Fig. 2C and D) (12). The collective decline in these four vascular constituents strongly support plasma volume expansion (from previous contraction) during the normalization of serum [Na+] from 112 to 135 mmol·L−1, from day 1 to day 2 (Fig. 1A). While hypovolemic-mediated hyponatremia has been documented in asymptomatic ultramarathon runners (8,8,41) and Ironman™ Triathletes (20), severe symptomatic EAH with encephalopathy and biochemical signs of volume depletion are highly unusual (10). Volume depletion in this patient was mainly confounded by: 1) higher sweat sodium concentrations due to nonacclimatization to the relative high heat and humidity and 2) alteration in normal racing dietary habits during the event (i.e., the Vegemite [493 mg sodium per Tbsp] he typically ingests during long rides was replaced by grape jelly [15 mg sodium per Tbsp] because his Vegemite was confiscated by customs officials at the airport). Of lesser impact, chronic alcohol intake is more commonly associated with the hypovolemic variant of hyponatremia (29), while angiotensin receptor/calcium channel blockers rarely cause hyponatremia (28).

Mechanistically, sustained plasma volume contraction from underreplaced sodium losses may provide a nonosmotic stimulus to both AVP secretion and thirst stimulation (5,6,14,16,27,33). This baroreceptor-mediated physiological response favors the preservation of plasma volume over the maintenance of plasma tonicity, when circulatory collapse is imminent (27). This uncommon variant of SIADH has been carefully documented in subjects made sodium deficient over 11 d (33). When coupled with modest overdrinking, however, hypovolemic-induced SIADH can lead to signs and symptoms of euvolemic SIADH (7,21,30). The latter scenario was confirmed in this patient on day 1, whereas urine osmolality (583 mOsm·kg−1) was above plasma osmolality (44) while urine [Na+] was above 30 mmol·L−1 (9). The pathophysiological difference between hypovolemic versus euvolemic SIADH likely resides in the robust volemic stimulus to AVP secretion.

The concomitant decrease in serum cations, potassium ([K+]) and calcium ([Ca++]), during the normalization of serum [Na+] (Fig. 1; days 1 to 2) also would support volume depletion as the primary pathogenic factor in the development of EAH. Dilutional EAH from an overhydration mechanism would dilute all extracellular (ECF) constituents proportionately. The resulting increase in serum [Na+] would be accompanied by concomitant increases in all other electrolytes (18,46), as excess free water is eventually excreted upon nonosmotic AVP suppression (50). In this patient, all extracellular fluid compartment osmoles (serum [K+], [Ca++], urea, total protein and glucose [data not shown]) decreased while serum [Na+] increased (days 1 to 2). This phenomenon suggests that cellular size (and tonicity) were being protected by the extrusion of intracellular osmoles, as postulated previously (26,34) and clearly demonstrated in cerebral adaptations to chronic hyponatremia (47).

Lastly, support for the volume depletion variant of EAH is provided by the paradoxical expansion of both mean corpuscular volume (MCV) and mean platelet volume (MPV), after the normalization of serum [Na+] (Fig. 3). The increase in cellular size was unexpected, as osmotic water movement across cell membranes typically flows down a concentration gradient from areas of lower concentration to areas of higher concentration until osmotic equilibrium is reached (47). Thus, acute hyponatremia is generally associated with increases in cellular size which contribute to encephalopathy, pulmonary edema, and peripheral edema (4). The reversal of hyponatremia should then trigger an osmotically induced decrease in cellular size, and not the opposite (cellular expansion), as shown here. Previous reports on marathon runners (25), and in a runner completing a 24-h challenge (43), demonstrate the maintenance of MCV with concomitant maintenance of normonatremia. However, Twerenbold et al. (49) documented a −0.58 fl decrease in MCV in 13 females who drank enough water to decrease their serum [Na+] levels from 137.6 to 131.3 mmol·L−1, over 4 h of running. This suggests that the linear relationship between osmolality and cell size is not perfect for all body cells (40) and warrants further investigation in humans.

Previous investigations demonstrate that both red blood cells (corpuscles) (11,43,51) and platelets (1,13) are responsive to osmotic stress. However, cells may not act as true osmometers when 25% to 30% of the body’s extracellular fluid ions are reduced from low-sodium diets plus profuse sweating (33,34). When the extracellular fluid compartment is reduced from both sodium and (concomitant) water losses, osmotically induced cellular swelling appears to be impaired (33,34). Of particular note, the paradoxical cellular expansion with the normalization of hypovolemic hyponatremia would support osmotic shock (32) as a precursor to rhabdomyolysis, as previously seen in hospitalized patients (24,42) and ultramarathon runners (8). While there is little doubt that this patient’s tonic-clonic seizure plus long duration cycling contributed to skeletal muscle breakdown (17), CK levels from exertional rhabdomyolysis generally peak between 1 and 2 d postexercise (37). This patient’s CK peaked on day 4 (Fig. 1C) after the cessation of exercise plus seizure activity. This which would support the concept of osmotic shock-induced rhabdomyolysis, mostly seen after recovery from the hypovolemic variant of hyponatremia, as hypothesized elsewhere (8).

The recommended treatment for acute EAH with encephalopathy, with or without noncardiogenic pulmonary edema, is hypertonic saline. This treatment was administered once the diagnosis of EAH was confirmed. Accordingly, this patient’s serum [Na+] returned to the normal range (>135 mmol·L−1) within 24 h. He was later administered 0.9% saline to treat the subsequent rhabdomyolysis (and prevent acute kidney injury) for which he remained normonatremic. However, it appeared that the return of total body water in all fluid compartments was delayed but eventually restored by the time of discharge. Given clear evidence for volume depletion as the primary pathophysiological mechanism for the development of severe, symptomatic EAH, we recommend that this patient ingest sodium according to taste (and habit) and ingest fluids according to osmotic or volemic thirst stimulation (6). As suggested elsewhere, fluid and sodium intake should be individually customized (3) to prevent EAH in future.

In conclusion, the contributions of underreplaced sweat sodium losses in the pathogenesis of severe symptomatic EAH remain widely debated (19,39). This case provides serial biochemical evidence to support extracellular fluid volume depletion in association with relative dilutional EAH. The presence of volume depletion, with relative extracellular sodium dilution, suggests that clinically relevant extracellular sodium losses play a pathogenic role in the development of EAH as a variant of (hypovolemic-induced) SIADH. We encourage subsequent validation in future, augmenting similar biochemical trajectories with: fluid intake, body weight, and cardiovascular (i.e., heart rate and blood pressure) data. This multilayered approach would assist in clarifying the more subtle volemic classifications of EAH that are well documented in hospitalized patients and clinical settings (i.e., thiazide diuretic use, protracted vomiting, and diarrhea).

The authors declare no conflict of interest and do not have any financial disclosures.

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