Do Hyponatremia or Its Underlying Mechanisms Associate With Mortality Risk in Observational Data?

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Objectives: Whether unaccounted determinants of hyponatremia, rather than water excess per se, primarily associate with mortality in observational studies has not been explicitly examined. Design: Retrospective cohort study of the association between hyponatremia and mortality, stratified by outpatient diuretic use in three strata. Setting: An inception cohort of 13,661 critically ill patients from a tertiary medical center. Measurements and Main Results: Admission serum sodium concentrations, obtained within 12 hours of admission to the ICU, were the primary exposure. Hyponatremia was associated with 1.82 (95% CI, 1.56–2.11; p < 0.001) higher odds of mortality, yet differed according to outpatient diuretic use (multiplicative interaction between thiazide and serum sodium < 133 mEq/L; p = 0.002). Although hyponatremia was associated with a three-fold higher (odds ratio, 3.11; 95% CI, 2.32–4.17; p < 0.001) odds of mortality among those prescribed loop diuretics, no increase of risk was observed among thiazide diuretic users (odds ratio, 0.87; 95% CI, 0.47–1.51; p = 0.63). When examined as a continuous variable, each one mEq/L higher serum sodium was associated with 8% (odds ratio, 0.92; 95% CI, 0.90–0.94; p < 0.001) lower odds of mortality in loop diuretic patients and 5% (odds ratio, 0.95; 95% CI, 0.93–0.96, p < 0.001) lower in diuretic naïve patients, but was not associated with mortality risk among thiazide users (odds ratio, 0.99; 95% CI, 0.95–1.02; p = 0.45). Conclusions: Hyponatremia is not uniformly associated with increased mortality, but differs according to diuretic exposure. Our results suggest that the underlying pathophysiologic factors that lead to water excess, rather water excess itself, account in part for the association between hyponatremia and poor outcomes. More accurate estimations about the association between hyponatremia and outcomes might influence clinical decision-making.