Sex-specific risks of death in patients hospitalized for hyponatremia: a population-based study

This nationwide observational registry study reports two important findings: an almost fivefold increased lethality within 1-year after hospitalization for hyponatremia and a gender-associated difference where hyponatremia increased lethality nearly twice as much in men compared with women.

The present study is unique in focusing on lethality in patients hospitalized due to hyponatremia. After adjustment for a factors of prognostic importance, hospitalization due to hyponatremia was independently associated with a markedly increased lethality. Furthermore, we studied a subgroup free from previously identified comorbidities. Interestingly, the independent association between hyponatremia and lethality remained in this healthier group.

The association between hyponatremia and lethality has been explored extensively over the last decades, and reports invariably show that hyponatremia predicts both in-hospital [13‐16] and future lethality [17‐19], for a wide range of diseases.

The question whether hyponatremia directly contributes to lethality or merely reflects the severity of an underlying disease is under debate [10]. Previous epidemiologic studies have demonstrated cumulative lethality rates from 6 to 29% depending on the underlying disease [10, 13, 20]. In a narrative review of hyponatremia and lethality Hoorn and Zietse [10] found nine studies that appeared to favor a direct contribution of hyponatremia to lethality while six studies instead pointed towards an effect mediated through the underlying disease [10, 13, 14, 16, 18, 20‐30]. The authors concluded that there were no convincing data confirming that hyponatremia per se attributes to lethality [10]. Which may then be the potential mechanisms that links hyponatremia with death? One suggested mechanism is hyponatremia-induced oxidative stress [31]. Another hypothesis is the activation of the vasopressor system. A prospective cohort study by Eckart et al. published in 2018, with laboratory data from 6962 individuals at the emergency department reported a strong association between vasopressin levels, mirrored by copeptin, and lethality [32]. In an experimental model on aged rats Barsony et al. showed that chronic hyponatremia is associated with reduction in bone mineral density, hypogonadism, sarcopenia, and cardiac fibrosis [33]. Hence, there is no specific culprit causative mechanism that can explain the association between hyponatremia and death.

So far very few studies have reported on the impact of gender on hyponatremia and lethality [8, 16]. We found that men hospitalized due to hyponatremia faced a subsequent twofold risk for death compared with women. A similar increased lethality in men with hyponatremia was reported in the previously mentioned study by Eckart et al. [33]. Gender differences in sodium metabolism are perhaps most obvious in acute hyponatremia, with women at considerable risk of cerebral edema, whereas men rarely suffer this complication [34]. However, acute hyponatremia is rare, and differences at a population level between men and women more likely relates to chronic hyponatremia. Wald et al. [16] examined in-hospital lethality among 53,236 adults at a medical center in Boston, USA, and Mohan et al. [8] utilized data from a population-based cross-sectional study of 14,697 adults from the US to examine all-cause lethality over a period of 7 years. Contrary to our findings, both groups found hyponatremic women to be at significantly greater risk of dying than hyponatremic men. However, differences in methodology, and severity of hyponatremia, make comparisons hard. In the study by Wald et al. a majority (80%) of patients suffered from mild hyponatremia (133–137 mmol/L), and in the study by Mohan et al. hyponatremia was defined as a s-sodium of <133 mmol/L or <136 mmol/L, depending on current reference ranges. In our cohort, sodium was significantly lower, with an estimated mean of 122 mmol/L, based on validation data [9, 12]. In the hospital setting, drug induced hyponatremia appears to be more common, and sodium levels lower, in women than in men [35, 36]. In our study, it was evident that females were more frequently exposed to treatment with SSRIs and thiazide diuretics, while males had a greater burden of comorbidities associated with a worse prognosis. However, the adjustment procedure ought to control for most of these effects. In addition, the subgroup without previously known comorbidity showed similar gender-associated differences. Thus, the higher lethality in men hospitalized due to hyponatremia cannot be fully explained by a greater burden of comorbidity. A potential explanation could be that male cases in our study were exposed to lower sodium concentrations. Unfortunately, we did not have access to laboratory data and could not adjust for sodium levels.

Some limitations should be considered when interpreting our results. Firstly, the lack of laboratory and anthropometric data disables us from analyzing the effect of different sodium levels and anthropometric data on prognosis. Secondly, the study is based on a previous matched case-control study, which may have inflated the relative risk for the cases compared with prospective cohort studies where both cases and controls are sampled from a hospitalized population. However, in our multivariable analyses we adjusted for frailty.

In conclusion, patients hospitalized for hyponatremia faced a markedly increased subsequent lethality that was independent of concomitant disease. This increase was nearly twice as large among men compared with women.