Hyponatremia and mortality: how innocent is the bystander?

For those who are not electrolyte enthusiasts, hyponatremia can be a frustrating disorder. Dealing with hyponatremia means considering various and often opposite scenarios. Does the patient have hypovolemic, euvolemic, or hypervolemic hyponatremia? Is it acute or chronic? Symptomatic or asymptomatic? Do I want to correct rapidly or more slowly? Shall I give normal saline, hypertonic saline, or water restriction? And—every resident’s nightmare—which of the impossible formulas shall I use to calculate the correction rate? These challenges may be the reason that the management of hyponatremia is still suboptimal (1– 3). This is worrisome not only because hyponatremia counts as the most common electrolyte disorder in hospitalized patients but also because it is associated with increased mortality. The association between hyponatremia and mortality has been demonstrated in numerous studies (4 –9), but causality has been difficult to prove. Therefore, two possibilities remain (Figure 1): (1) Hyponatremia is a direct cause of death, or (2) severe underlying disease is the cause of death and hyponatremia is merely another complication of this underlying disease. In this issue, Chawla et al. (10) elegantly rephrase the issue of hyponatremia and mortality as, “Do patients die with or from hyponatremia?” The investigators first show mortality rates in a large sample of hospitalized patients with hyponatremia (serum sodium 135 mmol/L). Similar to previous observations (9), mortality rose as serum sodium dropped. Surprising, however, this trend reversed when serum sodium reached values of 120 mmol/L, when mortality rates started to decrease again. The final result was a parabolic relationship between serum sodium and mortality. On the basis of these observations, Chawla et al. formulate an interesting hypothesis (10): That patients with moderate hyponatremia have more severe underlying disease than those with severe hyponatremia and therefore higher mortality rates. The patients with severe hyponatremia, they argue, were likely admitted because their serum sodium was so low, not because they were so ill. In the remainder of the article, the authors seek to confirm this hypothesis by performing a detailed chart review of 53 fatal cases with serum sodium 120 mmol/L and 35 survivors with serum sodium 110 mmol/L. Indeed, the authors note that more than half of the fatal cases had severe conditions associated with high mortality rates, including sepsis and acute kidney injury. These disorders were largely absent in survivors, whose more severe hyponatremia was largely attributed to the use of thiazides and antidepressants. Importantly, hyponatremia’s most dangerous and potentially fatal complications, cerebral edema and the osmotic demeylination syndrome, were rarely observed. Thus, the authors conclude that patients die with and not from hyponatremia. This is an interesting conclusion that will definitely stir debate on the value of actively treating hyponatremia. The study is also an interesting example of how detailed chart reviews sometimes provide more clinical insight than sophisticated statistics. Two limitations of the study, however, should be noted. First, the study was retrospective, and, therefore, the quality of the information was dependent on the quality of the charts. Second, the groups of “survivors” and “deaths” were not ideal for comparison because they differed in not one but two crucial aspects (different serum sodium cutoff and different outcome). Instead, it would have been better to compare all patients who had a serum sodium concentration of 110 to 120 mmol/L with all patients who had a serum sodium concentration 110 mmol/L. If patients with a serum sodium between 110 and 120 mmol/L would have had more comorbidity than the group with a serum sodium 110 mmol/L, then this would have made a stronger case for the authors’ hypothesis. Does this study prove hyponatremia to be an innocent bystander in mortality? Not entirely. The nuance comes from a third possibility (Figure 1): Hyponatremia may contribute to organ dysfunction and therefore indirectly contribute to mortality. For example, emerging data implicate hyponatremia in falls (11), osteoporosis (12), and fractures (13–15), suggesting an effect on the nervous system and bone. Little is known about the effects of hyponatremia on other organs, such as the heart, although a recent study identified hyponatremia as an independent predictor of myocardial infarction in community patients (16). More is known about the metabolic adverse effects of hypernatremia, which can aggravate peripheral insulin resistance (17), impair hepatic gluconeogenesis (18), and induce a negative inotropic response (19). Thus, Department of Internal Medicine–Nephrology, Erasmus Medical Center, Rotterdam, Netherlands