Commentary on Treatment of Severe Hyponatremia

Introduction

In this Evidence-Based Nephrology review, Sterns (1) summarizes the available evidence relating to the safety of treatment for severe symptomatic hyponatremia. The sources of evidence include animal experimental models, numerous single-center patient series of osmotic demyelination syndrome, and observational cohort studies (both prospective and retrospective) of hyponatremia. He also discusses how this evidence has supported recent consensus reached by European and American guidelines. Among his conclusions and observations are the following:

• Results from animal models show that acute hyponatremia causes cerebral edema, whereas adaptive responses to osmolar changes within the brain protect against cerebral edema in the setting of chronic hyponatremia.

• Even in cases of patients who have severe chronic hyponatremia, fatal cerebral edema is extremely uncommon.

• In experimental models, rapid correction of chronic hyponatremia (>48-hours duration) can cause osmotic injury because of the rapid development of a transcellular osmotic gradient in the brain, whereas acute hyponatremia is not susceptible to such injury from rapid correction.

• Six patient series have reported osmotic demyelination syndrome after the rapid correction of hyponatremia (encompassing between six and 21 patients each). However, such reports cannot provide valid conclusions regarding safe rates of correction that would avoid the complications of osmotic demyelination syndrome, because correction rates in patients without such complications were not examined.

• Six prior observational cohort studies (encompassing retrospective and prospective methods) support the hypothesis that more rapid correction of severe hyponatremia increases the risk of osmotic demyelination syndrome. However, precise estimates of this risk are difficult to estimate because of methodologic differences between the studies.

• There have been no prior randomized, controlled trials comparing the efficacy and safety of different correction strategies or protocols for severe symptomatic hyponatremia.

• A single ongoing randomized trial will compare bolus hypertonic saline with slow infusions in patients with moderately severe or severe symptomatic hyponatremia. This study is designed to detect differences in the rate of overcorrection rather than adverse clinical outcomes.

• Current consensus guidelines recommend the emergent treatment of hyponatremia with severe symptoms (e.g., seizures, deep somnolence, and cardiorespiratory arrest) with hypertonic saline, with the goal of increasing serum sodium initially by approximately 5 mEq/L and subsequent therapeutic limits of a ≤8-mEq/L increase per day in patients with chronic hyponatremia.

Patient-Control Studies of Rare Outcomes

For outcomes that occur infrequently, the patient-control study design can be an ideal strategy for evaluating suspected risk factors for disease. Osmotic demyelination syndrome is a rare and serious neurologic condition that may develop after the treatment of chronic hyponatremia. Mechanistic studies strongly suggest that rapid correction of hyponatremia is the likely cause of osmotic demyelination syndrome; however, the effect of specific fluid correction strategies on the development of this condition remains uncertain. Prospective studies to address this question, including clinical trials and cohort studies, are limited by the need to evaluate very large groups of patients who are hyponatremic to obtain sufficient osmotic demyelination syndrome outcomes for comparison among different correction strategy groups. Some cohort studies have focused on patients who have severe hyponatremia to increase the incidence of osmotic demyelination syndrome seen in the study; however, this approach suffers from limited external validity, because results may not necessarily apply to the majority of patients with hyponatremia who have more mild disturbances in serum sodium. Patient series have also described osmotic demyelination syndrome occurring after rapid correction of hyponatremia; however, such studies lack comparison groups and are further limited by the tendency to describe select groups of patients who may not represent typical people with hyponatremia.

Case-control studies could efficiently evaluate the effect of differing fluid correction strategies on the occurrence of osmotic demyelination syndrome if reliable information regarding these treatments could be obtained. The use of integrated electronic medical record systems may be ideal for this purpose. First, investigators would select cases: patients who developed osmotic demyelination syndrome after treatment for hyponatremia. Ideally, the diagnosis of osmotic demyelination syndrome among case patients would include clinical and radiographic evidence of the disease confirmed by experts after chart review. Second, the investigators would select controls: patients who did not develop osmotic demyelination syndrome after hyponatremia treatment. Definitive exclusion of osmotic demyelination syndrome among control patients may not be feasible given the often subtle manifestations of this condition. Nonetheless, the overall rarity of osmotic demyelination syndrome among patients with hyponatremia suggests that this condition would be unlikely among potential controls. The investigators could elect to match case and control individuals according to their initial plasma sodium level, the underlying cause of hyponatremia, and the severity of acute illness to more effectively isolate the effect of different fluid correction strategies on the development of osmotic demyelination syndrome; however, matching would preclude evaluation of whether the matching characteristics are themselves associated with osmotic demyelination syndrome. After construction of the case-control study population, the investigators could then compare different fluid correction strategies, including correction rates and fluid types, between cases and controls, thereby estimating the association of these factors with the risk of osmotic demyelination syndrome.

The use of a case-control study design to assess potential risk factors for osmotic demyelination syndrome would be susceptible to confounding; the underlying characteristics of patients who receive certain fluid correction strategies could themselves be a cause of osmotic demyelination syndrome. However, the strong biologic rationale supporting rapid correction as the primary cause of this rare condition and the paucity of other known risk factors for the condition mitigate the concern of confounding to some degree. In contrast to prospective studies, the patient-control design could efficiently identify a group of case patients with osmotic demyelination syndrome and a suitable group of control patients without this condition to investigate the effect of administered treatments on this outcome.

Disclosures

S.S. has received research grants from Otsuka Pharmaceutical, Inc.