Hyponatremia occurs in up to 42% of hospitalized patients and has been associated with increased mortality. Hypertonic saline is used to manage symptomatic hyponatremia. Undertreatment of hyponatremia can result in cerebral edema, whereas overtreatment can produce permanent neurologic deficits secondary to osmotic demyelination syndrome (ODS).

Two strategies that have been utilized to manage symptomatic hyponatremia include slow continuous infusion (SCI) or rapid intermittent bolus (RIB) of hypertonic saline. However, there is a paucity of information comparing the efficacy and safety of these modes of administration in patients with moderately severe or severe symptomatic hyponatremia.  

The SALSA (Efficacy and Safety of Rapid Intermittent Correction Compared with Slow Continuous Correction with Hypertonic Saline in Patients with Moderately Severe or Severe Symptomatic Hyponatremia) was a prospective, investigator-initiated, multicenter, open-label, randomized clinical trial that helped clarify the role of treatment options. Patients aged > 18 years with moderately severe (i.e., nausea, headache, drowsiness, generalized weakness, malaise) to severe symptoms (i.e., vomiting, stupor, seizure, coma with a Glasgow Coma Scale [GCS] score of <8) of hyponatremia and a glucose-corrected (sNa32) of <125 mmol/L were included in the study. The exclusion criteria were extensive and included polydipsia, arterial hypotension, liver disease, uncontrolled diabetes, pregnancy, and history of cardiac surgery.

The primary outcome was the incidence of overcorrection, which was defined as an increase in sNa by greater than 12 mmol/L in the first 24 hours or an increase in sNa >18 mmol/L within 48 hours. Secondary outcomes included efficacy and safety; the presence or absence of symptoms 24 and 48 hours posthypertonic 3% saline; the first time an increase in sNa of >5 mmol/L after treatment initiation occurred; time for treatment initiation to a sNa >130 mmol/L; incidence of target correction rate, defined as achieving sNa of 5 to 9 mmol/L within 24 hours and sNa of 10 to 17 mmol/L or >130 mmol/L within 48 hours; length of hospital stay; need for additional treatment; incidence of ODS or relowering treatment (i.e., dextrose 5% and/or intravenous desmopressin 2 mcg); and change in GCS between pretreatment and 24 and 48 hours after treatment. Both an intention to treat (ITT) and per protocol (PP) analyses were conducted.

The initial infusion rate of hypertonic saline 3% was based on hyponatremia symptom severity with a treatment goal to increase sNa level by 5 to 9 mmol/L with symptom relief within the first 24 hours and to increase sNa by 10 to 17 mmol/L or >130 mmol/L with symptom relief during the first 48 hours following hypertonic saline administration.

The mean age of the study population was 73.1 years, and the mean sNa concentration at baseline was 118.2 mmol/L. Two patients presented with seizures, five with an altered mental state, and 38 had vomiting.

For the primary outcome, investigators found that in the ITT, overcorrection occurred in 17.2% of the RIB group and 24.2% of the SCI group, which was not significantly different. Similarly, in the PP analysis, overcorrection occurred in 19.4% of RIB and 26.0% of SCI treated patients, also not statistically significantly different.

There were no differences in most secondary outcomes either by ITT or PP analyses. However, additional treatment was need in 90.8% of the RIB group compared with 74.7% of the SCI group (P = .005; number needed-to-treat [NNT] 6.2). Regarding safety, there were no cases of ODS in either group. The RIB group had a lower incidence of relowering treatment compared with the SCI group (41.4% vs. 57.1%, P = .04; NNT 6.3).

Analyses of posthoc endpoints found that in the ITT analysis, the proportion of patients achieving target correction rate within 1 hour was higher in the RIB group than the SCI group (32.2% vs. 17.6%, P = .02; NNT 6.8). However, this finding was not significant via PP analysis.

The authors concluded that while both RIB and SIC hypertonic saline therapies are safe and effective for the management of moderately severe to severe symptomatic hyponatremia, RIB is associated with a lower incidence of therapeutic relowering treatment and was better at improving sNa concentrations at 1 hour compared with SIC, thereby making RIB the preferred management of sodium repletion.

This study provides useful information for pharmacists in the institutional setting who manage patients with hyponatremia.

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