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Importance: Few high-quality studies have clarified whether hypertonic saline is best administered as slow continuous infusion (SCI) therapy or rapid intermittent bolus (RIB) therapy for symptomatic severe hyponatremia.
Objective: To compare the risk of overcorrection in RIB and SCI with hypertonic saline in patients with symptomatic hyponatremia.
Design, Setting, and Participants: This prospective, investigator-initiated, multicenter, open-label, randomized clinical trial enrolled 178 patients older than 18 years with moderately severe to severe hyponatremia and glucose-corrected serum sodium (sNa) levels of 125 mmol/L or less. Recruitment took place from August 24, 2016, until August 21, 2019, across emergency departments and wards of 3 general hospitals in the Republic of Korea.
Interventions: Either RIB or SCI of hypertonic saline, 3%, for 24 to 48 hours stratified by the severity of clinical symptoms.
Main Outcome and Measures: The primary outcome was overcorrection at any given period, defined as increase in the sNa level by greater than 12 or 18 mmol/L within 24 or 48 hours, respectively. Secondary and post hoc outcomes included efficacy and safety of the treatment approaches. The sNa concentrations were measured every 6 hours for 2 days.
Results: The 178 patients (mean [SD] age, 73.1 [12.2] years; 80 (44.9%) male; mean [SD] sNa concentrations, 118.2 [5.0] mmol/L) were randomly assigned to the RIB group (n = 87) or the SCI group (n = 91). Overcorrection occurred in 15 of 87 (17.2%) and 22 of 91 (24.2%) patients in the RIB and SCI groups, respectively (absolute risk difference, -6.9% [95% CI, -18.8% to 4.9%]; P = .26). The RIB group showed lower incidence of relowering treatment than the SCI group (36 of 87 [41.4%] vs 52 of 91 [57.1%] patients, respectively; absolute risk difference, -15.8% [95% CI, -30.3% to -1.3%]; P = .04; number needed to treat, 6.3). Groups did not differ in terms of efficacy in increasing sNa concentrations nor improving symptoms, but RIB, when compared with SCI, showed better efficacy in achieving target correction rate within 1 hour (intention-to-treat analysis: 28 of 87 (32.2%) vs 16 of 91 (17.6%) patients, respectively; absolute risk difference, 14.6% [95% CI, 2%-27.2%]; P = .02; number needed to treat, 6.8; per-protocol analysis: 21 of 72 (29.2%) vs 12 of 73 (16.4%) patients, respectively; absolute risk difference, 12.7% [95% CI, -0.8% to 26.2%]; P = .07). The statistical significance of the intention-to-treat and per-protocol analyses were similar for all outcomes except for achieving the target correction rate within 1 hour.
Conclusions and Relevance: This randomized clinical trial found that both RIB and SIC therapies of hypertonic saline for treating hyponatremia were effective and safe, with no difference in the overcorrection risk. However, RIB had a lower incidence of therapeutic relowering treatment and tended to have a better efficacy in achieving sNa within 1 hour than SCI. RIB could be suggested as the preferred treatment of symptomatic hyponatremia, which is consistent with the current consensus guidelines.
Trial Registration: ClinicalTrials.org Identifier: NCT02887469.
This well done randomized trial demonstrates, perhaps counterintuitively, that rapid intermittant boluses of 3% saline are at least as safe and effective as continuous infusions for correcting hyponatremia (< 126) in adults. Given that the results tended to favor boluses that are easier to monitor and perform, there seems little reason to use continuous infusions in these patients.
With the clear prevalence of symptomatic hyponatremia being quite low (as evidenced by the low sample size over a sufficient time period), it is unclear whether these findings yield any clinical relevance.
In this very interesting trial of correction of symptomatic hyponatremia, the authors test bolus 3% saline versus infusion. Not surprisingly, they found that bolus corrects better at 1 hr (which would be expected given faster completion of overall therapy), but slow infusion needed re-correction more often. Interestingly, most of the patients studied achieved their hyponatremia over a considerable time period (thiazide diuretics, alcoholism). Rapid correction goes against the adage that "if they got there slowly, take them back slowly." In my mind, we may need to adjust our slow infusions if they are too aggressive, but the role for rapid correction should be limited to those with very serious symptoms (seizure) and those who got there very acutely (marathon runners). Especially in hospital systems with multiple hand-offs, I worry about rapid correction of "treating a number" causing more harm than good.
It would have been helpful to see the details of the 2 intervention groups.
EXCELLENT article. Important information.