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Original Investigation
October 26, 2020

Risk of Overcorrection in Rapid Intermittent Bolus vs Slow Continuous Infusion Therapies of Hypertonic Saline for Patients With Symptomatic Hyponatremia: The SALSA Randomized Clinical Trial

Author Affiliations
  • 1Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Republic of Korea
  • 2Department of Emergency Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
  • 3Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
  • 4Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
  • 5Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
  • 6Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
JAMA Intern Med. Published online October 26, 2020. doi:10.1001/jamainternmed.2020.5519
Key Points

Question  What are the risks of overcorrection in rapid intermittent bolus (RIB) and slow continuous infusion (SCI) therapies in patients with symptomatic hyponatremia?

Findings  In this randomized clinical trial of 178 patients who received either RIB or SCI of hypertonic saline, 3%, for 48 hours, overcorrection occurred in 17.2% in the RIB group and 24.2% in the SCI group.

Meaning  Both RIB and SCI therapies of hypertonic saline for treating symptomatic hyponatremia are effective and safe, with no difference in the overcorrection risk; however, RIB could be suggested as the preferred treatment of symptomatic hyponatremia, which is consistent with the current consensus guidelines.

Abstract

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

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    1 Comment for this article
    EXPAND ALL
    Hypertonic saline by bolus or infusion
    Richard Sterns, MD | University of Rochester School of Medicine and Dentistry
    I commend Baek and co-workers for completing a difficult, randomized controlled trial comparing 3% saline by bolus (2 ml/kg every 6 hrs) to 3% saline by continuous infusion (0.5 ml/kg per hour) for symptomatic hyponatremia [1]. The study, however, fails to define the best way to resolve life-threatening hyponatremic symptoms or to prevent overcorrection and osmotic demyelination syndrome (ODS).

    An American Expert Panel recommended bolus 3% saline for seizures/coma or herniation risk posed by rapid onset of hyponatremia or intracranial pathology [2]. Only 7 of the 145 patients studied met these criteria (2 with seizures and 5 with
    stupor). European guidelines include nausea, headache and vomiting [3]; Baeck et al’s study added malaise and weakness [1]. Such non-specific symptoms are ominous when caused by acute self-induced water intoxication or post-operative intravenous fluids; they are both common and benign when hyponatremia develops more slowly [4].

    In addition to a lower bar for starting therapy, the study’s regimen was more aggressive than the regimen in the European guidelines, which advocate repeat boluses until a 5 mEq/L increase is achieved (sufficient even for impending herniation) [3]. In this study, 3% saline was continued for 48 hours until symptom resolution or a sodium increase within 1 mEq/L of the limits that defined overcorrection (>10 mEq/L in 24 hours or 18 mEq/L in 48 hours) [1]. Consequently, re-lowering therapy with D5W and/or desmopressin was often needed (41% for bolus and 52% for continuous infusion). Resolution of persistent non-specific symptoms is a subjective end-point making the study’s findings difficult to generalize.

    Severe ODS is most common in alcoholic patients with serum sodium  105 mEq/L; unless there is advanced liver disease, ODS is vanishingly rare with serum sodium >120 mEq/L [4]. In this study, mean serum sodium was 118 mEq/L, liver disease was an exclusion criterion, and only 5 patients were alcoholic. Subtle cases of ODS would have been missed because rigorous neurological exams and MRI imaging were not done in the days following treatment.

    No cases of ODS were identified and time to symptom resolution did not differ for the two regimens. Not surprisingly, at 1 hour, correction after bolus therapy was greater, since 5 x as much hypertonic saline had been given. At other times, outcomes were similar, including rates of overcorrection (even though the bolus regimen provided 2/3 the volume provided by continuous infusion) [1].

    Studies of patients with more severe symptoms and/or greater risk of ODS are needed.


    References

    1. Baek SH, Jo YH, Ahn S, Medina-Liabres K, Oh YK, Lee JB, Kim S. Risk of Overcorrection in Rapid Intermittent Bolus vs Slow Continuous Infusion Therapies of Hypertonic Saline for Patients With Symptomatic Hyponatremia: The SALSA Randomized Clinical Trial. JAMA Internal Medicine. 2020 Oct 26.
    2. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. The American journal of medicine. 2013 Oct 1;126(10):S1-42.
    3. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrology Dialysis Transplantation. 2014 Apr 1;29(suppl_2):i1-39.
    4. Sterns RH. Treatment of severe hyponatremia. Clinical Journal of the American Society of Nephrology. 2018 Apr 6;13(4):641-9.
    CONFLICT OF INTEREST: None Reported
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