Critical Care, Critical Care Alert

Critical Care Alert: The SALSA Randomized Clinical Trial

Critical Care Alert

ARTICLE
Baek SH, Jo YH, Ahn S, et al. 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 Intern Med. 2021;181(1):81–92.

OBJECTIVE
To compare the safety and efficacy of RIB and SCI therapy with hypertonic saline in patients with symptomatic hyponatremia

BACKGROUND
Symptomatic hyponatremia is a commonly encountered electrolyte abnormality in the emergency department. Treatment generally consists of 3% hypertonic saline therapy. There are two methods of hypertonic saline administration that are used; rapid intermittent bolus (RIB) and slow continuous infusion (SCI). Currently, both European and American guidelines recommend RIB therapy while UpToDate® suggests either RIB or SCI.1-3 RIB therapy is often preferred as it is thought of as working quicker, having a lower risk of overcorrection, and does not require calculations.4

DESIGN
Prospective, multicenter, open-label, randomized clinical trial

POPULATION
178 adult patients in 3 Korean hospitals with moderately severe to severe symptomatic hyponatremia with glucose-corrected serum sodium levels (sNa) of 125 mmol/L or less

  • Mean (SD) age: 73.1 (12.2) years
  • Mean sNa concentration: 118.2 (5.0) mmol/L
  • Cause of hyponatremia
    • Thiazide diuretics: 29.8%
    • Syndrome of inappropriate antidiuretic hormone secretion (SIADH): 29.2%
    • Adrenal insufficiency: 16.3%
    • Decreased extracellular cellular fluid volume due to nonrenal sodium loss: 14.0%
    • Increased extracellular fluid volume: 10.7%

Exclusion Criteria

  • Primary polydipsia
  • Hypotension
  • Pregnant or breastfeeding
  • Liver disease/decompensated liver cirrhosis
  • Uncontrolled diabetes mellitus
  • Recent ACS/cardiac surgery/sustained VT or VF
  • Recent cerebral edema/increased intracranial pressure

STUDY MEASUREMENTS

  • Incidence of overcorrection (defined as an increase in sNa of > 12 mmol/L in 24 hours or > 18 mmol/L in 48 hours (primary outcome)
  • Incidence of relowering treatment
  • Time to increase of sNa of 5 mmol/L or greater
  • Efficacy of achieving target correction rate within 1 hour
  • Symptom resolution at 24 and 48 hours
  • Time to achievement of sNa of 130 mmol/L or greater
  • Incidence of target corrective rate (5-9 mmol/L sNa in 24 hours and 10-17 mmol/L sNa or 130 mmol/L sNa in 48 hours)
  • Length of hospital stay
  • Incidence of additional treatment
  • Incidence of osmotic demyelination syndrome (ODS)
  • Change in Glasgow Coma Score (GCS)

METHODS

  • RIB therapy consisted of 2 mL/kg 3% NaCl given every six hours
  • SCI therapy consisted of5 mL/kg/hour 3% NaCl
  • The goal rate of correction was 5-9 mmol/L sNa in 24 hours and 10-17 mmol/L sNa or 130 mmol/L sNa in 48 hours.
  • sNa was measure every 6 hours for 48 hours
  • Relowering therapy consisted of a D5 infusion at 10 ml/kg over 1 hour and/or desmopressin 2 μg and was used if the sNa level increased ≥10 mmol/L in the first 24 hours or ≥18 mmol/L in 48 hours

KEY RESULTS

  • No significant difference in the incidence of overcorrection between RIB and SCI groups; 15 of 87 (17.2%) patients and 22 of 91 (24.2%) respectively (absolute risk difference, −6.9% [95% CI, −18.8% to 4.9%]; P = .26)
  • RIB showed a lower incidence of relowering treatment than SCI (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 [NNT], 6.3)
  • RIB achieved target correction rate within 1 hour more frequently than SCI (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; NNT, 6.8)
  • RIB required additional treatment more frequently than SCI; 79 of 87 (90.8%) patients and 68 of 91 (74.7%) patients respective (absolute risk difference, 16.1% [95% CI, 5.3%-26.9%]; P = .005; NNT, 6.2)
  • There was no difference between RIB and SCI in other safety and efficacy outcomes

STRENGTHS

  • One of very few randomized clinical trial to compare RIB to SCI in patients with symptomatic hyponatremia
  • Included both emergency department and inpatient patients
  • Multicenter

LIMITATIONS

  • Larger than expected number of patients excluded, most often due to protocol violation; this was likely due to a lack of familiarity with RIB among Korean physicians
  • A much higher incidence of overcorrection in this study was observed than expected. For this reason UpToDate® recommends using a more conservative approach to RIB and SCI than used in this study; 1 ml/kg bolus and 0.25 ml/kg/hr infusion respectively (half the values used in this study)
  • The study was not powered to detect the rare but feared complication of ODS
  • Differences between Korean patients and American patients may limit generalizability

EM TAKE-AWAYS
Limited clinical trials exist comparing the safety and efficacy of RIB vs SCI in the treatment of symptomatic hyponatremia. This randomized clinical trial found that RIB and SCI are both safe and effective in the treatment of hyponatremia. While the protocol in this study resulted in more overcorrection than expected for both the RIB and SCI group, the RIB group was found to have a lower incidence of relowering therapy and an increased achieved target correction rate within 1 hour. Other studied safety and efficacy outcomes were not significantly different between the groups. Owing to its increased simplicity, speed, and lower incidence of relowering therapy, RIB therapy should be considered the preferred therapy for emergency department management of symptomatic hyponatremia, consistent with current guidelines.


REFERENCES

  1. Spasovski G, Vanholder R, Allolio B, et al. Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170(3):G1-G47.
  2. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10)(suppl 1):S1-S42.
  3. Sterns, RH. Overview of the treatment of hyponatremia in adults. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2021.
  4. Baek SH, Jo YH, Ahn S, et al. 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 Intern Med. 2021;181(1):81–92.

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