Efficacy and Safety of Rapid Intermittent Compared With Slow Continuous Correction in Severe Hyponatremia Patients

Efficacy and Safety of Rapid Intermittent Correction Compared With Slow Continuous Correction With Hypertonic Saline in Patient With Moderately Severe or Severe Symptomatic Severe Hyponatremia (SALSA Trial)

This study will investigate efficacy and safety of rapid intermittent correction compared with slow continuous correction with hypertonic saline in patient with moderately severe or severe symptomatic severe hyponatremia

Study Overview

• Status: Completed
• Conditions: Hyponatremia Symptomatic
• Intervention / Treatment: Drug: 3% hypertonic saline

Detailed Description

Moderate to severe symptomatic hyponatremia requires prompt treatment with hypertonic saline. The extent and rate of increase in serum sodium (sNa) levels during treatment are critical. Several methods for continuous infusion of hypertonic saline were used to guide rate of fluid administered to achieve the required serum sodium target. As based on static model, they had a bias to over-correction of hyponatremia. Alternative approach to treatment with hypertonic fluid is to use small, fixed boluses to achieve controlled increments in sNa. However, there was no high quality evidence on whether hypertonic saline are best given in continuous infusion (preferred by most) or bolus injection. The aim of present study, a multi-center (Seoul National University Bundang Hospital [2016.8~], Seoul National University Boramae Medical Center [2016. 9~], Hallym University Dongtan Sacred Heart Hospital [2017.7~]), randomized, open labelled, controlled clinical trial, is to investigate efficacy and safety of rapid intermittent correction compared with slow continuous correction with hypertonic saline in patient with moderately severe or severe symptomatic severe hyponatremia. A total 178 patients, who suffer from symptomatic severe hyponatremia, will be enrolled and randomly assigned to receive either intermittent bolus infusion or slow continuous infusion by 3% hypertonic saline. Subjects will take different rate of 3% hypertonic saline for 24-48 hours stratified by severity of clinical symptoms. Serum sodium will be measured at every six hours during two days.

• Study Type: Interventional
• Enrollment (Actual): 178
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Boramae Hospital
  • Gyeonggi-do
    • Hwaseong-si, Gyeonggi-do, Korea, Republic of, 445-907
      • Hallym University Dongtan Sacred hospital
    • Seongnam, Gyeonggi-do, Korea, Republic of, 13605
      • Seoul National University Bundang Hospital Clinical Trial Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• In emergency setting (2016.6-) and/or inpatients at ward (2018.9-)
• Glucose corrected serum sodium ≤125 mmol/L

• Patients with moderately severe or severe symptom

  • Moderately severe

    :Nausea without vomiting Drowsy, Headache General weakness, myalgia

  • Severe :Vomiting, Stupor, Seizures, Coma (Glasgow Coma Scale ≤8)
• written consent

Exclusion Criteria:

• Pseudohyponatremia: serum osmolality > 275 mOsm/kg

  - If the serum osmolality is > 275 mOsm/kg but the BUN is ≥ 30 mg/dL, the patients can be registered if calculated serum osmolality (2 x plasma [Na] + [Glucose]/18) is <275 mOsm/kg

• Primary polydipsia: urine osmolality ≤ 100 mOsm/kg
• Glucose corrected serum sodium >125 mmol/L
• Arterial hypotension (SBP <90mmHg and MAP <70mmHg)
• Anuria or urinary outlet obstruction

• Liver disease

  • transaminase levels >3 times the upper limit normal
  • Known LC with ascites or diuretics use or PSE Hx or Varix Hx
• Uncontrolled diabetes mellitus (HbA1C > 9%)
• Women who are pregnant or breast feeding
• History of cardiac surgery excluding PCA, acute myocardial infarction, sustained ventricular tachycardia, ventricular fibrillation, acute coronary syndrome, cebrovascular trauma, and increased intracranial pressure within the 3 months prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intermittent bolus group; <<Within 6hr>>; Moderately Severe : 3% saline 2ml/kg over 20min *1 (unknown bwt 100ml); Severe :3% saline 2ml/kg over 20min *2 (unknown bwt 100ml) <additional treatment> Repeat 3% saline 2ml/kg over 20min at every sample time point (at 1/6hr) till Na 5-9 mmol/L inc from initial Na and sx relief <<During 6-24hr>> - Moderately Severe or Severe : Repeat 3% saline 2ml/kg over 20min at every sample time point(at 12/18/24hr) till Na 5-9 mmol/L inc from initial Na and sx relief <<During 24-48hr>>; Moderately Severe or Severe : Repeat 3% saline 2ml/kg over 20min at every sample time point (at 30/36/42/48hr) till Na 10-17 mmol/L inc from initial Na or Na ≥ 130mmol and sx relief	Drug: 3% hypertonic saline; The same as above
Active Comparator: slow continuous infusion group; <<Within 24hr>> - Moderately Severe: 3% saline 0.5ml/kg/hr (unknown bwt 25ml/hr) - Severe: 3% saline 1ml/kg/hr (unknown bwt 50ml/hr) Infusion protocol modification as below by Na at every sample time point (at 1/6/12/18/24 hr) If Na 5-9 mmol/L inc from initial Na and sx relief : stop 3% saline infusion regardless of △ Na if △ Na inc <0.5mmol/hr or △ Na inc <3mmol/6hr : add 0.25ml/kg/hr, restart 0.5ml/kg/hr if previously stopped if △ Na inc ≥0.5mmol/hr or △ Na inc ≥ 3mmol/6hr : maintain infusion rate <<During 24-48hr>> - Moderately Severe and Severe Infusion protocol modification as below by Na at every sample time point (at 30/36/42/48hr) If Na 10-17 mmol/L inc from initial Na or Na ≥ 130mmol and sx relief : stop 3% saline infusion regardless of △ Na if △ Na inc <1.5mmol/6hr : add 0.25ml/kg/hr or restart 0.25ml/kg/hr if previously stopped if △ Na inc ≥ 1.5mmol/6hr : maintain infusion rate	Drug: 3% hypertonic saline; The same as above

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of overcorrection rate at any given period	Increase in sNa by >12 mmol/L within 24 hours or Increase in sNa by >18 mmol/L within 48 hours All subjects receive hypertonic saline by intermittent bolus or slow continuous infusion for 48 hours, serum Na will be measured.	up to 48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rapid improvement of symptoms	Change of symptoms from baseline to 24 hours after hypertonic fluid treatment	up to 24 hours
Time from treatment initiation to an increase of serum Na ≥ 5 mmol/L		up to 48 hours
Incidence of target correction rate	Target correction rate is defined by achieved serum Na <10 mmol/L within 24 hours, achieved serum Na <18 mmol/L within 48 hours	up to 48 hours
Time to serum Na >130 mmol/L	Time from treatment initiation to achieved serum Na> 130mmol/L	up to 48 hours
Length of hospital stay		up to 8 weeks
Incidence of additional treatment	Additional treatment is performed if symptom is not relieved or undercorrection develops (achieved Na < 5mmol/L with 24 hours or achieved Na <12mmol/L within 48 hours)	up to 48 hours
Incidence of osmotic demyelinating syndrome confirmed by ICD -10 code or MRI		up to 48 hours
Incidence of relowering treatment	Relowering treatment is performed as below if achieved serum Na is <10 mmol/L within 24 hours, achieved serum Na is <18 mmol/L within 48 hours.; discontinuing ongoing active treatment; start infusion of 10ml/kg of 5% dextrose over 1hr ± desmopressin 2mcg IV	up to 48 hours
Change of Glasgow coma scale (GCS) ≤8	Change in GCS of hyponatremia symptoms at pretreatment, 24 hours, and 48 hours after treatment	up to 48 hours

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: National Research Foundation of Korea
• Investigators: Principal Investigator: Seon Ha Baek, PhD, Hallym University Dongtan Sacred hospital

Publications and helpful links

General Publications

• Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. doi: 10.1530/EJE-13-1020. Print 2014 Mar. Erratum In: Eur J Endocrinol. 2014 Jul;171(1):X1.
• 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 Intern Med. 2021 Jan 1;181(1):81-92. doi: 10.1001/jamainternmed.2020.5519.
• Lee A, Jo YH, Kim K, Ahn S, Oh YK, Lee H, Shin J, Chin HJ, Na KY, Lee JB, Baek SH, Kim S. Efficacy and safety of rapid intermittent correction compared with slow continuous correction with hypertonic saline in patients with moderately severe or severe symptomatic hyponatremia: study protocol for a randomized controlled trial (SALSA trial). Trials. 2017 Mar 29;18(1):147. doi: 10.1186/s13063-017-1865-z.

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): September 30, 2019
• Study Completion (Actual): September 30, 2019

Study Registration Dates

• First Submitted: August 1, 2016
• First Submitted That Met QC Criteria: August 29, 2016
• First Posted (Estimate): September 2, 2016

Study Record Updates

• Last Update Posted (Actual): April 9, 2020
• Last Update Submitted That Met QC Criteria: April 7, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Treatment; Hyponatremia; Hypertonic saline; Osmotic demyelination syndrome
• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyponatremia
• Other Study ID Numbers: B1605346003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No