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

Hypernatremia Clinical Trial

— SALSAII  

Official title:

Efficacy and Safety of Rapid Intermittent Correction Compared With Slow Continuous Correction in Patients With Severe Hypernatremia (SALSA II Trial)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04949139
• Other study ID #: B-2104-680-003
• Status: Recruiting
• Phase: Phase 4
• Start date: May 1, 2021
• Est. completion date: May 31, 2026

Study information

• Verified date: August 2023
• Source: Seoul National University Hospital
• Contact: Sejoong Kim, PhD
• Phone: +821094964899
• Email: sejoong2[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the efficacy and safety of rapid intermittent correction and slow correction with an electrolyte-free solution in patients with severe hypernatremia (glucose-corrected serum sodium, ≥ 155 mmol/L).

Description:

Hypernatremia is defined as serum sodium (sNa) levels above 145 mmol/L and is caused by abnormalities in water balance, mainly in children, elderly, and critically ill patients. It occurs in 3% of hospitalized patients and in 9% of critically ill patients. Hypernatremia indicates hypertonic hyperosmolality and causes water outflow, resulting in cell dehydration. Most of the symptoms and signs of hypernatremia are due to brain abnormalities, which can progress to hyperventilation, muscle weakness, consciousness (lethargy), and coma. The short-term mortality rate of hypernatremia is 50%-60%. Decreased osmotic pressure in the extracellular fluid during correction of hyponatremia can cause cellular edema and permanent brain damage. The recommended sNa correction rate for acute hypernatremia is up to 1 mmol/L/h, whereas that for chronic hypernatremia is less than 0.5 mmol/L/h (approximately 10 mmol/L/day). However, these correction rates have only been studied and proven in pediatric patients. A recent study conducted on adults revealed that rapid correction (more than 0.5 mmol/L/h) was not associated with a higher risk for mortality, seizures, and alteration of consciousness. Several studies reported that excessively slow rates of sNa correction were associated with higher mortality, whereas rapid rates demonstrated lower mortality. There are no established guidelines for the Na correction rate for hypernatremia. The European and American guidelines recommend infusion of electrolyte-free water (10 mL/kg over 1 h or 3 mL/kg/h) for the management of overcorrection of hyponatremia. In the previously published SALSA I trial, 10 mL/kg over 1 h was applied as a method of re-lowering treatment in overly rapid correction of hyponatremia. However, this rapid intermittent bolus of electrolyte-free water has never been applied to treat hypernatremia.

The aim of this prospective, randomized, open-labeled, multi-center, and investigator-initiated trial is to determine whether a rapid and intermittent bolus of electrolyte-free water in hypernatremia can increase the incidence of rapid decrease in sNa level and increase the survival time compared to the slow continuous administration method. A total of 166 patients with severe hypernatremia will be enrolled and randomly assigned to receive either intermittent bolus or slow continuous infusion of 5% dextrose water. The participants will be divided into three groups according to age and sex and will receive 5% dextrose water for 2 days at different correction rates. Serum sodium will be measured every 3 h from the beginning to 6 h, followed by every 6 h until 48 h. In addition, urine sodium and potassium levels will be measured at baseline and 24 h. The PP (Per Protocol) analysis will be applied to enrolled participants who is infused with 75-125% of total planned volume of 5% dextrose water.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 144
• Est. completion date: May 31, 2026
• Est. primary completion date: May 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients who visit the emergency department and in-patients over 18 years

• Severe hypernatremia: glucose-corrected serum sodium = 155 mmol/L

• Written consent

Exclusion Criteria:

• Arterial hypotension requiring inotropes or vasopressors (systolic blood pressure < 90 mmHg and mean arterial pressure < 70 mmHg)

• Anuria or bilateral urinary outlet obstruction

• Uncontrolled diabetes mellitus (HbA1C > 9%) or glucose at baseline > 500 mg/dL or uncontrolled diabetic ketoacidosis or uncontrolled hyperosmolar hyperglycemic syndrome

• Decompensated liver cirrhosis (LC) - Known LC with ascites or diuretic use or hepatic encephalopathy or varix

• End-stage renal disease receiving renal replacement therapy

• Uncontrolled Heart failure (regardless of LVEF)

• Women who are pregnant or breast feeding

• Patients with the following conditions within 30 days prior to randomization:

1. History of cardiac surgery excluding PCA, acute myocardial infarction, sustained ventricular tachycardia, ventricular fibrillation, acute coronary syndrome, and admission for heart failure

2. Uncontrolled increase of intracranial pressure

• The subjects judged by investigators to have difficulty continuing the trial were also excluded.

• The case the subjects does not consent to the study

Related Conditions & MeSH terms

• Hypernatremia

Intervention

Drug:
• Dextrose 5% in water
Reducing the sodium concentration

Locations

Country	Name	City	State
Korea, Republic of	Hallym University Dongtan Sacred Heart Hospital	Hwaseong	Gyeonggi-do

Sponsors (1)

Lead Sponsor	Collaborator
Seoul National University Hospital

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (11)

Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med. 2000 May 18;342(20):1493-9. doi: 10.1056/NEJM200005183422006. No abstract available. — View Citation

Alshayeb HM, Showkat A, Babar F, Mangold T, Wall BM. Severe hypernatremia correction rate and mortality in hospitalized patients. Am J Med Sci. 2011 May;341(5):356-60. doi: 10.1097/MAJ.0b013e31820a3a90. — View Citation

Bataille S, Baralla C, Torro D, Buffat C, Berland Y, Alazia M, Loundou A, Michelet P, Vacher-Coponat H. Undercorrection of hypernatremia is frequent and associated with mortality. BMC Nephrol. 2014 Feb 21;15:37. doi: 10.1186/1471-2369-15-37. — View Citation

Cabassi A, Tedeschi S. Severity of community acquired hypernatremia is an independent predictor of mortality: a matter of water balance and rate of correction. Intern Emerg Med. 2017 Oct;12(7):909-911. doi: 10.1007/s11739-017-1693-x. Epub 2017 Jul 1. No abstract available. — View Citation

Chauhan K, Pattharanitima P, Patel N, Duffy A, Saha A, Chaudhary K, Debnath N, Van Vleck T, Chan L, Nadkarni GN, Coca SG. Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients. Clin J Am Soc Nephrol. 2019 May 7;14(5):656-663. doi: 10.2215/CJN.10640918. Epub 2019 Apr 4. — View Citation

Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999 Apr;106(4):399-403. doi: 10.1016/s0002-9343(99)00055-8. — View Citation

Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care. 2013 Apr;28(2):216.e11-20. doi: 10.1016/j.jcrc.2012.05.001. Epub 2012 Jul 2. — View Citation

Qian Q. Hypernatremia. Clin J Am Soc Nephrol. 2019 Mar 7;14(3):432-434. doi: 10.2215/CJN.12141018. Epub 2019 Feb 6. No abstract available. — View Citation

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. — View Citation

Sterns RH, Silver SM. Salt and water: read the package insert. QJM. 2003 Aug;96(8):549-52. doi: 10.1093/qjmed/hcg102. No abstract available. — View Citation

Sterns RH. Evidence for Managing Hypernatremia: Is It Just Hyponatremia in Reverse? Clin J Am Soc Nephrol. 2019 May 7;14(5):645-647. doi: 10.2215/CJN.02950319. Epub 2019 Apr 4. No abstract available. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Target correction rate	Change in Na by = 6 mmol/L and < 12 mmol/L from the initial level or Na = 150 mmol/L within 24 hours Change in Na by = 12 mmol/L and < 24 mmol/L from the initial level or Na = 150 mmol/L within 48 hours	up to 48 hours
Other	Incidence of undercorrection:	sNa < 6 mmol/L within 3/6/12/24 hours sNa < 12 mmol/L within 48 h	up to 48 hours
Other	Length of hospital stay	Length of hospital stay	up to 8 weeks
Other	Number of uses of desmopressin	number of uses of demopressin	up to 48 hours
Other	Incidence of overcorrection	Na > 12 mmol/L within 24 h or > 24 mmol/L within 48 h at any given period	up to 48 hours
Other	Incidence of cerebral edema documented via brain CT at 48 hours in patients with overcorrection	incidence of cerebral edema	up to 48 hours
Other	Incidence of osmotic demyelinating syndrome confirmed by ICD-10 code or MRI	incidence of ODS	up to 48 hours
Other	Glasgow coma scale at pretreatment, 6 hours, 24 hours, and 48 hours	Glasgow coma scale can range from 3 (completely unresponsive) to 15 (responsive).	up to 48 hours
Other	In-hospital mortality	mortality rate	up to 28 days
Other	Incidence of administrated intravenous volume of = 3 L/day, except for fluids administrated according to the protocol	incidence of adminitrated intravenous volume of = 3 L/day	up to 48 hours
Primary	efficacy : Incidence of rapid change in sNa level within 24 hours defined as follows	Change in sNa by = 6 mmol/L or Na = 150 mmol/L within 24 hours All subjects will receive 5% dextrose water by rapid intermittent bolus or slow continuous infusion for 48 h, and sNa levels will be measured.	up to 24 hours
Secondary	the 28-day survival rate	survival rate	up to 28 days
Secondary	difference in sNa levels 6 hours after the initial test	Gap of sodium level between 6 hours and initial level	up to 6 hours
Secondary	volume of 5% dextrose water infused during 48 hours	Volume	up to 48 hours
Secondary	Incidence of rapid change in sNa level within 48 hours defined as follows	Change in sNa by = 12 mmol/L or Na = 150 mmol/L within 48 hours	up to 48 hours