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

NCT ID: NCT04949139

Last Updated: 2025-08-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 178 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-01
• Study Completion Date: 2025-02-22

Brief 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).

Detailed 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.

Conditions

Hypernatremia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rapid intermittent bolus group

A : males < 65 ; B : females < 65 or males ≥ 65 ; C : females ≥ 65 yrs

<During the first 3 h>

Primary treatment over 1h A: 5DW 8 B: 5DW 7 C: 5DW 6 mL/kg

If undercorrected, Repeat the 5DW amount infused during primary treatment after 3 h

<At 3-24 h> Modify protocol based on sNa at each time point (6/12/18/24 h)

Check U/S ratio at 0 h

• undercorrection < 0.5: repeat the amount infused during primary treatment q 3 h

≥ 0.5: repeat the amount infused during primary treatment q 6 h

• target correction < 0.5: repeat the amount infused during primary treatment q 6 h ≥ 0.5: stop the infusion

<At 24-48 h> Modify protocol based on sNa at each time point (30/36/42/48 h)

Check U/S ratio at 24 h

• undercorrection < 0.5: repeat the amount infused during primary treatment q 3 h

≥ 0.5: repeat the amount infused during primary treatment q 6 h

• target correction < 0.5: repeat the amount infused during primary treatment q 6 h ≥ 0.5: stop the infusion

Group Type: ACTIVE_COMPARATOR

Dextrose 5% in water

Intervention Type: DRUG

Reducing the sodium concentration

Slow continuous infusion group

Participants will be divided into three groups same as above

<During the first 3 h>

Primary treatment A: 5DW 1.8 B: 5DW 1.57 C: 5DW 1.35 mL/kg/h

Modify protocol as described below based on sNa measurement at 3 h

• undercorrection: maintain the infusion rate
• target correction: stop the infusion

<At 3-24 h> Modify protocol based on sNa measurement at each time point (6/12/18/24 h)

Check U/S ratio at 0 h

• undercorrection

< 0.5: increase the infusion rate to twice that of the primary treatment

≥ 0.5: maintain the infusion rate

• target correction

< 0.5: maintain the infusion rate

≥ 0.5: stop the infusion

<At 24-48 h> Modify protocol based on sNa measurement at each time point (30/36/42/48 h)

Check U/S ratio at 24 h

• undercorrection

< 0.5: increase the infusion rate to twice that of the primary treatment

≥ 0.5: maintain the infusion rate

• target correction

< 0.5: maintain the infusion rate

≥ 0.5: stop the infusion

Group Type: ACTIVE_COMPARATOR

Dextrose 5% in water

Intervention Type: DRUG

Reducing the sodium concentration

Interventions

Dextrose 5% in water

Reducing the sodium concentration

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Seoul National University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sejoong Kim, PhD

Role: STUDY_DIRECTOR

Seoul National University Bundang Hospital

Locations

Hallym University Dongtan Sacred Heart Hospital

Hwaseong-si, Gyeonggi-do, South Korea

Countries

South Korea

References

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.

Reference Type: BACKGROUND

PMID: 30728169 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30948456 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10225241 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 10816188 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31064771 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28669048 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22762930 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24559470 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21358313 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12897339 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24569125 (View on PubMed)

Other Identifiers

B-2104-680-003

Identifier Type: -

Identifier Source: org_study_id