Insulin Dextrose Infusion vs Nebulized Salbutamol vs Combination of Salbutamol and Insulin Dextrose in Acute Hyperkalemia (InSaKa)

InSaKa Trial: Insulin Dextrose Infusion Versus Nebulized Salbutamol Versus Combination of Salbutamol and Insulin Dextrose in Acute Hyperkalemia: a Randomized Clinical Trial

Hyperkalemia is a common electrolyte disorder, especially among patients with chronic kidney disease, diabetes mellitus, or heart failure. Globally, the reported incidence of hyperkalemia varies from 1.1 to 10 per 100 hospitalizations, depending on the patient cohort and comorbidities. Hyperkalemia is a potentially life-threatening electrolyte disturbance that can be fatal if left untreated. Several studies have established the association between hyperkalemia and all-cause mortality. Because of the deleterious cardiac effects of hyperkalemia, its management is an emergency intervention. However, robust evidence is lacking to guide the emergency management of patients with hyperkalemia. Emergency treatment approaches are largely based on small studies, anecdotal experience, and traditionally accepted practice patterns within institutions. Therefore, a rigorous evaluation of the first-line treatments of hyperkalemia in emergency departments is needed and a large scale randomized clinical trial is warranted before robust recommendations for clinical practice can be made. Our clinical trial will improve the safety of patients with acute hyperkalemia and will help clinicians in their day by day practice to choose the treatment that significantly reduces morbidity and mortality during acute hyperkalemia management. Our results will be delivered in a timely fashion, owing to the high prevalence of hyperkalemia in the emergency department setting and to the commitment of the INI-CRCT network of Excellence, along with ED specialists used to work jointly.

the primary objective of our trial is to compare insulin/dextrose intravenous infusion, nebulized salbutamol or combination of nebulized salbutamol and insulin/dextrose intravenous infusion to reduce serum potassium concentration at 60 minutes, as first-line treatment, in emergency departments.

Study Overview

• Status: Recruiting
• Conditions: Hyperkalemia
• Intervention / Treatment: Drug: Salbutamol; Drug: Insulin Aspart

Detailed Description

InSaKa trial is a therapeutic, controlled, open label, with parallel groups of treatment in a 1:1:1 ratio, multi-centre, national and randomized clinical trial to compare insulin/dextrose intravenous infusion, nebulized salbutamol or combination of salbutamol and insulin/dextrose to reduce serum potassium levels at 60 minutes. Eligible patients will be recruited in the emergency department and included in the study after testing for inclusion and non-inclusion criteria. Patients will be eligible for the randomization if they had a serum potassium concentration superior or equal to 6 mmol per liter. Randomization, which will be performed centrally, will be stratified 1) according to the serum potassium level at baseline of the initial treatment phase (6 to < 6.5 mmol per liter [moderate hyperkalemia] AND superior or equal to 6.5 mmol per liter [severe hyperkalemia]), and 2) according to the prescription or not of intravenous diuretics during the 6 previous hours. The protocol will be approved by the ethical committee (random allocation) of the IRB. All patients will provide written informed consent and the study will be performed in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice. All electrocardiograms will be read at a core electrocardiographic laboratory. At the time of screening, patients who meet all the inclusion and do not have non-inclusion criteria will be assigned to one of the 3 groups of treatment. The serum potassium will be then measured at 60 minutes. If the patient still has hyperkalemia at 60 minutes, the patient will be re-administered a treatment, left at the discretion of the physician in charge. This treatment might include insulin/dextrose intravenous infusion, nebulized salbutamol, the combination of nebulized salbutamol and insulin/dextrose intravenous infusion, bicarbonate, diuretics or dialysis. Especially, bicarbonate should be prescribed in case of metabolic acidosis or hypovolemic shock, and diuretics in case of acute heart failure. Importantly, if the patient has a major cardiovascular event before 60 minutes, all these treatments might be prescribed at the discretion of the physician in charge, if the clinical situation requires one or more of these therapeutic options, and based on up-to-date clinical practice guidelines and recommendations. Serum potassium levels will be measured at local laboratories at baseline and 60, 180 minutes and 24 hours. They will perform a visual inspection and a validated semi-quantitative test on each blood sample as an assessment for hemolysis. An independent adjudication committee will adjudicate all major cardiovascular events. The trial will be monitored by a Data Safety Monitoring Board.

• Study Type: Interventional
• Enrollment (Estimated): 525
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Emmanuel MONTASSIER; Phone Number: 02 53 48 20 38; Email: emmanuel.montassier@chu-nantes.fr

Study Locations

• France
  • Agen, France
    • Recruiting
    • Agen Hospital
    • Contact: Albert TRINC DUC
  • Angers, France
    • Recruiting
    • Angers University Hospital
    • Contact: Bruno CARNEIRO
  • Bobigny, France
    • Not yet recruiting
    • Avicenne University Hospital
    • Contact: Anne-Laure FERAL-PIERSSENS
  • Clermont-Ferrand, France
    • Recruiting
    • University Hospital, Clermont-Ferrand
    • Contact: Jeannot SCHMIDT
  • Colombes, France
    • Active, not recruiting
    • Louis Mourier Hospital
  • Grenoble, France
    • Recruiting
    • University Hospital, Grenoble
    • Contact: Maxime MAIGNAN
  • Nancy, France
    • Recruiting
    • Nancy University Hospital
    • Contact: Tahar CHOUIHED
  • Nantes, France
    • Recruiting
    • Nantes University Hospital
    • Contact: Emmanuel Montassier
  • Nice, France
    • Active, not recruiting
    • Nice university hospital
  • Paris, France
    • Recruiting
    • Lariboisière Hospital
    • Contact: Xavier EYER
  • Paris, France
    • Recruiting
    • La Pitié Salpêtrière University Hospital
    • Contact: Yonathan FREUND
  • Paris, France
    • Recruiting
    • Saint Antoine University Hospital
    • Contact: Pierre-Clément THIEBAUD
  • Poitiers, France
    • Recruiting
    • Poitiers university hospital
    • Contact: Olivier MIMOZ
  • Rennes, France
    • Recruiting
    • Rennes university hospital
    • Contact: Nicolas Peschanski, PhD
  • Strasbourg, France
    • Not yet recruiting
    • Strasbourg university hospital
    • Contact: Pierrick LE BORGNE
  • Tours, France
    • Recruiting
    • Tours university Hospital
    • Contact: Paul-Louis MARTIN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient older than 18 years old
• Patient admitted to the emergency department,
• Patient with local laboratory serum potassium level superior or equal to 5,5 mmol/l,
• Patient who provide written informed consent prior to participation in the study

Exclusion Criteria:

• Hemolysis or thrombocytosis > 106/mm3 or hyperleukocytosis > 105/mm3 on the first blood sample suspecting a pseudohyperkalemia,
• Diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome,
• Pregnant or lactating woman, women with childbearing potential who didn't have effective contraception*,
• Patient expected to require emergency intubation and ventilation,
• Patient expected to require dialysis, diuretics or bicarbonate within the first 60 minutes,
• Patient with heart rhythm disorders or high grade atrioventricular bloc who require urgent medication as soon as admission or serum potassium level result,
• Hypersensitivity to the tested active substance or excipients,
• Acute coronary syndrome,
• Patient not affiliated to a health insurance plan,

• Patient under guardianship, curatorship or safeguard of justice.

  • The contraceptives considered as highly effective and acceptable by CTFG recommendations will be considered effective under this protocol. The list of contraceptives considered as highly effective and acceptable by CTFG recommendations is detailed in Appendix 7

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Salbutamol; Patients in this experimental group will receive : 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air);	Drug: Salbutamol; 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air) 10 units of regular insulin (rapid-acting, insuline asparte, intravenous injection) as an intravenous bolus with 500 ml of 10% dextrose in water administered over a 30-minute period.; Other Names: Salbutamol and Hyperkaliemia
Active Comparator: Insuline + dextrose; Patients in the experimental group will receive : 10 units of regular insulin (rapid-acting, insuline asparte, intravenous injection) as an intravenous bolus with 500 ml of 10% dextrose in water administered over a 30-minute period	Drug: Insulin Aspart; Patients in the experimental group will receive either: 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air); OR; 10 units of regular insulin (rapid-acting, insuline asparte, intravenous injection) as an intravenous bolus with 500 ml of 10% dextrose in water administered over a 30-minute period plus 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air). The nurse will start by giving the 10 units of insulin and the dextrose, and then, immediately, she will start the nebulization of salbutamol.; Other Names: Insulin and Hyperkaliemia
Experimental: Insuline + Dextrose + Salbutamol; Patients in the experimental group will receive either: 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air); OR; 10 units of regular insulin (rapid-acting, insuline asparte, intravenous injection) as an intravenous bolus with 500 ml of 10% dextrose in water administered over a 30-minute period plus 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air). The nurse will start by giving the 10 units of insulin and the dextrose, and then, immediately, she will start the nebulization of salbutamol.	Drug: Salbutamol; 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air) 10 units of regular insulin (rapid-acting, insuline asparte, intravenous injection) as an intravenous bolus with 500 ml of 10% dextrose in water administered over a 30-minute period.; Other Names: Salbutamol and Hyperkaliemia; Drug: Insulin Aspart; Patients in the experimental group will receive either: 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air); OR; 10 units of regular insulin (rapid-acting, insuline asparte, intravenous injection) as an intravenous bolus with 500 ml of 10% dextrose in water administered over a 30-minute period plus 10 mg of salbutamol nebulized in 30 minutes (with oxygen 8 liters per minute or with air). The nurse will start by giving the 10 units of insulin and the dextrose, and then, immediately, she will start the nebulization of salbutamol.; Other Names: Insulin and Hyperkaliemia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in the absolute serum potassium level from baseline to 60 minutes	The primary outcome of our trial will be mean change in the absolute serum potassium level from baseline to 60 minutes (measured in mmol/l), and will be aggregated using median and interquartile.	60 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in the serum potassium level from baseline to 180 minutes and 24 hours		180 minutes and 24 hours
Proportion of patients who had a serum potassium level of 4 mmol/l to less than 4.9 mmol/l at 60, 180 minutes and 24 hours		60 minutes, 180 minutes and 24 hours
Proportion of patients who require re-treatment or dialysis at 60, 180 minutes and 24 hours		60 minutes, 180 minutes and 24 hours
Proportion of patients with adverse effects at 60 and 180 minutes	Proportion of patients with adverse effects at 60 and 180 minutes : Hypokalemia (serum potassium level <3.5 mmol/l and <4 mmol/l); Hypomagnesemia (serum magnesium level of less than 0.58 mmol per liter); Hypoglycemia (serum glucose level < 4.0 mmol/l); Hyperglycemia (serum glucose level > 10.0 mmol/l); Gastrointestinal disorders: i. Diarrhea ii. Nausea iii. Vomiting f. Tachycardia (> 130/min) g. Tremor	60 minutes and 180 minutes
Proportion of patients with heart rhythm disorders or high grade atrioventricular bloc that required urgent medication during the first 180 minutes		180 minutes
Proportion of patients with electrocardiographic abnormalities, at 60, 180 minutes and 24 hours	Proportion of patients with electrocardiographic abnormalities, at 60, 180 minutes and 24 hours , including: Auricular extrasystoles; Ventricular extrasystoles; Atrioventricular block; QRS Interval Prolongation (> 120 ms); QT interval prolongation (> 500 ms)	60 minutes 180 minutes and 24 hours
Proportion of major cardiovascular events at 60, 180 minutes and 24 hours	Proportion of major cardiovascular events at 60, 180 minutes and 24 hours : cardiac arrest; stroke; acute heart failure; complete atrioventricular block with ventricular rate under 30 bpm; ventricular fibrillation; ventricular tachycardia	60minutes 180 minutes and 24 hours

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Investigators: Principal Investigator: Jacques LEVRAUT, Nice University Hopsital; Principal Investigator: Maxime MAIGNAN, University Hospital, Grenoble; Principal Investigator: Jeannot SCHMIDT, University Hospital, Clermont-Ferrand; Principal Investigator: Meïssa KARE, Agen Hospital; Principal Investigator: Tahar CHOUIHED, Central Hospital, Nancy, France; Principal Investigator: Florent MAILLET, Louis Mourier Hospital; Principal Investigator: Quentin DELANNOY, La Pitié Salpêtrière University Hospital; Principal Investigator: Nicolas MARJANOVIC, Poitiers university hospital; Principal Investigator: Bruno CARNEIRO, Angers University Hospital; Principal Investigator: Paul-Louis MARTIN, Tours university Hospital; Principal Investigator: Pierrick LE BORGNE, University Hospital, Strasbourg, France; Principal Investigator: Nicolas PESCHANSKI, Rennes university hospital; Principal Investigator: Pierre-Clément THIEBAUD, Saint Antoine University Hospital; Principal Investigator: Anne-Laure FERAL-PIERSSENS, Avicenne University Hospital; Principal Investigator: Xavier EYER, Lariboisière Hospital

Publications and helpful links

General Publications

• Montassier E, Lemoine L, Hardouin JB, Rossignol P, Legrand M. Insulin glucose infusion versus nebulised salbutamol versus combination of salbutamol and insulin glucose in acute hyperkalaemia in the emergency room: protocol for a randomised, multicentre, controlled study (INSAKA). BMJ Open. 2020 Aug 26;10(8):e039277. doi: 10.1136/bmjopen-2020-039277.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2019
• Primary Completion (Estimated): December 20, 2025
• Study Completion (Estimated): June 20, 2026

Study Registration Dates

• First Submitted: July 5, 2019
• First Submitted That Met QC Criteria: July 5, 2019
• First Posted (Actual): July 9, 2019

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: insulin; salbutamol; hyperkaliema
• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia; Hypoglycemic Agents; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Insulin; Insulin, Globin Zinc; Insulin Aspart; Albuterol
• Other Study ID Numbers: RC19_0048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Trial data are not publicly available owing to data privacy, but access to the anonymised dataset can be obtained from the corresponding author on reasonable request.
• IPD Sharing Access Criteria: the dataset can be obtained from the corresponding author on reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No