Clinical trial NCT04012138: Insulin Dextrose Infusion vs Nebulized Salbutamol vs Combination of Salbutamol and Insulin Dextrose in Acute Hyperkalemia
Official title: InSaKa Trial: Insulin Dextrose Infusion Versus Nebulized Salbutamol Versus Combination of Salbutamol and Insulin Dextrose in Acute Hyperkalemia: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hyperkalemia
Keywords: hyperkaliema
insulin
salbutamol
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2019-07-09
Enrollment: 525
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model 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.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean change in the absolute serum potassium level from baseline to 60 minutes
timeFrame: 60 minutes
Secondary outcomes:
measure: Mean change in the serum potassium level from baseline to 180 minutes and 24 hours
timeFrame: 180 minutes and 24 hours
measure: 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
timeFrame: 60 minutes, 180 minutes and 24 hours
measure: Proportion of patients who require re-treatment or dialysis at 60, 180 minutes and 24 hours
timeFrame: 60 minutes, 180 minutes and 24 hours
measure: Proportion of patients with adverse effects at 60 and 180 minutes
timeFrame: 60 minutes and 180 minutes
measure: Proportion of patients with heart rhythm disorders or high grade atrioventricular bloc that required urgent medication during the first 180 minutes
timeFrame: 180 minutes
measure: Proportion of patients with electrocardiographic abnormalities, at 60, 180 minutes and 24 hours
timeFrame: 60 minutes 180 minutes and 24 hours
measure: Proportion of major cardiovascular events at 60, 180 minutes and 24 hours
timeFrame: 60minutes 180 minutes and 24 hours
Other outcomes:
Locations:
city: Agen
country: France
facility: Agen Hospital
city: Angers
country: France
facility: Angers University Hospital
city: Bobigny
country: France
facility: Avicenne University Hospital
city: Clermont-Ferrand
country: France
facility: University Hospital, Clermont-Ferrand
city: Colombes
country: France
facility: Louis Mourier Hospital
city: Grenoble
country: France
facility: University Hospital, Grenoble
city: Nancy
country: France
facility: Nancy University Hospital
city: Nantes
country: France
facility: Nantes University Hospital
city: Nice
country: France
facility: Nice University Hospital
city: Paris
country: France
facility: La Pitié Salpêtrière University Hospital
city: Paris
country: France
facility: Lariboisiere Hospital
city: Paris
country: France
facility: Saint Antoine University Hospital
city: Poitiers
country: France
facility: Poitiers University Hospital
city: Rennes
country: France
facility: Rennes University Hospital
city: Strasbourg
country: France
facility: Strasbourg University Hospital
city: Tours
country: France
facility: Tours University Hospital
Study officials:
affiliation: Nice University Hopsital
name: Julie CONTENTI
role: PRINCIPAL_INVESTIGATOR
affiliation: Saint Antoine University Hospital
name: Pierre-Clément THIEBAUD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Grenoble
name: Maxime MAIGNAN
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Clermont-Ferrand
name: Jeannot SCHMIDT
role: PRINCIPAL_INVESTIGATOR
affiliation: Agen Hospital
name: Meïssa KARE
role: PRINCIPAL_INVESTIGATOR
affiliation: Central Hospital, Nancy, France
name: Tahar CHOUIHED
role: PRINCIPAL_INVESTIGATOR
affiliation: Avicenne University Hospital
name: Anne-Laure FERAL-PIERSSENS
role: PRINCIPAL_INVESTIGATOR
affiliation: Louis Mourier Hospital
name: Florent MAILLET
role: PRINCIPAL_INVESTIGATOR
affiliation: La Pitié Salpetrière University Hospital
name: Quentin DELANNOY
role: PRINCIPAL_INVESTIGATOR
affiliation: Poitiers University Hospital
name: Nicolas MARJANOVIC
role: PRINCIPAL_INVESTIGATOR
affiliation: Angers University Hospital
name: delphine DOUILLET
role: PRINCIPAL_INVESTIGATOR
affiliation: Tours University Hospital
name: Paul-Louis MARTIN
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Strasbourg, France
name: Pierrick LE BORGNE
role: PRINCIPAL_INVESTIGATOR
affiliation: Lariboisière Hospital
name: Xavier EYER
role: PRINCIPAL_INVESTIGATOR
affiliation: Rennes University Hospital
name: Nicolas PESCHANSKI
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.