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

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.

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