Epinephrine versus Isoprenaline During Out-of-Hospital Cardiac Arrest with Non-Shockable Rhytm (EPISO)

Phase 3

Withdrawn

Conditions: Cardiac arrest

Interventions: Drug: Isoprenaline Only Product

Registration Number: 2024-516074-29-00

Lead Sponsor: Odense University Hospital

Brief Summary: To determine whether the use of isoprenaline increases the chance of sustained return of spontaneous circulation during out-of-hospital cardiac arrest with non-shockable rhythm compared with epinephrine.

Detailed Description: Background: Out-of-hospital cardiac arrest (OHCA) is the leading cause of death in industrialized countries. During OHCA, the patient will present with either a non-shockable or a shockable rhythm. A shockable rhythm is treated by defibrillation, which means delivering an electrical shock through the heart to reestablish normal cardiac electric activity. If a shockable rhythm is defibrillated early, chances of survival can exceed 50%. However, if the shockable rhythm remains untreated, it will deteriorate into a non-shockable rhythm with dismal survival rates of 1-5%. Epinephrine increases the chance of return of spontaneous circulation (ROSC), however, there is increasing evidence that use of epinephrine is associated with severe neurological impairment in survivors. Isoprenaline is a pro-arrhythmic drug used to treat bradycardia. The drug has structural resemblance to epinephrine, however, it has no effect on alfa-adrenoceptors in the cerebral bloodflow and only stimulates beta-adrenoceptors. These pro-arrhythmic properties may induce cardiac electrical activity during OHCA with a non-shockable rhythm, converting it to a shockable rhythm treatable by defibrillation, while preserving microcirculatory cerebral blood flow.

Hypothesis: Injection of isoprenaline in bystander witnessed OHCAs with asystole increases the chance of ROSC at hospital arrival compared with the injection of epinephrine.

Population: According to the Danish Cardiac Arrest Registry, the annual incidence of OHCAs in the Region of Southern Denmark is about 1200, half of which are bystander witnessed. In the recent 2022 report, the incidence of non-shockable first rhythm among these was 1,044 out of 1,233 patients (85%), of which about 9 out of 10 had asystole. Therefore, an annual number of 450 bystander witnessed OHCAs with non-shockable rhythm could be eligible for study entry, however, despite eligibility, previous study have found that about 20-25% of patients are not enrolled in similar OHCA trials, and the expected annual number of enrollments will therefore be 360 OHCAs.

Settings: The study will take place in the Region of Southern Denmark. The Region has 42 EMS ambulance stations and 6 physician-manned vehicles with a median response time of about 8 minutes. The EMS ambulance has an emergency medical technician (EMT) and an EMT assistant, trained in analysing shockable/non-shockable rhythms and administering intravenous drugs according to the advanced life support algorithm.

Intervention: On EMS arrival, OHCA patients will be randomly assigned to receive an intravenous injection of isoprenaline or to receive an intravenous injection of adrenaline in a 1:1 ratio.

Study design: A randomized-controlled trial.

Main outcome: Main outcome is ROSC at hospital arrival. Secondary outcomes are conversion from non-shockable to shockable rhythm, 30-day survival with good neurological outcome (Cerebral Performance Category Scale of 1 or 2).

Power analysis: Thirty-day survival among OHCAs with non-shockable rhythm is reported at 1-5%. In a Danish study, the conversion of a non-shockable rhythm to a shockable rhythm increased the rate of ROSC at hospital arrival to 14.5% compared with 8.4% for sustained non-shockable rhythms. Thirty-day survival in the two groups were 4.2% versus 1.2%, respectively. According to this study, about 1 in 8 non-shockable rhythms converted to a shockable rhythm. Presuming that isoprenaline injection may double the conversion to shockable rhythm to 1 in 4 non-shockable rhythms, this would increased chance of ROSC at hospital arrival to approximately 13%. Therefore, assuming a conservative difference estimate of about 5% (estimate of 13% in the intervention group and 8% in the control group), this study will require a total sample size of 1178 patients with 589 OHCAs in each group (power value of 0.80 and significance level of 0.05) to evaluate the hypothesis. An inclusion time of approximately 3.5 years is therefore to be expected.

Recruitment & Eligibility

Status: Not authorised

Sex: Not specified

Target Recruitment: 1178

Inclusion Criteria

Men and women with bystander and/or emergency medical service personnel witnessed out-of-hospital cardiac arrest.

Age ≥18 years.

Initial rhythm non-shockable rhythm (PEA or asystole).

Advanced life support initiated or continued by EMS personnel.

Exclusion Criteria

Cardiac arrest caused by or suspected to be caused by blunt trauma, penetrating trauma, or burn injury.

Cardiac arrest caused by or suspected to be caused by drowning, hanging, strangulation, and foreign body airway obstruction.

IV epinephrine already administered prior to EMS arrival.

Prior enrollment in the trial.

Patient with cardiac arrest at nursing homes.

Known or apparent pregnancy.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control group	Isoprenaline Only Product	Epinephrine (adrenaline)
Intervention group	Isoprenaline Only Product	Isoprenaline

Primary Outcome Measures

Name	Time	Method
Sustained return of spontaneous circulation of at least 20 minutes.		Sustained return of spontaneous circulation of at least 20 minutes.

Secondary Outcome Measures

Name	Time	Method
Conversion from non-shockable to shockable rhythm		Conversion from non-shockable to shockable rhythm
Favorable neurological outcome at hospital discharge		Favorable neurological outcome at hospital discharge
ROSC at hospital arrival		ROSC at hospital arrival
Thirty-day survival		Thirty-day survival

Trial Locations

Locations (2): Odense University Hospital
🇩🇰
Odense C, Denmark
Rigshospitalet
🇩🇰
Copenhagen Oe, Denmark
Odense University Hospital
🇩🇰Odense C, Denmark
Laura Sarkisian
Site contact
+4527859444
Laura.Sarkisian2@rsyd.dk