PARAMEDIC2 Trial Research Articles

401 Adrenaline for traumatic cardiac arrest: a post hoc analysis of the PARAMEDIC2 trial

401 Adrenaline for traumatic cardiac arrest: a post hoc analysis of the PARAMEDIC2 trial

Temporal Changes in Epinephrine Dosing in Out-of-Hospital Cardiac Arrest: A Review of EMS Protocols across the United States.

Administration of epinephrine has been associated with worse neurological outcomes for survivors of out-of-hospital cardiac arrest. The publication of the 2018 PARAMEDIC-2 trial, a randomized and double-blind study of epinephrine in out-of-hospital cardiac arrest, provides the strongest evidence to date that epinephrine increases return of spontaneous circulation (ROSC) but not neurologically intact survival. This study aims to determine if Emergency Medical Services (EMS) cardiac arrest protocols have changed since the publication of PARAMEDIC-2. States in the US utilizing mandatory or model state-wide EMS protocols, including Washington DC, were included in this study. The nontraumatic cardiac arrest protocol as of January 1, 2018 was compared to the protocol in effect on January 1, 2021 to determine if there was a change in the administration of epinephrine. Protocols were downloaded from the relevant state EMS website. If a protocol could not be obtained, the state medical director was contacted. A 2021 state-wide protocol was found for 32/51 (62.7%) states. Data from 2018 were available for 21/51 (41.2%) states. Of the 11 states without data from 2018, all follow Advanced Cardiac Life Support (ACLS) guidelines in the 2021 protocol. Five (15.6%) of the states with a state-wide protocol made a change in the cardiac arrest protocols. Maximum cumulative epinephrine dose was limited to 4mg in Maryland and 3mg in Vermont. Rhode Island changed epinephrine in shockable rhythms to be administered after three cycles of cardiopulmonary resuscitation (CPR) and an anti-arrhythmic. Rhode Island also added an epinephrine infusion as an option. No states removed epinephrine administration from their cardiac arrest protocol. Simple statistical analysis was performed with Microsoft Excel. Several states have adjusted cardiac arrest protocols since 2018. The most frequent change was limiting the maximum cumulative dosage of epinephrine. One state changed timing of epinephrine dosing depending on the rhythm and also provided an option of an epinephrine infusion in place of bolus dosing. While the sample size is small, these changes may reflect the future direction of prehospital cardiac arrest protocols. Significant limitations apply, including the exclusion of local and regional protocols which are more capable of quickly adjusting to new research. Additionally, this study is only focused on EMS in the United States.

P089 Media coverage of the PARAMEDIC-2 trial: an analysis of print media reports

P089 Media coverage of the PARAMEDIC-2 trial: an analysis of print media reports

Patient safety incidents and medication errors during a clinical trial: experience from a pre-hospital randomized controlled trial of emergency medication administration

To assess and evaluate patient safety incidents and in particular, medication errors, during a large multi-center pre-hospital trial of emergency therapy (PARAMEDIC2), in order to inform and improve future pre-hospital medicines trials. The PARAMEDIC2 trial was undertaken across five NHS Ambulance Services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out -of-hospital cardiac arrest unresponsive to initial resuscitation were randomly assigned to 1mg intravenous adrenaline or matching placebo. Records were reviewed to identify trial medication errors involving documentation and/or clinical protocol errors occurring in trial participants. Causes of medication errors, including root cause analysis where available, were reviewed to identify patterns and themes contributing to these errors. Eight thousand sixteen patients were enrolled, of whom 4902 received trial medication. A total of 331 patient safety incidents was reported, involving 295 patients, representing an overall rate of 3.6% of these, 166 (50.2%) were documentation errors while 165 (49.8%) were clinical protocol/medication errors. An overall rate of 0-4.5% was reported across all five ambulance services, with a mean of 2.0%. These errors had no impact on patient care or the trial and were all resolved CONCLUSION: The overall medication error rate of 1.8% primarily consisted of administration of open-label adrenaline and confusion with trial medication packs. A similar number of patients had documentation errors. This study is the first to provide data on patient safety incidents relating to medication errors encountered during a pre-hospital trial of emergency medication administration and will provide supporting data for planning future trials in this area.

Bayesian group sequential designs for phase III emergency medicine trials: a case study using the PARAMEDIC2 trial

BackgroundPhase III trials often require large sample sizes, leading to high costs and delays in clinical decision-making. Group sequential designs can improve trial efficiency by allowing for early stopping for efficacy and/or futility and thus may decrease the sample size, trial duration and associated costs. Bayesian approaches may offer additional benefits by incorporating previous information into the analyses and using decision criteria that are more practically relevant than those used in frequentist approaches. Frequentist group sequential designs have often been used for phase III studies, but the use of Bayesian group sequential designs is less common. The aim of this work was to explore how Bayesian group sequential designs could be constructed for phase III trials conducted in emergency medicine.MethodsThe PARAMEDIC2 trial was a phase III randomised controlled trial that compared the use of adrenaline to placebo in out-of-hospital cardiac arrest patients on 30-day survival rates. It used a frequentist group sequential design to allow early stopping for efficacy or harm. We constructed several alternative Bayesian group sequential designs and studied their operating characteristics via simulation. We then virtually re-executed the trial by applying the Bayesian designs to the PARAMEDIC2 data to demonstrate what might have happened if these designs had been used in practice.ResultsWe produced three alternative Bayesian group sequential designs, each of which had greater than 90% power to detect the target treatment effect. A Bayesian design which performed interim analyses every 500 patients recruited produced the lowest average sample size. Using the alternative designs, the PARAMEDIC2 trial could have declared adrenaline superior for 30-day survival with approximately 1500 fewer patients.ConclusionsUsing the PARAMEDIC2 trial as a case study, we demonstrated how Bayesian group sequential designs can be constructed for phase III emergency medicine trials. The Bayesian framework enabled us to obtain efficient designs using decision criteria based on the probability of benefit or harm. It also enabled us to incorporate information from previous studies on the treatment effect via the prior distributions. We recommend the wider use of Bayesian approaches in phase III clinical trials.Trial registrationPARAMEDIC2 Trial registration ISRCTN, ISRCTN73485024. Registered 13 March 2014, http://www.isrctn.com/ISRCTN73485024

The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial

PurposeTo examine the time to drug administration in patients with a witnessed cardiac arrest enrolled in the Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) randomised controlled trial.MethodsThe PARAMEDIC2 trial was undertaken across 5 NHS ambulance services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out-of-hospital cardiac arrest who were unresponsive to initial resuscitation attempts were randomly assigned to 1 mg intravenous adrenaline or matching placebo according to treatment packs that were identical apart from treatment number. Participants and study staff were masked to treatment allocation.Results8016 patients were enrolled, 4902 sustained a witnessed cardiac arrest of whom 2437 received placebo and 2465 received adrenaline. The odds of return of spontaneous circulation decreased in both groups over time but at a greater rate in the placebo arm odds ratio (OR) 0.93 (95% CI 0.92–0.95) compared with the adrenaline arm OR 0.96 (95% CI 0.95–0.97); interaction OR: 1.03, 95% CI 1.01–1.05, p = 0.005. By contrast, although the rate of survival and favourable neurological outcome decreased as time to treatment increased, the rates did not differ between the adrenaline and placebo groups.ConclusionThe rate of return of spontaneous circulation, survival and favourable neurological outcomes decrease over time. As time to drug treatment increases, adrenaline increases the chances of return of spontaneous circulation. Longer term outcomes were not affected by the time to adrenaline administration. (ISRCTN73485024).

Phenomenological study exploring ethics in prehospital research from the paramedic’s perspective: experiences from the Paramedic-2 trial in a UK ambulance service

ObjectivesWe set out to investigate paramedics’ views of ethics and research, drawing on experiences from Paramedic-2, a randomised controlled trial comparing epinephrine and placebo in out-of-hospital cardiac arrest (OHCA).MethodsAn interpretative...

'PARAMEDIC-2: Big study, small result'.

The PARAMEDIC-2 trial demonstrated that the use of adrenaline compared with placebo in out-of-hospital cardiac arrest (OHCA) resulted in a small increase in 30-day survival, but was associated with a higher number of survivors with severe neurological impairment. These findings received a lot of attention, and generated a widespread discussion about the role of adrenaline in cardiac arrest. In this point of view, we aim to place the PARAMEDIC-2 results in the right perspective by comparing the relative effect of adrenaline to other determinants of cerebral blood flow.

Rethinking the role of epinephrine in cardiac arrest: the PARAMEDIC2 trial

Epinephrine (adrenaline) is the most commonly used medication in cardiac arrest, and is the only drug recommended by the American Heart Association (AHA) for all arrests regardless of cardiac rhythm (1). The use of epinephrine in cardiac arrest originated from studies in the 1960’s, when epinephrine was found to improve survival in dog models of asphyxia (2). Physiologically, epinephrine produces some effects that may be helpful and others that may be harmful. It is an agonist at both beta- and alpha-adrenergic receptors. The alpha effects cause peripheral vasoconstriction, which in turn leads to increased blood flow in the central circulation, improving perfusion of the heart and brain. These effects are potentially beneficial, and have been hypothesized to increase the likelihood of return of spontaneous circulation (ROSC) among cardiac arrest patients. The beta-adrenergic effects increase cardiac rate, contractility, and automaticity; these effects are potentially deleterious, leading to arrhythmias and increased myocardial oxygen demand.

Adrenaline in patients with out-of-hospital cardiac arrest : PARAMEDIC2 trial

Adrenaline in patients with out-of-hospital cardiac arrest : PARAMEDIC2 trial

Pre-hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest (PARAMEDIC-2): Trial protocol

Despite its use since the 1960s, the safety or effectiveness of adrenaline as a treatment for cardiac arrest has never been comprehensively evaluated in a clinical trial. Although most studies have found that adrenaline increases the chance of return of spontaneous circulation for short periods, many studies found harmful effects on the brain and raise concern that adrenaline may reduce overall survival and/or good neurological outcome. The PARAMEDIC-2 trial seeks to determine if adrenaline is safe and effective in out-of-hospital cardiac arrest.This is a pragmatic, individually randomised, double blind, controlled trial with a parallel economic evaluation. Participants will be eligible if they are in cardiac arrest in the out-of-hospital environment and advanced life support is initiated. Exclusions are cardiac arrest as a result of anaphylaxis or life threatening asthma, and patient known or appearing to be under 16 or pregnant.8000 participants treated by 5 UK ambulance services will be randomised between December 2014 and August 2017 to adrenaline (intervention) or placebo (control) through opening pre-randomised drug packs. Clinical outcomes are survival to 30 days (primary outcome), hospital discharge, 3, 6 and 12 months, health related quality of life, and neurological and cognitive outcomes (secondary outcomes).Trial registration (ISRCTN73485024).