Title: Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest (Paramedic 2)
Funder: Department of Health and Social Care

Abstract: OVERVIEW: This proposal is for a pragmatic, randomised, double blind, placebo controlled trial to determine if, in adults with out of hospital cardiac arrest (OHCA), treatment with intravenous adrenaline compared to placebo improves 30 day survival and other clinical, patient focused and economic outcomes. DESIGN: Double blind, individual patient randomised placebo controlled trial with internal pilot study. The internal pilot (6 months duration) will test that the components of this new study work together effectively (i.e. recruitment rate, compliance with allocated intervention and data collection and follow-up). SETTING: Prehospital care. Five NHS Ambulance Services Trusts have obtained Board approval to participate (London, South Central, North East, Welsh and West Midlands). TARGET POPULATION: Patients with out of hospital cardiac arrest (OHCA) in whom resuscitation is attempted. INCLUSION CRITERIA: Patients will be enrolled if they meet the following criteria (1) out of hospital cardiac arrest (2) Advanced life support initiated and/or continued by ambulance service clinician. EXCLUSION CRITERIA: (1) Known or appear pregnant (2) Known or appear to be aged under 16 (3) Cardiac arrest secondary to anaphylaxis or life-threatening asthma (4) Adrenaline given prior to arrival of ambulance service clinician HEALTH TECHNOLOGY BEING ASSESSED: Intravenous adrenaline compared to placebo. MEASUREMENT OF COST AND OUTCOME: Primary clinical outcome: Survival to 30 days post-cardiac arrest. Secondary clinical outcomes: Survived event (return of spontaneous circulation (ROSC) on arrival at hospital); survival and neurological status at hospital discharge, 3 months and 6 months; hospital length of stay; intensive care length of stay. Patient focused secondary outcomes: Health related quality of life (SF-12 and EQ-5D-5L) at 3 and 6 months; cognition (mini mental state examination (MMSE), IQCODE and “Two Simple Questions”); post-traumatic stress (PTSD civilian checklist (PCL-C)); anxiety and depression (Hospital Anxiety and Depression Scale (HADS)) at 3 months. Primary economic outcome: Incremental cost per quality-adjusted life year (QALY) gained from the perspective of the NHS and personal social services (PSS). Secondary economic outcomes: Cost of critical care stay (level 2/3 days); cost of hospital stay; utilisation of NHS and PSS resources after discharge; broader resource utilisation after discharge. Neurological outcome: We will measure the Modified Rankin Score (mRS) at hospital discharge, 3 and 6 months. We selected mRS over Cerebral Performance Category as it is more sensitive to detect mild cognitive impairment, it can be reliably extracted from medical records and is a predictor of long term survival. There is emerging international consensus (Utstein 2012/13) that mRS should be the primary measure of neurological outcome in cardiac arrest trials. MRS is a 7 point scale ranging mRS 0 (no symptoms) to 6 (dead). Other functional outcomes and health related quality of life: We will assess cognitive function using mini-mental state examination(MMSE), the informant questionnaire cognitive decline evaluation (IQCODE) and the two simple questions tool as supplementary assessments of cognitive function. The presence of post traumatic stress disorder and depression will be measured by the PTSD Civilian Checklist (PCL-C) and Hospital Anxiety and Depression Scale (HADS). Two of these measures (PCL-C and HADS) are being used as part of a multi-centre follow-up for people surviving a critical illness (Intensive Care Outcome Network study) which can be used as a reference population. The SF-12 and EQ-5D-5L will be used to the measure health-related quality of life of survivors. SAMPLE SIZE: We propose a sample size of 8,000. This will have 90% power to achieve a statistically significant (p<0.05) result if the true treatment difference is a risk ratio of 1.33 (2% change in 30 day survival from a baseline rate of 6% in adrenaline group). TIMELINE: The project is scheduled to last 54 months. This will include initial set up and pilot study (0-6 months), 36 months active recruitment (see below), 6 months follow-up, 6 months analysis and reporting. Our partner ambulance services resuscitate approximately 11,000 cardiac arrests a year. Approximately 80% of these patients will be eligible. This gives maximum of approximately 26,000 eligible patients over the 3 years. This figure is consistent with observed recruitment rates observed in the PARAMEDIC trial. We have modelled recruitment to allow for a staggered start to recruitment. We have allowed time for training and a gradual improvement in recruitment as confidence grows. We plan to train staff and open new ambulance stations to recruitment sequentially over the duration of the trial. We aim to train 25% of ambulance staff (i.e. all participating staff at 25% of stations) over the first 6 months progressing to 60% by 12 months and 75% by month 15 to end of trial. This is a conservative estimate from the PARAMEDIC trial which trained >90% of eligible staff. We have included a gradual increase in recruitment rates from 2% to 30% of the total eligible population by the end of the trial. EXPERTISE: The research proposal builds on the experience of an existing team and established network of ambulance services. The team have gained invaluable knowledge and experience of the practical issues of running OHCA trials in the UK. The study will be co-ordinated by a registered Clinical Trials Unit with a track record in this field. The research team comprises senior and experienced clinician researchers with operational experience of OHCA, senior ambulance service personnel, expert clinical triallists and methodological researchers, health economics, project management and patient / public representatives.

Lay abstract: Around 30,000 people experience sustain sudden cessation of heart function (cardiac arrest) each year in the UK. Initial resuscitation efforts are effective in restarting the heart in about 1 in 4 cases (25%), but over half of these patients subsequently die in intensive care as a consequence of severe brain damage. These dire outcomes are costly to patients and their families many of whom either lose a loved one or are burdened with providing on-going care. Despite the major burden on NHS resources to treat this condition (e.g. provision of intensive care, cardiac catheterisation, therapeutic cooling), there are relatively few trials to inform treatment guidelines compared to other conditions (e.g. cancer, heart disease). Adrenaline, a naturally occurring hormone, injected into a vein, has been used as a treatment for cardiac arrest for decades. The evidence supporting its use is based around its ability to increase blood supply to the heart leading to improved short-term outcomes (restarting the heart). More recently, harmful side effects of adrenaline treatment in cardiac arrest have been recognised (greater subsequent cardiac instability, reduced blood flow to the brain worsening brain damage). In parallel, data from other studies in cardiac arrest has challenged the reliance on short term outcomes as surrogates for more patient focused longer term outcomes (survival to go home from hospital, survival without brain damage). One example of this is a randomised controlled trial of a mechanical chest compression device (Autopulse). The study found no difference in short term outcome (being alive at 4 hours) but long term outcomes were worse (with a greater proportion of patients sustaining brain damage). There is reasonable information from randomised controlled trials and observational studies that adrenaline improves short term outcomes. However, no studies have found that adrenaline improves the long term outcomes that are prioritised by patients (e.g. going home from hospital, returning to work, being able to function independently). Data have recently emerged that raise concern about the potential for overall harm from adrenaline administration in cardiac arrest. Re-analysis of the largest randomised trial to date, based on whether patients actually received adrenaline or not, confirmed improved short term outcome but worse overall survival and greater brain damage. Four observational studies (including more than 450,000 patients in total), which carefully adjusted for potential confounding factors, all found similar patterns (improved initial survival but lower overall survival and increased brain damage). We propose a large, pragmatic trial to resolve this uncertainty. Working with 5 NHS ambulance services, patients in cardiac arrest will be randomly assigned (in equal numbers) to receive adrenaline or matching placebo. We will determine the effect of adrenaline from a clinical (long term survival), patient focused (brain function, health related quality of life) and cost effectiveness perspective. The study will recruit 8000 patients and will provide a definitive answer as to whether adrenaline is an effective treatment for cardiac arrest. The results will be immediately fed into an established process for evaluation of evidence from which international and UK clinical guidelines are produced and subsequently implemented in the NHS.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR