Clinical PaperOutcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial☆
Introduction
Drugs like epinephrine and amiodarone are still recommended in the current international guidelines of Advanced Life Support (ALS) during cardiac arrest,1, 2 although their outcome benefit on survival to hospital discharge is debated. Especially, the use of adrenaline is questioned.3 In intention-to-treat analysis in a randomized controlled out-of-hospital cardiac arrest (OHCA) study, the intravenous line insertion and drug administration group had improved short term outcome without improved survival rate to hospital discharge.4 A before and after Canadian study of OHCA similarly failed to find any change in outcome after introducing intravenous drug administration and endotracheal intubation into local resuscitation protocols.5 In a large Swedish OHCA registry study, which included patients where some ambulance personnel were allowed to give adrenaline and some were not, patients receiving adrenaline were 57% less likely to be alive after one month in a multivariate logistic regression analysis adjusting for all known confounders compared to those who had not received adrenaline.6
This apparent contrast in results could be due to various factors. Non-randomized registry studies do not intend to prove causality, and there might be unknown factors not adjusted for in regression analysis. Patients with rapid return of spontaneous circulation (ROSC) such as those with ventricular fibrillation (VF) and ROSC after the first defibrillation attempt might never have had time for adrenaline injection. These patients, with very good prognosis, would thereby end in the no-drug group impacting on the data interpretation. Our randomized study was analyzed on an intention-to-treat basis.4 As expected; some patients in the intravenous group had achieved ROSC before adrenaline could be given, while some in the no-intravenous group received adrenaline for different reasons. For example, it was permitted to place the IV line 5 min after ROSC. If re-arrest occurred, adrenaline could be administered if indicated by the CPR guidelines.7
Non-randomized, observational registry data from before and after studies are often used to explore therapeutic issues in cardiac arrest. These studies always compare when a certain therapy was actually administered vs. when it was not. Although many confounding factors may be identified in clinical registry data, significant unknown factors may exist. We have therefore performed a post hoc analysis of our previously published data4 comparing outcomes for patients who actually received adrenaline to those who did not, and included a multivariate regression analysis as in the Swedish registry study.6
Section snippets
Materials and methods
We conducted a prospective cohort study using clinical trial population.4 The randomized trial was designed to evaluate the effect of intravenous access and medication in cardiac arrest resuscitation.
Patient allocation (Fig. 1).
Resuscitation was attempted in 1183 patients, and 851 of 946 those eligible were successfully randomized. Thirty-seven of 433 patients randomized to the No-IV arm received adrenaline and 85 of 418 patients randomized to the IV arm did not receive adrenaline. Three cases were excluded as we were unable to determine drug administration, leaving 367 patients in the adrenaline group and 481 patients in the no-adrenaline group.
Table 1.
Baseline demographics and CPR quality (Table 1).
There was no difference in proportion of patients presenting with
Discussion
The results from our previously published randomized controlled trial of intravenous access and drugs administration during OHCA would suggest that an EMS system opting to include intravenous drug administration in their cardiac arrest treatment protocol could expect increased survival to hospital admission, but no increase in survival to hospital discharge. In this post hoc analysis the actual use of adrenaline was associated with increased short-term survival, but with 48% less survival to
Conclusions
Receiving adrenaline was associated with improved short-term survival, but decreased survival to hospital discharge and survival with favourable neurological outcome after OHCA. This post hoc survival analysis is in contrast to the previous intention-to-treat analysis of the same data, but agrees with previous non-randomized registry data. This shows limitations of non-randomized or non-intention-to-treat analyses.
Conflict of interest
Olasveengen and Sunde have no conflicts to declare. Steen is a member of the board of directors for Laerdal Medical and The Norwegian Air Ambulance. Wik is the principle investigator for a multi-centre mechanical chest compression device study sponsored by Zoll.
Acknowledgements
We thank all physicians and paramedics working in the Oslo EMS Service. The study was supported by grants from South-Eastern Norway Regional Health Authority, Oslo University Hospital, Norwegian Air Ambulance Foundation, Laerdal Foundation for Acute Medicine and Anders Jahres Fund.
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.11.011.