BMJ 2013;347:f7268 doi: 10.1136/bmj.f7268 (Published 10 December 2013)

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EDITORIALS Adrenaline for out of hospital cardiac arrest? More data, but still no definitive answers Theresa Mariero Olasveengen researcher Department of Research and Development and Department of Anaesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital, PB 4956 Nydalen, N-0424 Oslo, Norway

In a linked article (doi:10.1136/bmj.f6829), Nakahara and colleagues from Japan write another chapter in the long running saga of the administration of adrenaline (epinephrine) during cardiac arrest.1 Despite being in widespread use for decades, no one has proved that adrenaline improves neurologically intact survival after cardiac arrest, although this observational propensity matched analysis might be the closest yet. The authors show that patients who received adrenaline during a cardiac arrest outside of hospital had a significantly better chance of survival to hospital discharge than matched controls who received no adrenaline. However, no meaningful difference was seen in overall neurologically intact survival. Two randomised controlled trials have previously tried to determine a causal association between adrenaline and survival after out of hospital cardiac arrest, but both had limitations. The first study was designed to test the hypothesis that intravenous drug administration would lead to inferior quality of cardiopulmonary resuscitation and thereby inferior outcome.2 This hypothesis could not be confirmed because both arms of the study had good quality cardiopulmonary resuscitation and the study was not powered to detect small differences in survival to hospital discharge. The second study was a double blind randomised placebo controlled trial that did not manage to enrol enough eligible patients, so was underpowered to detect small differences in survival to hospital discharge.3 Both trials found significantly improved short term survival, but these initial improvements in outcome were not translated into increased survival to hospital discharge.

The obvious question with adrenaline during cardiac arrest is whether the drug is simply enabling us to restore cardiac function in patients with severe and unsurvivable neurological damage. It is a question for which we have no answer. It is hard to dismiss a drug that can get us part of the distance if we believe novel strategies for protecting the brain are plausible. The additional data from this current study are difficult to interpret. Although the authors argue that they have made important methodological progress in the search for the real effects of adrenaline by adjusting for “time dependent imbalance of severity,” observational data do not establish causality. Such data are not immune to potential confounding, however well

adjusted the analyses. Researchers using propensity score matching in retrospective cohort studies will always be limited to adjusting for the factors that we know have an impact on survival. The substantial regional variation in survival that has been well documented cannot be explained by the characteristics of patients and emergency medical services that we currently collect in our registries. Much of the variability in outcome remains unexplained.4 For example, the authors recognise the limitations of comparing patients treated by ambulance systems that administered adrenaline with controls who were treated by systems that did not give adrenaline. It is likely that ambulance systems that led the way in providing advanced life support were superior to those that did not in other ways. In addition, as time went by, more systems implemented the administration of adrenaline for cardiac arrest. In addition, the criteria for eligibility for one group or another changed with time, and it is unclear how these changes affect the pseudo-randomisation process.

Important regional differences should also be recognised. Survival after cardiac arrest is worse in Japanese registries than is typically reported in Europe, Australia, and North America.5 6 Differences in case mix are reflected in differences in initial cardiac rhythms. Patients in Japanese registries more commonly present with asystole and pulseless electrical activity—rhythms associated with far worse outcomes than ventricular fibrillation. The roughly 5% of patients from the All-Japan Utstein Registry analysed by Nakahara and colleagues seem more similar to typical European cardiac arrest populations with regard to case mix and outcomes but with one striking difference. Although current outcome studies in settings with modern post-resuscitation care (such as hypothermia) typically report a good neurological outcome in about 90% of survivors,7 less than half of survivors in this current analysis had a good neurological outcome. Survivors with initial ventricular fibrillation who received adrenaline in Nakahara and colleagues’ study had a higher risk of ending up with poor neurological outcome than those who were resuscitated without adrenaline. Although the authors did not evaluate this statistically, a simple analysis performed from the data in table 2 showed a relative risk of 1.20 (95% confidence interval 1.03 to 1.38; P=0.01).

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BMJ 2013;347:f7268 doi: 10.1136/bmj.f7268 (Published 10 December 2013)

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Nakahara and colleagues’ study is in many ways a follow-up to a previously published propensity matched retrospective cohort study from the same registry. Hagihara and colleagues suggested adrenaline might be associated with decreased survival, Nakahara and colleagues demonstrate the opposite using data from the same registry.8 Although the current paper might have used an improved version of propensity matching for patients with cardiac arrest, the fact that the same data produced opposite results with a slight adjustment of the same statistical method is a reason for caution.

So what does all of this mean? Will these findings change practice? The 2010 guidelines of advanced life support recommend that adrenaline “should be considered.”9 Despite the new data, we should carry on as usual—for those who already use adrenaline for cardiac arrest there is no compelling reason to stop. On the other hand, there is no need to rush to introduce adrenaline in emergency medical systems with staff who are not currently trained to do so.

With this important addition to the “adrenaline in cardiac arrest” puzzle, the resuscitation community eagerly awaits new randomised controlled trials to provide more definitive answers Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None.

For personal use only: See rights and reprints

Provenance and peer review: Commissioned; not externally peer reviewed. 1

2 3 4 5 6 7 8 9

Nakahara S, Tomio J, Takahashi H, Ichikawa M, Nishida M, Morimura N, et al. Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study. BMJ 2013;347:f6829. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009;302:2222-9. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation 2011;82:1138-43. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300:1423-31. Hasegawa K, Tsugawa Y, Camargo CA Jr, Hiraide A, Brown DF. Regional variability in survival outcomes of out-of-hospital cardiac arrest: the All-Japan Utstein Registry. Resuscitation 2013;84:1099-107. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies. Resuscitation 2010;81:1479-87. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013; published online 17 Nov. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161-8. Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, Smith GB, et al. European Resuscitation Council guidelines for resuscitation 2010 section 4. Adult advanced life support. Resuscitation 2010;81:1305-52.

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Adrenaline for out of hospital cardiac arrest?

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