Adrenaline for cardiocirculatory arrest and cardiopulmonary resuscitation has become a hot topic of discussion since most recent studies have shown that the rate of restoration of spontaneous circulation and short-term survival increase, but long-term survival does not, when using adrenaline during cardiopulmonary resuscitation.1–3 However, these studies should be read carefully.
Adrenaline is a widely accepted drug and component of cardiopulmonary resuscitation. The guidelines for cardiopulmonary resuscitation published by the European Resuscitation Council and the International Liaison Committee on Resuscitation (ILCOR)4 in 2010 stated that, despite the widespread use of adrenaline during cardiopulmonary resuscitation and several studies involving vasopressin, no placebo-controlled study has shown that the routine use of any vasopressor at any stage during human cardiocirculatory arrest increases neurologically intact survival to hospital discharge.5,6 The present evidence is described as being insufficient to support or to refute the routine use of adrenaline. Nevertheless, adrenaline represents a cornerstone in the cardiopulmonary resuscitation algorithm. The guidelines also state that, despite the lack of human data, the use of adrenaline is recommended, based largely on animal data and increased short-term survival in humans.5 Up to now adrenaline has been inevitable, as a result of a ‘grandfather rule’, in cardiopulmonary resuscitation. We should remember that adrenaline has been used for more than five decades in cardiopulmonary resuscitation. Animal studies have shown the importance of vasopressors, and especially adrenaline, in a cardiocirculatory arrest model in rats and pigs.7,8 No animal with a cardiocirculatory arrest of 7-min duration could be resuscitated using placebo instead of a vasopressor during cardiopulmonary resuscitation.7 The main reason not to change the status of adrenaline was an ethical one; in addition, randomised placebo-controlled trials are impractical, adrenaline has a traditional and historical status and it would be impossible to provide appropriate indemnity.
Since these statements were made, more information has become available. Therefore, the current recommendations on cardiopulmonary resuscitation must be re-evaluated in the light of new investigations. In 2009, Olasveengen et al.3 from Norway published the first randomised controlled trial comparing intravenous access with no intravenous access during cardiopulmonary resuscitation, which subsequently prompted an intense discussion with accompanying editorials in Resuscitation and elsewhere.9 In 2011, Jacobs et al.2 published the first randomised placebo-controlled trial comparing adrenaline with placebo in Resuscitation. In this investigation, patients suffering an out-of-hospital cardiac arrest were randomised to adrenaline (n = 272) or placebo (n = 262), and restoration of spontaneous circulation, hospital admission and survival to hospital discharge (cerebral performance category score 1 or 2) were studied as the primary endpoints. For all patients, the proportion of those with prehospital restoration of spontaneous circulation (23.5 vs. 8.4%, P < 0.001) and with hospital admission (25.4 vs. 13.0%, P < 0.001) differed significantly between the adrenaline and the placebo group. The survival to hospital discharge (4.0 vs. 1.9%) and the survival with cerebral performance category score 1 or 2 (81.8 vs. 100%) did not differ between the groups. However, as the study was terminated early, the appropriate sample size of 2213 patients per group was not reached, and it was underpowered, therefore, for the primary endpoint. The accompanying editorial by Soar and Nolan10 stated that the investigators had planned a multicentre study with 5000 patients, but the study had to be terminated long before that, despite appropriate ethical approval and initial agreement, because four out of five emergency medical services decided not to participate in the study. Moreover, serious concerns were raised in the press and by the public.
After the initial intention-to-treat-analysis published by Olasveengen et al.,3 a post-hoc analysis of their trial has been published.11 Short-term survival (admission to hospital) was better in the adrenaline group than in the no adrenaline group [odds ratio (OR): 2.5; 95% confidence interval (CI): 1.9 to 3.4], but survival to hospital discharge (OR: 0.5; 95% CI: 0.3 to 0.8) and survival with favourable neurological outcome (OR: 0.4; 95% CI: 0.2 to 0.7) after out-of-hospital cardiac arrest were worse.
In 2012, Hagihara et al.1 published an analysis of a Japanese cardiopulmonary resuscitation registry from 2005 to 2008 in the Journal of the American Medical Association. The article was accompanied by an outstanding editorial from Callaway.12 Hagihara et al. compared two groups of patients receiving adrenaline or no adrenaline up to hospital admission. In the first part of the study, they compared 15 030 patients receiving adrenaline with 402 158 patients not receiving adrenaline. The two groups differed significantly concerning patient characteristics (including sex, eyewitness, origin of cardiac arrest, bystander cardiopulmonary resuscitation and prehospital emergency medical service treatment, but excluding patient age). Patients suffering from ventricular fibrillation had the same rate of restoration of spontaneous circulation (22.3 vs. 21.1%, P = 0.21), but the 1-month survival rate (21.3 vs. 15.4%, P < 0.001), cerebral performance category score 1 or 2 (13.5 vs. 6.1%, P < 0.001) and overall performance category 1 or 2 (13.5 vs. 6.2%, P < 0.001) were better in the no-adrenaline group (n = 29 103) than in the adrenaline group (n = 2054). In patients with asystole and pulseless electrical activity, restoration of spontaneous circulation (4.4 vs. 18.2%, P < 0.001) and 1-month survival rate (3.4 vs. 3.8%, P < 0.001) were lower in the no-adrenaline group and cerebral performance category score 1 or 2 (1.3 vs. 0.6%, P < 0.001) and overall performance category 1 or 2 (1.3 vs. 0.7%, P < 0.001) were better in the no-adrenaline group (n = 181 561) than in the adrenaline group (n = 5942). In the multivariate regression analysis, adrenaline was associated with a higher rate of restoration of spontaneous circulation but a significantly worse 1-month survival rate and neurological outcome. In an editorial by Kreutzinger and Wenzel13 on the frustration of neutral clinical studies in cardiopulmonary resuscitation, it was speculated that the ‘good’ patients were included in the group that did not receive adrenaline. Therefore, the authors performed a propensity-matched study (comparing 13 401 patients who received adrenaline and 13 401 patients who did not) to identify two groups of patients without significant differences in their characteristics. The results were similar to the first analysis. However, this investigation needs to be interpreted with caution because this was a registry study and not a randomised controlled trial. Furthermore, in 2005, paramedics were not allowed to give adrenaline; however, 190 patients in the adrenaline group had received adrenaline in that year. Interestingly, the emergency technicians were allowed up to 90 s to establish intravenous access, which might have negatively influenced chest compression and ventilation. Finally, no information was provided about in-hospital treatment standards and it was not known whether the patients were treated using Standard Operating Procedures for postresuscitation care (postresuscitation care bundles), including percutaneous coronary intervention or therapeutic hypothermia. Sunde et al.14 have shown that survival and good neurological outcome are highly dependent on implementation of treatment bundles. Nevertheless, the origin of cardiac arrest was only presumed by the first in-hospital clinician (of unknown qualification), only the 1-month and not the 1-year survival rate was reported and it is not known whether patients received adrenaline after being admitted to hospital.
Hayashi et al.15 published an important study in Circulation Journal in 2012. They reported the outcome of patients treated in an adrenaline-capable Emergency Medical Services system. The initial results seem to confirm the aforementioned investigations: comparison of the adrenaline group (n = 1013) with the no-adrenaline group (n = 1013) showed a better restoration of spontaneous circulation before hospital arrival (29.3 vs. 13.4%, P < 0.001), comparable results for in-hospital restoration of spontaneous circulation (50.4 vs. 47.3%, P = 0.094), for hospital admission (42.6 vs. 41.0%, P = 0.385) and 1-month survival (13.5 vs. 12.0%, P = 0.245), and a reduced rate of neurologically intact 1-month survival (4.1 vs. 6.1%, P = 0.028) in the adrenaline group. Interestingly, the authors showed, in a subgroup analysis, better restoration of spontaneous circulation for patients treated within a 10-min interval between call until adrenaline administration (crude OR: 6.03; 95% CI: 1.47 to 24.69, adjusted OR: 6.34; 95%CI: 1.49 to 27.02).15 Keeping in mind that the downtime is relevant to the outcome, the authors concluded that the effectiveness of adrenaline after out-of-hospital cardiac arrest depends on the time of administration. Of note, data from the Japanese Circulation Society Resuscitation Science Study (JCS-ReSS) show that the presence of a physician on the emergency response vehicle doubles the 1-month survival rate and the number of cerebral performance category score 1 or 2 patients.16 Thus, these data should be analysed with a focus on the Japanese registry data.
According to the editorial by Callaway,12 the most exciting scientific progress occurs when new research challenges conventional wisdom. Up to now, however, the presented studies with their associated limitations have not been able to drive changes to the current cardiopulmonary resuscitation guidelines.
In conclusion, two randomised controlled trials and a cardiopulmonary resuscitation registry analysis1–3 could not show that adrenaline is inferior to placebo for short-term survival. Adrenaline should be investigated in well designed randomised, controlled trials, including documented in-hospital management with postresuscitation care bundles.17 We warn against refusing to administer adrenaline to patients suffering from out-of-hospital cardiac arrest. Indeed, the current data raise more questions than answers: why do studies show such large differences in restoration of spontaneous circulation rates; how is restoration of spontaneous circulation defined; perhaps adequate cardiopulmonary resuscitation is much better in terms of outcome than minimal circulation; are non-physician-based emergency medical services comparable to physician-based emergency medical services; what dose is right and at which time point during cardiopulmonary resuscitation should adrenaline be given; and is it not just a platitude that patients who do not need adrenaline to reach restoration of spontaneous circulation have a better outcome? In the future, especially in the setting of registry trials, guideline adherence for the use of adrenaline needs to be critically questioned, as we know that strict adherence to guidelines is poor and that relevant variations in adrenaline doses can be seen. Only with good data and evidence should we change this essential part of the cardiopulmonary resuscitation algorithm.
Assistance with the Editorial: none declared.
Financial support and sponsorship: none declared.
Conflicts of interest: BWB is chairman of the European Resuscitation Council (ERC) and chairman of the German Resuscitation Council.
Comment from the Editor: This article was checked and accepted by the Editors, but was not sent for external peer-review. BWB is an associate editor of the European Journal of Anaesthesiology.
1. Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA
2. Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomized double-blind placebo-controlled trial. Resuscitation
3. Olasveengen TM, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA
4. Hinkelbein J, Böttiger BW. The message is clear to save an additional 100 000 lives per year in Europe: ‘harder and faster for cardiopulmonary resuscitation’!. Eur J Anaesthesiol
5. Deakin CD, Nolan JP, Soar J, et al. European Resuscitation Council Guidelines for Resuscitation 2010. Section 4. Adult advanced life support. Resuscitation
6. Deakin CD, Morrison LJ, Morley PT, et al. Part 1: executive summary. 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Resuscitation
7. Popp E, Vogel P, Teschendorf P, Böttiger BW. Vasopressors are essential during cardiopulmonary resuscitation in rats: is vasopressin superior to adrenaline? Resuscitation
8. Meybohm P, Cavus E, Dörges V, et al. Revised resuscitation guidelines: epinephrine versus epinephrine/vasopressin in a pig model of cardiopulmonary resuscitation – a randomised, controlled trial: 13AP2-4. Eur J Anaesthesiol
2007; 24 (Suppl 39):165.
9. Böttiger BW, Teschendorf P, Bernhard M, Nolan J. Adrenaline: more questions than answers. Resuscitation
10. Soar J, Nolan JP. Adrenaline: proven benefit in cardiac arrest at last? Resuscitation
11. Olasveengen TM, Wik L, Sunde K, Steen PA. Outcome when adrenaline (epinephrine) was actually given vs. not given: post hoc analysis of a randomized clinical trial. Resuscitation
12. Callaway CW. Questioning the use of epinephrine to treat cardiac arrest. JAMA
13. Kreutzinger J, Wenzel V. Overcoming frustration about neutral clinical studies to cardiopulmonary resuscitation. Resuscitation
14. Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation
15. Hayashi Y, Iwami T, Kitamura T, et al.
Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest. Circulation
16. Kojima S, Matsui K, Seino Y, et al. A physician onboard the Advanced Life Support Unit has a clinical impact on outcome of witnessed patients with out-of-hospital cardiac arrest. Circulation
17. Stub D, Nichol G. Hospital care after resuscitation from out-of-hospital cardiac arrest: the emperor[Combining Acute Accent]s new clothes. Resuscitation