Is there a role for adrenaline during cardiopulmonary resuscitation?

REVIEW C URRENT OPINION Is there a role for adrenaline during cardiopulmonary resuscitation? Jerry P. Nolan a and Gavin D. Perkins b Purpose of review To critically evaluate the recent data on the influence adrenaline has on outcome from cardiopulmonary resuscitation. Recent findings Two prospective controlled trials in out-of-hospital cardiac arrest (OHCA) have indicated that adrenaline increases the rate of return of spontaneous circulation (ROSC), but neither was sufficiently powered to determine the long-term outcomes. Several observational studies document higher ROSC rates in patients receiving adrenaline after OHCA, but these also document an association between receiving adrenaline and worse long-term outcomes. Summary Appropriately powered prospective, placebo-controlled trials of adrenaline in cardiac arrest are essential if the role of this drug is to be defined reliably. Keywords adrenaline, cardiopulmonary resuscitation, epinephrine, outcome, return of spontaneous circulation INTRODUCTION Adrenaline has been an integral component of advanced life support from the birth of modern cardiopulmonary resuscitation (CPR) in the early 1960s. In guidelines written originally in 1961, Safar [1] recommended the use of very large doses of adrenaline: 10 mg intravenously or 0.5 mg intracardiac. When injected during cardiac arrest, adrenaline increases aortic relaxation (diastolic) pressure and, in animal studies, thereby augments coronary and cerebral blood flow [2,3]. In contrast, another animal study has shown that although adrenaline improves myocardial blood flow during ventricular fibrillation cardiac arrest, it does not improve the myocardial oxygen balance (measured by determining intramyocardial adenosine triphosphate and lactate values) [4]. Recent prospective, randomized trials [5,6 ] and observational studies [7,8,9] have challenged the value of using adrenaline in cardiac arrest, and this view is supported by the findings from systematic reviews of vasopressors in cardiac arrest [10,11]. These and other relevant studies are discussed in detail in this review. CURRENT GUIDELINES The treatment recommendation on the use of vasopressors published in 2010 by the International Liaison Committee on Resuscitation stated: Although there is evidence that vasopressors (adrenaline or vasopressin) may improve return of spontaneous circulation (ROSC) and short-term survival, there is insufficient evidence to suggest that vasopressors improve survival to discharge and neurological outcome. There is insufficient evidence to suggest the optimal dosage of any vasopressor in the treatment of adult cardiac arrest. Given the observed benefit in short-term outcomes, the use of adrenaline or vasopressin may be considered in adult cardiac arrest [12]. The 2010 European Resuscitation Council (ERC) guidelines for ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest stated: give adrenaline after the third shock once chest compressions have resumed, and then repeat every 3 5 min during cardiac arrest (alternate cycles) [13]. If the initial monitored rhythm is pulseless electrical a Royal United Hospital, Bath and b University of Warwick, Heart of England NHS Foundation Trust, Coventry, UK Correspondence to Jerry P. Nolan, FRCA, FCEM, FRCP, FFICM, Consultant in Anaesthesia and Intensive Care Medicine, Royal United Hospital, Combe Park, Bath, BA1 3NG, UK. Tel: +44 1225 825056; e-mail: jerry.nolan@nhs.net Curr Opin Crit Care 2013, 19:169 174 DOI:10.1097/MCC.0b013e328360ec51 1070-5295 ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins www.co-criticalcare.com Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

Cardiopulmonary resuscitation KEY POINTS When given during cardiac arrest, adrenaline increases aortic relaxation pressure and increases coronary and cerebral perfusion pressure. Adrenaline increases the chances of achieving return of spontaneous circulation. There is no evidence of long-term benefit for adrenaline in cardiac arrest and observational studies suggest that its long-term outcomes may be worse. Large, placebo-controlled clinical trials are essential. activity (PEA) or asystole, give adrenaline 1 mg as soon as venous access is achieved. These guidelines are followed by healthcare professionals throughout most of Europe and in many other countries. RANDOMIZED CONTROLLED TRIALS OF ADRENALINE COMPARED TO PLACEBO A trial published in 1995 compared adrenaline 10 mg with placebo in 194 cardiac arrest patients [14]. Although the trial was conducted in hospital, it included in-hospital and out-of-hospital cardiac arrests. An additional 145 patients who were eligible but not randomized received adrenaline 1 mg and were included in the analysis. There was no difference in the immediate survival or survival to hospital discharge between those receiving adrenaline 1 or 10 mg, or placebo, but the poor quality of the study design makes it impossible to draw any reliable conclusions. In a study undertaken in Oslo, Norway, 851 patients with out-of-hospital nontraumatic cardiac arrest (all rhythms) were randomized to intravenous cannulation with injection of drugs (including adrenaline) vs. no intravenous cannula or drugs until after ROSC had been achieved [5]. The patients in the intravenous group had a higher rate of ROSC (40 vs. 25%; P < 0.001), hospital admission (43 vs. 29%; P < 0.001) and admission to the intensive care unit (ICU) (30 vs. 20%; P ¼ 0.002). The higher rate of ROSC was seen only in the patients with initial nonshockable rhythms (asystole and PEA): 29 vs. 11% (P < 0.001); the rate of ROSC was 59 vs. 53% (P ¼ 0.35) in those patients with an initial rhythm of ventricular fibrillation/ventricular tachycardia. There was no significant difference in survival to hospital discharge between the intravenous and no intravenous groups (10.5 vs. 9.2%; P ¼ 0.61). The survival with favourable outcome [cerebral performance category (CPC) 1 2: 9.8 vs. 8.1%; P ¼ 0.45] and the survival at 1 year (10 vs. 8%; P ¼ 0.53) did not differ significantly between the groups. There was no difference between the groups in the quality of CPR (hands-off ratio, median: 15 vs. 14%; P ¼ 0.16) and, importantly, in both groups therapeutic hypothermia was used in just over 70% of those admitted to the ICU. These results were based, correctly, on an intention-to-treat analysis, and many patients allocated to the intravenous drug group did not actually receive adrenaline. Furthermore, the study included the use of all drugs vs. no drugs it was not simply an adrenaline vs. no adrenaline trial. In a post hoc analysis of this Norwegian study, outcomes were examined according to whether the patient had actually received adrenaline [15 ]. Treatment with adrenaline (n ¼ 367) was associated with a greater chance of being admitted to hospital [odds ratio (OR) 2.5; 95% confidence interval (CI) 1.9 3.4]. However, the chance of survival to hospital discharge was reduced by half in those given adrenaline [24 of 367 (7%) vs. 60 of 481 (13%); OR 0.5; 95% CI 0.3 0.8] as were the number of neurologically intact (CPC 1 or 2) survivors [19 of 367 (5%) vs. 57 of 481 (11%); OR 0.4; 95% CI 0.2 0.7]. These effects persisted after adjustment for confounding factors (ventricular fibrillation, response interval, witnessed arrest, sex, age and tracheal intubation). Although these results are of interest, a per protocol analysis is likely to introduce unmeasured bias, making reliable interpretation difficult. The only double-blind, randomized placebocontrolled trial of adrenaline in out-of-hospital cardiac arrest (OHCA) was undertaken in Western Australia [6 ]. The primary endpoint of this study was survival to hospital discharge and the investigators had planned originally to enrol 5000 patients based on the power calculation using this endpoint. Unfortunately, several ambulance services were unable to participate and ultimately only 601 out of 4103 patients screened for inclusion underwent randomization and, of these, 534 were included in the final analysis. The rate of ROSC was three times higher in those receiving adrenaline [64 of 272 (23.5%) vs. 22 of 262 (8.4%); OR 3.4; 95% CI 2.0 5.6]. Survival to hospital discharge was no different between the groups: adrenaline 11 (4.0%) vs. placebo 5 (1.9%; OR 2.2; 95% CI 0.7 6.3). Unlike the Norwegian study, this Australian study documented higher ROSC rates with adrenaline in both shockable and nonshockable rhythms. This study ended up being grossly underpowered for the primary outcome (survival to hospital discharge) and it leaves the resuscitation community uncertain about the role of adrenaline in the treatment of cardiac arrest. 170 www.co-criticalcare.com Volume 19 Number 3 June 2013 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

Role for adrenaline Nolan and Perkins OBSERVATIONAL TRIALS OF ADRENALINE IN CARDIOPULMONARY RESUSCITATION Prehospital randomized placebo-controlled trials are challenging to undertake as evidenced by the experience of Jacobs et al. [6 ]. Observational studies enable large quantities of data to be collected, but they rely on statistical risk adjustment to remove the inherent biases. The Swedish ambulance cardiac arrest registry was started in 1990. A multivariate analysis (including age, sex, place of arrest, bystander CPR, initial arrhythmia, witnessed and cause) of this registry (n ¼ 10 966) published in 2002 documented a lower 1-month survival amongst the 42.4% of patients who received adrenaline (OR 0.43; 95% CI 0.27 0.66) [16]. The impact of adrenaline on survival to discharge after OHCA was evaluated in a before-and-after study undertaken during 2002 2004 in Singapore [9]. There was no significant difference in survival to discharge in the preadrenaline phase compared with the adrenaline phase (1.0 vs. 1.6%; OR 1.7; 95% CI 0.6 4.5). In contrast to many other studies, in this study, there was also no difference in the rate of ROSC between the two phases (preadrenaline 17.9% vs. adrenaline 15.7%; OR 0.9; 95% CI 0.6 1.2). One of several limitations of this study was that only 44.2% of patients actually received adrenaline in the adrenaline phase. The Ontario Prehospital Advanced Life Support (OPALS) study also used a before-and-after design to evaluate the impact of adding tracheal intubation and drug administration to an optimized rapid defibrillation programme [17]. The rate of admission to hospital increased significantly in the advanced life support (ALS) phase [152 of 1391 (10.9%) vs. 621 of 4247 (14.6%); P < 0.001], but the rate of survival to hospital discharge was unchanged [69 (5.0%) vs. 217 (5.1%); P ¼ 0.83]. During the ALS phase, 95.8% of patients received adrenaline. Given that other drugs and tracheal intubation were also included in the ALS phase, it is difficult to make firm conclusions about the impact of adrenaline, but the results are notably similar to those documented in the later prospective controlled studies. In a single-centre study from Fukuoka, Japan, 492 patients with OHCA were analysed retrospectively and divided into those receiving adrenaline (n ¼ 49) and those not receiving adrenaline (n ¼ 443) before arrival at hospital [8]. There was no difference in the rates of ROSC or survival to hospital discharge, but given the very few patients receiving adrenaline before hospital arrival, the study is grossly underpowered to determine any meaningful outcomes. The largest observational study to date on the use of adrenaline in cardiac arrest involves 417 188 OHCAs in Japan (Table 1) [7 ]. In propensitymatched (statistical adjustment for potential confounders) patients, use of adrenaline was associated with a ROSC rate 2.5 times higher (adjusted OR 2.51; 95% CI 2.24 2.80; P < 0.001), but a 1-month survival rate approximately half of that achieved in those not given adrenaline (adjusted OR 0.54; 95% CI 0.43 0.68; P < 0.001). Although this is a very large study and the authors have made great efforts to eliminate bias by using multiple and comprehensive statistical analyses, there is still a strong possibility that hidden confounders account for their findings. Another limitation is that generalizability is limited by the fact that in both groups the rate of survival with good neurological outcome is much lower than those reported from most other countries [18]. Table 1. Outcome based on multivariate analyses of patients with out-of-hospital cardiac arrest according to adrenaline administration, 2005 2008, Japan Outcome Total cases Adrenaline No adrenaline Odds ratio n (%) n (%) (95% CI) ROSC Unadjusted 417 155 2786 (18.5) 23 042 (5.7) 3.75 (3.59 3.91) Adjusted a 391 046 2556 (18.6) 21 629 (5.7) 2.36 (2.22 2.50) 1-Month survival Unadjusted 417 186 805 (5.4) 18 906 (4.7) 1.15 (1.07 1.23) Adjusted a 391 046 733 (5.3) 17 677 (4.7) 0.46 (0.42 0.51) CPC 1 or 2 Unadjusted 417 187 205 (1.4) 8903 (2.2) 0.61 (0.53 0.70) Adjusted a 391 046 187 (1.4) 8329 (2.2) 0.31 (0.26 0.36) CPC, cerebral performance category; ROSC, return of spontaneous circulation. Data from [7 ]. a Adjusted for age, sex, bystander witnessed, cause, bystander CPR (by type), presence of emergency life-saving technician, presence of physician in ambulance, advanced life support performed by physician, intervals, first documented rhythm, defibrillation, advanced airway, intravenous cannulation. 1070-5295 ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins www.co-criticalcare.com 171 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

Cardiopulmonary resuscitation The Resuscitation Outcomes Consortium (ROC) Investigators analysed drug use amongst 16 221 OHCAs attended by 74 emergency medical services (EMS) agencies [19]. Adrenaline was used in approximately 80% of ALS-treated cardiac arrests and there was an inverse association between adrenaline dose and survival to discharge; however, this finding was unadjusted for confounders. In another observational study from the Osaka group in Japan, investigators studied the impact of timing of adrenaline administration in OHCA [20]. Of 3161 patients analysed, 1013 (32.0%) received adrenaline. Those receiving adrenaline had a significantly lower rate of neurologically intact (CPC 1 or 2) 1-month survival than those not receiving adrenaline (4.1 vs. 6.1%, P ¼ 0.028). In patients with an initial rhythm of ventricular fibrillation, those receiving adrenaline within 10 min of the call time had a higher rate of neurologically intact 1-month survival compared with those not receiving adrenaline [6 of 9 (66.7%) vs. 75 of 301 (24.9%); OR 6.03; 95% CI 1.5 24.7], but there are so few patients receiving early adrenaline that it is impossible to draw reliable conclusions about the timing of adrenaline administration and its impact on outcome. RATIONALIZING THE FINDINGS FROM RANDOMIZED CONTROLLED TRIALS AND OBSERVATIONAL STUDIES Taken together, the findings from randomized trials and observational studies indicate that giving adrenaline in OHCA increases the rate of ROSC, but that longer term outcomes (survival to hospital discharge and neurologically favourable survival) are either worse or, at best, neutral. The observational studies showing worse long-term outcome after adrenaline administration may be misleading if there are confounders that have not been fully adjusted for in the statistical analyses. For example, most of these studies do not adjust for the duration of the resuscitation attempt; yet, patients who respond rapidly to initial treatment (e.g. defibrillation) will have the best outcomes. In general, only those with longer resuscitation attempts might be expected to receive adrenaline. Alternatively, it is entirely possible that adrenaline is genuinely harmful when given in cardiac arrest. Of those patients who reach hospital alive after OHCA, but who subsequently die before hospital discharge, the majority die from neurological injury [21,22 ]. Although adrenaline helps in achieving ROSC, it may have adverse effects, particularly on the brain, heart and immune system that outweigh any of its short-term benefits. Reduced microvascular blood flow and exacerbating cerebral injury In a pig model of cardiac arrest, although adrenaline increased mean aortic pressure during CPR, through its alpha 1 -agonist action, it reduced cerebral microcirculatory blood flow and increased cerebral ischaemia (as determined by reduced cerebral oxygen tension and increased cerebral carbon dioxide tension) [23]. Impaired microvascular blood flow was seen to persist for several minutes after adrenaline administration in a further animal study [24]. In another pig study involving active compression decompression CPR in combination with an impedance threshold device, adrenaline increased coronary perfusion pressure and cerebral perfusion pressure, but carotid blood flow was decreased [25]. Adrenaline was also associated with a decrease in end-tidal carbon dioxide values, which the authors ascribed to reductions in tissue perfusion. Cardiovascular toxicity Adrenaline also has adverse effects on the myocardium mediated by b-receptor stimulation. In a further analysis of the Norwegian intravenous vs. no intravenous trial, ECG downloads were analysed from 101 patients who received adrenaline and 73 who did not; all of these patients had an initial rhythm of PEA [26 ]. Adrenaline increased the frequency of transitions from PEA to ROSC and extended the time window for ROSC to develop. However, this was at a cost of greater cardiovascular instability after ROSC, with a higher rate of re-arresting. These observations are consistent with other studies that link adrenaline with ventricular arrhythmias and increased post-rosc myocardial dysfunction [27]. In human studies with patients with sepsis [28] or acute lung injury [29], b-agonist stimulation is similarly linked to cardiovascular instability and reduced survival [30]. A systematic review of b-blocker treatment in animal models of cardiac arrest found fewer shocks were required for defibrillation, myocardial oxygen demand was reduced and postresuscitation myocardial stability improved with fewer arrhythmias and improved survival [31 ]. The same review identified several case reports and two small prospective trials point towards a beneficial effect of b-blockade in patients presenting with cardiac arrest because of ventricular fibrillation/ventricular tachycardia. Metabolic effects Adrenaline is associated with the development of lactic acidosis [32]. High concentrations of lactate and slow lactate clearance after ROSC are associated 172 www.co-criticalcare.com Volume 19 Number 3 June 2013 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

Role for adrenaline Nolan and Perkins with poor outcomes [33,34]. Adrenaline also induces stress hyperglycaemia which is associated with poorer outcomes following cardiac arrest [35,36]. Immunomodulation and predisposition to infection Infective complications, especially early-onset pneumonia, are common after OHCA and associated with worse outcomes [37]. In a single-centre observational study, investigators carefully reviewed the case notes, charts, laboratory and imaging results amongst 138 consecutive patients admitted to intensive care following OHCA for evidence of infection [38 ]. Of the 138 patients, 135 (97.8%) had at least one positive marker of infection. Microbiological samples were taken from 78 patients (56.5%), of which 43 (55.1%; 95% CI 44.1 65.7) were positive. Patients treated with early antibiotics had better outcomes [mortality rate 56.6% (30 of 53) compared with 75.3% (64 of 85); P ¼ 0.025]. The use of therapeutic hypothermia has been linked to an increased risk of infection [37]. There is also a well recognized association between the sympathetic nervous system and immune response. b-adrenoceptors are present on many of the cells that contribute to innate immunity including macrophages, T lymphocytes and neutrophils [39]. Animal and human studies have documented reductions in neutrophil chemotaxis [40], oxidative burst, and degranulation in response to b-agonist stimulation [41]. In addition, downregulation of inflammatory cytokines (e.g. TNF-a, IL-8, IL-8 and IL-1b) and increased release of anti-inflammatory cytokines (e.g. IL-10) may reduce the host defence to infection. It is possible these effects may contribute to an increased susceptibility to postresuscitation sepsis. EFFECT OF DOSE Another factor to be considered is the dose of adrenaline. The current 1-mg bolus dose of adrenaline was derived from animal studies in the 1960s [42 44]. Several studies have documented harm from using higher doses of adrenaline [45], but there have been no investigations of smaller doses (e.g. 1 mg/kg) or infusions of adrenaline in clinical studies [26 ]. THE NEED FOR FUTURE TRIALS The accumulating evidence highlights the urgent need for further appropriately powered high-quality randomized controlled trials. The emerging data suggest several experimental strategies could be considered, including comparing adrenaline to alpha 2 agonists, adrenaline with b-blockade, lower dose adrenaline or adrenaline as a continuous infusion. We suggest the most pressing need is for a definitive trial comparing standard dose adrenaline (1 mg every 3 5 min) to placebo. Until there is clarity about the effect of adrenaline on long-term outcomes, the best comparator (placebo or standard dose adrenaline) for future trials remains unknown. CONCLUSION Use of adrenaline in cardiac arrest increases the chance of achieving ROSC, but randomized controlled trials have failed to show that this is translated into increased rates of survival to hospital discharge and observational studies show an association between adrenaline and worse long-term survival. Appropriately powered placebo-controlled clinical trials of adrenaline in cardiac arrest are essential to determine whether patients benefit from being given this drug [30,42]. In the mean time, current guidelines dictate that most patients with cardiac arrest will continue to be given adrenaline. Acknowledgements None. Conflicts of interest J.P.N. and G.D.P. receive an honorarium as editor-inchief and editor of the journal Resuscitation. 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