Effect of intravenous adrenaline before arrival at the hospital in out-of-hospital cardiac arrest

Open ArchivePublished:August 13, 2012DOI:https://doi.org/10.1016/j.jjcc.2012.07.001

      Abstract

      There is some evidence in prospective randomized clinical trials that the administration of adrenaline (AD) before admission for the treatment of out-of-hospital cardiac arrest did not improve survival to hospital discharge. The aim of this study was to evaluate our real-world experience regarding the efficacy of intravenous AD in out-of-hospital cardiac arrest at our university hospital. In this retrospective study, we enrolled and divided 644 patients into AD (AD administration before arrival at the hospital) and non-AD (no AD administration before arrival at the hospital) groups. The patient characteristics including age, sex, percentage of cardiac cause, location of cardiac arrest, and witnessed arrest were similar between the AD and non-AD groups. There were no significant differences between the AD and non-AD groups with regard to return of spontaneous circulation, survival to hospital admission, survival to hospital discharge, or good neurologic recovery at hospital discharge in all patients. In addition, we excluded the data of patients with extrinsic cause. We analyzed whether intravenous AD before arrival in patients with intrinsic cause was effective. The outcomes in the AD group were similar to those in the non-AD group. In conclusion, our study indicated that AD administration before arrival at the hospital for the treatment of out-of-hospital cardiac arrest did not improve the clinical outcome.

      Keywords

      1. Introduction

      Early access, early cardiopulmonary resuscitation (CPR), early defibrillation, and early advanced care, including the use of intravenous drugs, should improve survival in sudden cardiac arrest. The administration of adrenaline (AD) has been advocated during CPR in cardiac arrest for decades [
      Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Emergency Cardiac Care Committee and Subcommittees. American Heart Association. Part IX. Ensuring effectiveness of communitywide emergency cardiac care.
      ]. The 2005 guidelines of both the American Heart Association and the European Resuscitation Council recommend its use [
      2005 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Part 4: advanced life support.
      ,
      • 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, part 7.2: management of cardiac arrest
      ]. AD was shown to be an independent predictor of a poor outcome in a large retrospective registry study [
      • Holmberg M.
      • Holmberg S.
      • Herlitz J.
      Low chance of survival among patients requiring adrenaline or intubation after out-of-hospital cardiac arrest in Sweden.
      ]. AD has been shown to have beneficial short-term effects in animal studies [
      • Pearson J.W.
      • Redding J.S.
      Epinephrine in cardiac resuscitation.
      ,
      • Michael J.R.
      • Guerci A.D.
      • Koehler R.C.
      • Shi A.Y.
      • Tsitlik J.
      • Chandra N.
      • Niedermeyer E.
      • Rogers M.C.
      • Traystman R.J.
      • Weisfeldt M.L.
      Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardiopulmonary resuscitation in dogs.
      ]. On the other hand, there has been some concern regarding the potential harmful effects of AD on post cardiac arrest myocardial function and cerebral function, and there is little evidence from clinical trials that the use of AD for the treatment of cardiac arrest improves survival [
      • Ristagno G.
      • Sun S.
      • Tang W.
      • Castillo C.
      • Weil M.H.
      Effects of epinephrine and vasopressin on cerebral microcirculatory flows during and after cardiopulmonary resuscitation.
      ,
      • Tang W.
      • Weil M.H.
      • Sun S.
      • Noc M.
      • Yang L.
      • Gazmuri R.J.
      Epinephrine increases the severity of postresuscitation myocardial dysfunction.
      ]. The survival outcomes in human studies have been controversial [
      • Gazmuri R.J.
      • Nolan J.P.
      • Nadkarni V.M.
      • Arntz H.R.
      • Billi J.E.
      • Bossaert L.
      • Deakin C.D.
      • Finn J.
      • Hammill W.W.
      • Handley A.J.
      • Hazinski M.F.
      • Hickey R.W.
      • Jacobs I.
      • Jauch E.C.
      • Kloeck W.G.
      • et al.
      Scientific knowledge gaps and clinical research priorities for cardiopulmonary resuscitation and emergency cardiovascular care identified during the 2005 International Consensus Conference on ECC and CPR Science with Treatment Recommendations. A consensus statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Stroke Council; and the Cardiovascular Nursing Council.
      ,
      • Herlitz J.
      • Ekstrom L.
      • Wennerblom B.
      • Axelsson A.
      • Bang A.
      • Holmberg S.
      Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference?.
      ,
      • Ong M.E.
      • Tan E.H.
      • Ng F.S.
      • Panchalingham A.
      • Lim S.H.
      • Manning P.G.
      • Ong V.Y.
      • Lim S.H.
      • Yap S.
      • Tham L.P.
      • Ng K.S.
      • Venkataraman A.
      Cardiac Arrest and Resuscitation Epidemiology Study Group
      Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest.
      ].
      Several prospective randomized clinical trials have recently indicated that the use of AD before admission for the treatment of out-of-hospital cardiac arrest (OHCA) did not improve survival to hospital discharge [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ,
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ]. In a prospective, randomized controlled trial, patients with intravenous access and drug administration had higher rates of short-term survival with no statistically significant improvements in survival to hospital discharge or long-term survival compared to patients who received advanced cardiac life support (ACLS) without intravenous drug administration following OHCA [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ]. In addition, Jacobs et al. reported that patients who received AD during cardiac arrest had no statistically significant improvement in survival to hospital discharge, although there was a significantly improved likelihood of achieving return of spontaneous circulation (ROSC) in a double-blind randomized placebo-controlled trial [
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ].
      Therefore, in this study, we aimed to evaluate our real-world experience regarding the efficacy of intravenous AD before arrival at the hospital in OHCA from the Fukuoka University Registry (FU-Registry).

      2. Methods

      2.1 Study patients and design

      Six hundred forty-four patients who experienced cardiac arrest between April 2006 and March 2011 at the Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, Japan were enrolled. The enrollment was performed using our database of FU-Registry. Our protocol was approved by the hospital ethics committee. Patients received either ACLS with intravenous AD before arrival at the hospital (AD group) or ACLS without intravenous AD before arrival at the hospital (non-AD group). Intravenous AD was given after the initiation of CPR and initial defibrillation (if appropriate) following successful placement of an intravenous line consistent with ACLS standards according to the modified 2005 American Heart Association guidelines [
      • 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, part 7.2: management of cardiac arrest
      ]. The paramedics were able to provide ACLS and defibrillation with automated external defibrillators.
      The patient characteristics (age, sex, and medical history), cardiac arrest circumstances (arrest location, witnessed, bystander CPR, defibrillation, AD given), electrocardiographic (ECG) rhythms, emergency medical services (EMS) response times, and outcomes were recorded by EMS personnel and subsequently by physicians. The ambulance crew recorded the time of arrival at the patient's side, the time when CPR was started, the time of defibrillation, the time when transport to the hospital was started, and the time of arrival at the hospital. The immediate outcome was reported as dead on arrival, dead in emergency room, or admitted to hospital alive.
      The initial cardiac arrest rhythm was defined as ventricular fibrillation (VF), pulseless ventricular tachycardia (VT), pulseless electrical activity (PEA), or asystole. Shockable rhythm was defined as VF and pulseless VT. PEA and asystole are non-shockable rhythms. The initial rhythm was based on information obtained from the first ECG recording after arrival of the ambulance crew and on whether or not the patient was defibrillated.

      2.2 Study outcomes

      The primary endpoint was survival to hospital discharge with secondary endpoints of ROSC, survival to hospital admission, and good neurologic recovery at hospital discharge. Cerebral Performance Category (CPC) at hospital discharge was used as a neurological outcome. CPC scores are defined as: 1 – normal function; 2 – mild to moderate disability; 3 – severe disability; 4 – vegetative state; and 5 – dead. The patients with survival to hospital discharge were divided into two groups: fully awake and other. Good neurologic recovery was defined as CPC 1 or 2.

      2.3 Statistical analysis

      Differences in patient and study characteristics were assessed using Pearson's chi-square test and the t-test for categorical and continuous data, respectively. Odds ratios (OR) and 95% confidence intervals were derived for primary and secondary outcomes. Logistic regression was used to adjust for potential confounders on the effect of treatment with AD on primary and secondary outcomes. Analysis was performed on an intention-to-treat basis and per-protocol basis using StatView 5.0 statistical software. All statistical tests were two-sided with a significance level of 0.05.

      3. Results

      3.1 Patient characteristics

      Six-hundred forty-four patients who experienced OHCA were enrolled (Fig. 1). Of those, 131 patients were not eligible due to insufficient medical records, cardiac arrest in our hospital, and transfer from another hospital. We also excluded 21 patients with age younger than 18 years. Therefore, this study included 492 adult patients: 49 with AD administration and 443 without AD administration. Table 1 shows the characteristics of all patients in the AD and non-AD groups. Characteristics such as age, gender, percentage (%) of cardiac cause, location of cardiac arrest, initial rhythm, and defibrillation before arrival at the hospital were similar in both groups. The incidence of witnessed cardiac arrest by bystander in the AD group was significantly higher than that in the non-AD group. In patients with intrinsic cause, there were no significant differences in those characteristics between the groups (data not shown). The cause of arrest in all cases is shown in Table 2. There were 333 with intrinsic causes and 159 with extrinsic causes. There were no differences in the cause between the AD and non-AD groups.
      Figure thumbnail gr1
      Fig. 1Study profile. ER, emergency room; AD, adrenaline.
      Table 1Patient characteristics.
      All (n = 492)Non-AD group (n = 443)AD group (n = 49)P value

      Non-AD versus AD
      Age (years)64 ± 1864 ± 1863 ± 180.882
      Male, n (%)324 (66)291 (66)33 (67)0.816
      Indoor location of cardiac arrest, n (%)379 (77)342 (77)37 (76)0.79
      Cardiac arrest before ambulance arrival, n (%)443 (90)398 (90)45 (91)0.658
      Bystander CPR, n (%)261 (53)236 (53)25 (51)0.764
      Witnessed cardiac arrest, n (%)
       By bystander167 (34)141 (32)26 (53)0.003
       By ambulance crew47 (10)43 (10)4 (8)0.727
      Initial cardiac arrest rhythm, n (%)
       Pulseless electrical activity139 (28)124 (28)15 (30)0.706
       Ventricular fibrillation/tachycardia75 (15)63 (14)12 (25)0.059
       Asystole277 (56)255 (58)22(45)0.087
      Defibrillation before arrival at the hospital, n (%)84 (17)71 (16)13 (27)0.071
      Intravenous access before arrival at the hospital, n (%)143 (29)94 (21)49 (100)<0.001
      Onset – call (min)4.3 ± 6.74.5 ± 7.13.7 ± 4.10.527
      Call – arrival at patient's side (min)7.7 ± 4.27.6 ± 4.08.4 ± 5.50.169
      Arrival at patient's side – arrival at the hospital (min)18.3 ± 6.318.4 ± 6.318.1 ± 6.10.805
      Arrival at patient's side – adrenaline i.v. (min)23.6 ± 8.025.1 ± 7.112.3 ± 5.4<0.001
      Cardiac arrest on arrival at the hospital, n (%)437 (89)397 (90)40 (82)0.092
      Cardiac arrest rhythm on arrival at the hospital, n (%)
       Pulseless electrical activity104 (24)94 (24)10 (24)0.919
       Ventricular fibrillation/tachycardia29 (7)24 (6)5 (12)0.132
       Asystole303 (69)278 (70)25 (61)0.232
      Table 2Cause of cardiac arrest.
      All (n = 492)Non-AD group (n = 443)AD group (n = 49)
      Intrinsic cause, n (%)333 (68)298 (67)35 (71)
       Cardiologic disease169 (34)147 (33)22 (45)
       Respiratory disease23 (5)19 (4)4 (8)
       Neurological disease22 (5)20 (5)2 (4)
       Digestive disease9 (2)9 (2)0 (0)
       Others (unknown)110 (22)103 (23)7 (14)
      Extrinsic cause, n (%)159 (32)145 (33)14 (29)
       Trauma53 (11)50 (11)3 (6)
       Neck hanging54 (11)51 (12)3 (6)
       Airway trouble28 (6)22 (5)6 (12)
       Drowning16 (3)14 (3)2 (4)
       Others8 (2)8 (2)0 (0)

      3.2 Outcomes for patients in the AD and non-AD groups

      Table 3 shows the results of the analysis for primary and secondary outcomes stratified according to AD administration. In all patients, the incidences of ROSC, survival to hospital admission, survival to discharge, and good neurologic recovery in the AD group were similar to those in the non-AD group (Table 3a). In a comparison of the AD group to the non-AD group, the OR was 0.88 for ROSC (p = 0.808) for survival to hospital admission, 1.16 (p = 0.724) for survival to discharge, and 0.52 (p = 0.445) for good neurologic recovery at hospital discharge. In addition, we also excluded the data of patients with extrinsic cause and analyzed whether intravenous AD before arrival in patients with intrinsic cause was effective in Table 3b. The outcomes in the AD group were similar to those in the non-AD group.
      Table 3Outcomes for patients in the AD and non-AD groups in all patients (a) and patients with intrinsic cause (b).
      a. All patients
      OutcomesNon-AD group (n = 443), n (%)AD group (n = 49), n (%)OR (95% CI)P value
      Return of spontaneous circulation (ROSC)204 (46)21 (43)0.88 (0.48–1.59)0.671
      Survival to hospital admission155 (35)18 (37)1.08 (0.56–1.99)0.808
      Survival to hospital discharge64 (14)8 (16)1.16 (0.52–2.58)0.724
      Good neurologic recovery at hospital discharge (CPC 1–2)28 (44)2 (25)0.43 (0.08–2.29)0.321
      b. Patients with intrinsic cause
      OutcomesNon-AD group (n = 298), n (%)AD group (n = 35), n (%)OR (95% CI)P value
      Return of spontaneous circulation (ROSC)144 (48)15 (43)0.80 (0.40–1.63)0.541
      Survival to hospital admission104 (35)13 (37)1.10 (0.53–2.28)0.793
      Survival to hospital discharge40 (13)6 (17)1.33 (0.52–3.42)0.547
      Good neurologic recovery at hospital discharge (CPC 1–2)22 (55)2 (33)0.41 (0.07–2.50)0.333
      AD, adrenaline; OR, odds ratio; CI, confidence interval; CPC, Cerebral Performance Category. Data of good neurologic recovery are shown in the patients with survival to hospital discharge.
      We also evaluated the efficacy of AD in patients with shockable OHCA in Table 4. In patients with shockable OHCA (all cause or intrinsic cause cases), the incidences of ROSC, survival to hospital admission, survival to discharge, and good neurologic recovery in the AD group were similar to those in the non-AD group. Thus, there were no significant differences between the AD and non-AD groups in terms of the clinical outcomes.
      Table 4Outcomes for patients in the AD and non-AD groups in patients with shockable OHCA.
      a. All patients
      OutcomesNon-AD group (n = 63), n (%)AD group (n = 12), n (%)OR (95% CI)P value
      Return of spontaneous circulation (ROSC)47 (75)7 (58)0.48 (0.13–1.72)0.257
      Survival to hospital admission44 (70)7 (58)0.61 (0.17–2.15)0.436
      Survival to hospital discharge29 (46)3 (25)0.39 (0.10–1.58)0.188
      Good neurologic recovery at hospital discharge (CPC 1-2)19 (66)2 (67)1.05 (0.09–13.08)0.968
      b. Intrinsic cause
      OutcomesNon-AD group (n = 58), n (%)AD group (n = 11), n (%)OR (95% CI)P value
      Return of spontaneous circulation (ROSC)44 (76)6 (55)0.38 (0.10–1.45)0.156
      Survival to hospital admission41 (71)6 (55)0.50 (0.13–1.85)0.298
      Survival to hospital discharge27 (47)3 (27)0.43 (0.10–1.79)0.246
      Good neurologic recovery at hospital discharge (CPC 1–2)18 (67)2 (67)1.00 (0.08–12.56)>0.999
      AD, adrenaline; OHCA, out-of-hospital cardiac arrest; OR, odds ratio; CI, confidence interval; CPC, Cerebral Performance Category. Data of good neurologic recovery are shown in the patients with survival to hospital discharge.

      4. Discussion

      AD has been a standard of ACLS care since its inception. In the present study that considered real-world experience, the administration of AD before arrival at the hospital for the treatment of OHCA did not improve ROSC, survival to hospital admission, survival to hospital discharge, or good neurologic recovery at hospital discharge.
      AD is thought to aid resuscitation mainly by its α-adrenergic effects. The survival outcomes in human studies have been controversial [
      • Gazmuri R.J.
      • Nolan J.P.
      • Nadkarni V.M.
      • Arntz H.R.
      • Billi J.E.
      • Bossaert L.
      • Deakin C.D.
      • Finn J.
      • Hammill W.W.
      • Handley A.J.
      • Hazinski M.F.
      • Hickey R.W.
      • Jacobs I.
      • Jauch E.C.
      • Kloeck W.G.
      • et al.
      Scientific knowledge gaps and clinical research priorities for cardiopulmonary resuscitation and emergency cardiovascular care identified during the 2005 International Consensus Conference on ECC and CPR Science with Treatment Recommendations. A consensus statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Stroke Council; and the Cardiovascular Nursing Council.
      ,
      • Herlitz J.
      • Ekstrom L.
      • Wennerblom B.
      • Axelsson A.
      • Bang A.
      • Holmberg S.
      Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference?.
      ,
      • Ong M.E.
      • Tan E.H.
      • Ng F.S.
      • Panchalingham A.
      • Lim S.H.
      • Manning P.G.
      • Ong V.Y.
      • Lim S.H.
      • Yap S.
      • Tham L.P.
      • Ng K.S.
      • Venkataraman A.
      Cardiac Arrest and Resuscitation Epidemiology Study Group
      Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest.
      ]. However, the potential adverse effects of AD include decreased total forward cardiac output, increased myocardial oxygen consumption, myocardial dysfunction post-resuscitation, and increased intrapulmonary shunting [
      • Paradis N.A.
      • Martin G.B.
      • Rivers E.P.
      • Goetting M.G.
      • Appleton T.J.
      • Feingold M.
      • Nowak R.M.
      Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation.
      ,
      • Niemann J.T.
      • Criley J.M.
      • Rosborough J.P.
      • Niskanen R.A.
      • Alferness C.
      Predictive indices of successful cardiac resuscitation after prolonged arrest and experimental cardiopulmonary resuscitation.
      ]. We did not confirm a previous observational finding that intravenous AD was an independent predictor for a poor outcome [
      • Holmberg M.
      • Holmberg S.
      • Herlitz J.
      Low chance of survival among patients requiring adrenaline or intubation after out-of-hospital cardiac arrest in Sweden.
      ]. Our results are consistent with those of a multicenter study by Stiell et al., who found no difference in survival after implementing intravenous drug administration during OHCA [
      • Stiell I.G.
      • Wells G.A.
      • Field B.
      • Spaite D.W.
      • Nesbitt L.P.
      • De Maio V.J.
      • Nichol G.
      • Cousineau D.
      • Blackburn J.
      • Munkley D.
      • Luinstra-Toohey L.
      • Campeau T.
      • Dagnone E.
      • Lyver M.
      Ontario Prehospital Advanced Life Support Study Group
      Advanced cardiac life support in out-of-hospital cardiac arrest.
      ], and two recent prospective randomized clinical trials [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ,
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ]. This study showed that AD administration before admission had no significant effect on short-term survival, and there is no reason to expect any difference in long-term survival or neurologic recovery.
      Patients with intravenous access and drug administration had higher rates of short-term survival (more frequently ROSC) [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ]. ROSC is an increasingly important clinical endpoint regarding the influence of post-resuscitation care interventions on survival to hospital discharge [
      • Nolan J.P.
      • Morley P.T.
      • Hoek T.L.
      • Hickey R.W.
      Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation.
      ,
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • Aibiki M.
      • Berg R.A.
      • Böttiger B.W.
      • Callaway C.
      • Clark R.S.
      • Geocadin R.G.
      • Jauch E.C.
      • Kern K.B.
      • Laurent I.
      • Longstreth W.T.
      • Merchant R.M.
      • Morley P.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      ]. Jacobs et al. clearly demonstrated that AD was superior to placebo for achieving ROSC [
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ]. A clinical study that evaluated high-dose AD showed that it improved short-term results without improving long-term outcomes [
      • Vandycke C.
      • Martens P.
      High dose versus standard dose epinephrine in cardiac arrest.
      ]. In our study, we found no difference in short-term effects (ROSC and survival to hospital admission). The negative post-resuscitation effects of AD have also been reported to be more prominent after longer, more clinically relevant periods of cardiac arrest (e.g. 4–6 min) than after short periods of cardiac arrest (e.g. 2 min) [
      • Angelos M.G.
      • Butke R.L.
      • Panchal A.R.
      • Torres C.A.
      • Blumberg A.
      • Schneider J.E.
      • Aune S.E.
      Cardiovascular response to epinephrine varies with increasing duration of cardiac arrest.
      ]. This difference may have influenced our results, but we do not have sufficient data regarding the duration of cardiac arrest. Moreover, we did not know the dose of AD in this study, and randomized trials of AD in cardiac arrest have compared high-dose versus standard-dose AD, without reference to placebo or the non-administration of AD [
      • Stiell I.G.
      • Hebert P.C.
      • Weitzman B.N.
      • Wells G.A.
      • Raman S.
      • Stark R.M.
      • Higginson L.A.
      • Ahuja J.
      • Dickinson G.E.
      High-dose epinephrine in adult cardiac arrest.
      ,
      • Brown C.G.
      • Martin D.R.
      • Pepe P.E.
      • Stueven H.
      • Cummins R.O.
      • Gonzalez E.
      • Jastremski M.
      A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group.
      ,
      • Gueugniaud P.Y.
      • Mols P.
      • Goldstein P.
      • Pham E.
      • Dubien P.Y.
      • Deweerdt C.
      • Vergnion M.
      • Petit P.
      • Carli P.
      A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group.
      ]. All of these trials demonstrated that high-dose AD was superior for achieving ROSC, however, they failed to demonstrate better survival to hospital discharge.
      Since AD administration was not associated with the clinical outcome, we also analyzed contributors to patient outcome in all patients (Supplementary Figure). Logistic regression modeling was performed to control for the effect of potential confounders on the relationship between AD administration and patient outcome. Independent predictors for ROSC were witnessed arrest and cardiac cause and defibrillation before arrival at the hospital, those for survival to hospital admission were witnessed arrest, cardiac cause, and initial shockable rhythm, that for survival to discharge was witnessed arrest. Thus, in this study, witnessed arrest was a common and strong predictor for ROSC, survival to hospital admission, and survival to discharge. In addition, in patients with intrinsic cause, witnessed arrest was a common and strong predictor for ROSC and survival to hospital admission (data not shown). Witnessed arrest, but not AD administration before arrival at the hospital, may strongly affect the clinical outcome. To support this observation, some trials have demonstrated that AD is superior for achieving ROSC, however they failed to demonstrate better survival to hospital discharge [
      • Brown C.G.
      • Martin D.R.
      • Pepe P.E.
      • Stueven H.
      • Cummins R.O.
      • Gonzalez E.
      • Jastremski M.
      A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group.
      ,
      • Gueugniaud P.Y.
      • Mols P.
      • Goldstein P.
      • Pham E.
      • Dubien P.Y.
      • Deweerdt C.
      • Vergnion M.
      • Petit P.
      • Carli P.
      A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group.
      ].
      • Supplementary Figure

        Odds ratios (OR) of all patients for ROSC (a), survival to hospital admission (b), survival to discharge (c) and good neurologic recovery at hospital discharge (d). ROSC, return of spontaneous circulation; CI, confidence interval; CPR, cardiopulmonary resuscitation; AD, adrenaline; CPC, Cerebral Performance Category. Data of good neurologic recovery are shown in the patients with survival to hospital discharge.

      Several studies have identified dissimilar etiologies in subgroups with shockable and nonshockable rhythms [
      • Spaulding C.M.
      • Joly L.M.
      • Rosenberg A.
      • Monchi M.
      • Weber S.N.
      • Dhainaut J.F.
      • Carli P.
      Immediate coronary angiography in survivors of out-of-hospital cardiac arrest.
      ], and it seems reasonable that there are differences in treatment strategies [
      • Wenzel V.
      • Krismer A.C.
      • Arntz H.R.
      • Sitter H.
      • Stadlbauer K.H.
      • Lindner K.H.
      European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group
      A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation.
      ]. Fifteen percent of our patients had a shockable rhythm. Well-controlled prospective randomized clinical trials have shown higher percentages of patients with a shockable rhythm (33% [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ] and 45% [
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ]). Thus, the factor of an initial shockable rhythm was included in logistic regression modeling. An initial shockable rhythm was an independent predictor for survival to hospital admission, but not for survival to discharge. However, our study was not powered for this analysis and no conclusions should be drawn.
      In this study, there were several specific patient characteristics and clinical outcomes compared to those as previously reported. As noted before, the incidence of shockable rhythm was relatively low in this study. In addition, the incidence of survival to hospital discharge (15%) was relatively high compared to previous reports (10% [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ] and 3% [
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ]), and the incidence of cardiac cause (34%) was relatively low (70% [
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      ] and 90% [
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial.
      ]). These differences may also affect the efficacy of AD administration.

      4.1 Study limitations

      This study has several limitations. First, it was a retrospective clinical study and not a placebo-controlled, randomized study. Second, we were unable to assess the influence of CPR quality or the timing of AD administration during resuscitation on our findings. AD administration varied depending on the successful establishment of intravenous access and variations in resuscitation procedures. In addition, we did not exclude the possibility that other drug regimens might improve the outcome. Third, sudden cardiac arrests were induced by intrinsic and extrinsic causes. Intrinsic cause mainly contained cardiologic diseases, such as acute myocardial infarction [
      • Ishihara M.
      • Sato H.
      Thirty years trend in acute myocardial infarction undergoing coronary angiography at a tertiary emergency center in Japan.
      ] and ventricular fibrillation including Brugada syndrome [
      • Ohkubo K.
      • Watanabe I.
      • Okumura Y.
      • Kofune M.
      • Nagashima K.
      • Mano H.
      • Sonoda K.
      • Nakai T.
      • Kasamaki Y.
      • Hirayama A.
      Prevalence of prominent J waves in patients presenting with ventricular fibrillation without structural heart disease: a single-center study.
      ]. Since we did not have enough information about them, it might affect the efficacy of intravenous AD. Fourth, only 10% of the patients in this study received AD from paramedics, which is much less than in previous reports. This contributes to why the study was underpowered for the endpoint. Finally, this is a single-center study and the results may not be generalized to systems with different training, infrastructure, treatment protocols, or quality of CPR.

      5. Conclusions

      Our study indicated that the use of AD administration before arrival at the hospital for the treatment of OHCA did not improve clinical outcomes in real-world experience at our university hospital. The findings of this study are clinically important in that they did not support the continued use of AD in cardiac arrest as currently recommended.

      Conflicts of interest

      No conflicts of interest to declare.

      Acknowledgments

      We thank the physicians, nurses, and EMS personnel for their cooperation.

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