Resuscitation 83 (2012) Contents lists available at SciVerse ScienceDirect. Resuscitation

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1 Resuscitation 83 (2012) Contents lists available at SciVerse ScienceDirect Resuscitation jo u rn al hom epage : Clinical paper A randomised, double-blind, multi-centre trial comparing vasopressin and adrenaline in patients with cardiac arrest presenting to or in the Emergency Department, Marcus Eng Hock Ong a,b,, Ling Tiah c, Benjamin Sieu-Hon Leong d, Elaine Ching Ching Tan c, Victor Yeok Kein Ong d, Elizabeth Ai Theng Tan e, Bee Yen Poh f, Pin Pin Pek a, Yuming Chen e a Department of Emergency Medicine, Singapore General Hospital, Outram Road, Singapore , Singapore b Office of Clinical Sciences, Duke-NUS Graduate Medical School, 8 College Road, Singapore , Singapore c Accident and Emergency Department, Changi General Hospital, 2 Simei Street 3, Singapore , Singapore d Emergency Medicine Department, National University Hospital, 5 Lower Kent Ridge Road, Singapore , Singapore e Singapore Clinical Research Institute, 31 Biopolis Way, Nanos #02-01, Singapore , Singapore f Department of Pharmacy, Singapore General Hospital, Outram Road, Singapore , Singapore a r t i c l e i n f o Article history: Received 8 November 2011 Received in revised form 3 February 2012 Accepted 5 February 2012 Keywords: Death Sudden Cardiac Cardiopulmonary resuscitation Vasopressins Epinephrine Cardiovascular agents Vasoconstrictor agents a b s t r a c t Objective: To compare vasopressin and adrenaline in the treatment of patients with cardiac arrest presenting to or in the Emergency Department (ED). Design: A randomised, double-blind, multi-centre, parallel-design clinical trial in four adult hospitals. Method: Eligible cardiac arrest patients (confirmed by the absence of pulse, unresponsiveness and apnea) aged >16 (aged > 21 for one hospital) were randomly assigned to intravenous adrenaline (1 mg) or vasopressin (40 IU) at ED. Patients with traumatic cardiac arrest or contraindication for cardiopulmonary resuscitation (CPR) were excluded. Patients received additional open label doses of adrenaline as per current guidelines. Primary outcome was survival to hospital discharge (defined as participant discharged alive or survival to 30 days post-arrest). Main results: The study recruited 727 participants (adrenaline = 353; vasopressin = 374). Baseline characteristics of the two groups were comparable. Eight participants (2.3%) from adrenaline and 11 (2.9%) from vasopressin group survived to hospital discharge with no significant difference between groups (p = 0.27, RR = 1.72, 95% CI = ). After adjustment for race, medical history, bystander CPR and prior adrenaline given, more participants survived to hospital admission with vasopressin (22.2%) than with adrenaline (16.7%) (p = 0.05, RR = 1.43, 95% CI = ). Sub-group analysis suggested improved outcomes for vasopressin in participants with prolonged arrest times. Conclusions: Combination of vasopressin and adrenaline did not improve long term survival but seemed to improve survival to admission in patients with prolonged cardiac arrest. Further studies on the effect of vasopressin combined with therapeutic hypothermia on patients with prolonged cardiac arrest are needed Elsevier Ireland Ltd. All rights reserved. 1. Introduction Intravenous adrenaline (epinephrine) has been used since 1906 to treat cardiac arrest. 1 However, there have been few formal A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi: /j.resuscitation Clinical trial registration: NCT Corresponding author at: Department of Emergency Medicine, Singapore General Hospital, Outram Road, Singapore , Singapore. Tel.: ; fax: address: marcus.ong.e.h@sgh.com.sg (M.E.H. Ong). evaluations to determine the value of adrenaline for cardiac arrest, and clinical trials have not been able to show any benefit with intravenous adrenaline (compared to placebo or no treatment) in the field. 2 6 More recently, vasopressin has been used in patients with cardiac arrest. In human studies on vasopressin, clinical trials have produced conflicting results. Stiell et al., 7 found no difference in survival with vasopressin vs. adrenaline for in-patient cardiac arrests. Wenzel et al., 8 in their sub-analysis, found improved survival with vasopressin in asystolic patients with out-of-hospital cardiac arrest (OHCA). It had been suggested that patients with prolonged down-times in asystole might benefit more from vasopressin than adrenaline, as vasopressin has a more prolonged /$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved. doi: /j.resuscitation

2 954 M.E.H. Ong et al. / Resuscitation 83 (2012) effect and better maintains coronary perfusion pressure. 9 Another more recent OHCA trial found that the combination of vasopressin and adrenaline did not improve outcome for OHCA compared to adrenaline alone. 10 Mukoyama et al., 11 also did not find any benefits of repeated doses of vasopressin or adrenaline. A previous study on OHCA patients in Singapore found that the mean time emergency medical services (EMS) took to respond to patients was close to 10 min; bystander CPR rate was also low (22.1%). 12 We hypothesised that patients conveyed to the Emergency Department (ED) in our local setting (who would have prolonged periods of cardiac arrest) might show increased survival with vasopressin in addition to usual treatment with adrenaline, compared to treatment with adrenaline alone. The purpose of the current study was to compare vasopressin and adrenaline in the treatment of cardiac arrest in patients presenting to the ED, including pre-hospital and ED arrests. In particular, we aimed to see if there was increased survival with vasopressin in addition to usual treatment with adrenaline, compared to treatment with adrenaline alone, as our patients would also receive open label doses of adrenaline at the ED and prehospital if they were conveyed by the national ambulance service. 2. Methods 2.1. Study design This was a randomised, double-blind, multi-centre, paralleldesign trial to compare vasopressin and adrenaline in the treatment of patients with cardiac arrest presenting to the ED, including prehospital and ED arrests. The study period was 9 March 2006 to 19 January The study was approved by the hospitals Institutional Review Boards Setting Singapore is a city-state with a land area of km 2 and a population of 4.8 million. The island s EMS system is run by the Singapore Civil Defence Force, which at the time of the study operated 32 ambulances. Emergency ambulance patients are delivered to the country s six major public hospitals that are equipped with modern EDs. This study involved four adult public hospitals in Singapore. Ambulances in Singapore have been manned by specifically trained paramedics who are able to provide basic life support and defibrillation with automated external defibrillators. They are not certified to perform endotracheal intubation, but do give adrenaline intravenously and use laryngeal mask airway (LMA) devices. Paramedics only pronounce death for obvious decapitation, rigor mortis, or dependant lividity. All other cardiac arrest patients are conveyed to the ED and there is no protocol for termination of resuscitation in the field. Paramedics will typically spend minimal time on scene before loading and going. By protocol, OHCA patients will typically get a maximum of 3 shocks at scene (if in ventricular fibrillation (VF)), 2 attempts for LMA insertion, 2 attempts at intravenous insertion and one dose of adrenaline at scene before transport. Further doses were allowed en-route. Time of collapse was determined from ambulance records, based on paramedic recordings of EMS witnessed arrest or history given by bystanders. Unwitnessed collapses with unknown time of collapse were not analysed for Collapse to Arrival Selection of participants All patients above age 16 with cardiac arrest, as confirmed by the absence of pulse, unresponsiveness, and apnoea were eligible to enter the trial (age 21 and above for one hospital, due to local ethics requirements). The exclusion criteria included traumatic cardiac arrest or when CPR was contraindicated (e.g., for those obviously dead as defined by the presence of decomposition, rigor mortis, or dependant lividity). Patients were enrolled into the trial if all eligibility criteria were met. Due to the emergent nature of cases involved, if consent could not be immediately obtained from the participant s family, delayed consent applied Randomisation Participants were randomised to either adrenaline (1 mg) or vasopressin (40 IU) on a 1:1 basis. Randomisation was stratified by site, with varying block sizes of four and six, via the use of a randomisation envelope provided by the Singapore Clinical Research Institute. The randomisation list was generated by the trial statistician. Study drugs were pre-prepared, in coded 10 ml syringes with identical appearance, by the trial pharmacist, according to the randomised list. The drugs were placed in the randomisation envelopes and kept in the ED. Initial drug stability tests done by our team showed that vasopressin in this preparation had >90% activity up to 1 month after dilution. All study drugs were replaced if not used within 3 weeks, and expiry dates were tracked by the study co-ordinator. All participants, assessors, and other personnel except the pharmacist and trial statistician were blinded to treatment. Once participant met eligibility criteria, the attending doctors administered the trial drug in sequential order according to the randomisation list Treatment plan All cardiac arrests occurring in ED or presenting to ED would have resuscitation initiated while being assessed for eligibility. Defibrillation was performed for patients with VF or ventricular tachycardia (VT) according to Advanced Cardiac Life Support guidelines (ACLS, 2005). 13 Eligible participants were administered study drug as the first drug upon arrival at ED, and CPR continued. If patient remained in cardiac arrest, treatment proceeded according to ACLS guidelines, including giving further open label doses of adrenaline. Participants who were successfully resuscitated were admitted to the intensive care units (ICU) for further management. Participants were followed-up by a study co-ordinator at 30 days post-primary event either in the hospital or at home, if the participant survived to 30 days post-event, and similarly at 1 year. The neurological status of survivors was assessed by study co-ordinator at 30 days and 1 year after the primary event. Unblinding of the study treatment was performed at the end of the trial when all participants completed follow-up, data collection for major endpoints was completed, and database was locked Outcome measures The primary outcome measure for the study was survival to hospital discharge, which was defined as the participant leaving the hospital alive or survival to 30 days post cardiac arrest, whichever came first. The secondary outcome measures included ROSC, which was defined as the presence of any palpable pulse detected by manual palpation of a major artery. Survival to admission was defined as the presence of a pulse upon discharge from ED and admittance to the wards. Neurological status on discharge or at 30 days post-arrest was assessed using Glasgow-Pittsburgh outcome categories. 14 The cerebral performance categories (CPC) evaluate only cerebral performance capabilities while the overall performance categories (OPC) evaluate the actual overall performance. CPC and OPC 1

3 M.E.H. Ong et al. / Resuscitation 83 (2012) indicate good cerebral and overall performance; CPC and OPC 2 and 3 indicate moderate and severe cerebral and overall disability, respectively; CPC and OPC 4 indicate coma, vegetative state; and CPC and OPC 5 indicate brain dead or death Primary data analysis The previously reported survival rate in Singapore for OHCA was 2%. 15 Using this as a baseline, to detect a 5% absolute improvement in survival to discharge between vasopressin and adrenaline (7% vs. 2%) with a two sided test size of 5% and power of 90% required 360 eligible participants in each study arm. The sample size was calculated using Chi-square test, with the assumption that the population followed a normal distribution. A planned, blinded, safety monitoring interim was carried out when 300 participants were enrolled in the study. The safety monitoring committee (SMC) consisted of two independent clinicians and one statistician. The interim analysis found no unexpected risks or survival rates with administration of vasopressin. Should there have been any unexpected survival rates, an early interim analysis would have been conducted by the SMC. A significant difference of p < in survival rate between the two treatment groups needed to be observed on two successive occasions before the committee could propose termination of the study in lieu of the outstanding benefit of vasopressin. Data management was carried out using Clintrial application software version 4.2. All statistical analyses were made on an intention-to-treat basis for both groups and performed using SAS version 9.1. Statistical significance was set at p < The baseline characteristics, medical history and index event were described for both groups. Comparisons of outcomes between groups were assessed using Pearson Chi-square test or Fisher s exact test when appropriate. The p-value, relative risks (RR) with associated 95% confidence interval (CI) are presented. Multivariate analysis using eight variables was performed and reported. The analysis was based on an a priori multivariate model derived from factors known in the literature to affect survival. Cox regression model with fixed time points was performed to derive RR and for adjusting relevant covariates (race, medical history, bystander CPR and previous adrenaline given). The adjusted p-values and RRs with associated 95% CI were presented. 3. Results 3.1. Characteristics of study participants From 9 March 2006 to 19 January 2009, 790 patients were assessed for eligibility. Recruitment ceased after the planned sample size was reached. A total of 63 patients were excluded, with 34 not meeting inclusion criteria and 29 declining consent. Of the 29 patients who declined consent, 22 died at ED, 7 were admitted but subsequent outcomes were unknown. The analysis included 727 participants, 353 allocated to adrenaline and 374 allocated to vasopressin (Fig. 1). Three patients were lost to follow-up after discharge, hospital or discharge outcomes were recorded, but 1 year follow-up data was missing. Tables 1 and 2 show the characteristics of the study participants. Regarding first cardiac rhythm presenting at the ED, 503 (69.2%) participants were in asystole and 138 (19.0%) were in PEA rhythm. This includes both pre-hospital and ED arrests. There Fig. 1. CONSORT chart trial outline.

4 956 M.E.H. Ong et al. / Resuscitation 83 (2012) Table 1 Demographics and characteristics of study participants. Variables Adrenaline group, n = 353 Vasopressin group, n = 374 p-value Male, 242 (68.6) 263 (70.3) 0.61 Race, 0.20 Chinese 243 (68.8) 239 (63.9) Malay 53 (15.0) 55 (14.7) Indian 41 (11.6) 50 (13.4) Others 16 (4.6) 30 (8.0) Age (years), mean (SD) 64.9 (15.4) 64.6 (14.2) 0.75 Age (years), median (range) 66.3 ( ) 65.4 ( ) Medical history, With medical history 247 (70.0) 288 (77.0) 0.09 Ischaemic heart disease/other evident structural heart disease 131 (37.1) 134 (36.8) 0.15 Diabetes mellitus 110 (31.2) 121 (32.4) 0.23 Chronic obstructive pulmonary disease/asthma 27 (7.7) 37 (9.9) 0.16 Cerebrovascular accident 42 (11.9) 39 (10.4) 0.15 Hyperlipidemia 88 (24.9) 73 (19.5) 0.02 Hypertension 167 (47.3) 190 (50.8) 0.22 Chronic renal failure 26 (7.4) 30 (8.0) 0.22 Cancer 25 (7.1) 30 (8.0) 0.22 No medical history 51 (14.5) 44 (11.8) Unknown medical history 55 (15.5) 42 (11.2) Non-study drug administration, Adrenaline given before study drug 88 (24.9) 114 (30.5) 0.10 Adrenaline given after study drug 334 (94.6) 361 (96.5) 0.21 Vasopressin given before study drug 0 0 Vasopressin given after study drug 0 2 Amount of non-study drug administered, mean (SD) Adrenaline given before study drug (mg) 1.1 (0.9) 1.1 (0.7) 0.45 Adrenaline given after study drug (mg) 3.1 (2.1) 2.9 (1.8) 0.08 Patient brought to ED a by, 0.41 EMS b ambulance 296 (83.9) 325 (86.9) Private ambulance 26 (7.4) 25 (6.7) Private transport 15 (4.2) 8 (2.1) Others 16 (4.5) 16 (4.3) a Emergency Department. b Emergency Medical Services. Table 2 Characteristics of arrest. Witnessed arrest, 265 (75.1) 265 (70.9) 0.20 Bystander Ambulance crew Hospital staff Bystander CPR a, 50 (14.2) 62 (16.6) 0.37 Pre-ED b defibrillation, 73 (20.7) 74 (19.8) 0.56 First cardiac rhythm at ED, 0.55 Ventricular fibrillation 28 (7.9) 22 (5.9) Ventricular tachycardia 2 (0.6) 4 (1.1) Pulseless electrical activity/idioventricular 72 (20.4) 66 (17.6) Asystole 238 (67.4) 265 (70.9) Collapse to arrival in ED, Number of patients who collapsed before arrival in ED 282 (79.9) 303 (81.0) 0.29 Time of collapse to arrival in ED (min), median (range) c 35 (0 87) 36 (0 264) Number of patients who collapsed after arrival in ED (in-hospital collapse) 32 (9.1) 20 (5.4) Collapse to ROSC d, Number of patients with ROSC 106 (30.6) 119 (52.9) Time from collapse to ROSC (min), median (range) 38 (3 145) 43 (2 287) 0.04 Cause of arrest Cardiac etiology 302 (85.6) 325 (86.9) 0.62 a Cardiopulmonary resuscitation. b Emergency Department. c Median is used because the time from collapse to arrival in ED was not normally distributed. d Return of spontaneous circulation. were 585 (80.5%) participants who collapsed before they arrived in ED. The mean time interval from collapse to their arrival in ED was 38.1 ± 19.8 min. Of the total sample, 202 (27.8%) were given adrenaline before the study drug and 695 (95.6%) were given adrenaline after the study drug. An additional dose of vasopressin was given after the study drug to two (0.3%) participants, as part of routine care of one of the institutions. The two treatment groups were comparable except slightly more participants with a medical history were randomised to the vasopressin than to the adrenaline group Main results Table 3 shows the study survival outcomes. Eight participants (2.3%) from adrenaline and 11 (2.9%) from vasopressin group survived to hospital discharge or 30 days post-arrest, with no

5 M.E.H. Ong et al. / Resuscitation 83 (2012) Table 3 Study survival outcomes. Variable Adrenaline, n = 353 (%) Vasopressin, n = 374 (%) p-value/rr b (95% CI c ) Adjusted p-value/rr (95% CI) d Return of spontaneous circulation 106 (30) 119 (31.8) ( ) ( ) Survival to admission a 59 (16.7) 83 (22.2) ( ) ( ) Survival to discharge or 30 days post-arrest 8 (2.3) 11 (2.9) ( ) ( ) a Patient discharged from Emergency Department alive and admitted to ward. b Relative risk of survival associate with vasopressin compare to adrenaline, or relative risk of death associated with adrenaline compared to vasopressin. c Confidence interval. d Cox regression was used to adjust for race, medical history, bystander CPR, and adrenaline given before study drug. Table 4 Cerebral performance categories and overall performance categories scores at 30 days and 1 year post arrest. Neurological status Cerebral performance categories Overall performance categories Adrenaline (n = 8) Vasopressin (n = 11) All participants (n = 19) Adrenaline (n = 8) Vasopressin (n = 11) All participants (n = 19) On discharge or at 30 days Categories Categories Neurological status Cerebral performance categories Overall performance categories Adrenaline (n = 6) Vasopressin (n = 8) All participants (n = 14) Adrenaline (n = 6) Vasopressin (n = 8) All participants (n = 14) At 1 year post arrest Categories Categories Three (1 in adrenaline and 2 in vasopressin) patients were lost to follow up and 2 deaths occurred (each in adrenaline and vasopressin) after discharge or 30 days post arrest. significant difference between groups even after adjusting for covariates (p = 0.27, RR = 1.72, 95% CI = ). 225 (30.9%) participants had ROSC 106 (30.0%) from adrenaline and 119 (31.8%) from vasopressin group, with no significant difference between groups even after adjusting for covariates (p = 0.33, RR = 1.15, 95% CI = ). A greater proportion of participants survived to admission with vasopressin (22.2%) than with adrenaline (16.7%) (p = 0.06 RR = 1.18, 95% CI = ). The difference was statistically significant after adjusting for covariates (p = 0.05, RR = 1.43, 95% CI = ). There was no significant difference between the two study groups regarding good neurological function of participants who survived to hospital discharge or to 1 year (Table 4). Table 5 shows the multivariate analysis for ROSC, survival to admission, and survival to hospital discharge or 30 days post-arrest. No significant differences were found in the sub-groups regarding ROSC or survival to discharge. However, the sub-group analysis for those with PEA rhythm showed a higher survival to admission for the vasopressin group (p = 0.02, RR = 1.30, 95% CI = ). Fig. 2 shows the association of ROSC rates, survival rates to admission, and survival rates to discharge or 30 days by time intervals from collapse to arrival in ED. Significantly more participants in the vasopressin group than in the adrenaline group survived to admission during the time intervals from collapse to arrival in ED of min (p = 0.05, RR = 1.22, 95% CI = ) and min (p = 0.05, RR = 1.11, 95% CI = ). 4. Discussion Using the ED setting for this study meant that the main focus was on patients with prolonged cardiac arrest. We found that the combination of vasopressin and adrenaline did not improve long term survival compared to adrenaline alone, but seemed to improve survival to admission in patients with prolonged cardiac arrest. The sub-group analysis suggested that this benefit is most pronounced in the group with a collapse to arrival in ED interval from 15 to 45 min. However, this did not translate to a long term survival benefit. It was initially observed that patients with cardiac arrest had extremely high circulating levels of endogenous vasopressin. 16 Subsequent animal studies confirmed that vasopressin improved vital organ perfusion during cardiac arrest. Compared to adrenaline, vasopressin achieved significantly higher coronary perfusion Fig. 2. Survival and return of spontaneous circulation rate return of spontaneous circulation, survival to admission, and survival to discharge or 30 days post-arrest by time interval from collapse to arrival at emergency departments.

6 958 M.E.H. Ong et al. / Resuscitation 83 (2012) Table 5 Multivariate analysis for return of spontaneous circulation, survival to admission and survival to hospital discharge or 30 days post-arrest. Return of spontaneous circulation Survival to admission Survival to discharge/30 days post arrest Sub-groups, n (adrenaline vs. vasopressin) p-value Relative risk (95% CI) Vasopressin Adrenaline p-value Relative risk (95% CI) Vasopressin Adrenaline p-value Relative risk (95% CI) Vasopressin Adrenaline 94 (35.5) 88 (33.2) 0.58; 0.97 ( ) 54 (20.4) 66 (24.9) 0.21; 1.06 ( ) 8 (3.0) 11 (4.2) 0.48; 1.01 ( ) Witnessed cardiac arrest, 530 (265 vs. 265) 19 (26.0) 19 (25.7) 0.96; 1.00 ( ) 7 (9.6) 15 (20.3) 0.07; 1.13 ( ) 0 (0.0) 2 (2.7) 0.50; 1.03 ( ) Pre-ED defibrillation performed/shockable rhythm, 147 (73 vs. 74) 12 (24.0) 19 (30.7) 0.44; 1.10 ( ) 6 (12.0) 14 (22.6) 0.15; 1.14 ( ) 1 (2.0) 1 (1.6) 1.00; 1.00 ( ) Bystander CPR performed, 112 (50 vs. 62) 78 (25.8) 81 (25.7) 0.97; 1.00 ( ) 42 (13.9) 55 (17.5) 0.23; 1.04 ( ) 5 (1.7) 9 (2.9) 0.32; 1.01 ( ) 14 (46.7) 13 (50.0) 0.80; 1.07 ( ) 8 (26.7) 12 (46.2) 0.13; 1.36 ( ) 2 (6.7) 6 (23.1) 0.13; 1.21 ( ) 30 (41.7) 34 (51.5) 0.25; 1.20 ( ) 14 (19.4) 25 (37.9) 0.02; 1.30 ( ) 2 (2.8) 3 (4.6) 0.67; 1.02 ( ) Cause of arrest cardiac etiology, 617 (302 vs. 315) Ventricular fibrillation/ventricular tachycardia, 56 (30 vs. 26) Pulseless electrical activity/idioventricular, 138 (72 vs. 66) Asystole, 503 (238 vs. 265) 56 (23.5) 67 (25.3) 0.65; 1.02 ( ) 36 (15.1) 44 (16.6) 0.65; 1.02 ( ) 4 (1.7) 1 (0.4) 0.19; 0.99 ( ) Time from collapse to arrival in ED 50 (51.0) 36 (38.7) 0.09; 0.80 ( ) 31 (31.6) 27 (29.0) 0.70; 0.96 ( ) 6 (6.1) 8 (8.6) 0.51; 1.03 ( ) 40 (30.5) 45 (33.6) 0.60; 1.05 ( ) 27 (20.6) 32 (23.9) 0.52; 1.04 ( ) 2 (1.5) 5 (3.7) 0.45; 1.02 ( ) <15 min, 192 (98 vs. 93) Medical history of ischaemic heart disease/heart disease, 265 (131 vs. 134) pressure, myocardial blood flow and total cerebral blood flow. 17,18 Initial human studies on the use of vasopressin in prolonged cardiac arrest showed significantly improved coronary perfusion pressures. 19 Our sub-group analysis also suggested that vasopressin has short-term benefits for patients with prolonged cardiac arrest. Although our main hypothesis was not confirmed, we found that in our sample of patients presenting with VF or VT, there were more survivors to discharge (see Table 5) with vasopressin compared with adrenaline; this was however, not statistically significant. A randomised clinical trial by Lindner et al., 20 comparing vasopressin and adrenaline in refractory VF also found that a larger proportion of patients were successfully resuscitated with vasopressin, as compared to adrenaline (40% vs. 15%, p = 0.16). A similar situation is noted in patients with witnessed cardiac arrest in our study; this raises possibilities for further investigation. In Asian EMS settings, cultural and societal norms usually do not permit pronouncement of death by paramedics in the field. Thus transport to the hospital with ongoing CPR is common, and resuscitation usually continues in the ED. It is interesting to note in this study, that 38 ± 20 min after onset of cardiac arrest, ROSC could be achieved in substantial numbers of patients. Due to the very high proportion of asystolic ( 69%) and PEA ( 19%) patients, it is not surprising that overall survival in our study was low Strengths and limitations Strengths of this study include the large sample size and the inclusion of participants in typical Asian ED settings. The latter strength contributes to making the results generalisable to patients arriving at the ED with prolonged cardiac arrest. One limitation of this study was that since it was conducted over a relatively long period, results might have been affected by secular trends. Variations in post-resuscitation care can affect survival to discharge status, and it is difficult to account for variations between institutions or individual hospital providers. During the study period, we were unaware of any major change in ED protocols or ICU treatment, but it is possible that variations in individual and hospital practice could affect the study results in ways that are difficult to determine. A related limitation was that treatment protocols for EMS or ED were not mandated. Thus, other drugs usually given in ACLS like atropine, amiodarone or lidocaine would have been given according to clinician preferences and practice. It is also noted in this study that more than 90% of patients were given adrenaline after administration of study drug. This meant that patients in the adrenaline group were given repeated doses of adrenaline, while those in the vasopressin group were given only a single dose of vasopressin and multiple doses of adrenaline. Also, the fact that the EMS in our country rarely pronounce death in the field may have resulted in selection bias through recruitment of a high number of patients who had no chance of survival regardless of any medical interventions. Nevertheless, we feel the blinded randomisation process would have equalised both study groups sufficiently. We were also limited by the small number of survivors to discharge, due to the large number of patients presenting in asystole or PEA. We found the improvement in survival to discharge rate with vasopressin was lower than the hypothesised 7%. Another limitation was that Time of Collapse was based on reporting by the paramedics, which might be subjected to recall bias. Lastly, we did not collect information on the initial cardiac arrest rhythm at the time of collapse, which could also potentially

7 M.E.H. Ong et al. / Resuscitation 83 (2012) confound the effect of vasopressin on the presenting rhythms of patients in the ED. We also did not collect ambulance response times. A study by Niemann et al., 21 reported that patients with an initial rhythm of VT or VF at the time of arrest, and who subsequently converted to asystole or PEA at the ED, had poorer outcomes compared to those whose initial cardiac arrest rhythms were asystole or PEA Future research Further studies on the effect of vasopressin on patients with prolonged cardiac arrest are needed. In particular, our finding of improved short-term survival over adrenaline needs to be confirmed. Also, this trial was conducted before post-resuscitation hypothermia was introduced to the hospitals involved. Hypothermia has been shown to improve survival after ROSC in patients admitted after cardiac arrest. 22,23 It is not known whether survival to hospital discharge and neurologic survival could be improved with vasopressin and subsequent hypothermia. If so, a stronger argument for vasopressin could be made. 5. Conclusions Combination of vasopressin and adrenaline did not improve long term survival compared to adrenaline alone, but seemed to improve survival to admission in patients with prolonged cardiac arrest. Further studies combining vasopressin with hypothermia post-cardiac arrest can be explored to determine if this combination will have any benefits for long-term survival. Conflict of interest All the authors have neither commercial nor personal associations or any sources of support that might pose a conflict of interest in the subject matter or materials discussed in this manuscript. Role of the funding source The study was funded by National Medical Research Council, Ministry of Health, Singapore (NMRC/0673/2002); Singapore Health Services Pivotal Trials Grant, Singapore (PTC01/2006/006); and Singapore General Hospital Research Fund, Singapore (SRF#145/08). The funding sources had no involvement in the study design, collection, analysis, and interpretation of data, writing of manuscript, and in the decision to submit the manuscript for publication. Acknowledgements We would like to acknowledge the participation and great support of the nurses and doctors from Department of Emergency Medicine, AH; Accident and Emergency Department, CGH; Emergency Medicine Department, NUH; and Department of Emergency Medicine, SGH. We would also like to thank the following: At Singapore General Hospital: V. Anantharaman, Lim Swee Han, Mark Leong, R. Ponampalam, Fatimah Lateef, Evelyn Wong, Ho Khoy Kheng, Rabind A Charles, Jean Lee, Adeline Ngo, Chew Huck Chin, Annitha D/O Annathurai, Oh Jen Jen, Gary Choa, Lee Soo Boon, Chan Sze Ling, Tsang Wing Yee, Susan Yap, Janie Lim Ee Woon, Hannah Jono, Pauline Ang. At Changi General Hospital: Goh Siang Hiong, Mohan Tiru, Lee Wee Yee, Goh Pak Liang, Lim Hoon Chin, Lee Shu Woan, Tan Wee Ping, Camlyn Tan, Tan Hock Heng, Ang Shiang-Hu, Jimmy Goh, Jackson Lim, Lai Shieh Mei, Goh E Shuan, Yvonne Goh, Thng Shin Ying, Arron Ang, Carol Lee. At National University Hospital: Peter Manning, Shirley Ooi Beng Suat, Suresh Pillai, Seet Chong Meng, Peng Li Lee, Malcolm Mahadevan, Ong Pei Yuin, Rakhee Yash Pal, Brandon Koh, Irwani Bte Ibrahim, Quek Lit Sin, Sim Tiong Beng, Lee Kuan Wee, Lee Sock Koon, Amila Punyadasa, Goh Ee Ling. At Alexandra Hospital: Charles Chan Johnson, Francis Lee, James Peregrine Travers, Sim Tiong Peng, Toh Khai San. 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