Clinical trials on demodynamic-directed cardiopulmonary resuscitation have been limited. The aim of this study is to investigate whether Augmented-Medication CardioPulmonary Resuscitation (AMCPR) would improve the odds of return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest.
This is a double-blind, single-center, randomized placebo-controlled trial that will be conducted in the emergency department of a tertiary, university-affiliated hospital in Seoul, Korea. A total of 148 adult patients with nontraumatic, nonshockable, out-of-hospital cardiac arrest who have an initial diastolic blood pressure above 20 mmHg will be randomly assigned to two groups of 74 patients (a 1:1 ratio). Patients will receive an intravenous dose of 40 IU of vasopressin with epinephrine, or a placebo with epinephrine. The primary endpoint is a sustained ROSC (over 20 minutes). Secondary endpoints are enhanced diastolic blood pressure, end-tidal carbon dioxide levels, acidosis, and lactate levels during resuscitation.
AMCPR is a trial about tailored medication for select patients during resuscitation. This is the first randomized control trial to identify patients who would benefit from vasopressin for achieving ROSC. This study will provide evidence about the effect of administration of vasopressin with epinephrine to increase ROSC rate.
ClinicalTrials.gov identifier: NCT03191240. Registered on June 19, 2017.
A combination of vasopressin and epinephrine for patients with out-of-hospital cardiac arrest has shown not to improve outcomes.
We propose the Augmented-Medication CardioPulmonary Resuscitation (AMCPR) trial to determine whether the addition of vasopressin in refractory cardiac arrest patients with low diastolic blood pressure during cardiopulmonary resuscitation improves return of spontaneous circulation rate.
Out-of-hospital cardiac arrest (OHCA) is a major public health burden contributing to morbidity and mortality worldwide [
Although resuscitation guidelines remain uniform across all cardiac arrest patients, individualizing resuscitation to appropriate hemodynamic goals rather than using a standard “one-size-fits-all” cardiopulmonary resuscitation (CPR) seems a promising strategy in highly monitored patients. Previous randomized controlled animal studies established that hemodynamic-directed targeted CPR results in superior outcomes compared to standard CPR [
The aim of the study is to determine whether the addition of vasopressin in refractory cardiac arrest patients during CPR improves ROSC rate. We therefore designed the Augmented-Medication CardioPulmonary Resuscitation (AMCPR) trial. We hypothesized that the addition of vasopressin when patients cannot achieve a diastolic blood pressure over 20 mmHg with epinephrine during CPR, would improve outcomes.
The trial protocol was approved by the Institutional Review Board of Asan Medical Center (No. 2017-0669) and the Ministry of Food and Drug Safety in Korea. The requirement for informed consent was waived by the Ethics Committee because of the emergent need for treatment in cardiac arrest. The legal representatives of the patients were later informed about the trial.
We will conduct a randomized, double-blind, placebo-controlled, single-center trial among patients with nontraumatic OHCA in the emergency department of an urban, tertiary hospital, located in Seoul, Korea.
Adult patients (above 18 years old) with nontraumatic, nonshockable OHCA and with diastolic blood pressure below 20 mmHg measured by invasive radial or femoral arterial line at presentation will be included. The following exclusion criteria apply: patients with traumatic cardiac arrest, patients with a signed donot-resuscitate order, patients with an underlying terminal-state disease without an active treatment plan, patients with failed arterial line insertion within 6 minutes, patients receiving extracorporeal membrane oxygenation, patients with a prehospital downtime longer than 60 minutes, patients with successful ROSC before hospital arrival or ROSC within 6 minutes, and patients with diastolic blood pressure above 20 mmHg for 6 minutes during resuscitation.
The patients will be randomly assigned in a 1:1 ratio via a random number generator to either the intervention group or the placebo group. The trial administration nurse will open a premade, concealed, uniquely numbered, but otherwise identical-appearing card containing a treatment (i.e., vasopressin or placebo). Then, he/she will prepare the vasopressin (40 IU) or saline placebo. During the trial, all emergency physicians, nurses, and interns will be unaware of which drugs will be used. Unblinding will only take place in case of an unexpected serious adverse reaction. After randomization, patients will receive either 1 mg of epinephrine and 40 IU of vasopressin or 1 mg of epinephrine and saline placebo in separate injections less than 10 seconds apart. If ROSC is not achieved within the following 3 minutes, patients will be administered one more vasopressin (40 IU) or placebo with epinephrine injection. After that, only 1 mg of epinephrine will be administered every 3 minutes for both groups. Other conventional drugs, including amiodarone, calcium, or bicarbonate will also be administered at the clinician’s discretion and no other drugs will be administered.
Advanced cardiac life support will be administered in accordance with the last international guidelines and local procedures [
All data will be anonymized and collected according to Utstein guidelines using a database designed with Microsoft Access (Microsoft Corp., Redmond, WA, USA) by independent blinded researchers [
The primary outcome will be sustained ROSC defined as the spontaneous return of a palpable pulse and measurable blood pressure longer than 20 minutes. Secondary outcomes are (1) survival to discharge, (2) good neurologic recovery at discharge (Cerebral Performance Category 1 or 2) [
Risks to participants in this study may be minimal. There are no previous reports about harmful effects of administration of vasopressin up to 80 IU for patients with OHCA during resuscitation. Therefore, we have no predefined adverse events for this trial.
Data analysis will be performed with the intention-to-treat set, the full analysis set, and the per-protocol analysis set. The sample size was calculated based on an expected difference of 25%. We assumed that 30% of patients in the control group would achieve ROSC. For the P-value of 0.05 and the statistical power of 0.80, a total sample size of 74 patients will be required in each group. Assuming a 15% dropout rate, we will enroll 174 patients. All collected data will be analyzed using descriptive methods according to the intervention and control group. For continuous variables, mean with standard deviation or median with interquartile range will be presented depending on normality. For binary variables, number with percentage will be reported. Analysis will employ the t-test or the Mann-Whitney U-test for continuous variables and the chi-square test or Fisher exact test for categorical variables. Statistical significance will be considered as a P-value less than 0.05. All statistical analysis will be conducted using IBM SPSS ver. 27.0 (IBM Corp., Armonk, NY, USA).
Vasopressors have been considered key elements for improving chance of ROSC for patients with out-of-hospital cardiac arrest. Despite vasopressin being more effective than epinephrine in animal studies, past meta-analysis of clinical studies showed no evident benefit of vasopressin over epinephrine in human CPR [
The current guidelines suggest monitoring diastolic blood pressures and improving the quality of resuscitation when the level of diastolic blood pressures is lower than 20 mmHg [
The patients will receive 40 IU of vasopressin just after administration of 1 mg epinephrine and receive one more repeated dose of both if ROSC is not achieved. This dosage of vasopressin has been proven to be safe without serious adverse outcomes in past clinical trials [
Enrollment of the patients started from August 2017. Along with a recent trial with in-hospital cardiac arrest patients, this study will provide valuable evidence about the effectiveness of the addition of vasopressin to epinephrine among patients with refractory low organ perfusion pressure in resuscitation of OHCA. If this treatment is shown to be effective, the use of an arterial line for monitoring diastolic blood pressure and administration of additional vasopressors could be a promising treatment strategy for patients with OHCA.
Supplementary material is available at
SPIRIT (Standard Protocol Items: Recommendations for Clinical Interventional Trials) checklist for trials.
No potential conflict of interest relevant to this article was reported.
This study was supported by a grant from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (No. 2017IT0669).
Conceptualization: WYK, SMR; Data curation: JK, YJK; Formal analysis: DKO, JK; Funding acquisition: WYK; Investigation: SMK, SIH; Methodology: DKO, JK, BC; Project administration: WYK; Visualization: JK, YJK, SMR, SMK, SIH, BC; Writing–original draft: DKO, JK; Writing–review & writing: YJK, SMR, WYK.
All authors read and approved the final manuscript.
Trial flowchart. DNR, do not resuscitate; ED, emergency department; ROSC, return of spontaneous circulation; VF, ventricular fibrillation; VT, ventricular tachycardia.
Trial schedule. a)Assessment of survival discharge, favorable neurologic outcome (Cerebral Performance Category 1 or 2). b)Terminations of cardiopulmonary resuscitation were decided by emergency medicine physicians on duty after return of spontaneous circulation or declaration of death.