Clinical trial NCT02260258
Conditions: Cardiac Arrest
Keywords: Cardiac Arrest, NMB, Neuromuscular Blockade, Rocuronium
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2014-10-01; Completion date: 2019-05-29
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate if neuromuscular blockade improves lactate clearance (and preliminary secondary clinical outcome measures) as compared to usual care in post-cardiac arrest patients undergoing targeted temperature management.

Detailed description:
Out-of-hospital cardiac arrest (OHCA) occurs in more than 300,000 patients in the United States each year with an estimated mortality of greater than 90%. Unfortunately, we currently have little to offer in terms of treatment other than supportive care for the post-cardiac arrest patient. Neuromuscular blockade (NMB) is sometimes utilized in post-arrest patients particularly for the prevention of shivering. However, usage of NMB remains controversial and current American Heart Association (AHA) recommendations are to minimize utilization. Recent prospective randomized trials in patients with acute respiratory distress syndrome suggest a mortality benefit from NMB and an excellent safety profile. Furthermore, observational trials in both sepsis and post-cardiac arrest show that the use of NMB is associated with improved survival. Given this, we hypothesize that continuous NMB will be beneficial in post-arrest patients. In order to test this hypothesis, we propose a multi-center, randomized, open-label, phase II trial in post-CA patients comparing sustained NMB administration for 24 hours to standard of care after return of spontaenous circulation (ROSC). We will enroll adult, comatose OHCA patients with ROSC and will utilize an already existing clinical trials network for the completion of the study. Patients will be randomized to receive either rocuronium for 24 hours or to receive placebo with usual care. Previous data from our group has suggested that lactate levels in the post-arrest patient are a good surrogate marker for mortality. We have therefore chosen to utilize lactate levels at 24 hours as the primary endpoint for the current trial. Secondarily we will evaluate clinical endpoints including length of stay (LOS), in-hospital mortality, and good neurological outcome. We will perform a sub-study of inflammatory markers and oxygen consumption.

Arms: arm 1: Patients will receive a bolus dose of 1 mg/kg, then a continuous intravenous (IV) infusion as per standard intensive care unit practice.

Of note, protocol allows for use of cistatracurium in place of rocuronium for either reasons of drug-shortage or clinical conditions (if institutional preferences for dose adjustment in liver or renal insufficiency arise). arm 2: Patients will receive 100 mL of normal saline over 5-10 minutes at the beginning of the study in addition to usual care.
Interventions: intervention 1: Rocuronium intervention 2: Normal Saline
Intervention descriptions: intervention 1: Neuromuscular Blockade intervention 2: Normal Saline

Protocol documents:
Prot_001.pdf: 
1 
 
Clinical Trial Protocol/Statistical Analysis Plan 
 
Continuous Neuromuscular Blockade following Successful Resuscitation from Cardiac 
Arrest: A Randomized Controlled Trial 
 
Clinical Trial Identifier: NCT02260258 
 
Authors: Ari Moskowitz, MD; Anne V. Grossestreuer, PhD; Lars W. Andersen, MD, MPH, PhD, 
DMSc; Mathias J. Holmberg, MD, MPH; Katherine M. Berg, MD; Maureen Chase, MD, MPH, 
Michel N. Cocchi, MD; Michael W. Donnino, MD 
 
Principal investigator: 
Michael W. Donnino, MD 
Director of Center for Resuscitation Science 
Associate Professor of Medicine, Harvard Medical School 
Attending Physician in Emergency and Critical Care Medicine, BIDMC 
 
Coordinating Center: 
Beth Israel Deaconess Medical Center 
West Clinical Campus 2nd Floor 
One Deaconess Road, Boston MA 02215 
Phone: 617-754-2295 
Fax: 617-754-2350 
Email: mdonnino@bidmc.harvard.edu 
 
Funded By: 
The American Heart Association 
The National Institutes of Health 
 
Revision History: 
v1: May 30th, 2019 
v2: June 7th, 2019 
 
 


2 
 
Table of Contents 
 
Background and Rationale 
3 
Study Overview 
3 
Study Design and Setting 
3 
Trial Participants 
3 
Randomization and Intervention 
4 
Study Registration and Monitoring 
4 
Outcomes and Definitions 
4 
Primary Outcome and Sample Size Estimation 
4 
Secondary Outcomes 
4 
Statistical Analysis 
5 
General Principles 
5 
Baseline Characteristics 
5 
Analysis of Primary Outcome 
5 
Analysis of Secondary Outcomes 
6 
Additional Planned Analyses 
6 
Statistical Software 
6 
Appendix 
6 
Appendix Figure 1 
6 
Appendix Table 1 - Cohort Characteristics 
7 
Appendix Table 2 - Sedatives and Off-Protocol Paralytics 
9 
Appendix Table 3 - Outcomes 
9 
References 
10 
 
 
 
 


3 
 
Background and Rationale 
Two randomized trials published in 2002 found improved mortality and neurologic morbidity 
among out-of-hospital cardiac arrest (OHCA) victims with initial shockable rhythms (pulseless 
ventricular tachycardia and ventricular fibrillation) treated with therapeutic hypothermia targeting 
a temperature of 32℃-33℃ as compared to placebo.1,2 A more recent, larger randomized trial 
comparing temperature controlled to 33℃ vs 36℃ did not demonstrate a significant difference in 
outcomes.3 In the earlier therapeutic hypothermia studies, neuromuscular blockade (NMB) was 
administered throughout the cooling period in the intervention group but not the control group. In 
contrast, paralytic use was minimized in both groups in the more recent study comparing 33℃ to 
36℃. Thus, the use of NMB is a potential unrecognized confounder from the earlier hypothermia 
studies.  
 
Multicenter observational data has previously demonstrated that continuous NMB following 
cardiac arrest may be associated with improved lactate clearance and reduced mortality.4 NMB 
may improve post-cardiac arrest outcomes through a number of mechanisms including the 
reduction of global oxygen consumption, prevention of  patient-ventilator dyssynchrony, 
reduction of metabolic demand, reduction of inflammation, or other unidentified pathways.5 The 
presently reported phase II trial, in addition to a similar phase II trial published by an affiliated 
cardiac arrest clinical trials group in South Korea6, tested the hypothesis that early, continuous 
neuromuscular blockade following cardiac arrest will improve blood lactate levels and potentially 
clinical outcomes as compared to usual care.  
Study Overview 
Study Design and Setting 
This was a phase II, multi-center, randomized trial of continuous neuromuscular blockade using 
rocuronium vs. usual care in patients who had sustained return of spontaneous circulation 
(ROSC) but remained unresponsive after cardiac arrest. Enrolling sites were five urban tertiary 
care centers in the United States. The trial coordinating center gathered and analyzed the data, 
and vouches for the accuracy and completeness of the data and for the fidelity of the trial to the 
protocol. Written informed consent was obtained from the legally authorized representatives of 
all patients.  
 
Trial Participants 
Adult patients (aged ≥18 years) who experienced a cardiac arrest and subsequently had 
sustained ROSC (≥20 minutes) but remained comatose (i.e. not following commands) and were 
undergoing TTM targeting between 32℃ and 36℃ were enrolled in the study. An additional 
inclusion criterion of a minimum serum lactate level of ≥2mmol/L was added after the 42nd 
patient was enrolled. Patients were excluded if they had a traumatic etiology of cardiac arrest, 
were already receiving continuous neuromuscular blockade for clinical purposes, were not 
expected by the physician team to survive 24-hours, had been undergoing TTM for ≥6 hours, 
had a pre-arrest modified Rankin scale score of 4 or higher, or were members of a protected 
population (including prisoners, pregnant patients, and the developmentally disabled). Patients 
who had received a single-dose of a neuromuscular blocking agent, most commonly during 


4 
 
tracheal intubation, could be enrolled in the study so long as the drug had worn off and there 
were no immediate plans for additional neuromuscular blockade administration.  
 
Patient flow through the trial will be displayed in a CONSORT diagram (see Appendix Figure 1 
for shell figure). 
 
Randomization and Intervention 
Patients were randomized to continuous NMB or usual care in blocks of four and in a 1:1 ratio. 
The randomization was stratified by study site and by the presence of shock, defined as the use 
of any vasopressor at the time of randomization. The random sequence was generated by an 
independent statistician who was not involved in the conduct of the study. The site-specific 
allocation sequences were maintained by the research pharmacies at each site for the duration 
of the study.  
 
Patients in the continuous NMB arm received a rocuronium bolus of 1.0mg/kg followed by a 
continuous infusion of rocuronium for a total of 24-hours. The infusion of rocuronium was titrated 
to 1-2 out of 4 twitches on a train-of-four peripheral nerve stimulator. To minimize any difference 
in the time between randomization and receipt of the study drug between the two groups, 
patients in the usual care arm were administered a small volume of normal saline to mark the 0-
hour time point. All patients undergoing TTM, including those who received continuous NMB, 
were deeply sedated per local site protocol. Use of the Columbia anti-shivering protocol was 
recommended to clinical teams, but adherence was not mandated.7 
 
Study Registration and Monitoring 
The trial was registered at clinicaltrials.gov (NCT02260258) and was approved by the 
institutional review boards of all enrolling institutions.  
 
A Data Safety and Monitoring Board (DSMB) evaluated and monitored the trial for safety. There 
were no pre-specified stopping rules for futility or efficacy. No statistical interim analyses were 
performed.   
Outcomes and Definitions 
Primary Outcome and Sample Size Estimation 
The primary outcome of the study is change in serum lactate level measured between 0-hours 
and 24-hours after the receipt of study drug. This outcome was chosen as lactate is a 
continuous variable which is highly correlated with hospital survival in cardiac arrest patients.8 
The 24-hour time point was selected as it was drawn after completion of the rocuronium infusion 
but not so late that a significant proportion of patients may have already died. Based on 
conservative estimates drawn from observational data4, a sample size of 80 patients was 
specified to detect a predicted mean difference in 24-hour lactate of 2.0mmol/L (±3.2mmol/L) 
with 80% power assuming a two-sided test and an alpha of 0.05. 
 
Secondary Outcomes 
● Lactate change between 0- and 12-hours after administration of study drug 
● Lactate change between 0- and 36-hours after administration of study drug 
● Shock-free days 
○ Shock-free days measured as days alive and free of shock (<6 hours receiving a 
vasopressor) over the first 7 days after enrollment. 


5 
 
● Ventilator-free days 
○ Ventilator-free days measured as days alive and free of invasive mechanical 
ventilation (<6 hours with an endotracheal tube) over the first 7 days after 
enrollment. 
● Length of initial Intensive Care Unit (ICU) stay truncated at 28-days 
○ Includes only the initial stay in the ICU and does not include ICU readmission 
● Length of initial hospital stay truncated at 28-days 
○ Includes only the initial hospital stay and does not include any readmissions 
● Survival to hospital discharge 
● Neurologic outcome at hospital discharge 
○ As defined using the Modified Rankin Scale 
● Biomarker measures (available at 0-hours and 24-hours) 
○ Interleukin (IL)-1β, IL-6, IL-8, IL-10, and TNF-ɑ 
○ Neuron specific enolase [NSE] 
○ S100 calcium-binding protein B (S100B) 
● Muscle weakness assessed using a modified Medical Research Council scale 
 
 
A table of outcomes by treatment group will be included (see Appendix Table 3). 
Statistical Analysis 
General Principles 
All initial analyses will be performed in a modified intention-to-treat (modified ITT) population, 
defined as all randomly assigned subjects who received any study drug (rocuronium or the 
saline time marker). The primary analysis for the outcome of lactate at 24-hours will be repeated 
in the per-protocol population including only those patients who were alive at 24-hours and 
received either 24-hours of continuous rocuronium (if so assigned) compared to those who 
received usual care without any neuromuscular blockade medication after the time 0-hour point.    
 
Baseline Characteristics 
A description of the baseline characteristics will be presented by treatment group (see Appendix 
Table 1). Categorical variables will be summarized by frequencies and percentages. 
Percentages will be calculated according to the number of patients for whom data are available. 
Continuous variables will be summarized using means (standard deviations, SD) or medians 
(interquartile range, IQR). Statistical tests will not be used to compare baseline characteristics 
between groups. A table describing sedative and off-protocol paralytic use in each arm will be 
included (Appendix Table 2) 
 
Analysis of Primary Outcome 
The primary outcome is lactate change between 0-hours and 24-hours after enrollment. The 
group difference in change from the time of study drug administration (0-hours) to 24-hours will 
be assessed using a linear mixed effects model. Lactate values will be log-transformed for this 
analysis if they are not approximately normally distributed. Fixed effects will include the 
allocated treatment, shock stratification, time point (0-hour, 12-hour, and 24-hour), and the 
interaction between treatment and time point. Study site will be included as a random intercept. 
The usual care group will be the reference variable for group, and baseline (0-hour) will be the 


6 
 
reference variable for time. Means and 95% confidence intervals of lactate over time will be 
presented, by treatment, using longitudinal plots (see appendix Figure 2) 
 
Analysis of Secondary Outcomes 
The following outcomes will be summarized using mean ± SD or median (IQR) and linear 
regression using the above described linear mixed model will be performed to assess the 
differences between treatment groups.  
● ICU length of stay 
● Hospital length of stay 
● Time to shock reversal 
● Time to liberation from mechanical ventilation 
● Biomarker measures (regression controlled for baseline level of each biomarker) 
● Muscle weakness score 
 
The following outcomes will be summarized using frequencies and percentages and logistic 
regression will be performed to assess the differences between treatment groups.  
● Neurologic outcome at hospital discharge 
● Survival to hospital discharge 
 
Subgroup Analyses 
 
The primary outcome analysis will be additionally performed in each of the below subgroups. 
 
• 
Shock and non-shock stratification groups  
• 
Shockable and non-shockable initial rhythms 
• 
Cardiac arrest location  
 
Additional Planned Analyses 
Additional planned analyses of total body oxygen consumption and cellular oxygen consumption 
for those patients in whom these variables are available will be performed.  
 
Statistical Software 
Stata (version 14, StataCorp, College Station, Tx) will be used for all analyses.  
Appendix 
Appendix Figure 1 
 


7 
 
 
 
Appendix Figure 2 - Change in Lactate over Time 
 
 
Appendix Table 1 - Cohort Characteristics 
 
Variable 
NMB 
Usual Care 
Demographics 
 
 
Age (Median, IQR)  
 
Sex (%Female)  
 
Race (%White)  
 


8 
 
Past Medical History 
 
 
Congestive heart failure  
 
Atrial fibrillation  
 
Coronary artery disease  
 
Prior cardiac arrest  
 
Chronic pulmonary disease  
 
Kidney disease  
 
Active malignancy  
 
Arrest Characteristics 
 
 
Location (%OHCA) 
 
 
Initial Rhythm (% Non-
shockable) 
 
 
Estimated no-flow time 
(median, IQR) 
 
 
Estimated low-flow time 
(median, IQR) 
 
 
Arrest duration (minutes, 
median, IQR) 
 
 
Witnessed (%yes) 
 
 
Bystander CPR provided 
(%yes) 
 
 
Arrest etiology (%cardiac) 
 
 
Characteristics at Enrollment 
 
 
pH (median, IQR) 
 
 
pCO2 (median, IQR) 
 
 
pO2 (median, IQR)  
 
 
Shock stratification (% shock)  
 
STEMI present (%yes) 
 
 
Target temperature (median, 
IQR) 
 
 


9 
 
Received any paralytic prior 
to enrollment (%yes) 
 
 
 
Appendix Table 2 - Sedatives and Off-Protocol Paralytics 
 
Variable 
NMB 
Usual Care 
Sedation and Analgesia 
(% receiving) 
0hr 
12hr 
24hr 
36hr 
0hr 
12hr 
24hr 
36hr 
Propofol  
 
 
 
 
 
 
 
Midazolam  
 
 
 
 
 
 
 
Lorazepam  
 
 
 
 
 
 
 
Dexmedetomidine  
 
 
 
 
 
 
 
Fentanyl  
 
 
 
 
 
 
 
Paralytic (% receiving) 
 
 
 
 
 
 
 
 
Bolus Rocuronium  
 
 
 
 
 
 
 
Continuous Rocuronium  
 
 
 
 
 
 
 
Bolus Cisatracurium  
 
 
 
 
 
 
 
Continuous Cisatracurium  
 
 
 
 
 
 
 
 
Appendix Table 3 – Outcomes 
 
Variable 
NMB 
Usual Care 
Effect estimate (95% 
confidence interval) 
Lactate Level (mmol/L, median, IQR)  
 
 
0-hour  
 
 
12-hour  
 
 
24-hour  
 
 
36-hour  
 
 
Clinical Outcomes 
 
 
 
ICU LOS (days, median, IQR) 
 
 
 


10 
 
Hospital LOS (days, median, IQR) 
 
 
 
Discharge CPC ≤2 (%) 
 
 
 
Muscle Weakness Score (median, 
IQR) 
 
 
 
Hospital Survival (% survived) 
 
 
 
 
References 
1. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve 
the neurologic outcome after cardiac arrest. N. Engl. J. Med. 2002;346(8):549–556. 
2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-
hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 2002;346(8):557–563. 
3. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C 
versus 36°C after cardiac arrest. N. Engl. J. Med. 2013;369(23):2197–2206. 
4. Salciccioli JD, Cocchi MN, Rittenberger JC, et al. Continuous neuromuscular blockade is 
associated with decreased mortality in post-cardiac arrest patients. Resuscitation. 
2013;84(12):1728–1733. 
5. Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers in early acute 
respiratory distress syndrome. N. Engl. J. Med. 2010;363(12):1107–111 
6. Lee BK, Cho IS, Oh JS, Choi WJ, Wee JH, Kim CS, Kim WY, Youn CS. Continuous 
neuromuscular blockade infusion for out-of-hospital cardiac arrest patients treated with 
targeted temperature management: A multicenter randomized controlled trial. PLoS 
One. 2018 Dec 17;13(12):e0209327 
7. Choi HA, Ko S-B, Presciutti M, et al. Prevention of shivering during therapeutic 
temperature modulation: the Columbia anti-shivering protocol. Neurocrit. Care. 
2011;14(3):389–394. 
8. Donnino MW, Andersen LW, Giberson T, et al. Initial lactate and lactate change in post-
cardiac arrest: a multicenter validation study. Crit. Care Med. 2014;42(8):1804–1811. 

SAP_000.pdf: 
1 
 
Statistical Analysis Plan 
 
Continuous Neuromuscular Blockade following Successful Resuscitation from Cardiac 
Arrest: A Randomized Controlled Trial 
 
Clinical Trial Identifier: NCT02260258 
 
Authors: Ari Moskowitz, MD; Anne V. Grossestreuer, PhD; Lars W. Andersen, MD, MPH, PhD, 
DMSc; Mathias J. Holmberg, MD, MPH; Katherine M. Berg, MD; Maureen Chase, MD, MPH, 
Michel N. Cocchi, MD; Michael W. Donnino, MD 
 
Principal investigator: 
Michael W. Donnino, MD 
Director of Center for Resuscitation Science 
Associate Professor of Medicine, Harvard Medical School 
Attending Physician in Emergency and Critical Care Medicine, BIDMC 
 
Coordinating Center: 
Beth Israel Deaconess Medical Center 
West Clinical Campus 2nd Floor 
One Deaconess Road, Boston MA 02215 
Phone: 617-754-2295 
Fax: 617-754-2350 
Email: mdonnino@bidmc.harvard.edu 
 
Funded By: 
The American Heart Association 
The National Institutes of Health 
 
Revision History: 
v1: May 30th, 2019 
v2: June 7th, 2019 
 
 


2 
 
Table of Contents 
 
Background and Rationale 
3 
Study Overview 
3 
Study Design and Setting 
3 
Trial Participants 
3 
Randomization and Intervention 
4 
Study Registration and Monitoring 
4 
Outcomes and Definitions 
4 
Primary Outcome and Sample Size Estimation 
4 
Secondary Outcomes 
4 
Statistical Analysis 
5 
General Principles 
5 
Baseline Characteristics 
5 
Analysis of Primary Outcome 
5 
Analysis of Secondary Outcomes 
6 
Additional Planned Analyses 
6 
Statistical Software 
6 
Appendix 
6 
Appendix Figure 1 
6 
Appendix Table 1 - Cohort Characteristics 
7 
Appendix Table 2 - Sedatives and Off-Protocol Paralytics 
9 
Appendix Table 3 - Outcomes 
9 
References 
10 
 
 
 
 


3 
 
Background and Rationale 
Two randomized trials published in 2002 found improved mortality and neurologic morbidity 
among out-of-hospital cardiac arrest (OHCA) victims with initial shockable rhythms (pulseless 
ventricular tachycardia and ventricular fibrillation) treated with therapeutic hypothermia targeting 
a temperature of 32℃-33℃ as compared to placebo.1,2 A more recent, larger randomized trial 
comparing temperature controlled to 33℃ vs 36℃ did not demonstrate a significant difference in 
outcomes.3 In the earlier therapeutic hypothermia studies, neuromuscular blockade (NMB) was 
administered throughout the cooling period in the intervention group but not the control group. In 
contrast, paralytic use was minimized in both groups in the more recent study comparing 33℃ to 
36℃. Thus, the use of NMB is a potential unrecognized confounder from the earlier hypothermia 
studies.  
 
Multicenter observational data has previously demonstrated that continuous NMB following 
cardiac arrest may be associated with improved lactate clearance and reduced mortality.4 NMB 
may improve post-cardiac arrest outcomes through a number of mechanisms including the 
reduction of global oxygen consumption, prevention of  patient-ventilator dyssynchrony, 
reduction of metabolic demand, reduction of inflammation, or other unidentified pathways.5 The 
presently reported phase II trial, in addition to a similar phase II trial published by an affiliated 
cardiac arrest clinical trials group in South Korea6, tested the hypothesis that early, continuous 
neuromuscular blockade following cardiac arrest will improve blood lactate levels and potentially 
clinical outcomes as compared to usual care.  
Study Overview 
Study Design and Setting 
This was a phase II, multi-center, randomized trial of continuous neuromuscular blockade using 
rocuronium vs. usual care in patients who had sustained return of spontaneous circulation 
(ROSC) but remained unresponsive after cardiac arrest. Enrolling sites were five urban tertiary 
care centers in the United States. The trial coordinating center gathered and analyzed the data, 
and vouches for the accuracy and completeness of the data and for the fidelity of the trial to the 
protocol. Written informed consent was obtained from the legally authorized representatives of 
all patients.  
 
Trial Participants 
Adult patients (aged ≥18 years) who experienced a cardiac arrest and subsequently had 
sustained ROSC (≥20 minutes) but remained comatose (i.e. not following commands) and were 
undergoing TTM targeting between 32℃ and 36℃ were enrolled in the study. An additional 
inclusion criterion of a minimum serum lactate level of ≥2mmol/L was added after the 42nd 
patient was enrolled. Patients were excluded if they had a traumatic etiology of cardiac arrest, 
were already receiving continuous neuromuscular blockade for clinical purposes, were not 
expected by the physician team to survive 24-hours, had been undergoing TTM for ≥6 hours, 
had a pre-arrest modified Rankin scale score of 4 or higher, or were members of a protected 
population (including prisoners, pregnant patients, and the developmentally disabled). Patients 
who had received a single-dose of a neuromuscular blocking agent, most commonly during 


4 
 
tracheal intubation, could be enrolled in the study so long as the drug had worn off and there 
were no immediate plans for additional neuromuscular blockade administration.  
 
Patient flow through the trial will be displayed in a CONSORT diagram (see Appendix Figure 1 
for shell figure). 
 
Randomization and Intervention 
Patients were randomized to continuous NMB or usual care in blocks of four and in a 1:1 ratio. 
The randomization was stratified by study site and by the presence of shock, defined as the use 
of any vasopressor at the time of randomization. The random sequence was generated by an 
independent statistician who was not involved in the conduct of the study. The site-specific 
allocation sequences were maintained by the research pharmacies at each site for the duration 
of the study.  
 
Patients in the continuous NMB arm received a rocuronium bolus of 1.0mg/kg followed by a 
continuous infusion of rocuronium for a total of 24-hours. The infusion of rocuronium was titrated 
to 1-2 out of 4 twitches on a train-of-four peripheral nerve stimulator. To minimize any difference 
in the time between randomization and receipt of the study drug between the two groups, 
patients in the usual care arm were administered a small volume of normal saline to mark the 0-
hour time point. All patients undergoing TTM, including those who received continuous NMB, 
were deeply sedated per local site protocol. Use of the Columbia anti-shivering protocol was 
recommended to clinical teams, but adherence was not mandated.7 
 
Study Registration and Monitoring 
The trial was registered at clinicaltrials.gov (NCT02260258) and was approved by the 
institutional review boards of all enrolling institutions.  
 
A Data Safety and Monitoring Board (DSMB) evaluated and monitored the trial for safety. There 
were no pre-specified stopping rules for futility or efficacy. No statistical interim analyses were 
performed.   
Outcomes and Definitions 
Primary Outcome and Sample Size Estimation 
The primary outcome of the study is change in serum lactate level measured between 0-hours 
and 24-hours after the receipt of study drug. This outcome was chosen as lactate is a 
continuous variable which is highly correlated with hospital survival in cardiac arrest patients.8 
The 24-hour time point was selected as it was drawn after completion of the rocuronium infusion 
but not so late that a significant proportion of patients may have already died. Based on 
conservative estimates drawn from observational data4, a sample size of 80 patients was 
specified to detect a predicted mean difference in 24-hour lactate of 2.0mmol/L (±3.2mmol/L) 
with 80% power assuming a two-sided test and an alpha of 0.05. 
 
Secondary Outcomes 
● Lactate change between 0- and 12-hours after administration of study drug 
● Lactate change between 0- and 36-hours after administration of study drug 
● Shock-free days 
○ Shock-free days measured as days alive and free of shock (<6 hours receiving a 
vasopressor) over the first 7 days after enrollment. 


5 
 
● Ventilator-free days 
○ Ventilator-free days measured as days alive and free of invasive mechanical 
ventilation (<6 hours with an endotracheal tube) over the first 7 days after 
enrollment. 
● Length of initial Intensive Care Unit (ICU) stay truncated at 28-days 
○ Includes only the initial stay in the ICU and does not include ICU readmission 
● Length of initial hospital stay truncated at 28-days 
○ Includes only the initial hospital stay and does not include any readmissions 
● Survival to hospital discharge 
● Neurologic outcome at hospital discharge 
○ As defined using the Modified Rankin Scale 
● Biomarker measures (available at 0-hours and 24-hours) 
○ Interleukin (IL)-1β, IL-6, IL-8, IL-10, and TNF-ɑ 
○ Neuron specific enolase [NSE] 
○ S100 calcium-binding protein B (S100B) 
● Muscle weakness assessed using a modified Medical Research Council scale 
 
 
A table of outcomes by treatment group will be included (see Appendix Table 3). 
Statistical Analysis 
General Principles 
All initial analyses will be performed in a modified intention-to-treat (modified ITT) population, 
defined as all randomly assigned subjects who received any study drug (rocuronium or the 
saline time marker). The primary analysis for the outcome of lactate at 24-hours will be repeated 
in the per-protocol population including only those patients who were alive at 24-hours and 
received either 24-hours of continuous rocuronium (if so assigned) compared to those who 
received usual care without any neuromuscular blockade medication after the time 0-hour point.    
 
Baseline Characteristics 
A description of the baseline characteristics will be presented by treatment group (see Appendix 
Table 1). Categorical variables will be summarized by frequencies and percentages. 
Percentages will be calculated according to the number of patients for whom data are available. 
Continuous variables will be summarized using means (standard deviations, SD) or medians 
(interquartile range, IQR). Statistical tests will not be used to compare baseline characteristics 
between groups. A table describing sedative and off-protocol paralytic use in each arm will be 
included (Appendix Table 2) 
 
Analysis of Primary Outcome 
The primary outcome is lactate change between 0-hours and 24-hours after enrollment. The 
group difference in change from the time of study drug administration (0-hours) to 24-hours will 
be assessed using a linear mixed effects model. Lactate values will be log-transformed for this 
analysis if they are not approximately normally distributed. Fixed effects will include the 
allocated treatment, shock stratification, time point (0-hour, 12-hour, and 24-hour), and the 
interaction between treatment and time point. Study site will be included as a random intercept. 
The usual care group will be the reference variable for group, and baseline (0-hour) will be the 


6 
 
reference variable for time. Means and 95% confidence intervals of lactate over time will be 
presented, by treatment, using longitudinal plots (see appendix Figure 2) 
 
Analysis of Secondary Outcomes 
The following outcomes will be summarized using mean ± SD or median (IQR) and linear 
regression using the above described linear mixed model will be performed to assess the 
differences between treatment groups.  
● ICU length of stay 
● Hospital length of stay 
● Time to shock reversal 
● Time to liberation from mechanical ventilation 
● Biomarker measures (regression controlled for baseline level of each biomarker) 
● Muscle weakness score 
 
The following outcomes will be summarized using frequencies and percentages and logistic 
regression will be performed to assess the differences between treatment groups.  
● Neurologic outcome at hospital discharge 
● Survival to hospital discharge 
 
Subgroup Analyses 
 
The primary outcome analysis will be additionally performed in each of the below subgroups. 
 
• 
Shock and non-shock stratification groups  
• 
Shockable and non-shockable initial rhythms 
• 
Cardiac arrest location  
 
Additional Planned Analyses 
Additional planned analyses of total body oxygen consumption and cellular oxygen consumption 
for those patients in whom these variables are available will be performed.  
 
Statistical Software 
Stata (version 14, StataCorp, College Station, Tx) will be used for all analyses.  
Appendix 
Appendix Figure 1 
 


7 
 
 
 
Appendix Figure 2 - Change in Lactate over Time 
 
 
Appendix Table 1 - Cohort Characteristics 
 
Variable 
NMB 
Usual Care 
Demographics 
 
 
Age (Median, IQR)  
 
Sex (%Female)  
 
Race (%White)  
 


8 
 
Past Medical History 
 
 
Congestive heart failure  
 
Atrial fibrillation  
 
Coronary artery disease  
 
Prior cardiac arrest  
 
Chronic pulmonary disease  
 
Kidney disease  
 
Active malignancy  
 
Arrest Characteristics 
 
 
Location (%OHCA) 
 
 
Initial Rhythm (% Non-
shockable) 
 
 
Estimated no-flow time 
(median, IQR) 
 
 
Estimated low-flow time 
(median, IQR) 
 
 
Arrest duration (minutes, 
median, IQR) 
 
 
Witnessed (%yes) 
 
 
Bystander CPR provided 
(%yes) 
 
 
Arrest etiology (%cardiac) 
 
 
Characteristics at Enrollment 
 
 
pH (median, IQR) 
 
 
pCO2 (median, IQR) 
 
 
pO2 (median, IQR)  
 
 
Shock stratification (% shock)  
 
STEMI present (%yes) 
 
 
Target temperature (median, 
IQR) 
 
 


9 
 
Received any paralytic prior 
to enrollment (%yes) 
 
 
 
Appendix Table 2 - Sedatives and Off-Protocol Paralytics 
 
Variable 
NMB 
Usual Care 
Sedation and Analgesia 
(% receiving) 
0hr 
12hr 
24hr 
36hr 
0hr 
12hr 
24hr 
36hr 
Propofol  
 
 
 
 
 
 
 
Midazolam  
 
 
 
 
 
 
 
Lorazepam  
 
 
 
 
 
 
 
Dexmedetomidine  
 
 
 
 
 
 
 
Fentanyl  
 
 
 
 
 
 
 
Paralytic (% receiving) 
 
 
 
 
 
 
 
 
Bolus Rocuronium  
 
 
 
 
 
 
 
Continuous Rocuronium  
 
 
 
 
 
 
 
Bolus Cisatracurium  
 
 
 
 
 
 
 
Continuous Cisatracurium  
 
 
 
 
 
 
 
 
Appendix Table 3 – Outcomes 
 
Variable 
NMB 
Usual Care 
Effect estimate (95% 
confidence interval) 
Lactate Level (mmol/L, median, IQR)  
 
 
0-hour  
 
 
12-hour  
 
 
24-hour  
 
 
36-hour  
 
 
Clinical Outcomes 
 
 
 
ICU LOS (days, median, IQR) 
 
 
 


10 
 
Hospital LOS (days, median, IQR) 
 
 
 
Discharge CPC ≤2 (%) 
 
 
 
Muscle Weakness Score (median, 
IQR) 
 
 
 
Hospital Survival (% survived) 
 
 
 
 
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