Trial Outcomes & Findings for Reevaluation Of Systemic Early Neuromuscular Blockade (NCT NCT02509078)

NCT ID: NCT02509078

Last Updated: 2019-08-13

Results Overview

The percentage of subjects alive at study day 90. Those subjects discharged home prior to day 90 were counted as alive at day 90.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1008 participants
• Primary outcome timeframe: 90 days after randomization
• Results posted on: 2019-08-13

Participant Flow

Participant milestones

Measure	Early Neuromuscular Blockade (NMB) Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Overall Study STARTED	502	506
Overall Study COMPLETED	501	505
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Measure	Early Neuromuscular Blockade (NMB) Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Overall Study Protocol Violation	1	1

Baseline Characteristics

Reevaluation Of Systemic Early Neuromuscular Blockade

Baseline characteristics by cohort

Measure	Early Neuromuscular Blockade (NMB) n=501 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 Participants Use of non-study NMB will be discouraged.	Total n=1006 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	348 Participants n=5 Participants	358 Participants n=7 Participants	706 Participants n=5 Participants
Age, Categorical >=65 years	153 Participants n=5 Participants	147 Participants n=7 Participants	300 Participants n=5 Participants
Age, Continuous	56.6 years STANDARD_DEVIATION 14.7 • n=5 Participants	55.1 years STANDARD_DEVIATION 15.9 • n=7 Participants	55.8 years STANDARD_DEVIATION 15.3 • n=5 Participants
Sex: Female, Male Female	210 Participants n=5 Participants	236 Participants n=7 Participants	446 Participants n=5 Participants
Sex: Female, Male Male	291 Participants n=5 Participants	269 Participants n=7 Participants	560 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	64 Participants n=5 Participants	54 Participants n=7 Participants	118 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	410 Participants n=5 Participants	421 Participants n=7 Participants	831 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	27 Participants n=5 Participants	30 Participants n=7 Participants	57 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) Asian	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	61 Participants n=5 Participants	79 Participants n=7 Participants	140 Participants n=5 Participants
Race (NIH/OMB) White	360 Participants n=5 Participants	343 Participants n=7 Participants	703 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	63 Participants n=5 Participants	69 Participants n=7 Participants	132 Participants n=5 Participants
Region of Enrollment United States	501 participants n=5 Participants	505 participants n=7 Participants	1006 participants n=5 Participants

PRIMARY outcome

Timeframe: 90 days after randomization

The percentage of subjects alive at study day 90. Those subjects discharged home prior to day 90 were counted as alive at day 90.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=501 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Hospital Mortality to Day 90 Alive at Day 90	288 Participants	289 Participants
Hospital Mortality to Day 90 Dead Prior to Day 90	213 Participants	216 Participants

SECONDARY outcome

Timeframe: 28 days after randomization

Population: The overall number of participants analyzed reflects the number of patients that had sufficient data to allow for calculation of the outcome measure.

Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=500 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Mean Ventilator Free Days to Day 28	9.6 days Standard Deviation 10.4	9.9 days Standard Deviation 10.9

SECONDARY outcome

Timeframe: 28 days after randomization

Population: The overall number of participants analyzed reflects the number of patients that had sufficient data to allow for calculation of the outcome measure.

SOFA (Sepsis-related Organ Failure Assessment) was used to determine criteria for an organ failure free day. Scores were based on four of the six SOFA organ categories: Coagulation, Liver, Cardiovascular, and Renal. Each category was scored 0-4; 0 being normal functioning and 4 being the most abnormal. A patient was considered failure free on each day alive with SOFA scores below 2 for all four organ systems.

Ref: Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996. 22(7): p. 707-10.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=480 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=479 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Mean Organ Failure Free Days to Day 28	12.4 days Standard Deviation 11.3	12.5 days Standard Deviation 11.5

SECONDARY outcome

Timeframe: 28 days after randomization

Population: The overall number of participants analyzed reflects the number of patients that had sufficient data to allow for calculation of the outcome measure.

ICU free days is defined as the number of days between randomization and day 28 in which the patient is in the ICU (for any part of a day).

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=500 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
ICU Free Days to Day 28	9.0 days Standard Deviation 9.4	9.4 days Standard Deviation 9.8

SECONDARY outcome

Timeframe: 28 days after randomization

Hospital free days are days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=501 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Mean Hospital Free Days to Days 28	5.7 days Standard Deviation 7.8	5.9 days Standard Deviation 8.1

SECONDARY outcome

Timeframe: 3 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=212 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=196 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)	3.3 score on a scale Standard Deviation 2.7	3.0 score on a scale Standard Deviation 2.7

SECONDARY outcome

Timeframe: 3 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=207 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=194 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
EuroQol (EQ-5D-5L): Health Related Quality of Life	0.66 score on a scale Interval 0.41 to 0.82	0.73 score on a scale Interval 0.44 to 0.83

SECONDARY outcome

Timeframe: 6 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=145 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=122 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45	38 participants	31 participants

SECONDARY outcome

Timeframe: 3 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=154 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=133 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
MoCA-Blind: Montreal Cognitive Assessment	22.2 score on a scale Standard Deviation 5.2	22.8 score on a scale Standard Deviation 4.8

SECONDARY outcome

Timeframe: 6 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=180 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=156 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)	2.7 score on a scale Standard Deviation 2.4	2.7 score on a scale Standard Deviation 2.4

SECONDARY outcome

Timeframe: 12 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=128 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=119 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)	2.9 score on a scale Standard Deviation 2.6	2.4 score on a scale Standard Deviation 2.3

SECONDARY outcome

Timeframe: 6 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=176 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=155 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
EuroQol (EQ-5D-5L): Health Related Quality of Life	0.74 score on a scale Interval 0.57 to 0.83	0.79 score on a scale Interval 0.55 to 0.83

SECONDARY outcome

Timeframe: 12 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=127 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=119 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
EuroQol (EQ-5D-5L): Health Related Quality of Life	0.75 score on a scale Interval 0.57 to 0.83	0.77 score on a scale Interval 0.57 to 0.86

SECONDARY outcome

Timeframe: 6 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range:

26 or greater.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=138 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=114 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
MoCA-Blind: Montreal Cognitive Assessment	22.8 score on a scale Standard Deviation 4.8	23.2 score on a scale Standard Deviation 5.1

SECONDARY outcome

Timeframe: 12 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range:

26 or greater.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=99 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=88 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
MoCA-Blind: Montreal Cognitive Assessment	23.3 score on a scale Standard Deviation 4.9	24.0 score on a scale Standard Deviation 4.4

SECONDARY outcome

Timeframe: 12 months after randomization

Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.

Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported.

Outcome measures

Measure	Early Neuromuscular Blockade (NMB) n=103 Participants Patients will receive cisatracurium besylate for the first 48 hours of the trial. cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=94 Participants Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45	21 participants	38 participants

Adverse Events

Early Neuromuscular Blockade (NMB)

Serious events: 28 serious events

Other events: 19 other events

Deaths: 213 deaths

Control: No Routine Early NMB

Serious events: 21 serious events

Other events: 15 other events

Deaths: 216 deaths

Serious adverse events

Measure	Early Neuromuscular Blockade (NMB) n=501 participants at risk Patients will receive cisastracurium besylate for the first 48 hours of the trial. cisastracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisastracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 participants at risk Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Blood and lymphatic system disorders Methemoglobinemia	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders AV Block complete	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Atrial Fibrillation with RVR	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Bradycardia	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Cardiac Arrest	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.40% 2/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Myocardial Infarction	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Tachycardia Supraventricular	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Torsades De Pointe	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Ventricular Tachycardia	0.40% 2/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
General disorders Death	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
General disorders Necrosis of left foot	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
General disorders Reaction Febrile	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Cerebral Infartion	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders CVA	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Hemmorage Brain	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Seizure	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Stroke	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Subdural Effusion	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Airway Obstruction	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Embolus Pulmonary	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Hypoxemia	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Laceration Diaphragm	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.99% 5/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Vascular disorders Hypotension	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Heart Block Av 3rd Degree	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Metabolism and nutrition disorders Hyperkalemia	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Bleeding Intracranial	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Cerebral Infarction	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Hemorrhage Brain	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Polyneuropathy	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Nervous system disorders Subarachnoid Hemorrhage	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Aspiration Pneumonia	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Pneumomediastinum	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.40% 2/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Vascular disorders Hematoma	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.

Other adverse events

Measure	Early Neuromuscular Blockade (NMB) n=501 participants at risk Patients will receive cisastracurium besylate for the first 48 hours of the trial. cisastracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisastracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.	Control: No Routine Early NMB n=505 participants at risk Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Vascular disorders Hemorrhage Retroperitoneal	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Vascular disorders Hypotension	1.2% 6/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Atrial Fibrillation Paroxysmal	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Bradycardia	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Cardiac Arrhythmia (Nos)	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Severe Prolonged Bradycardia	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Tachycardia	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Injury, poisoning and procedural complications Paralysis Awareness	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Musculoskeletal and connective tissue disorders Myopathy	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Apnea	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Pneumomediastinum	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.79% 4/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Subcutaneous Emphysema And Pneumomediastinum	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Vascular disorders Superficial Venous Thrombus	0.20% 1/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.00% 0/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Cardiac Arrest	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.40% 2/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Cardiac disorders Vasovagal Reaction	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Gastrointestinal disorders Ileus	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Infections and infestations Pneumonia	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.
Respiratory, thoracic and mediastinal disorders Stoma Leak	0.00% 0/501 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.	0.20% 1/505 • Subjects were assessed for occurrence of adverse events from time of randomization through study day 7 (five days after infusion of study drug) or ICU discharge, whichever occurred first.

Additional Information

Katie Oldmixon

Mass General Hospital (PETAL Clinical Coordinating Center)

Phone: 617-726-4777

Email: coldmixon@mgh.harvard.edu

Results disclosure agreements

• Principal investigator is a sponsor employee In addition to the restriction on the PI for sponsor to review results prior to public release within 60 days, there is a network provision: The Publications Committee of the PETAL Network must review and approve all pre-submission PETAL Network studies before publication or presentation. Manuscripts comparing outcomes of PETAL study endpoints from one center to the reminder of the group are not permitted.
• Publication restrictions are in place

Restriction type: OTHER