ROSE: Reevaluation Of Systemic Early Neuromuscular Blockade

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02509078
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 1,008
• Locations: 44
• Arms: 2
• Actual Duration (Months): 39
• Patients Per Site: 22.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study evaluates whether giving a neuromuscular blocker (skeletal muscle relaxant) to a patient with acute respiratory distress syndrome will improve survival. Half of the patients will receive a neuromuscular blocker for two days and in the other half the use of neuromuscular blockers will be discouraged.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome	Drug: Cisatracurium Besylate	Phase 3

Detailed Description

PRIMARY OBJECTIVE:

To assess the efficacy and safety of early neuromuscular blockade in reducing mortality and morbidity in patients with moderate-severe ARDS, in comparison to a control group with no routine early neuromuscular blockade (NMB).

PRIMARY HYPOTHESIS:

Early neuromuscular blockade will improve mortality prior to discharge home before day 90, in patients with moderate-severe ARDS.

The trial will accrue a maximum of 1408 patients. Patients will be recruited from the emergency departments, intensive care units and other acute care areas of the PETAL Network Clinical Centers and randomized to the active (NMB) or control. The overall strategy is to screen, consent, and enroll early, every newly intubated, acutely ill or post-operative, eligible patient at each site, using clinically obtained pulse oximetry and blood gases.

By preventing active expiration, and/or patient ventilator dyssynchrony, neuromuscular blockade may create a more homogenous distribution of airway pressures and tidal volumes, preventing barotrauma/volutrauma and "atelectrauma" resulting in less ventilator-induced lung injury.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1008 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reevaluation Of Systemic Early Neuromuscular Blockade
• Actual Study Start Date: Jan 4, 2016
• Actual Primary Completion Date: Jul 3, 2018
• Actual Study Completion Date: Apr 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Early Neuromuscular Blockade (NMB) Patients will receive cisatracurium besylate for the first 48 hours of the trial.	Drug: 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.; Other Names: Nimbex
No Intervention: Control: No Routine Early NMB Use of non-study NMB will be discouraged.

Outcome Measures

Primary Outcome Measures

1. Hospital Mortality to Day 90 [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.

Secondary Outcome Measures

1. Mean Ventilator Free Days to Day 28 [28 days after randomization]

   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.

2. Mean Organ Failure Free Days to Day 28 [28 days after randomization]

   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.

3. ICU Free Days to Day 28 [28 days after randomization]

   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).

4. Mean Hospital Free Days to Days 28 [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.

5. Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) [3 months after randomization]

   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.

6. EuroQol (EQ-5D-5L): Health Related Quality of Life [3 months after randomization]

   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

7. PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 [6 months after randomization]

   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.

8. MoCA-Blind: Montreal Cognitive Assessment [3 months after randomization]

   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.

9. Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) [6 months after randomization]

   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.

10. Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) [12 months after randomization]

    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.

11. EuroQol (EQ-5D-5L): Health Related Quality of Life [6 months after randomization]

    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

12. EuroQol (EQ-5D-5L): Health Related Quality of Life [12 months after randomization]

    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

13. MoCA-Blind: Montreal Cognitive Assessment [6 months after randomization]

    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.

14. MoCA-Blind: Montreal Cognitive Assessment [12 months after randomization]

    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.

15. PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 [12 months after randomization]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Age > 18 years

2. Presence of all of the following conditions for < 48 hours:

1. PaO2/FiO2 < 150 with PEEP >/= 8 cm H2O OR, if ABG not available, SaO2/FiO2 ratio that is equivalent to a PaO2/FiO2 < 150 with PEEP >/= 8 cm H2O , and a confirmatory SaO2/FiO2 ratio that is again equivalent 1-6 hours later

1. Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules.

2. Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.

Patients must be enrolled within 48 hours of meeting inclusion criteria.

Exclusion Criteria:

1. Lack of informed consent

2. Continuous neuromuscular blockade at enrollment

3. Known pregnancy

4. Currently receiving ECMO therapy

5. Chronic respiratory failure defined as PaCO2 > 60 mm Hg in the outpatient setting

6. Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing

7. Actual body weight exceeding 1 kg per centimeter of height

8. Severe chronic liver disease defined as a Child-Pugh score of 12-15 (Appendix A2)

9. Bone marrow transplantation within the last 1 year

10. Expected duration of mechanical ventilation of < 48 hours

11. Decision to withhold life-sustaining treatment; except in those patients committed to full support except cardiopulmonary resuscitation if an actual cardiac arrest occurs

12. Moribund patient not expected to survive 24 hours; if CPR provided, assess for moribund status greater than 6 from CPR conclusion

13. Diffuse alveolar hemorrhage from vasculitis

14. Burns > 70% total body surface

15. Unwillingness to utilize the ARDS Network 6 ml/kg IBW ventilation protocol

16. Previous hypersensitivity or anaphylactic reaction to cisatracurium

17. Neuromuscular conditions that may potentiate neuromuscular blockade and/or impair spontaneous ventilation (Appendix A2)

18. Neurologic conditions undergoing treatment for intracranial hypertension

19. Enrollment in an interventional ARDS trial with direct impact on neuromuscular blockade and PEEP

20. 120 hours of mechanical ventilation

21. P/F < 200 mmHg at the time of randomization (if available)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Fresno	Fresno	California	United States	93701
2	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
3	UC Davis Medical Center	Sacramento	California	United States	95817
4	UCSF Medical Center	San Francisco	California	United States	94143
5	Stanford University Hospital	Stanford	California	United States	94305
6	Medical Center of Aurora	Aurora	Colorado	United States	80045
7	University of Colorado Hospital	Aurora	Colorado	United States	80045
8	Denver Health Medical Center	Denver	Colorado	United States	80204
9	Swedish Medical Center	Englewood	Colorado	United States	80113
10	Indiana University Methodist Hospital	Indianapolis	Indiana	United States	46220
11	University Medical Center	New Orleans	Louisiana	United States	70112
12	Maine Medical Center	Portland	Maine	United States	04102
13	Tufts Medical Center	Boston	Massachusetts	United States	02111
14	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
15	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
16	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
17	Baystate Medical Center	Springfield	Massachusetts	United States	01199
18	St. Vincent's Hospital	Worcester	Massachusetts	United States	01608
19	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
20	Henry Ford Medical Center	Detroit	Michigan	United States	48025
21	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
22	Montefiore Medical Center	Bronx	New York	United States	10467
23	Mt. Sinai Hospital	New York	New York	United States	10029
24	Wesley Long Hospital	Greensboro	North Carolina	United States	27403
25	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
26	Summa Akron City Hospital	Akron	Ohio	United States	44304
27	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
28	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
29	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
30	Oregon Health and Science University	Portland	Oregon	United States	97239
31	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
32	UPMC Presbyterian/Mercy/Shadyside	Pittsburgh	Pennsylvania	United States	15261
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37221
34	Intermountain Medical Center	Murray	Utah	United States	84107
35	McKay-Dee Hospital	Ogden	Utah	United States	84403
36	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
37	University Hospital	Salt Lake City	Utah	United States	84132
38	LDS Hospital	Salt Lake City	Utah	United States	84143
39	University or Virginia Health System	Charlottesville	Virginia	United States	22903
40	VCU Medical Center	Richmond	Virginia	United States	23298
41	Harborview Medical Center	Seattle	Washington	United States	98104
42	University of Washington Medical Center	Seattle	Washington	United States	98104
43	Swedish Hospital Cherry Hill	Seattle	Washington	United States	98122
44	Swedish Hospital First Hill	Seattle	Washington	United States	98122

Sponsors and Collaborators

• Massachusetts General Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: David A. Schoenfeld, PhD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol - Oct 12, 2017
• Statistical Analysis Plan - Apr 12, 2018

More Information

Additional Information:

• Website for the PETAL Network

Publications

None provided.

• Responsible Party: Boyd Taylor Thompson, Prinicipal Investigator PETAL CCC, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02509078
• Other Study ID Numbers: PETAL01ROSE; 1U01HL123009-01
• First Posted: Jul 27, 2015
• Last Update Posted: Aug 13, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Boyd Taylor Thompson, Prinicipal Investigator PETAL CCC, Massachusetts General Hospital: ARDS; neuromuscular blocker; cisatracurium
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Cisatracurium

Study Results

Participant Flow

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Period Title: Overall Study
STARTED	502	506
COMPLETED	501	505
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB	Total
Arm/Group Description	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.	Use of non-study NMB will be discouraged.	Total of all reporting groups
Overall Participants	501	505	1006
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	348 69.5%	358 70.9%	706 70.2%
>=65 years	153 30.5%	147 29.1%	300 29.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.6 (14.7)	55.1 (15.9)	55.8 (15.3)
Sex: Female, Male (Count of Participants)
Female	210 41.9%	236 46.7%	446 44.3%
Male	291 58.1%	269 53.3%	560 55.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	64 12.8%	54 10.7%	118 11.7%
Not Hispanic or Latino	410 81.8%	421 83.4%	831 82.6%
Unknown or Not Reported	27 5.4%	30 5.9%	57 5.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	5 1%	3 0.6%	8 0.8%
Asian	10 2%	10 2%	20 2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	61 12.2%	79 15.6%	140 13.9%
White	360 71.9%	343 67.9%	703 69.9%
More than one race	2 0.4%	1 0.2%	3 0.3%
Unknown or Not Reported	63 12.6%	69 13.7%	132 13.1%
Region of Enrollment (participants) [Number]
United States	501 100%	505 100%	1006 100%

Outcome Measures

1. Primary Outcome

Title	Hospital Mortality to Day 90
Description	The percentage of subjects alive at study day 90. Those subjects discharged home prior to day 90 were counted as alive at day 90.
Time Frame	90 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Measure Participants	501	505
Alive at Day 90	288 57.5%	289 57.2%
Dead Prior to Day 90	213 42.5%	216 42.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Neuromuscular Blockade (NMB), Control: No Routine Early NMB
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Wald test for the difference of two prop
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -6.4 to 5.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value is a percentage

2. Secondary Outcome

Title	Mean Ventilator Free Days to Day 28
Description	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.
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Measure Participants	500	505
Mean (Standard Deviation) [days]	9.6 (10.4)	9.9 (10.9)

3. Secondary Outcome

Title	Mean Organ Failure Free Days to Day 28
Description	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.
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Measure Participants	480	479
Mean (Standard Deviation) [days]	12.4 (11.3)	12.5 (11.5)

4. Secondary Outcome

Title	ICU Free Days to Day 28
Description	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).
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Measure Participants	500	505
Mean (Standard Deviation) [days]	9.0 (9.4)	9.4 (9.8)

5. Secondary Outcome

Title	Mean Hospital Free Days to Days 28
Description	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.
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
Measure Participants	501	505
Mean (Standard Deviation) [days]	5.7 (7.8)	5.9 (8.1)

6. Secondary Outcome

Title	Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)
Description	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.
Time Frame	3 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	212	196
Mean (Standard Deviation) [score on a scale]	3.3 (2.7)	3.0 (2.7)

7. Secondary Outcome

Title	EuroQol (EQ-5D-5L): Health Related Quality of Life
Description	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
Time Frame	3 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	207	194
Median (Inter-Quartile Range) [score on a scale]	0.66	0.73

8. Secondary Outcome

Title	PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45
Description	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.
Time Frame	6 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	145	122
Number [participants]	38 7.6%	31 6.1%

9. Secondary Outcome

Title	MoCA-Blind: Montreal Cognitive Assessment
Description	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.
Time Frame	3 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	154	133
Mean (Standard Deviation) [score on a scale]	22.2 (5.2)	22.8 (4.8)

10. Secondary Outcome

Title	Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)
Description	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.
Time Frame	6 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	180	156
Mean (Standard Deviation) [score on a scale]	2.7 (2.4)	2.7 (2.4)

11. Secondary Outcome

Title	Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL)
Description	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.
Time Frame	12 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	128	119
Mean (Standard Deviation) [score on a scale]	2.9 (2.6)	2.4 (2.3)

12. Secondary Outcome

Title	EuroQol (EQ-5D-5L): Health Related Quality of Life
Description	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
Time Frame	6 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	176	155
Median (Inter-Quartile Range) [score on a scale]	0.74	0.79

13. Secondary Outcome

Title	EuroQol (EQ-5D-5L): Health Related Quality of Life
Description	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
Time Frame	12 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	127	119
Median (Inter-Quartile Range) [score on a scale]	0.75	0.77

14. Secondary Outcome

Title	MoCA-Blind: Montreal Cognitive Assessment
Description	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.
Time Frame	6 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	138	114
Mean (Standard Deviation) [score on a scale]	22.8 (4.8)	23.2 (5.1)

15. Secondary Outcome

Title	MoCA-Blind: Montreal Cognitive Assessment
Description	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.
Time Frame	12 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	99	88
Mean (Standard Deviation) [score on a scale]	23.3 (4.9)	24.0 (4.4)

16. Secondary Outcome

Title	PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45
Description	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.
Time Frame	12 months after randomization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Early Neuromuscular Blockade (NMB)	Control: No Routine Early NMB
Arm/Group Description	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.	Use of non-study NMB will be discouraged.
Measure Participants	103	94
Number [participants]	21 4.2%	38 7.5%

Adverse Events

Time Frame	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.
Arm/Group Title	Early Neuromuscular Blockade (NMB)		Control: No Routine Early NMB
Arm/Group Description	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.		Use of non-study NMB will be discouraged. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade.
All Cause Mortality
	Early Neuromuscular Blockade (NMB)		Control: No Routine Early NMB
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	213/501 (42.5%)		216/505 (42.8%)
Serious Adverse Events
	Early Neuromuscular Blockade (NMB)		Control: No Routine Early NMB
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/501 (5.6%)		21/505 (4.2%)
Blood and lymphatic system disorders
Methemoglobinemia	1/501 (0.2%)		0/505 (0%)
Cardiac disorders
AV Block complete	1/501 (0.2%)		0/505 (0%)
Atrial Fibrillation with RVR	1/501 (0.2%)		0/505 (0%)
Bradycardia	1/501 (0.2%)		0/505 (0%)
Cardiac Arrest	6/501 (1.2%)		0/505 (0%)
Myocardial Infarction	1/501 (0.2%)		0/505 (0%)
Tachycardia Supraventricular	1/501 (0.2%)		0/505 (0%)
Torsades De Pointe	1/501 (0.2%)		0/505 (0%)
Ventricular Tachycardia	2/501 (0.4%)		0/505 (0%)
Cardiac Arrest	0/501 (0%)		2/505 (0.4%)
Heart Block Av 3rd Degree	0/501 (0%)		1/505 (0.2%)
Myocardial Infarction	0/501 (0%)		1/505 (0.2%)
General disorders
Death	1/501 (0.2%)		0/505 (0%)
Necrosis of left foot	1/501 (0.2%)		0/505 (0%)
Reaction Febrile	1/501 (0.2%)		0/505 (0%)
Metabolism and nutrition disorders
Hyperkalemia	0/501 (0%)		1/505 (0.2%)
Nervous system disorders
Cerebral Infartion	1/501 (0.2%)		0/505 (0%)
CVA	1/501 (0.2%)		0/505 (0%)
Hemmorage Brain	1/501 (0.2%)		0/505 (0%)
Seizure	1/501 (0.2%)		0/505 (0%)
Stroke	3/501 (0.6%)		0/505 (0%)
Subdural Effusion	1/501 (0.2%)		0/505 (0%)
Bleeding Intracranial	0/501 (0%)		1/505 (0.2%)
Cerebral Infarction	0/501 (0%)		1/505 (0.2%)
Hemorrhage Brain	0/501 (0%)		1/505 (0.2%)
Polyneuropathy	0/501 (0%)		1/505 (0.2%)
Stroke	0/501 (0%)		1/505 (0.2%)
Subarachnoid Hemorrhage	0/501 (0%)		1/505 (0.2%)
Respiratory, thoracic and mediastinal disorders
Airway Obstruction	1/501 (0.2%)		0/505 (0%)
Embolus Pulmonary	1/501 (0.2%)		0/505 (0%)
Hypoxemia	1/501 (0.2%)		0/505 (0%)
Laceration Diaphragm	1/501 (0.2%)		0/505 (0%)
Pneumothorax	3/501 (0.6%)		0/505 (0%)
Aspiration	0/501 (0%)		1/505 (0.2%)
Aspiration Pneumonia	0/501 (0%)		1/505 (0.2%)
Pneumomediastinum	0/501 (0%)		2/505 (0.4%)
Pneumothorax	0/501 (0%)		5/505 (1%)
Vascular disorders
Hypotension	1/501 (0.2%)		0/505 (0%)
Hematoma	0/501 (0%)		1/505 (0.2%)
Hypotension	0/501 (0%)		1/505 (0.2%)
Other (Not Including Serious) Adverse Events
	Early Neuromuscular Blockade (NMB)		Control: No Routine Early NMB
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/501 (3.8%)		15/505 (3%)
Cardiac disorders
Atrial Fibrillation Paroxysmal	1/501 (0.2%)		0/505 (0%)
Bradycardia	1/501 (0.2%)		0/505 (0%)
Cardiac Arrhythmia (Nos)	1/501 (0.2%)		0/505 (0%)
Severe Prolonged Bradycardia	1/501 (0.2%)		0/505 (0%)
Tachycardia	1/501 (0.2%)		0/505 (0%)
Cardiac Arrest	0/501 (0%)		2/505 (0.4%)
Vasovagal Reaction	0/501 (0%)		1/505 (0.2%)
Gastrointestinal disorders
Ileus	0/501 (0%)		1/505 (0.2%)
Infections and infestations
Pneumonia	0/501 (0%)		1/505 (0.2%)
Injury, poisoning and procedural complications
Paralysis Awareness	1/501 (0.2%)		0/505 (0%)
Musculoskeletal and connective tissue disorders
Myopathy	1/501 (0.2%)		0/505 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	1/501 (0.2%)		0/505 (0%)
Pneumomediastinum	2/501 (0.4%)		0/505 (0%)
Pneumothorax	1/501 (0.2%)		0/505 (0%)
Subcutaneous Emphysema And Pneumomediastinum	1/501 (0.2%)		0/505 (0%)
Aspiration	0/501 (0%)		1/505 (0.2%)
Pneumomediastinum	0/501 (0%)		1/505 (0.2%)
Pneumothorax	0/501 (0%)		4/505 (0.8%)
Stoma Leak	0/501 (0%)		1/505 (0.2%)
Vascular disorders
Hypotension	6/501 (1.2%)		0/505 (0%)
Superficial Venous Thrombus	1/501 (0.2%)		0/505 (0%)
Hemorrhage Retroperitoneal	0/501 (0%)		1/505 (0.2%)
Hypotension	0/501 (0%)		2/505 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.