Clinical trial NCT02509078
Conditions: Acute Respiratory Distress Syndrome
Keywords: ARDS neuromuscular blocker cisatracurium
Sponsor: Massachusetts General Hospital
Start date: 2016-01-04; Completion date: 2019-04-04
Enrollment: 1008 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: Patients will receive cisatracurium besylate for the first 48 hours of the trial. arm 2: Use of non-study NMB will be discouraged.
Interventions: intervention 1: Cisatracurium Besylate
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_000.pdf: 
Reevaluation Of Systemic Early neuromuscular blockade 
 
ACRONYM: 
 
ROSE 
VERSION  
 
VERSION VII 
PROTOCOL CO-CHAIRS 
DEREK ANGUS, MD, MPH, FRCP 
 
 
PROFESSOR OF MEDICINE 
 
 
DEPARTMENT OF CRITICAL CARE MEDICINE 
 
 
 
 
 
 
 
 
 
                             
          
 
                                        MARC MOSS, MD 
 
 
PROFESSOR OF MEDICINE 
 
 
DIVISION OF PULMONARY AND CRITICAL CARE MEDICINE 
 
 
 
 
 
 
                                            
 
 
           
 
                                               
 
 
 
 
 
 
_________________________                    _____________ 
SITE INVESTIGATOR SIGNATURE                     DATE 
 
 


 
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Table of Contents 
1 ABBREVIATIONS & DEFINITIONS ............................................................................................. 5 
1.1 ABBREVIATIONS ................................................................................................................................................. 5 
1.2 DEFINITIONS ....................................................................................................................................................... 6 
2 TRIAL SUMMARY ........................................................................................................................... 8 
3 TRIAL DESCRIPTION ................................................................................................................... 11 
3.1 BACKGROUND .................................................................................................................................................. 11 
3.2 NEUROMUSCULAR BLOCKADE – POTENTIAL BENEFITS AND MECHANISMS .................................................... 11 
3.3 NEUROMUSCULAR BLOCKADE – POTENTIAL HARMS ....................................................................................... 12 
3.4 RECENT FRENCH CLINICAL TRIALS .................................................................................................................. 13 
3.5 CURRENT PRACTICE IN PETAL SITES AND CLINICAL EQUIPOISE ................................................................... 13 
3.6 EARLY NEUROMUSCULAR BLOCKADE FOR ARDS NEEDS REEVALUATION .................................................... 13 
3.7 ROSE IS AN EARLY TREATMENT TRIAL ........................................................................................................... 15 
3.8 OBJECTIVES...................................................................................................................................................... 15 
3.9 END POINTS ...................................................................................................................................................... 16 
3.9.1 
Primary outcome ................................................................................................................................. 16 
3.9.2 
Secondary outcomes............................................................................................................................ 16 
3.9.3 
Subgroups ........................................................................................................................................... 18 
4 STUDY POPULATION AND ENROLLMENT ............................................................................ 18 
4.1 NUMBER/SOURCE/SCREENING ........................................................................................................................ 18 
4.2 INCLUSION CRITERIA ........................................................................................................................................ 19 
4.3 EXCLUSION CRITERIA ....................................................................................................................................... 19 
4.3.1 
Reasons for Exclusions ................................................................................................................ 20 
4.4 RANDOMIZATION, AND STUDY INITIATION TIME WINDOW ............................................................................... 20 
4.5 INFORMED CONSENT ........................................................................................................................................ 21 
4.6 RANDOMIZATION ............................................................................................................................................... 21 
4.7 MINORITIES AND WOMEN ................................................................................................................................. 21 
5 STUDY PROCEDURES .................................................................................................................. 21 
5.1 EARLY NEUROMUSCULAR BLOCKADE GROUP ................................................................................................. 22 
5.1.1 
Initiation and dosage ..................................................................................................................... 22 


 
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5.1.2 
Sedation ............................................................................................................................................ 23 
5.1.3 
Stopping rules for neuromuscular blockade ........................................................................... 23 
5.1.4 
Confirmation of neuromuscular blockade................................................................................ 23 
5.2 CONTROL GROUP ............................................................................................................................................. 23 
5.2.1 
Minimizing neuromuscular blockade ......................................................................................... 23 
5.2.2 
Sedation ............................................................................................................................................ 24 
5.3 COMMON STRATEGIES FOR BOTH STUDY GROUPS .......................................................................................... 24 
5.3.1 
Study startup procedures ............................................................................................................. 24 
5.3.2 
Proning .............................................................................................................................................. 25 
5.3.3 
Ventilator procedures .................................................................................................................... 25 
5.3.4 
On-Study fluid management ........................................................................................................ 26 
5.3.5 
Glucose control ............................................................................................................................... 26 
5.3.6 
Rescue procedures ........................................................................................................................ 27 
6 DATA VARIABLES AND SPECIMENS ....................................................................................... 27 
6.1 BACKGROUND ASSESSMENTS ......................................................................................................................... 27 
6.2 BASELINE ASSESSMENTS ................................................................................................................................ 28 
6.3 ASSESSMENTS DURING STUDY........................................................................................................................ 28 
6.3.1 
Hemodynamic monitoring during study startup ................................................................................ 28 
6.3.2 
Reference measurements .................................................................................................................... 29 
6.3.3 
Specimen collection ............................................................................................................................ 31 
6.4 ASSESSMENTS AFTER HOSPITALIZATION ....................................................................................................... 31 
7 STATISTICAL CONSIDERATIONS ............................................................................................ 33 
8 DATA COLLECTION AND SITE MONITORING ..................................................................... 35 
9 RISK ASSESSMENT ....................................................................................................................... 36 
9.1 RISKS OF NEUROMUSCULAR BLOCKADE ......................................................................................................... 37 
9.2 RISKS OF HIGH PEEP ...................................................................................................................................... 37 
9.3 RISKS OF BLOOD DRAWS ................................................................................................................................ 37 
9.4 RISK OF DEATH ................................................................................................................................................ 37 
9.5 MINIMIZATION OF RISKS ................................................................................................................................... 37 
9.6 POTENTIAL BENEFITS ....................................................................................................................................... 38 


 
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9.7 RISKS IN RELATION TO ANTICIPATED BENEFITS ............................................................................................. 38 
10 HUMAN SUBJECTS ........................................................................................................................ 38 
10.1 SELECTION OF SUBJECTS ............................................................................................................................ 38 
10.2 JUSTIFICATION OF INCLUDING VULNERABLE SUBJECTS ............................................................................ 39 
10.3 INFORMED CONSENT..................................................................................................................................... 39 
10.4 CONTINUING CONSENT ................................................................................................................................. 39 
10.5 WITHDRAWAL OF CONSENT ......................................................................................................................... 39 
10.6 IDENTIFICATION OF LEGALLY AUTHORIZED REPRESENTATIVES ................................................................. 40 
10.7 JUSTIFICATION OF SURROGATE CONSENT .................................................................................................. 40 
10.8 ADDITIONAL SAFEGUARDS FOR VULNERABLE SUBJECTS .......................................................................... 41 
10.9 CONFIDENTIALITY.......................................................................................................................................... 41 
11 ADVERSE EVENTS ........................................................................................................................ 41 
11.1 SAFETY MONITORING .................................................................................................................................. 41 
11.2 SERIOUS ADVERSE EVENTS .......................................................................................................................... 42 
12 APPENDICES ................................................................................................................................... 44 
A1 S/F RATIO INCLUSION CRITERIA ........................................................................................................................ 44 
A2 EXCLUSION DEFINITIONS .................................................................................................................................. 45 
B  TIME-EVENTS SCHEDULE ................................................................................................................................... 46 
C  ADVERSE EVENT REPORTING AND UNANTICIPATED PROBLEMS ........................................................................ 47 
D    VENTILATOR PROCEDURES .............................................................................................................................. 50 
E    CONSERVATIVE FLUID MANAGEMENT APPROACH ............................................................................................ 54 
F    DE-IDENTIFIED DATA ELEMENTS FOR SCREENED, NON-ENROLLED SUBJECTS ............................................... 55 
G    NEUROMUSCULAR AND LONG TERM OUTCOMES ............................................................................................. 56 
H    DATA AND SAFETY MONITORING BOARD .......................................................................................................... 57 
I     AUDIT QUESTIONNAIRE .................................................................................................................................... 58 
J     CISATRACURIUM PACKAGE INSERT .................................................................................................................. 59 
K     SOFA SCORING SYSTEM ................................................................................................................................. 60 
L     COMMON RISK FACTORS FOR ARDS .............................................................................................................. 61 
13 REFERENCES ................................................................................................................................. 63 
 


 
1 ABBREVIATIONS & 
DEFINITIONS 
1.1 ABBREVIATIONS 
ACURASYS = The ARDS and Curarisation 
Systematique study investigators 
ARDS = Acute Respiratory Distress Syndrome 
BiPAP = Bilevel Positive Airway Pressure 
BMI = Body Mass Index 
BUN = Blood Urea Nitrogen 
CCC = Clinical Coordinating Center 
CPAP = Continuous Positive Airway Pressure 
DSMB = Data Safety Monitoring Board 
ECMO = Extracorporeal Membrane 
Oxygenation 
EDEN = Early versus Delayed Enteral Nutrition 
trial 
FACTT = Fluid and Catheter Treatment Trial 
FiO2 = Fraction of Inspired Oxygen 
GCS = Glasgow Coma Scale 
GRADE = Grading of Recommendations 
Assessment, Development and Evaluation 
IBW = Ideal Body Weight 
ICU = Intensive Care Unit 
IL-1β = Interleukin 1β 
IL-6 = Interleukin 6 
IL-8 = Interleukin 8 
IMV = Intermittent Mechanical Ventilation 
INR = International Normalized Ratio 
ITT = Intent to Treat 
IVRS = Interactive Voice Response System 
LAR=Legally Authorized Representative 
LTAC = Long Term Acute Care Facility 
 
 
 
 
mBW = Measured Body Weight 
MRC = Medical Research Council 
NHLBI = National Heart Lung and Blood 
Institute 
NMBA = Neuromuscular blocking agent 
OSCILLATE = Oscillation for Acute Respiratory 
Distress Syndrome Treatment Early 
PETAL = Prevention and Early Treatment of 
Acute Lung Injury  
P/F = PaO2/FiO2 ratio 
PaCO2 = Partial pressure of arterial carbon 
dioxide 
PaO2 = Partial pressure of arterial oxygen 
PAP = Pulmonary Artery Pressure 
PB = Barometric Pressure 
PBW = Predicted Body Weight 
PEEP = Positive End-Expiratory Pressure 
PIN = Personal Identification Number 
Pplat = Plateau pressure 
PROSEVA = Proning Severe ARDS Patients 
study investigators 
PTSD =  Post Traumatic Stress Disorder 
PS = Pressure Support Ventilation 
RASS = Richmond Agitation Sedation Scale 
S/F = SpO2/FiO2 ratio 
SOFA = sequential organ failure assessment 
SBP = Systolic Blood Pressure 
SBT = Spontaneous Breathing Trial 
SpO2 = Oxygen Saturation via pulse oximetry 
SUSAR = Serious and Unexpected Suspected 
Adverse Reactions 
SAEs= Adverse events that are serious and 
unexpected and have a reasonable possibility 
that the event was due to a study procedure 
VFD = Ventilator-free Days 
WBC = White Blood Cell


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1.2 
DEFINITIONS  
 
Adverse Event: Any untoward medical occurrence associated with the use of a drug or a study 
procedure, whether or not considered drug related. 
Adverse reaction: An adverse reaction means any adverse event caused by a drug.  An 
adverse reaction are a subset of all suspected adverse reactions where there is a reason to 
conclude that the drug caused the event. 
Assisted breathing: Any level of ventilatory support at pressures higher than the unassisted 
breathing thresholds. Completing 48 hours of UAB is defined as the date (calendar day) that the 
subject reaches exactly 48 hours of UAB. Example: if subject meets UAB at 1900 on 6/1/15 and 
does not return to assisted breathing, then the date of completing 48 hours of UAB would be 
6/3/15. 
Controlled Ventilation: Any mode with a backup rate that allows clinicians to either set tidal 
volume to a target or adjust pressures to target a tidal volume. Examples include volume assist 
control, pressure assist control, pressure regulated volume control. 
Extubation: Removal of an orotracheal, nasotracheal tube, or unassisted breathing with a 
tracheostomy 
Home: Level of residence or health care facility where the patient was residing prior to hospital 
admission. 
Intention to Treat (ITT):  All eligible and consented patients who undergo randomization will be 
included in the ITT cohort for the purposes of analyzing the primary and secondary study 
outcomes. 
Invasive Mechanical Ventilation: Assisted ventilation delivered by a nasotracheal, orotracheal, 
or tracheostomy tube 
Legal Representative: An individual, judicial, or other body authorized under applicable law to 
consent on behalf of a prospective patient to the patient's participation in the clinical study. 
Mortality prior to discharge home before day 90: This primary outcome includes deaths from 
all causes following randomization in any heath care facility prior to discharge home until study 
day 90. Study subjects still in a health care facility at study day 91 are considered alive for this 
endpoint. 
Funding: National Institutes of Health (National Heart Lung and Blood Institute) 
Sponsor: The Clinical Coordinating Center at Massachusetts General Hospital 
Study Day: The day of randomization is study day zero. The next day is study day one etc. 
Study Drug: Randomly assigned cisatricurium 


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Study hospital: Defined as the hospital where the patient was randomized and enrolled. 
Study withdrawal: Defined as permanent withdrawal from study before completion of study 
activities. This does not include those subjects who have completed the protocol procedures or 
stopped procedures because they have reached unassisted breathing. If a patient or surrogate 
requests withdrawal from the study the clinician should seek explicit permission to continue data 
collection. 
Suspected adverse reaction: any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the adverse event.  A suspected adverse reaction 
implies a lesser degree of certainty about causality that adverse reaction (21 CFR 312.32(a)) 
UAB (Unassisted Breathing): Spontaneously breathing with face mask, nasal prong oxygen, 
room air, T-tube breathing, tracheostomy mask breathing, CPAP ≤ 5 without PS or IMV 
assistance,  the use of noninvasive ventilation solely for sleep-disordered breathing, or use of a 
nasal high flow system.  


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2 TRIAL SUMMARY 
 
Title: Reevaluation Of Systemic Early neuromuscular blockade (ROSE) 
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. 
Hypothesis: Early neuromuscular blockade will improve mortality prior to discharge home 
before day 90, in patients with moderate-severe ARDS.     
Study Design: Multi-center, prospective, 2-arm, unblinded, randomized clinical trial of two 
management strategies of neuromuscular blockade (also called skeletal muscle relaxant and 
muscle relaxant).   
1. We will emphasize early screening and protocol initiation, and enroll a maximum of 1408 
patients with a confirmed and established PaO2/FiO2 < 150. 
✓ We will allow determination of PaO2/FiO2 inclusion criteria from SpO2 pulse 
oximetry measurement. 
2. Early neuromuscular blockade group 
✓ Patients will receive a cisatracurium besylate bolus of 15 mg, followed by a 
continuous infusion of 37.5 mg/hour for 48 hours.  
✓ We will protocolize deep sedation to Ramsay of 5-6 (RASS of -4 to -5, or Riker of 1-
2) before starting, and during, the 48 hour infusion. We do not mandate sedative type 
or dose. 
✓ We will protocolize high PEEP/FiO2 titration (based on published, safe, feasible high 
PEEP protocols). 
3. No routine early neuromuscular blockade group (control group) 
✓ We will recommend non-neuromuscular blockade interventions for refractory hypoxia 
and that neuromuscular blockade only be used for refractory elevated plateau 
pressure; treating clinicians can use neuromuscular blockade if thought necessary 
✓ We will recommend clinicians target light sedation titrated to a Ramsay 2-3 (RASS of 
0 to -1, or Riker 3-4) and/or perform daily sedation interruption. Higher doses of 
sedation will be allowed for respiratory distress, ventilator dyssynchrony, or hypoxia. 
We do not mandate sedative type or dose. 
✓ We will protocolize high PEEP/FiO2 titration (based on published, safe, feasible high 
PEEP protocols). 
4. Prone positioning 
✓ We will recommend sites wait at least 12 hours (as per PROSEVA[1]) before 
proning, and to avoid automatic use of neuromuscular blockade with proning. 
5. Other care 


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✓ We will protocolize low tidal volume ventilation and spontaneous breathing trials in 
both arms. 
✓ We will provide recommendations for conservative fluid management in both arms. 
Inclusion Criteria  
1. Age > 18 years 
2. Presence of all of the following conditions for < 48 hours 
i. 
(I) PaO2/FiO2 < 150 with PEEP > 8 cm H2O.a,b,c  
OR, IF ABG NOT AVAILABLE  
SpO2/FiO2 ratio that is equivalent to a PaO2/FiO2 < 150 with PEEP > 8 cm H2O 
(Appendix A1), and a confirmatory SpO2/FiO2 ratio between 1-6 hours after the 
initial Sp02/Fi02 ratio determination.  c,d 
ii. 
Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules 
iii. 
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 (Appendix L) 
a, If altitude >1000m, then PaO2/FiO2 < 150 x (PB/760). 
b These inclusion criteria ensure a non-transient, established hypoxia that persists despite elevated 
PEEP and time. Initial, post-intubation, PEEP is typically < 8 cm H2O. 
c The qualifying PaO2/FiO2 or the SpO2/FiO2 must be from intubated patients receiving at least 8 
cm H2O PEEP.  
d. When hypoxia is documented using pulse oximetry, a confirmatory SpO2/FiO2 ratio is required 
to further establish persistent hypoxia. Qualifying SpO2/FiO2 must use SpO2 values less than or 
equal to 96% Qualifying SpO2 must be measured at least 10 minutes after any change to FiO2.  
 
The 48-hour enrollment time window begins when criteria i-iii are met. Criteria may 
be met at either the Network or referring hospital. The first qualifying SpO2/FiO2 (not 
the confirmatory SpO2/FiO2) is used determine this time window. 
  
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 


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10. Expected duration of mechanical ventilation < 48 hours 
11. Decision to withhold life-sustaining treatment; except in those patients committed to 
full support except cardiopulmonary resuscitation 
12. Moribund patient not expected to survive 24 hours; if CPR provided, assess for 
moribund status  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. PaO2/FiO2 (if available) >200 after meeting inclusion criteria and before 
randomization Oxygenation may improve during the 48 hour enrollment window. This 
exclusion criterion ensures that patients with mild ARDS are not included in the 
study. 
21. Endotracheal ventilation for greater than 120 hours (5 days) 
22. Patient has completed lung transplant evaluation and has been officially listed for 
lung transplant by UNOS 
Randomization and Study Initiation Time Window: All patients must be enrolled and 
randomized within 48 hours of meeting inclusion criteria. After randomization, the low tidal 
volume protocol must be initiated within two hours (if not already being used). In the 
intervention arm, deep sedation followed by neuromuscular blockade must be initiated within 
four hours of randomization.  
Efficacy: The primary outcome is all-cause mortality prior to discharge home before day 90. 
1. 
Secondary outcomes: 
1. ICU acquired weakness 
2. IL-6 levels (plasma) 
3. Hospital mortality to day 28  
4. Ventilator free days to day 28 
5. Organ failure free days to day 28 
6. ICU-free days at day 28 
7. Hospital-free days at day 28 
8. Physiologic measures 
9. Long term outcome assessments 
10. Use of rescue procedures 


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11. Paralysis recall, in-hospital 
12. Supraventricular tachycardia and new onset atrial fibrillation 
Sample Size/Interim Monitoring: 
1. With a 35% mortality rate in the control arm and 27% mortality rate in the intervention 
arm, the maximum required total sample size is 1408 subjects. 
2. The principal analysis will be intent-to-treat, based upon randomization assignment. 
3. Trial progress will be evaluated by an independent Data and Safety Monitoring Board 
(DSMB) to determine if the study should stop for superiority of either Active or 
Control therapy. There will be two interim analyses and a final analyses conducted 
when approximately each successive 1/3 of the patients have been enrolled. 
3 TRIAL DESCRIPTION 
3.1 
BACKGROUND 
In 2010, the ACURASYS trial reported early neuromuscular blockade (also called skeletal 
muscle relaxant or muscle relaxant) administration improved adjusted survival for moderate to 
severe ARDS in a 340 patient trial conducted in 20 French ICUs.[2] While intriguing, this 
approach has not been widely adopted in the U.S., and key limitations exist. First, the trial was 
underpowered. Mortality benefit was noted only after statistical adjustment; crude 90d mortality 
did not differ. Control mortality was also lower than predicted (though higher than many recent 
ARDS trials)[3, 4] and the authors concluded “given the observed mortality in our placebo 
group, the current study was underpowered”. Second, the mechanism responsible for the 
improvement in outcome with neuromuscular blockade is unclear. One possible explanation is 
that neuromuscular blockade results in improvement in patient-ventilator asynchrony with 
subsequent reduction in ventilator-induced lung injury and inflammation. Third, assessment of a 
known side effect of the intervention, muscle paresis, has been criticized as inadequate. As a 
result of these concerns, the critical care community has collectively recommended another 
phase III clinical trial to definitively test the safety and efficacy of neuromuscular blockade in 
patients with ARDS.[5, 6]  
3.2 NEUROMUSCULAR BLOCKADE – POTENTIAL BENEFITS AND 
MECHANISMS 
One of the earliest ARDS Network trials demonstrated that low tidal volume ventilation led to an 
absolute reduction in mortality of 9%.[7] This ventilator strategy presumably reduced ventilator 
induced lung injury by avoiding alveolar over distension. Recent ARDS studies have examined 
whether ventilatory strategies such as high positive end expiratory pressure (PEEP) or high 
frequency oscillation may improve outcome. All of these trials have focused on adjusting the 
ventilator portion of the patient-ventilator interface. Therapies directed at reducing patient’s 
metabolic demands and improving the patient’s ability to interface with the ventilator, may also 
attenuate ventilator induced lung injury. Neuromuscular blockade may improve the patient 


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component of the patient-ventilator interface. Oxygen consumption of 
respiratory muscles normally represents only 1%-3% of cardiac output. Due 
to the decreased pulmonary compliance in ARDS, the work of breathing escalates and can 
constitute as much as 24% of the increased cardiac output[8]. These increases in cardiac output 
and blood flow across an injured pulmonary vasculature can generate higher filtration pressures 
and promote the formation of lung edema. By removing the ability of the respiratory muscles to 
contract, neuromuscular blockade reduces the oxygen consumption of these muscles, which in 
turn reduces cardiac output directed towards these muscles, increases the mixed venous partial 
pressure of oxygen, and can increase the partial pressure of oxygen in arterial blood. These 
same reductions in cardiac output diminish the volume of blood flow through the pulmonary 
capillaries, decrease the pulmonary vascular pressure gradient, and the accumulation of 
alveolar fluid.  Vigorous expiratory effort can also result in alveolar collapse and reduced end-
expiratory lung volumes. By preventing active expiration, neuromuscular blockade may create a 
more homogenous distribution of PEEP and tidal volumes, preventing barotrauma/volutrauma 
and “atelectrauma” resulting in less ventilator-induced lung injury[5] (See Figure 1). 
 
 
3.3 NEUROMUSCULAR BLOCKADE – POTENTIAL HARMS  
In the recent past, neuromuscular blockade was commonly used for ventilated patients with 
acute respiratory failure.[9] However, with its increased utilization, neuromuscular blockade was 
Figure 1 


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implicated in the development of a severe and persistent neuromuscular weakness[10], though 
this association has been recently challenged[11]. Due to the concerns for these long term 
debilitating side effects combined with the availability of more efficacious sedative agents, the 
prolonged use of neuromuscular blocking agents for critically ill patients who require mechanical 
ventilation diminished over time. 
3.4 RECENT FRENCH CLINICAL TRIALS 
Based on the rationale outlined above, Papazian and colleagues examined the efficacy of 
neuromuscular blockade for ARDS. Their first study was a randomized controlled trial to 
determine the effects of 48 hours of neuromuscular blockade on gas exchange in patients with 
severe ARDS[12]. All patients were heavily sedated to a Ramsay score of six before 
randomization. Patients randomized to neuromuscular blockade demonstrated significant 
improvements in PaO2/FiO2 ratio during the first five days of their ICU course when compared 
to placebo. A second study evaluated the effects of neuromuscular blockade on pulmonary and 
systemic markers of inflammation in patients with ARDS[13]. All patients underwent a 
bronchoalveolar lavage (BAL) before randomization and at 48 hours. Neuromuscular blockade 
resulted in a decrease in IL-1β, IL-6, and IL-8 levels in the BAL fluid at 48 hours. There was also 
a significant decrease in serum concentrations of IL-6 and IL-8 in the patients who received 
neuromuscular blockade. Similar to their first study, patients who received neuromuscular 
blockade had a significant improvement in their oxygenation. Their third and most prominent 
study (ACURASYS), as noted above, showed decreased mortality with early neuromuscular 
blockade [2].  
3.5 CURRENT PRACTICE IN PETAL SITES AND CLINICAL EQUIPOISE 
To determine the utilization of neuromuscular blockade for patients with moderate to severe 
ARDS, we surveyed the principal investigators of the current PETAL network hospitals. Overall, 
35 investigators answered the survey; representing all 12 PETAL sites. Only 11% of 
investigators stated that continuous neuromuscular infusions were commonly used for ARDS 
patients with a PaO2/FiO2 < 150 at their hospitals. In this survey, commonly was defined as 
between 80-100% of patients. The vast majority of these investigators (94%) were confident 
they would be able to randomize ARDS patients with a PaO2/FiO2 < 150 to a neuromuscular 
blockade protocol. Similarly, 100% of investigators would be able to follow a neuromuscular 
blockade protocol in the intervention arm of the study and enforce no routine use of 
neuromuscular blockade in the control arm.  
These survey results demonstrate that neuromuscular blockade is uncommonly used for ARDS 
patients with a PaO2/FiO2 < 150, and that PETAL sites would be able to effectively perform a 
randomized study of neuromuscular blockade for ARDS patients with a PaO2/FiO2 < 150. 
3.6 EARLY NEUROMUSCULAR BLOCKADE FOR ARDS NEEDS 
REEVALUATION 


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Despite the encouraging results of the Papazian studies, there are several compelling reasons 
why the PETAL Network should perform a second study of early neuromuscular blockade for 
ARDS. First and foremost, the pulmonary and critical care community has clearly learned that 
clinical trials often require replication and validation before the efficiency of a therapy is proven. 
In a review of 39 highly cited positive randomized clinical trials, the results were replicated in 
less than 50% of subsequent studies[14]. Relevant to critical care, the results of several 
landmark trials including intensive insulin therapy and activated protein C were not replicated in 
subsequent studies. The high rate of non-replication is a consequence of the ill-founded 
strategy of claiming conclusive research findings solely on the basis of one study whose p value 
< 0.05. The hesitancy to conclude the efficacy of a treatment based on a single trial may be 
especially true for studies that appear counterintuitive and question recent paradigms such as 
the routine use of neuromuscular blockade in critically ill patients. A second large randomized 
trial with positive results would elevate early neuromuscular blockade for ARDS to the highest 
GRADE level and the strongest recommendation based on modified Delphi methodology. 
Reservations about the Papazian trial were based on the following concerns about study 
design, statistical analysis, and adverse event reporting.   
1. Though the preplanned primary outcome was adjusted mortality, and the adjusted 
mortality rate was significantly different between the two groups (p = 0.04), crude 
mortality was not significantly different between the groups (p = 0.08). 
2. The infusion of neuromuscular blockade occurred during the first 48 hours of the study. 
However, the Kaplan-Meier curves achieved separation after Day 12 in regard to the 
probability of achieving unassisted breathing, and after Day 18 in regard to mortality. 
The delay in the observed treatment effect raises concerns about the direct effects of 
neuromuscular blockade on the positive outcomes in the clinical trial.  
3. Variables commonly used to assess the risk of ventilator induced lung injury, such as 
plateau pressure and tidal volume, were not different between the patients who received 
neuromuscular blockade and placebo, raising concerns about the biological plausibility 
of the therapy. 
4. A low PEEP strategy was used in both arms of the Papazian trial. For patients with 
moderate to severe ARDS, meta-analyses suggest that high PEEP strategies may result 
in improved outcomes including mortality [15]. Based upon the likelihood that 
atelectrauma may be more common with lower PEEP strategy, neuromuscular blockade 
may have a different effect for patients receiving a high PEEP strategy. 
5. All patients in the control arm of the Papazian trial received heavy sedation defined as a 
Ramsay score of six. The routine use of heavy sedation is associated with several 
deleterious outcomes including prolonged length of mechanical ventilation. Based on the 
results of our survey of PETAL investigators, 86% of respondents reported that the 
routine sedation goal for ARDS patients is not heavy sedation. Therefore, it is plausible 
that the positive results of the Papazian trial are related to the harmful and uncommon 
use of a heavy sedation strategy in the control arm. 


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6. Safety-related outcomes are commonly underreported in randomized controlled clinical 
trials resulting in misinterpretation and inadequate conclusions concerning the benefits 
of the intervention [16, 17]. The assessment of neuromuscular dysfunction was 
determined using only the MRC score to define weakness. In addition, the potential 
effects of neuromuscular blockade on the development of symptoms of post-traumatic 
stress disorder and paralysis recall were not determined. A better understanding of the 
long term risk associated with the use of neuromuscular blockade would allow clinicians 
to make a more informed decision about its utility in ARDS. 
7. Based on the strength of the previous clinical trials and the need to replicate their 
results, we propose to test the safety and efficacy of a 48 hour infusion of neuromuscular 
blockade for reducing mortality in patients with early ARDS. We hypothesize that early 
neuromuscular blockade will result in improved clinical outcomes, specifically hospital 
mortality prior to discharge home before day 90 in patients with moderate-severe ARDS.  
3.7 
ROSE IS AN EARLY TREATMENT TRIAL 
The goal of ROSE is to test early administration of neuromuscular blockade for 48 hours as 
close to the initial onset of moderate to severe ARDS as possible. All efforts will be made to 
emphasize very rapid enrollment as soon as this severity of ARDS is diagnosed. We believe 
early administration is crucial. Neuromuscular blockade is most likely to be effective in 
mediating lung injury and lung-injury induced non-pulmonary effects and inflammation, if 
administered early. In addition, though neuromuscular blockade is sporadically used in routine 
clinical practice, systematic early treatment is not widespread. Thus, if the null hypothesis of 
ROSE is rejected, this trial will significantly alter and improve current clinical care, leading to 
increased early treatment with neuromuscular blockade. 
Our approach will be to leverage the new PETAL infrastructure and philosophy to screen and 
enroll patients early using a suite of techniques adapted from prior successful early intervention 
trials, including Emergency Department trials (Section 4.1). We will also monitor time from 
inclusion criteria being met to enrollment, overall and by site, and regularly discuss with sites 
strategies to encourage very early enrollment. 
3.8 
OBJECTIVES 
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. 
Primary Hypothesis 
Early neuromuscular blockade will improve mortality prior to discharge home before day 90, in 
patients with moderate-severe ARDS. 
 


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3.9 
END POINTS 
Analyses will be conducted on an intention to treat basis.  
3.9.1 PRIMARY OUTCOME 
The primary outcome is all-cause mortality prior to discharge home before day 90. 
3.9.2 SECONDARY OUTCOMES 
1. ICU acquired weakness 
a. Manual muscle strength testing will be attempted at study day 7, and then every 7 
days thereafter, until hospital discharge or day 28 (whichever comes first). Patients 
will be defined as having ICU acquired weakness if their Medical Research Council 
(MRC) score is < 48 (or mean MRC < 4 for each muscle group tested)[18, 19]. 
b. Highest level of mobility will be assessed on study days 1-7 using the ICU Mobility 
Scale [20], and then every 7 days thereafter, until hospital discharge or day 28 
(whichever comes first). 
2. IL-6 levels (plasma) 
We will measure interleukin-6 (IL-6) at study entry and at 48 hours. A proposed 
mechanism of benefit of neuromuscular blockade is decreased ventilator-induced lung 
injury. Interleukin-6 is a pro-inflammatory cytokine that decreased in patients treated with 
a lung-protective low tidal volume ventilation strategy compared to control patients.[7] 
Furthermore, in pilot studies neuromuscular blockade was associated with decreased 
levels of IL-6.[13] Here, we hypothesize that compared to control subjects, subjects 
receiving neuromuscular blockade for 48 hours will have lower levels of IL-6, reflecting 
decreased ventilator-induced lung injury. As in the ARDS Network trials, analysis of 
covariance (ANCOVA) will be used to examine the impact of treatment with 
neuromuscular blockade on biomarker levels at 48 hours.  
3. Hospital mortality to day 28  
4. Ventilator free days to day 28 
Ventilator free days to day 28 are defined as the number of days from the time of 
initiating unassisted breathing to day 28 after randomization, assuming survival for at 
least two consecutive calendar days after initiating unassisted breathing and continued 
unassisted breathing to day 28. If a patient returns to assisted breathing and 
subsequently achieves unassisted breathing to day 28, VFDs will be counted from the 
end of the last period of assisted breathing to day 28. A period of assisted breathing 
lasting less than 24 hours and for the purpose of a surgical procedure will not count 
against the VFD calculation. If a patient was receiving assisted breathing at day 27 or 
dies prior to day 28, VFDs will be zero. Patients transferred to another hospital or other 
health care facility will be followed to day 28 to assess this endpoint. 


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5. Organ failure free days to day 28 
Organ failure is defined as present on any date when the most abnormal vital signs or 
clinically available lab value meets the definition of clinically significant organ failure 
according to SOFA scores (Appendix K).[21] Patients will be followed for development of 
organ failures to death, hospital discharge or study day 28, whichever comes first.  Each 
day a patient is alive and free of a given organ failure will be scored as a failure-free day. 
Any day that a patient is alive and free of all organ failures will represent days alive and 
free of all organ failure. 
6. ICU-free days at day 28 
7. Hospital-free days at day 28 
8. Physiologic measures to include: 
a) Oxygenation Index on study days 1-4,7 
b) PaO2 / FiO2 ratio on study days 1-4, 7 
c) Level of PEEP on study days 1-4, 7 
d) Plateau pressure on study day 1-4, 7 
e) Development of pneumothorax through day 7 
9. Long term outcome assessments 
We will assess seven measures after hospitalization: 
a) Disability: using Katz Activities of Daily Living (ADL)/Lawton Instrumental 
Activities of Daily Living Scale (IADL) plus two additional Nagi items 
b) Health-Related Quality of Life (including utilities): EuroQol (EQ-5D-5L)  
c) Self-rated health: 1 standard item 
d) Pain-interference: 1 standard item 
e) Post-traumatic Stress-like Symptoms: Post-Traumatic Stress Symptoms (PTSS-
14) 
f) Cognitive function: Montreal Cognitive Assessment (MoCA-Blind) or, via proxy, 
the Alzheimer’s Disease 8 (AD8) 
g) Subsequent return to work, hospital and ED use, and location of residence 
 
These measures will be collected through telephone interviews with patients or their LARs 
(Appendix G).   
 
10. Use of rescue procedures 
Rescue procedures will be chosen according to the practice at the clinical site. We will 
record the use of the following rescue procedures (yes/no) through study day 28: prone 
positioning, nitric oxide, epoprostenol sodium, high frequency ventilation, and ECMO. 
11. Paralysis recall, in-hospital 


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Paralysis recall assessment will be monitored once during hospitalization in all patients, 
using a modified Brice questionnaire [22, 23].  
12. Supraventricular tachycardia (SVT) or new onset atrial fibrillation (the occurrence of one 
or more episodes during the ICU stay will be recorded) 
3.9.3 SUBGROUPS 
A priori subgroups will include: pre-randomization PaO2/FIO2 < 120, and time from meeting 
ARDS severity criteria for study enrollment to start of cisatracurium infusion. 
4 STUDY POPULATION AND ENROLLMENT 
4.1 NUMBER/SOURCE/SCREENING 
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. The overall strategy is to screen and enroll early, every newly intubated, acutely ill or 
post-operative, patient at each site, using clinically obtained pulse oximetry and blood gases.  
Tactics will include: 
i. Follow up each screened patient on a daily basis 
Epidemiological studies have demonstrated that 90% of at risk patients will develop ARDS 
within 5 days. Prior ARDS Network trials have successfully used this “screen and follow” 
strategy in facilitating early enrollment of eligible patients.  
ii. Emergency Department (ED) screening and ICU hand-off 
In the Emergency Department (ED), every intubated patient will be assessed for inclusion and 
exclusion criteria. This assessment will either be in person or through electronic screening. If a 
long ICU bed wait time is predicted, patients can be enrolled in the ED. We will facilitate ED-ICU 
handoff with use of a unified screening log (to be used for both ED and ICU screening), joint 
inservice training by site PIs to ED and ICU faculty, and coordination by research staff for 
enrolled patients. When patients are enrolled in the ED, research staff in the ED will call the ICU 
research staff to report name, medical record number, diagnoses, destination, and time of 
administration of study drug. This communication will occur before patients leave the ED. 
iii. ICU screening 
Every new ICU admission receiving mechanical ventilation will be screened. This will include but 
not be limited to admissions from the ED, wards, and operating room. We will also assess 
patients transferred from outside hospitals. The enrollment window for these patients will include 
the time elapsed since admission at the outside hospital including during transfer.  
iv. Study clinician availability for consent 


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Each site will have dedicated study physicians and coordinators who are certified and trained in 
human subjects protection and understand the study protocol. 
4.2 INCLUSION CRITERIA 
1. Age > 18 years 
2. Presence of all of the following conditions for < 48 hours: 
i. 
(I) PaO2/FiO2 < 150 with PEEP > 8 cm H2O.a,b,c 
          OR, IF ABG NOT AVAILABLE  
SpO2/FiO2 ratio that is equivalent with a PaO2/FiO2 < 150 with PEEP > 8 cm H2O 
(Appendix A1), and a confirmatory SpO2/FiO2 ratio between 1-6 hours after the 
initial Sp02/Fi02 ratio. c,d,          
ii. 
Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules 
iii. 
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 (Appendix L) 
a If altitude >1000m, then PaO2/FiO2 < 150 x (PB/760). 
b, These inclusion criteria ensure a non-transient, established hypoxia that persists despite elevated 
PEEP and time. Initial, post-intubation, PEEP is typically < 8 cm H2O. 
c The qualifying PaO2/FiO2 or the SpO2/FiO2 must be from intubated patients receiving at least 8 
cm H2O PEEP.    
d When hypoxia is documented using pulse oximetry, a confirmatory SpO2/FiO2 ratio is required to 
further establish persistent hypoxia. Qualifying SpO2/FiO2 must use SpO2 values less than or 
equal to 96%.  Qualifying SpO2 must be measured at least 10 minutes after any change to FiO2. 
 
The 48-hour enrollment time window begins when criteria i-iii are met. Criteria may be 
met at either the Network or referring hospital. The first qualifying SpO2/FiO2 (not the 
confirmatory SpO2/FiO2) is used determine this time window.  
4.3 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 < 48 hours 


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11. Decision to withhold life-sustaining treatment; except in those patients committed to full 
support except cardiopulmonary resuscitation 
12. Moribund patient not expected to survive 24 hours; if CPR provided, assess for 
moribund status  6 hours 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. PaO2/FiO2 (if available) >200 after meeting inclusion criteria and before randomization 
Oxygenation may improve during the 48 hour enrollment window. This exclusion 
criterion ensures that patients with mild ARDS are not included in the study. 
21. Endotracheal ventilation for > 5 days (120 hours)See Appendix A2 for specific exclusion 
criteria definitions. 
22. Patient has completed lung transplant evaluation and has been officially listed for lung 
transplant by UNOS 
4.3.1 REASONS FOR EXCLUSIONS 
Patients <18 years old are excluded because of limited clinical trial data with cisatracurium in 
these individuals. In addition, we will only be enrolling patients from adult ICUs, and the staff 
may be less well-trained in sedation and neuromuscular blockade practices in children. Patients 
with ARDS for >48 hours or on mechanical ventilation for > 120 hours are excluded because the 
PETAL network is charged to test early treatment. In addition, previous trials that suggested 
benefit from neuromuscular blockade used a 48 hour time interval. Criteria 2 and 4 exclude 
patients who are already receiving or likely to receive neuromuscular blockers as part of their 
clinical care. Exclusion criterion 3 is included because there are not sufficient data to support 
the use of cisatricurium in pregnant women during treatment for severe ARDS.  Criteria 5, 6, 7, 
8, 9, 10, 11, 12, 17and 22 exclude patients who may not survive to important study endpoints or 
whose underlying condition or ventilator management complicates assessment of the secondary 
endpoint of ventilator free days. Patients with diffuse alveolar hemorrhage (criterion 13) are 
excluded because the mechanism of lung injury is different from ARDS due to other causes. 
Patients with large burns (criterion 14) are also excluded as conservative fluid management 
may be contraindicated. 
4.4 RANDOMIZATION, AND STUDY INITIATION TIME WINDOW 
All patients must be randomized within 48 hours of meeting inclusion criteria. The window for 
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After randomization, the low tidal volume protocol must be initiated within two hours (if not 
already being used). In the intervention arm, deep sedation followed by neuromuscular 
blockade must be initiated within four hours of randomization. 
4.5 INFORMED CONSENT 
Informed consent will be obtained from each patient or legally authorized representative (LAR) 
prior to enrollment in the trial. No study procedures will be done prior to obtaining informed 
consent.  
Permission to approach patients and/or LARs will be requested from the attending physicians. 
All patients meeting inclusion criteria will be entered on a screening log. If the patient is not 
enrolled, the screening log will include information explaining why enrollment did not occur (e.g., 
exclusion criteria, attending physician denial, patient refusal) and a minimum data set to the 
extent allowed (Appendix F). 
4.6 RANDOMIZATION 
After obtaining a signed and dated informed consent from the subject or the subject’s LAR, the 
subject will be randomized via the coordinating center web based randomization system. Each 
research coordinator will have a unique Personal Identification Number (PIN) to access the 
randomization system. Each subject will receive a computer-generated study ID number and 
study arm assignment to neuromuscular blockade or control. An emailed confirmation will follow 
to the study site. Randomization will be stratified by institution at study entry. 
4.7 MINORITIES AND WOMEN 
Gender and racial patient subsets were considered by the NHLBI in selecting the PETAL 
Network Centers. The demographic profiles of the Centers selected for the Network show that 
the aggregate patient population contains representative proportions of minorities and women. 
Recruitment of minorities and women will be monitored by the PETAL Network Coordinating 
Center. If necessary, additional recruitment efforts will be made at specific centers to ensure 
that the aggregate patient sample contains appropriate gender and minority subsets. 
5 STUDY PROCEDURES 
Trials should be conducted in a setting reflective of best practice that can be clearly described 
and reproduced in a clinical non-trial setting. We therefore (i) selected centers already providing 
high quality standardized ICU care, (ii) will document the use of protocols and order sets at each 
center, (iii) monitor the provision and results of key processes of care, and (iv) implement strict 
protocols (with training, monitoring, and feedback) for the use of neuromuscular blockade and 
mechanical ventilation. Almost all PETAL centers have existing protocols and order sets for 
routine sedation management, glucose control, septic shock resuscitation, deep venous 
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5.1 EARLY NEUROMUSCULAR BLOCKADE GROUP  
5.1.1 INITIATION AND DOSAGE 
Study staff will ensure a Ramsay score of 5-6 (RASS of -4 to -5, or Riker of 1-2) is achieved and 
documented prior to initiation of neuromuscular blockade and that patients are receiving 
controlled modes of mechanical ventilation. We do not mandate sedative type or dose.  
Initiation of neuromuscular blockade must begin within 4 hours of randomization. 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 (Appendix J). 
We chose this fixed, relatively high dosage for simplicity (train of four titration imperfect and with 
limited evidence base [24-26]) and to help ensure effective neuromuscular blockade (clinical 
observation and train of four monitoring can lead to under-dosing). This dosage is the same as 
used in the ACURASYS trial. We chose cisatracurium as its metabolism is independent of 
hepatic and renal function.  
In the rare circumstance that neuromuscular blockage is deemed inadequate, (i) check the 
patient and the ventilator to confirm the correct reading,( ii) check the infusion rate and drug to 
confirm correct, ( iii) rebolus, using the below recommendation and call the CCC for further 
direction as needed. 
Recommendation: If the end-inspiratory plateau pressure remains greater than 32 cm of water 
for at least 10 minutes, it is recommended that the patient receive the administration of 
increasing doses of sedatives and decreasing tidal volume and positive end-expiratory pressure 
(if tolerated) before considering using open-labeled cisatracurium. If the treating physician still 
wants to administer a neuromuscular blocking agent, an open-label, rapid, intravenous injection 
of 20 mg of cisatracurium will be recommended for patients in the control or treatment arms of 
the study. If this rapid, intravenous injection results in a decrease of the end-inspiratory plateau 
pressure by less than 2 cm of water, a second injection of 20 mg of cisatracurium will be 
allowed. If after injection, the end-inspiratory plateau pressure does not decrease or decreases 
by less than 2 cm of water, cisatracurium boluses should not be administered again during the 
following 24-hour period. 
We chose to not blind cisatracurium administration as patients under neuromuscular blockade 
will have easily identifiable clinical characteristics such as absence of any movement. 
Therefore, true blinding of the study physicians and research coordinators is unlikely to occur. 
PETAL investigators are familiar with the performance of unblinded studies including the recent 
EDEN trial.[3] As the primary outcome variable is an objective measure (mortality), the risk of 
systematic bias with an unblinded study design is low. 
We will prepare and recommend safety plans to patients receiving neuromuscular blockade that 
include eye care, positioning, and pressure ulcer monitoring. 
 


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5.1.2 SEDATION 
The sedation dosage required to achieve Ramsay of 5-6 (RASS of -4 to -5, or Riker of 1-2) prior 
to cisatracurium administration should be continued for the 48 hour neuromuscular blockade 
period. After neuromuscular blockade ceases, sedation should be as in the control arm. We do 
not mandate sedative type or dose. 
5.1.3 STOPPING RULES FOR NEUROMUSCULAR BLOCKADE 
During the 48 hour study intervention period 
Neuromuscular blockade can be stopped if ventilator weaning criteria are met for PEEP/FIO2 
criteria of FiO2  0.40 and PEEP  8 cm (Appendix D), and maintained for at least 12 hours. If 
after the discontinuation of neuromuscular blockade, the oxygenation significantly worsens (> 2 
rightward steps on PEEP/FiO2 table required), neuromuscular blockade should be resumed. 
Neuromuscular blockade can also be stopped for investigator or clinician safety concerns. 
Stoppages for any other reasons will be recorded as protocol violations. 
In the rare event that extubation and reintubation occurs during the 48 hour time window (e.g., 
unplanned extubation, rapid clinical improvement prompting early extubation), neuromuscular 
blockade should be resumed after reintubation.  
After the 48 hour study intervention period 
Treating clinicians will be informed when the 48h period ends and that the cisatracurium infusion 
will be stopped at that time as a study intervention, while continuing sedation. After the 48 hour 
study intervention period, decisions on further use of neuromuscular blockade, including type of 
and dosing of the agent, will be as per the treating clinicians. 
5.1.4 CONFIRMATION OF NEUROMUSCULAR BLOCKADE 
In addition to the bedside clinical nurses’ routine monitoring of patients while on neuromuscular 
blockade infusion, research staff will assess these patients daily, and record set and actual 
ventilator rates, infusion rate and boluses.  
5.2 CONTROL GROUP 
Patients randomized to control will receive care as per their treating clinicians except for aspects 
of care outlined in section 5.3.  
5.2.1 MINIMIZING NEUROMUSCULAR BLOCKADE 
We will encourage sites to minimize neuromuscular blockade use in the control arm.  
Our goal is to respect clinician autonomy and protect patient safety, while preserving separation 
of treatment between arms. We will encourage non-neuromuscular blockade interventions for 
refractory hypoxia such as recruitment maneuvers, proning without neuromuscular blockade, 
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in the control arm is outweighed by the necessity of having a separation in neuromuscular 
blockade treatment between arms.  
Recommendation: If the end-inspiratory plateau pressure remains greater than 32 cm of water 
for at least 10 minutes, it is recommended that the patient receive the administration of 
increasing doses of sedatives and decreasing tidal volume and positive end-expiratory pressure 
(if tolerated) before considering using open-labeled cisatracurium. If the treating physician still 
wants to administer a neuromuscular blocking agent, an open-label, rapid, intravenous injection 
of 20 mg of cisatracurium will be recommended for patients in the control or treatment arms of 
the study. If this rapid, intravenous injection results in a decrease of the end-inspiratory plateau 
pressure by less than 2 cm of water, a second injection of 20 mg of cisatracurium will be 
allowed. If after injection, the end-inspiratory plateau pressure does not decrease or decreases 
by less than 2 cm of water, cisatracurium should not be administered again during the following 
24-hour period. 
5.2.2 SEDATION 
We provide sedation score targets; we do not mandate sedative type or dose. 
For patients not on neuromuscular blockade 
 TITRATE sedation as per clinician discretion 
 RECOMMEND: Ramsay of 2-3 (RASS 0 to -1 or Riker 3 to 4) OR absence of 
respiratory distress, and/or daily sedation breaks if no contraindication 
 DOCUMENT: reasons for sedation given for RASS < -1 
For patients that receive neuromuscular blockade 
Ramsay of 5-6 (RASS of -4 to -5, or Riker of 1-2) should be achieved prior to neuromuscular 
blockade and continued for the 48 hour infusion. 
5.3 COMMON STRATEGIES FOR BOTH STUDY GROUPS 
5.3.1 STUDY STARTUP PROCEDURES 
In both groups, we will use the following standardized, step-wise, startup procedures to collect 
hemodynamic safety data (Section 6.3.1) in the first 6 hours following randomization. These 
procedures will allow comparison of hemodynamics during study startup between groups, and 
will avoid simultaneous PEEP and sedation titration, which would render interpretation of 
hypotensive episodes challenging. Close oversight of study initiation should be provided by an 
intensive care attending and/or designee. 
1. Initiate low tidal volume ventilation within 2 hours, as per Section 5.3.3.). 
2. Adjust sedation to target sedation score (if not already at target) – deep sedation in the 
early neuromuscular blockade group, recommendation of light sedation in control group.  


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3. If in the neuromuscular blockade arm, start cisatracurium within 4 hours of 
randomization, as per section 5.1.1. 
4. Before increasing PEEP, a PETAL investigator or designee will determine hemodynamic 
appropriateness for PEEP increase using the following as guidelines: MAP > 55 or SBP 
> 80, no fluid bolus or vasopressor increase for  greater than 15 minutes. 
5. Peep will be gradually up-titrated as per Appendix D1. 
5.3.2 PRONING 
We will recommend sites wait at least 12 hours (as per PROSEVA[1]) before proning, and to 
avoid automatic use of neuromuscular blockade with proning. 
Based on the results of our survey of PETAL investigators, we expect modest use of proning in 
either arm of this study. Overall, half of the investigators reported that proning was initiated in 
less than 40% of ARDS patients with a P/F< 150.  
5.3.3 VENTILATOR PROCEDURES 
We will protocolize low tidal volume ventilation, weaning, and a high PEEP strategy (Appendix 
D). 
 
Low tidal volume ventilation 
We will use a simplified version of the ARDS network 6 ml/kg PBW lung protective ventilation 
protocol except that controlled modes of ventilation will be required during the period of 
neuromuscular blockade. If not already being used, a low tidal volume protocol for mechanical 
ventilation must be initiated within two hours of randomization in all patients. 
Weaning 
Since the time a patient achieves unassisted ventilation affects some secondary endpoints, and 
because recent evidence-based consensus recommendations have identified a best practice for 
weaning, a weaning strategy will also be controlled by protocol rules in accordance with these 
evidence-based recommendations. This will assure similar weaning methods and provide 
potential benefit to both study groups.  This weaning strategy is a simplified version of the 
protocolized weaning strategy used in prior ARDS Network studies (Appendix D). 
PEEP 
As a study procedure, all study patients will receive a high PEEP strategy based on previously 
deployed PEEP protocols [27-30]. The use of the high PEEP protocol will be required for up to 5 
days after randomization. We selected to protocolize high PEEP in all patients for the following 
reasons: 
1. To mitigate the possibility of differential PEEP use between arms.  
2. A presumptive physiologic benefit of neuromuscular blockade is reduction of 
atelectrauma, barotrauma, volutrauma, and heterogeneity in alveolar expansion.  A 


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higher PEEP strategy will limit atelectrauma and heterogeneity of alveolar expansion. It 
is also unknown if neuromuscular blockade adds additional protection over a higher 
PEEP strategy alone.  
3. Trials should test novel interventions on a background of “best care”. Secondary 
analyses and opinion leaders suggest high PEEP strategies may be beneficial in those 
ARDS patients with higher acuity.[15]  
If hypotension occurs with the use of a high PEEP protocol, the recommendation from the fluid 
management approach will be the administration of fluid boluses. (Appendix E) 
We will allow deviation from the high PEEP strategy, for limited situations: 
 If there is clinical concern that the use of high PEEP may be worsening oxygenation 
(e.g., oxygenation worsens with PEEP increases) at a FiO2 ≥ 0.5 for more than 2 hours, 
clinicians may trial lower PEEP. 
 If oxygenation worsens or is unchanged at the lower level of PEEP, the PEEP should be 
raised back to the previous level. 
 If oxygenation improves, the clinicians may choose to leave the PEEP at the lower level. 
Subsequently the clinician should decrease the FiO2 as tolerated until a listed 
combination on the PEEP/FiO2 chart is reached, and then continue to follow the 
PEEP/Fi02 protocol. 
 If hypotension, high plateau pressure (> 30 cm H20), and/or severe academia (pH < 
7.15) are present despite further tidal volume reduction, fluid boluses, and/or respiratory 
rate increase (Section 5.3.3. and Appendix D1), lower PEEP may be used. With the 
ROSE PEEP table (Appendix D1) as the starting point, reduce PEEP 2 cm H2O every 5-
15 minutes, until the physiologic parameters of concern have improved, as per the 
treating clinician and/or responsible investigator (e.g., reduce PEEP to the level that 
lowers plateau pressure to 30 cm H20). Later, try to return PEEP to a level consistent 
with the ROSE PEEP table, at least daily through study day 5. 
Lower PEEP may also be used if a study participant develops a pneumothorax, or is deemed at 
high risk for barotrauma (e.g., known multiple pulmonary cysts or bullae). 
5.3.4 ON-STUDY FLUID MANAGEMENT 
Fluid management during shock will be unrestricted. However, in patients not in shock, a 
conservative fluid approach will be recommended for all patients enrolled in the study.  This 
conservative fluid management approach will represent a simplification of the algorithm utilized 
in the ARDS Network FACTT study (see Appendix E)[31].   
5.3.5 GLUCOSE CONTROL  
Hyperglycemia has been associated with neuromuscular dysfunction. Each site will use their 
own standard management, including institution-specific insulin drip protocols, to maintain blood 


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sugars with a target upper blood glucose level ≤ 180 mg/dL. This range avoids marked 
hyperglycemia, while minimizing the risk of both iatrogenic hypoglycemia and other harms 
associated with a lower blood glucose target. 
5.3.6 RESCUE PROCEDURES 
If PaO2 ≥ 55 mmHg or SpO2 ≥ 88% with FIO2 of 1.0 cannot be maintained, clinicians may 
employ alternate therapies (rescue procedures). Rescue procedures will be chosen according to 
the practice at the clinical site, and may include repeated recruitment maneuvers, prone 
positioning, inhaled nitric oxide, inhaled epoprostenol sodium, high frequency ventilation, or 
ECMO. The participants will continue to be followed and included in the analysis on an 
intention-to-treat basis. The use of rescue procedures will constitute a secondary outcome. 
6 DATA VARIABLES AND SPECIMENS 
6.1 BACKGROUND ASSESSMENTS 
1. Demographic and Admission Data (including age, sex, race) 
2. Pertinent Medical History and Physical Examination (including Charlson co-morbidity 
score) 
3. Height; gender; measured Body Weight (mBW); calculated predicted body weight 
(PBW); body mass index (BMI) 
4. Time on ventilator prior to enrollment 
5. Type and location of endotracheal intubation 
 Pre-hospital, ED, ward, ICU, operation room, referring hospital 
6. Location when inclusion criteria met 
 Pre-hospital, ED, ward, ICU, operation room, referring hospital 
7. Type and location of ICU Admission 
 Medical 
 Surgical scheduled 
 Surgical unscheduled 
 Trauma 
8. Risk factors for ARDS (sepsis, aspiration, trauma, pneumonia, other) 
9. Ever smoker (>100 cigarettes in lifetime)?   
 If Yes, current smoker?   
 If ever smoker, estimate pack years [Pack years = (# packs per day) x (number of 
years smoked)] 
 If former smoker, when quit? 


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10. Survey of alcohol history (see Appendix I)  
11. Basic assessment of prior functioning  
6.2 BASELINE ASSESSMENTS 
The following information will be recorded during the 24-hour interval preceding randomization. 
If more than one value is available for this 24-hour period, the value closest to the time of 
randomization will be recorded. If no values are available from the 24 hours prior to 
randomization, then values will be measured post randomization but prior to initiation of 
cisatracurium (intervention arm) and within 4 hours (control arm). All values will be derived from 
clinically available data. 
1. History and physical examination 
Vital signs:  heart rate (beats / min), systemic systolic and diastolic BP (mmHg), body 
temperature (0C) (APACHE) 
2. Ventilator mode, set rate, actual rate, minute ventilation, tidal volume, FiO2, PEEP, I:E 
ratio, plateau, peak, and mean airway pressures  
3. Administration of the following medications (name) 
a) Intravenous sedatives 
b) Intravenous opioids 
c) Intravenous or enteral Corticosteroids  (>/= 20 methlyprenisolone equivalents)  
 
4. Presumed site of infection, if sepsis is the etiology of ARDS 
5. APACHE III score, including the acute physiology components and laboratory values 
6. APACHE III demographics plus history of: hypertension, prior myocardial infarction, 
congestive heart failure, peripheral vascular disease, prior stroke with sequelae, 
dementia, chronic pulmonary disease, arthritis, peptic ulcer disease 
7. SOFA Score: Cardiovascular, renal, respiratory, hepatic, and hematology organ function 
will be assessed using the SOFA methodology as described in Appendix K. 
8. Pneumothorax at time of randomization (Y/N) 
6.3 ASSESSMENTS DURING STUDY 
6.3.1 HEMODYNAMIC MONITORING DURING STUDY STARTUP 
For the first 4 hours after randomization, we will record the time that target PEEP/FiO2 and 
sedation score are achieved, the time of both the cisatracurium bolus and infusion, as well as 
the time of any fluid bolus or change in vasopressor use.  
Together with SOFA and adverse event data at 48 hours, this hemodynamic monitoring data will 
be used to report study process safety data to the DSMB. 


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6.3.2 REFERENCE MEASUREMENTS 
The following data will provide the basis for assessing protocol compliance and safety as well as 
between-group differences in several efficacy variables. Data for each of the variables will be 
recorded on the days shown in the Time-Events schedule (Appendix B) or until death, or 
discharge from the intensive care unit. Values will be derived from clinically available data.   
1. NMB Dosing 
a) Intervention Arm 
i. 
Time and dose of loading dose 
ii. 
Time of initiation of cisatracurium continuous infusion 
iii. 
Reason and duration of infusion hold during first 48 hours 
iv. 
Total dose of cisatricurium infusion during first 96 hours 
v. 
Name and total dose of other NMB during first 96 hours 
vi. 
Addition NMB administered after 96 hours (yes/no) 
b) Control Arm 
i. 
Name and total dose of any NMB used in the first 96 hours after 
randomization 
ii. 
Addition NMB administered after 96 hours (yes/no) 
 
Reference Measurements (Daily) 
The following parameters will be measured and recorded between 4:00 and 10:00 A.M. using 
the values closest to 8:00 A.M. on the days specified in the Time-Events schedule. The 
following conditions will be ensured prior to measurements: no endobronchial suctioning for 10 
minutes; no invasive procedures or ventilator changes for 30 minutes. All vascular pressures will 
be zero-referenced to the mid-axillary line.   
1. If receiving positive pressure ventilation: Ventilator mode, set rate, actual rate, 
minute ventilation, tidal volume, FiO2, PEEP, I:E ratio, plateau, peak, mean airway 
pressures, set peak flow, and set inspiratory time  
2. PaO2, PaCO2, pH, and SpO2 
Values for the following variables will be recorded for the dates shown in the Time-Events 
Schedule. If the measurements are not obtained during the 6-hour reference interval (4:00 to 
10:00 A.M.), then the value obtained closest in time to the reference interval on the respective 
date will be recorded. If more than one value is obtained during the reference interval, then the 
value obtained closest to 8:00 A.M. will be recorded. 
3. Rescue procedures used  
a) Proning 
b) Inhaled nitric oxide 
c) Epoprostenol sodium 
d) High frequency ventilation 


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e) ECMO 
 
4. Serum electrolytes and glucose 
5. Administration of the following medication infusions:  
a) Intravenous sedatives 
b) Intravenous opioids  
c) Enteral or intravenous corticosteroids ((>/= 20 methlyprenisolone equivalents)  
 
6. Sedation score: If RASS < -1 (or Riker < 3, Ramsay > 3), and sedation given, list reason 
given 
7. Was a sedation interruption performed? Y/N 
8. Modified SOFA 
9. Fluid intake and output/CVP if available 
10. ICU Mobility Scale: Score 0-10 (see Appendix M) 
Other Reference Measurements 
1. Manual muscle strength testing (MMT) screen and assessment on day 7, 14, 21 28 or until 
hospital discharge.  
2. Assessment of gross motor movement on study day 3. 
3. Paralysis recall assessment, in both study arms, one time during study hospitalization, using 
a modified Brice questionnaire [22, 23].  
To facilitate the ability of the patient to interact appropriately with the above measures, sedative 
agents will be titrated according to the institution’s sedation protocol.  The MMT and the 
Modified Brice questionnaire will be conducted in patients who meet the awakening and 
comprehension criteria. Awakening and comprehension will be determined based upon the 
response of the patient to five commands (“open/close your eyes,” “look at me,” “open your 
mouth and stick out your tongue,” “nod your head,” and “raise your eyebrows when I have 
counted to five”). If the patient can responds appropriately to all five of these orders, the patient 
will be considered awake and able to comprehend and the above measures will be attempted to 
be obtained.  
Additionally, prior to conducting the MMT the patient will be assessed for injuries or medical 
devices that would preclude the MMT assessment and for any safety barriers to strength 
training such as unstable shock, profound hypoxemia, unstable spine or airway, nonresponsive 
to verbal command (RASS -4 or -5). The Manual Muscle strength testing uses the MRC 
(Medical Research Council) score evaluates muscle strength with very good interobserver 
agreement, and was used in the ACURASYS trial [2, 32]. Introduced in 1970, the Brice 
questionnaire is a reliable and efficient method of detecting recall after sedation or general 


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anesthesia. This questionnaire avoids falsely identifying pre-sedation memories and 
experiences [22, 23].  
6.3.3 SPECIMEN COLLECTION 
Urine and plasma will be collected within 2 hours of randomization, at 24 hours (24 hours after 
randomization for control arm and 24 hours after starting cisatracurium for active patients), and 
at 48 hours (48 hours after randomization for control arm and 48 hours after starting 
cisatracurium for active patients), frozen, and stored for IL-6 measurement (at 2 hours and 48 
hours) and at a biorepository for future research. Total blood volume for these draws is 
approximately 15 ml/day, for a total of approximately 45 ml. When consent obtained, we will 
also obtain an additional 20 ml of whole blood for future RNA and DNA studies. Study samples 
will be sent to a central repository to be stored in accordance with good laboratory practices.  
Samples will be identified by a coded number during shipment and storage in the central 
repository. 
6.4 ASSESSMENTS AFTER HOSPITALIZATION 
These domains and instruments to assess after hospitalization status were selected by the 
PETAL Neuromuscular Blockade Protocol Committee in conjunction with the PETAL Long-Term 
Outcomes Committee. 
We will assess seven measures after hospitalization:  
1. Disability: using Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities of 
Daily Living Scale (IADL) plus two additional Nagi items 
2. Health-Related Quality of Life (including utilities): EuroQol (EQ-5D-5L)  
3. Self-rated health: 1 standard item 
4. Pain-interference: 1 standard item 
5. Post-traumatic Stress-like Symptoms: Post-Traumatic Stress Symptoms (PTSS-14) 
6. Cognitive function: Montreal Cognitive Assessment (MoCA-Blind) or, via proxy, the 
Alzheimer’s Disease 8 (AD8) 
7. Subsequent return to work, hospital and ED use, and location of residence 
These measures will be collected through telephone interviews with patients or their LARs 
(Appendix G).  Informed consent process will include text to facilitate future ancillary long term 
follow up studies and data collection.  All will be obtained at 3, 6, and 12 months except for post-
traumatic stress-like symptoms, which will only be obtained at 6 and 12 months.  All will be 
obtained in English or Spanish, from the patient wherever possible.  Most will be obtained from 
proxies when necessary, except as noted for self-rated health, pain interference and post-
traumatic stress-like symptoms. 
The assessments after follow-up will provide information about post-discharge deaths faster 
than is available from other sources, although the National Death Index will be used to verify 
date of death whenever possible (see below). 


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The Katz ADL is associated with multiple health outcomes among community-dwelling 
elders[36], and valid among nursing home residents[37]. The Lawton IADL is probably the most 
widely used self-report or informant-report IADL instrument. These assess a range of common 
functional activities, from walking and toileting to managing money and cooking meals.  We will 
use the precise wordings from the NIA-funded Health and Retirement Study for which US (and 
international) norms are available. These scales have been specifically shown to perform well 
when assessed by proxies for ICU survivors. [40] We will remove the 3 ADL/IADL items that are 
duplicative of the EQ-5D questions (using the EQ-5D instead), and will add two items from the 
Nagi scale [41]as implemented in the HRS.  
The EQ-5D[44] has US utilities[45] and is recommended for measurement of health-related 
quality of life among critical illness survivors.[46] It is quick and feasible in individuals with 
inattention and fatigue[47].  We will use the EQ-5D-5L version currently used by both the ANZIC 
RC in Australia and New Zealand and ICNARC in the United Kingdom.  We will not use the 
Visual Analog Scale as these follow-ups will be phone administered and the VAS is not 
necessary for health economic analysis. 
Self-rated health and pain-interference are two common single-item scales that are widely used.  
We will use the wordings from the SF-12. Because of the highly subjective nature of these 
domains, these will only be assessed by self-respondents. 
The Montreal Cognitive Assessment (MoCA) appears superior to the mini mental status 
examination and its derivatives for neurocognition assessment in critical illness survivors [48-
51], and allows rapid, reliable determination of cognitive impairment [52] in various clinical 
syndromes.[51, 53-55] The MOCA-Blind version is developed for phone administration. Among 
community-dwelling older individuals, MoCA scores were lower (more impairment) among 
patients with elevated levels of inflammatory cytokines.56 When patients are not able to respond 
themselves, the validated AD-8 [56]will be used to assess cognitive function by proxy. 
We will capture return to work status using the Improving Care of ALI Patients (ICAP) study 
questionnaire.[59] The Improving Care of Acute Lung Injury Patients employment instrument 
(ICAP-12) was designed to determine pre- and post-morbid employment status in a multi-center 
observational study of ARDS survivors[59, 60] and used externally in the NHLBI ARDS 
Network’s ARDS Long-term Outcomes Study (ALTOS) cohorts[61, 62].   We will also ask about 
recent hospital and Emergency Department use, and whether the patient is residing in a nursing 
home, at home, or elsewhere. 
We will also verify duration of survival for patients lost to follow-up or noted to have died using 
the Centers for Disease Control and Prevention’s National Death Index (NDI) and other federal 
databases. We will use each patient’s social security number (SSN) for an exact NDI match. 
We will also collect the patient’s Medicare identification number for patients in Medicare to allow 
assessment of post-discharge health care utilization without any respondent burden back on the 


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patient.  We will collect contact information for the patient and alternative contact information on 
up to 2 individuals. 
6.4.1 TOKENS OF APPRECIATION 
Each participant will receive a $10 token of appreciation after each 3-, 6- or 12-month interview, 
in the form of a gift card to a national chain of stores.  In addition, each participant will be mailed 
a reminder postcard prior to the 3- and 12-month interviews. Each participant will receive a $5 
token of appreciation for returning the postcard with updated contact information.  
Because of the importance of having an excellent response rate, we set aside some funds to 
avert refusals, specifically an increase from the original $10 to $20. This increased amount is 
based on prior studies[63] as well as conversations with personnel at the University of Michigan 
Health and Retirement Study (HRS), launched in 1992 and funded by the National Institute on 
Aging and the Social Security Administration. Their procedures have been well vetted, and are 
still in use in the 2014 fielding of the HRS. Research has shown that refusal conversions 
increase cooperation rates significantly for all incentive levels. 
Interviewers will be trained on how to avert refusals during the initial participant contact by 
addressing any concerns that the respondent may have. After gauging participation rates over 
the course of the study, study staff may find it necessary to offer an incentive of $20 during the 
initial contact. This will take place if the participant is hesitant during the initial contact in hopes 
that participation rates will increase. In the event that a respondent does not wish to participate 
in subsequent surveys after having completed their first survey, we will then offer an additional 
incentive of $10 for a total of $20. Once a participant is offered the higher incentive, they will 
receive that amount for each of the remainder of surveys that they complete. 
In no case will more than $20 be offered to avoid any potential for coercion, although examples 
of much higher incentives certainly exist in the literature. For example, Turnball et al recently 
published a study with incentives up to $50, and Robinson et al’s recent systematic review 
noted studies with incentives up to $160.[64][65] 
7 STATISTICAL CONSIDERATIONS 
NOTE: please see the detailed statistical analysis plan (SAP) that is a separate document 
Statistical Methods  
The primary outcome is intention to treat 90 day all cause in-hospital mortality, where in-hospital 
includes study hospital and LTAC. Subjects who are discharged home (defined as residence 
prior to admission) prior to day 90 will be assumed to be alive and censored at day 91.  
Sample size is based on a comparison of binomial proportions with an overall two-sided alpha 
level of 0.05 and power of 0.90.  With 35% mortality rate in controls and 27% rate in NMB the 
maximum required total samples size is 1408 subjects.  


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The presumed 35% mortality rate in the control group is based on several recently published 
clinical trials.[2, 27, 66] In the original Papazian study, mortality prior to discharge home before 
day 90 was 40.7% in the control group. Similarly in the multi-center clinical trial of high-
frequency oscillation for ARDS (OSCILLATE), the in-hospital mortality rate was 35% for the 
control group. In this study, control subjects received a high PEEP strategy. Finally in the ARDS 
subjects used to validate the new Berlin definition of ARDS, the mortality in those patients with 
moderate ARDS, defined as a P/F ratio between 100-200, was 32%. Though recent ARDSNet 
trials reported lower mortality in their primary outcome (EDEN ~23%, SAILS ~27%), these 
studies enrolled less severely ill patients (P/F < 300) and used a shorter duration mortality 
outcome (60 days). 
This trial will stop for superiority of either active or control and is designed with symmetric group 
sequential flexible stopping boundaries as described in Lan and DeMets (Reference Lan, K. K. 
G. and DeMets, D. L. (1983), Discrete sequential boundaries for clinical trials. Biometrika 70, 
659-663.) They specify that that at each look at the data the cumulative probability of exceeding 
the upper or lower boundary on that look or previous looks will be 0.025 t^4 under the null 
hypothesis of no difference between the treatments, where t is the information time, defined as 
the ratio of the effective sample size at the time of the look to the eventual sample size. We plan 
to have two interim and one final look that will be approximately evenly spaced.  However, the 
scheduling of the DSMB meetings may alter this schedule.    
Table 1 presents an illustration of the stopping boundaries at each of the three looks if they are 
equally spaced. The table presents stopping boundaries as both a required observed mortality 
difference and one-sided p-value. The columns under ‘Probability of Stopping’ present the 
probability of stopping at each stage under the null and alternative (NMB reduces mortality from 
35% to 27%) hypotheses respectively.  
Table 1 
* = These are one sided p values for the upper and lower boundaries. 
For example, the second stage analyses will take place when approximately 938 patients have 
been enrolled and the study would be stopped if the 90 day absolute mortality difference 
 
Active Superior 
Control Superior 
Probability of Stopping 
Number 
of 
Subjects 
Observed  
Mortality 
Difference 
Active-
Control 
P-value* 
 
Observed 
Mortality 
Difference  
Active-
Control 
P-value* 
 
Under the 
Null 
Hypothesis 
Under the 
Alternative 
Hypothesis 
470 
-0.146 
0.00031 
0.146 
0.99969 
0.001 
0.061 
938 
-0.078 
0.00479 
0.078 
0.99521 
0.010 
0.528 
1408 
-0.049 
0.02361 
0.049 
0.97639 
0.050 
0.900 


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exceeds 0.078. This corresponds to a one-sided p-value of 0.00479. If the alternative 
hypothesis is true then the probability of stopping at this stage is 0.528. 
Sample size and power under different mortality assumptions 
The table below shows the effect of changes in the power of the study as a function of the 
mortality rate on the treatment with the higher mortality.  We calculated the power under two 
assumptions. The first is that the absolute difference in mortality rates was 8% and the second 
was that the relative difference was 23% which is approximately 8% of the anticipated mortality 
of 35%.  The second row of the table shows the current assumptions.  Whether you fix the 
absolute or the relative difference, the power is above 80% as long as the null mortality rate is 
over 25%.  The power goes down to 73% if the mortality rate is 20% which is below the mortality 
rate observed in a ARDSNet studies except the placebo arm of ALTA [67]. Unlike prior 
ARDSNet studies including ALTA, ROSE seeks to enroll patients at the more severe end of the 
ARDS severity spectrum. 
Both methods of adaption have the problem that the direction of the sample size adjustment 
depends on whether you consider the absolute difference or the relative difference to be the 
important parameter. This choice is somewhat arbitrary. From the point of view of the utility of 
the treatment the absolute difference is important because it is directly related to the number 
needed to treat. That is, NNT=1/D.   On the other hand, if the sample is diluted by a proportion 
of patients who are not at risk of death then the relative decrease in mortality would stay the 
same while the absolute difference would decrease. Adaption based on the overall mortality rate 
has the additional problem that you don’t know whether the reduction is due to the null mortality 
rate or the alternative mortality rate. Adaption based on both observed mortality rates or the 
maximum mortality rate might require a p-value adjustment which would reduce the power of 
the study. If both mortality rates in this study were less than 20% then the DSMB should 
consider whether we had the right population to study for a treatment like induced 
neuromuscular blockade. 
Null Mortality 
Power at 8% Absolute 
Decrease in Mortality 
Power at ~23% Relative 
Decrease in Mortality 
45% 
86% 
97% 
   35% * 
90% 
90% 
30% 
93% 
85% 
25% 
96% 
79% 
20% 
98% 
73% 
  
 *Assumption used in the ROSE Protocol 
8 DATA COLLECTION AND SITE MONITORING 
Data Collection: The research coordinators will collect data and record it either on paper data 
sheets or in a custom-designed computer database. Data will be transferred to the Clinical 


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Coordinating Center on a prescribed basis through a web-based data collection program.  
 
Once daily, coordinators will enter data regarding ventilator and fluid management that can be 
analyzed for consistency with the supportive care protocols. Examples of data that will be 
recorded are: tidal volume, plateau pressure, PEEP, FiO2, fluid balance, blood pressure, use of 
vasopressors, infusions and bolus doses of diuretics. We will use the algorithms developed by 
ARDSNet investigators to assess data in PETAL subjects for consistency with protocol rules. 
For example, if at 22:50 on November 20, 2015 a tidal volume is within the range of 5.5-6.5 
ml/kg predicted body weight and plateau pressure is <= 30 cm H2O, then tidal volume for that 
date and time will be deemed "on-target." If the tidal volume is > 6.5 ml/kg PBW and pH is > 
7.15, then tidal volume for that date and time will be deemed "off-target." We will also assess 
FiO2, PEEP, plateau pressure, and fluid and diuretic management for consistency with protocol 
rules.  
 
The Clinical Coordinating Center will calculate a "%-on-target" value for each center for each of 
the monitored variables (# of dates on-target for a specific variable/# of opportunities to be on-
target for that specific variable). Principal Investigators and Co-Investigators at each Center will 
receive monthly reports of (1) % on-target for each of the specific variables in the most recent 
month, (2) % on-target for each of the variables since the beginning of a trial, and (3) a list of 
dates/times from the past month, the specific data that were entered for those dates/times, and 
determinations of on- or off-target. 
 
Investigators will use these reports to identify aspects of protocol management that can be 
improved at their Centers. The on-target performances of all centers will also be included, 
allowing investigators at each center to know how their center is performing relative to other 
PETAL Centers. On-target performances will be discussed during regular meetings of the 
Steering Committee. The Institutional Support Committee will provide advice and assistance to 
Centers that are not performing up to expectations. On-target data for the specific variables 
according to study group will be included in the primary reports of the results of the individual 
trials. 
 
Site Monitoring: Data quality will be reviewed remotely using front end range and logic checks 
at the time of data entry and back-end monitoring of data using SAS reports. Additionally, 
Clinical Center on site visits will be performed on a regular basis by the Clinical Coordinating 
Center to ensure that all regulatory requirements are being met and to monitor data quality. 
Patient records and case report forms will be examined on a spot check basis to evaluate the 
accuracy of the data entered into the database and monitor for protocol compliance. 
9 RISK ASSESSMENT 
This study involves randomization to early neuromuscular blockade, or a control arm with no 
routine neuromuscular blockade, for the first 48 hours. Compared to not being part of the study, 


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patients may have a higher, lower, or the same risk of death. In addition, all patients will receive 
a high PEEP strategy with specific exceptions detailed in Section 5.3.2. Neuromuscular 
blockade and high PEEP carry potential risks and potential offsetting benefits. 
9.1 RISKS OF NEUROMUSCULAR BLOCKADE 
Potential risks of cisatracurium are bradycardia (developed in 1 of 340 patients in ACURASYS; 
0.4% incidence per FDA package insert), hypersensitivity reaction (~0.2%) and ICU acquired 
weakness. The true risk and relationship between neuromuscular blockade and paresis is 
unclear and have been recently challenged12. An increased risk for the development of ICU 
acquired weakness was not observed in patients randomized to neuromuscular blockade in the 
ACURASYS trial. The accompanying deep sedation that is always given with neuromuscular 
blockade may result in hypotension requiring vasopressor support and/or a longer total period of 
sedation. The neuromuscular blockade and the accompanying deep sedation may decrease risk 
of pain or discomfort, but may also render detection of pain or discomfort more difficult.  
9.2 RISKS OF HIGH PEEP 
Historical risks of high levels of PEEP include pneumothorax and hypotension. However, in 
recent large randomized trials, no significant differences in pneumothorax or barotrauma, nor 
vasopressor use or circulatory and other organ failures were noted.[27-30]  
9.3 RISKS OF BLOOD DRAWS 
All patients will have blood drawn for research purposes. As almost all patients will have 
invasive lines placed for clinical purposes, risk of blood draws are essentially nil, as blood can 
be easily obtained from these lines. In the rare case an invasive line is not present, the risks of 
drawing blood are uncommon and include bleeding and bruising. Commonly, drawing blood is 
painful, and rarely, drawing blood can lead to infections at the site of the blood draw. 
9.4 RISK OF DEATH 
It is possible that one treatment arm may lead to more deaths; mortality will be monitored during 
the course of the study. 
9.5 MINIMIZATION OF RISKS 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to subjects are minimized by using 
procedures which are consistent with sound research design. There are several elements of 
study design inherent in the present protocol that meet this human subject protection 
requirement. Neuromuscular blockade is clinically used in ARDS; this trial studies early use. We 
limit study blockade to 48 hours; ICU acquired weakness has been most associated with long, 
uninterrupted infusion. Exclusion criteria prohibit participation of patients who might be at 
increased risk of prolonged paresis or harm from cisatracurium (e.g., myasthenia gravis, 
previous hypersensitivity reaction). We will assess for ICU acquired weakness in all study 
participants. The protocol entrains deep sedation prior to starting neuromuscular blockade to 
prevent paralysis recall. Neuromuscular blockade will be stopped for sustained severe 


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bradycardia. We will use a high PEEP protocol based on those used in multiple large clinical 
trials, that were shown safe, feasible, and of potential clinical benefit for the intended population 
or moderate to severe ARDS. The DSMB will be reviewing data as outlined above and will 
examine not only efficacy but safety (inclusive of mortality) and will reserve the right to halt the 
study at any time.  
9.6 POTENTIAL BENEFITS 
Study subjects may or may not receive any direct benefits from their participation in this study. 
High PEEP has been shown to improve oxygenation in ARDS, to be safe in multiple large trials, 
and of potential benefit in moderate-severe ARDS. Early neuromuscular blockade may result in 
lower mortality. 
9.7 RISKS IN RELATION TO ANTICIPATED BENEFITS 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that 
may reasonably be expected to result.”  Based on the preceding assessment of risks and 
potential benefits, the risks to subjects are reasonable in relation to anticipated benefits.   
Procedures – blood draws. The risks associated with these common clinical practices are 
small, however the knowledge gained in furthering our understanding of the pathophysiology 
and potentially leading to better and targeted therapy may be substantial.  
PTSS-14 Survey: There is a potential risk for identifying underlying mental health issues such 
as PTSD in the PTSS-14 survey. For subjects that are identified as having symptoms of PTSD, 
the research assistant will provide them information about national resources for additional 
mental health services. Treatments – High PEEP and neuromuscular blockade are clinically 
used in clinical practice. There is potential for benefit to society and individual patients should 
neuromuscular blockade prove to be of benefit. Should neuromuscular blockade, again 
consistent with clinical practices, prove to be harmful, the benefit will be in avoiding such 
therapies for future patients with ARDS.  
10 HUMAN SUBJECTS 
Each study participant or a LAR must sign and date an informed consent form. Institutional 
review board approval will be required before any subject is entered into the study. PETAL will 
use a central IRB. 
10.1 SELECTION OF SUBJECTS 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. The EDs, 
ICUs, and other acute care areas of PETAL sites will be screened to determine if any patient 
meets inclusion and exclusion criteria. Data that have been collected as part of the routine 
management of the subject will be reviewed to determine eligibility. No protocol-specific tests or 
procedures will be performed as part of the screening process. If any subjects meet criteria for 


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study enrollment, then the attending physician will be asked for permission to approach the 
patient or his/her LAR for informed consent. Study exclusion criteria neither unjustly exclude 
classes of individuals from participation in the research nor unjustly include classes of 
individuals from participation in the research. Hence, the recruitment of subjects conforms to the 
principle of distributive justice.  
10.2 JUSTIFICATION OF INCLUDING VULNERABLE SUBJECTS  
The present research aims to investigate the safety and efficacy of a type of treatment for 
patients with ARDS.  Due to the nature of ARDS and its risk factors (e.g., sepsis, trauma), the 
vast majority of these patients will have impaired decision-making capabilities. This study 
cannot be conducted if limited to enrolling only those subjects with retained decision-making 
capacity. Hence, subjects recruited for this trial are not being unfairly burdened with involvement 
in this research simply because they are easily available. 
10.3 INFORMED CONSENT 
Federal regulations 45 CFR 46.111(a)(5) require that informed consent will be sought from each 
prospective subject or the subject’s LAR. We anticipate almost all consents will be from the 
subject’s LAR, and thus the remainder of this section will focus on LARs. The one obtaining 
consent is responsible for ensuring that the LAR understands the risks and benefits of 
participating in the study, and answering any questions the LAR may have throughout the study 
and sharing any new information in a timely manner that may be relevant to the LAR’s 
willingness to permit the subject’s continued participation in the trial. The consenter will make 
every effort to minimize coercion. All study participants or their LARs will be informed of the 
objectives of the study and the potential risks. The informed consent document will be used to 
explain the risks and benefits of study participation to the LAR in simple terms before the patient 
is entered into the study, and to document that the LAR is satisfied with his or her understanding 
of the risks and benefits of participating in the study and desires to participate in the study.  The 
investigator is responsible for ensuring that informed consent is given by each LAR. This 
includes obtaining the appropriate signatures and dates on the informed consent document prior 
to the performance of any protocol procedures including administration of study agent. 
10.4 CONTINUING CONSENT 
Subjects for whom consent was initially obtained from a LAR, but who subsequently regain 
decision-making capacity while in hospital, will be approached for consent for continuing 
participation, including continuance of data acquisition. The consent form signed by the LAR 
should reflect that such consent will be obtained. 
10.5 WITHDRAWAL OF CONSENT 
Patients may withdraw or be withdrawn (by the LAR) from the trial at any time without prejudice. 
Data recorded up to the point of withdrawal will be included in the trial analysis, unless consent 
to use their data has also been withdrawn. If a patient or LAR requests termination of the trial 
drug during the treatment period, the drug will be stopped but the patient will continue to be 


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followed up as part of the trial. If a patient or LAR withdraws consent during trial treatment, the 
trial drug will be stopped but permission will be sought to access medical records for data 
related to the trial. If a patient or LAR wishes to withdraw from the trial after completion of trial 
treatment, permission to access medical records for trial data will be sought.   
 
10.6 IDENTIFICATION OF LEGALLY AUTHORIZED REPRESENTATIVES 
Many of the patients approached for participation in this research protocol will invariably have 
limitations of decision-making abilities due to their critical illness. Hence, most patients will not 
be able to provide informed consent.  Accordingly, informed consent will be sought from the 
potential subject’s legally authorized representative (LAR).   
Regarding proxy consent, the existing federal research regulations (‘the Common Rule’) states 
at 45 CFR 46.116 that “no investigator may involve a human being as a subject in 
research…unless the investigator has obtained the legally effective informed consent of the 
subject or the subject’s legally authorized representative”; and defines at 45 CFR 46 102 (c) a 
legally authorized representative (LAR) as “an individual or judicial or other body authorized 
under applicable law to consent on behalf of a prospective subject to the subject’s participation 
in the procedures(s) involved in the research.” The Office of Human Research Protections 
(OHRP) defined examples of “applicable law” as being state statutes, regulations, case law, or 
formal opinion of a State Attorney General that addresses the issue of surrogate consent to 
medical procedures. Such “applicable law” could then be considered as empowering the LAR to 
provide consent for subject participation in the research. Interpretation of “applicable law” may 
be state specific and will be addressed by the PETAL central IRB. 
According to a previous President’s Bioethics Committee (National Bioethics Advisory 
Committee (NBAC)), an investigator should accept a relative or friend of the potential subject 
who is recognized as an LAR for purposes of clinical decision making under the law of the state 
where the research takes place [68]. Finally, OHRP has stated in their determination letters that 
a surrogate could serve as a LAR for research decision making if such an individual is 
authorized under applicable state law to provide consent for the “procedures” involved in the 
research study [69].      
10.7 JUSTIFICATION OF SURROGATE CONSENT 
According to the Belmont Report, respect for persons incorporates at least two ethical 
convictions; first, that individuals should be treated as autonomous agents, and second, that 
person with diminished autonomy are entitled to protection. One method that serves to protect 
subjects is restrictions on the participation of subjects in research that presents greater than 
minimal risks. Commentators and research ethics commissions have held the view that it is 
permissible to include incapable subjects in greater than minimal risk research as long as there 
is the potential for beneficial effects and that the research presents a balance of risks and 
expected direct benefits similar to that available in the clinical setting [70]. Several U.S. task 


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forces have deemed it is permissible to include incapable subjects in research. For example, the 
American College of Physicians’ document allows surrogates to consent to research involving 
incapable subjects only  “if the net additional risks of participation are not substantially greater 
than the risks of standard treatment.” [71]. Finally, NBAC stated that an IRB may approve a 
protocol that presents greater than minimal risk but offers the prospect of direct medical benefits 
to the subject, provided that “the potential subject’s LAR gives permission…” [68] 
Consistent with the above ethical sensibilities regarding the participation of decisionally 
incapable subjects in research and the previous assessment of risks and benefits in the 
previous section, the present trial presents a balance of risks and potential direct benefits that is 
similar to that available in the clinical setting, with the exception of the additional blood draws.     
10.8 ADDITIONAL SAFEGUARDS FOR VULNERABLE SUBJECTS   
The present research will involve subjects who might be vulnerable to coercion or undue 
influence. As required in 45CFR46.111 (b), we recommend that sites utilize additional 
safeguards to protect the rights and welfare of these subjects. Such safeguards might include, 
but are not limited to: a) assessment of the potential subject’s capacity to provide informed 
consent, b) the availability of the LAR to monitor the subject’s subsequent participation and 
withdrawal from the study; c) augmented consent processes. The specific nature of the 
additional safeguards will be left to the discretion of the central IRB, in conjunction with the sites.   
10.9 CONFIDENTIALITY 
Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are 
adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. 
To maintain confidentiality, all laboratory specimens, evaluation forms, and reports will be 
identified only by a coded number.  The coded number will be generated by a computer, and 
only the study team will have access to the codes.  All records will be kept in a locked, 
password protected computer.  All computer entry and networking programs will be done with 
coded numbers only.  All paper case report forms will be maintained inside a locked office.  
Study information will not be released without the written permission of the patient, except as 
necessary for monitoring by the National Heart, Lung, and Blood Institute, and the PETAL 
Clinical Coordinating Center. 
11 ADVERSE EVENTS 
11.1 SAFETY MONITORING 
Assuring patient safety is an essential component of this protocol. Each participating 
investigator has primary responsibility for the safety of the individual participants under 
his or her care. The Investigators will determine daily if any adverse events occur during 
the period from enrollment through study day 7 (five days after infusion of study drug) or 
ICU discharge, whichever occurs first.   
The following adverse events will be collected in the adverse event case report forms: 


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• 
Serious adverse events 
• 
Nonserious adverse events that are considered by the investigator to be related 
to study drug or study procedures or of uncertain relationship (Appendix C2) 
• 
Adverse events that lead to permanent discontinuation of the study drug infusion  
• 
Hypersensitivity reactions to cisatracurium, severe prolonged bradycardia (heart 
rate < 50 for > 30 minutes), and paralysis recall  
• 
Hypotension or pneumothorax, considered by the investigator to be related to 
high PEEP, or of uncertain relationship. 
A clinical trial adverse event is any untoward medical event associated with the use of a 
drug or study procedure in humans, whether or not it is considered related to a drug or 
study procedure.   
After randomization, adverse events related to protocol procedures or occurring after the patient 
receives the first dose of study drug must be evaluated by the investigator. If the adverse event 
is judged to be reportable, as outlined above, then the investigator will report to the CCC their 
assessment of the potential relatedness of each adverse event to protocol procedure or study 
drug via electronic data entry. Investigators will assess if there is a reasonable possibility that 
the study drug or procedure caused the event, based on the criteria outlined in Appendix C2. 
Investigators will also consider if the event is unanticipated or unexplained given the patient’s 
clinical course, previous medical conditions, and concomitant medications.   
If a patient's treatment is discontinued as a result of an adverse event, study site personnel 
must report the circumstances and data leading to discontinuation of treatment in the adverse 
event case report forms.   
11.2 
SERIOUS ADVERSE EVENTS 
Serious adverse event collection begins after the patient or surrogate has signed informed 
consent and has received study drug or undergone study procedures.  If a patient experiences a 
serious adverse event after consent, but prior to receiving study drug, the event will NOT be 
collected unless the investigator feels the event may have been caused by a protocol 
procedure.  
Study site personnel must alert the CCC of any serious and study drug or study procedure 
related adverse event within 24 hours of investigator awareness of the event.  Alerts issued via 
telephone are to be immediately followed with official notification on the adverse event case 
report form. See Appendix C for reporting timelines for serious, unexpected, study related 
events (SAEs) and serious, unexpected suspected adverse reactions (SUSARs) 
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in 
one of the following outcomes: 
• 
Deaths  


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• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Prolonged inpatient hospitalization or rehospitalization 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if 
admission to the hospital or prolongation of hospitalization was a result of the adverse 
event. Emergency room visits that do not result in admission to the hospital should be 
evaluated for one of the other serious outcomes (e.g., life-threatening; required 
intervention to prevent permanent impairment or damage; other serious medically 
important event). 
• 
Persistent or significant disability/incapacity 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if 
the adverse event resulted in a substantial disruption of a person's ability to conduct 
normal life functions, i.e., the adverse event resulted in a significant, persistent or 
permanent change, impairment, damage or disruption in the patient's body 
function/structure, physical activities and/or quality of life. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Serious adverse events will be collected during the first 7 study days or until ICU discharge, 
whichever occurs first, regardless of the investigator's opinion of causation. Thereafter, serious 
adverse events are not required to be reported unless the investigator feels the events were 
related to either study drug or a protocol procedure. 
 
 


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12 APPENDICES 
A1 S/F RATIO INCLUSION CRITERIA 
Table 2 displays an equivalence table that determines the estimated P/F ratio from the Fi02 and 
Sp02. This data was generated by investigators at the University of Utah, on a cohort of critically ill 
patients with pneumonia.[72-78]. 
  
For altitude adjustment, we would recommend the practice from ARDS Network studies of multiplying 
the qualification threshold P/F by the ratio of average ambient to sea level barometric pressure (for 
Utah, it is 0.86*150 = 129; for Denver it is 0.84*150 = 126). 
Additional requirements for the use of the S/F ratio include: 
1. SpO2 between 80-96% 
2. SpO2 should be measured at least 10 minutes after any change in FiO2. 
3. PEEP ≥ 8 cm H20 
4. An adequate pulse oximeter waveform tracing 
 
 
 


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A2 EXCLUSION DEFINITIONS 
Child-Pugh Score [79] 
Premorbid values within 1 year of enrollment should be used. 
 
Points  
Class 
 
   5-6                A 
 
   7-9  
   B 
 
 
  ≥ 10  
   C 
 
 
 
 
 
  
Numerical Score for Increasing Abnormality 
Measurement 
1 
2 
3 
Ascites 
None 
Present 
Tense 
Encephalopathy 
None 
Grade I or II 
Grade III or IV 
Bilirubin (mg/dl) 
< 2 
2-3 
> 3 
Albumin (g/L) 
> 35 
28-35 
< 28 
Prothrombin time (sec. prolonged) 
1-4 
4-10 
> 10 
 
NOTE: If using INR instead of Prothrombin time for Child-Pugh calculation, points for INR 
are as follows: 
<1.7 = 1point 
1.7-2.3 = 2points  
>2.3 = 3points 
Neuromuscular Disease That May Potentiate Neuromuscular Blockade or Impair 
Spontaneous Ventilation 
1. Amyotrophic lateral sclerosis 
2. Guillain-Barré Syndrome 
3. Myasthenia gravis 
4. Upper spinal cord injury at level C5 or above 


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B  TIME-EVENTS SCHEDULE 
 
X=Required    
A=When available    
†= Data gathered at times indicated or until 48 hours UAB, whichever occurs first 
**=Collected once during study hospitalization 
B=Records clinically available creatinine, platelets, bilirubin, SBP and vasopressor use 
~=Data gathered on days 0-28 or until d/c from study hospital 
#=Measure during reference period (0600-1000); other values may be obtained closest to 0800 on the specified calendar 
date 
§=Also measure at 6 and12 months as part of Long Term Outcome. 
*= Assessed for days 1-28 once on day 28 or discharge 


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C  ADVERSE EVENT REPORTING AND UNANTICIPATED PROBLEMS 
As noted in section 11.2, investigators will report all adverse events that are serious and study 
drug or study procedure related to the CCC within 24 hours. The CCC will then notify the NHLBI 
and cIRB. 
The Medical Monitor at the CCC will work collaboratively with the reporting investigator to 
determine if a serious adverse event has a reasonable possibility of having been caused by the 
study drug or procedure, as outlined in 21 CFR 312.32(a)(1)I, and below (Appendix C2). The 
Medical Monitor will also determine if the event is unexpected. An adverse is considered 
“unexpected” if it is not listed in the investigator brochure or the study protocol (21 CFR 
312.32(a)). For this study, the cisatricurium (Nimbex®) package insert and the ACURASYS 
Study 2 serve as the investigator brochure. If a determination is made that a serious adverse 
event has a reasonable possibility of having been caused by the drug, it will be classified as a 
suspected adverse reaction.  If the suspected adverse reaction is unexpected, it will be 
classified as a serious unexpected suspected adverse reaction (SUSAR).   
The CCC will report all unexpected and study related deaths, SAEs, and SUSARs to the DSMB, 
NHLBI, and cIRB within 7 days after receipt of the report from a clinical site. A written report will 
be sent to the NHLBI, DSMB and the cIRB within 15 calendar days.  All unexpected and study 
related deaths and life threatening SUSARS will be reported to the FDA within 7 days; all other 
SUSARS will be reported to the FDA within 15 days.  The DSMB will also review all adverse 
events and clinical outcomes during scheduled interim analyses, including frequency of 
additional neuromuscular blockade use in both study groups, for the first 48 hours. If the DSMB 
determines that the overall rate of adverse events is higher in the cisatracurium group than the 
control group the cIRB and the FDA will be notified within 15 days of this determination (via an 
IND safety report (21 CFR 312.32(c)(1)(i)(A)). The CCC will distribute the written summary of 
the DSMB’s periodic review of adverse events to the cIRB in accordance with NIH guidelines 
(http://grants.nih.gov/grants/guide/notice-files/not99-107.html). 
C1. UNANTICIPATED PROBLEMS (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, associated with the 
study drug or study procedures within 24 hours. An unanticipated problem is defined as follows: 
any incident, experience, or outcome that meets all of the following criteria: 
 Unexpected, in terms of nature, severity, or frequency, given the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and the characteristics of the subject population 
being studied; 
 Related or possibly related to participation in the research, in this guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research; 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 


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recognized. 
C2. DETERMINING RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG OR 
PROCEDURES 
Investigators will be asked to grade the strength of the relationship of an adverse event to 
cisatracurium or study procedures as follows: 
 
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s 
clinical state or other therapies; and c) Evaluation of the patient’s clinical state indicates 
to the investigator that the experience is definitely related to study procedures. 
 
• 
Probably or Possibly Related: The event should be assessed following the same criteria 
for “Definitely Associated”. If in the investigator’s opinion at least one or more of the 
criteria are not present, then “probably” or “possibly” associated should be selected. 
 
• 
Probably Not Related: The event occurred while the patient was on the study but can 
reasonably be explained by the known characteristics of the patient’s clinical state or 
other therapies. 
 
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or 
by other modes of therapy administered to the patient. 
. 
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined. 
 
C3. CLINICAL OUTCOMES THAT MAY BE EXEMPT FROM ADVERSE EVENT 
REPORTING 
Study-specific clinical outcomes of ARDS, as outlined in Sections 3.8.1 and 3.8.2 (Primary and 
Secondary Outcomes) and Section 6.3 (Assessments During the Study) are exempt from 
adverse event reporting unless the investigator deems the event to be related to the 
administration of study drug or the conduct of study procedures (or of uncertain relationship). 
The following are examples of events that will be considered study specific clinical outcomes 
• 
Death not related to the study drug or procedures.   
• 
Cardiovascular events:  need for vasoactive drugs or fluids for hypotension or 
hypotension. 
• 
Respiratory events: decreased PaO2/FiO2, hypoxia, worsening acute respiratory 
distress syndrome, or respiratory failure. 
• 
Hepatic events: hepatic injury or liver dysfunction that leads to an increase from 
baseline in the serum level of bilirubin. 
• 
Renal events: renal failure, renal insufficiency, or renal injury that leads to an 
increase from baseline in serum creatinine. 
• 
Hematologic/coagulation events: coagulopathy, disseminated intravascular 
coagulation, thrombocytopenia, or thrombocytosis. 


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Note: Arrhythmias such as heart block, ventricular tachycardia or ventricular fibrillation are not 
considered study specific clinical outcomes and should be recorded as adverse events if they 
are serious events, are considered by the investigator to be related to study drug, or lead to 
discontinuation of the study drug infusion. 
C4. DECISION TREE FOR DETERMINING IF AN ADVERSE EVENT IS REPORTABLE 
 
 
Adapted from Ranieri VM, Thompson BT, Barie PS et al. Drotrecogin alfa (activated) in adults 
with septic shock. N Engl J Med. 2012 May 31;366 (22):2055-64. Epub 2012 May 22. PubMed 
PMID: 22616830 
 
 
 
 


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D    VENTILATOR PROCEDURES 
D.1 VENTILATOR MANAGEMENT 
A modified, simplified version of the ARDS Network lung protective lower tidal volume strategy 
will be used in this trial. This strategy, which was associated with unprecedented low mortality 
rates in three previous ARDS Network trials (ARMA, ALVEOLI, and FACTT), will ensure that 
study subjects receive the beneficial effects of lung protection as part of their participation in this 
trial[7, 30, 31].  For those patients who remain hospitalized and on mechanical ventilation, the 
ventilator and weaning protocols will be implemented up to day 90 of hospitalization. 
We will also use a modified version of the higher PEEP strategy used in several trials 
(ALVEOLI, LOV, EXPRESS, OSCILLATE). The use of the high PEEP protocol will be required 
for up to 5 days after randomization. This strategy has been repeatedly shown to improve 
oxygenation and to be safe. 
PETAL Network personnel have substantial experience in the application of both strategies from 
the completed trials noted above. 
1. Controlled modes of ventilation will be required during the period of neuromuscular 
blockade. Following neuromuscular blockade, any mode of ventilation capable of 
delivering the prescribed tidal volume (6ml/kg PBW, +/- 2ml/kg) may be used, provided 
the VT target is monitored and adjusted appropriately. During APRV, tidal volume is 
defined as the sum of the volume that results from the ventilator pressure-release and 
an estimation of the average spontaneous VT.   
2. Tidal Volume (Vt) Goal: 6 ml / kg PBW 
Predicted body weight (PBW) is calculated from age, gender, and height (heel to 
crown) according to the following equations: 
Males: PBW (kg) = 50 + 2.3 [height (inches) – 60] 
Females:  PBW (kg) = 45.5 + 2.3 [eight (inches) – 60] 
3. Measure and record inspiratory plateau pressure (Pplat) according to ICU routine (at 
least every four hours and after changes in Vt and PEEP recommended). 
4. If Pplat > 30 cm H20, reduce VT to 5 ml / kg and then to 4 ml / kg PBW if necessary to 
decrease Pplat to ≤ 30 cm H20. 
5. If VT < 6 ml / kg PBW and Pplat < 25 cm H20, raise VT by 1 ml / kg PBW to a maximum 
of 6 ml / kg. 
6. If “severe dyspnea" (more than 3 double breaths per minute or airway pressure remains 
at or below PEEP level during inspiration), then raise VT to 7 or 8 ml / kg PBW if Pplat 
remains below 30 cm H20.  If Pplat exceeds 30 cm H20 with VT of 7 or 8 ml / kg PBW, 
then revert to lower VT and consider more sedation. 
7. If pH < 7.15, VT may be raised and Pplat limit suspended (not required). 


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8. Oxygenation target: 55 mmHg < PaO2 < 80 mm Hg or 88% < SpO2 <  95%. When both 
PaO2 and SpO2 are available simultaneously, the PaO2 criterion will take precedence.   
9. Minimum PEEP = 5 cm H20 
10. Adjust FiO2 or PEEP upward within 5 minutes of consistent measurements below the 
oxygenation target range 
11. Adjust FiO2 or PEEP downward within 30 minutes of consistent measurements above 
the oxygenation target range.   
12. The below high PEEP strategy FiO2/PEEP table, modified from the ALVEOLI trial   , 
should be used in all patients. See Section 5.3.3 for when deviation is permitted. 
 
If a patient's PEEP/FiO2 is not compatible with the PEEP/FiO2 scale immediately after 
randomization either PEEP or FiO2 (or both) will be adjusted in steps, at intervals of 
5-15 minutes until the PEEP/FiO2 is compatible with the scale.  
NOTE:  A step is equal to 2 cm H2O of PEEP and/or FiO2 of 0.1. 
 
(Levels of PEEP in these FiO2 / PEEP scales represent levels set on the ventilator, not 
levels of total-PEEP, auto-PEEP, or intrinsic-PEEP.) 
13. No specific rules for respiratory rate, but incremental increase in the RR to maximum set 
rate of 35 if pH < 7.30. 
14. No specific rules about I:E. Recommend that duration of Inspiration be ≤ duration of 
Expiration. 
15. Bicarbonate is allowed (neither encouraged nor discouraged) if pH < 7.30. 
Changes in more than one ventilator setting driven by measurements of PaO2, pH, and Pplat 
may be performed simultaneously, if necessary. 
D.2  WEANING 
Commencement of weaning 
Patients will be assessed for the following weaning readiness criteria each day between 0600 
and 1000. If a patient procedure, test, or other extenuating circumstance prevents assessment 
for these criteria between 0600 and 1000, then the assessment and initiation of subsequent 
weaning procedures may be delayed for up to six hours. Patients can be assessed for weaning 
readiness criteria twice a day. 
1. At least 12 hours since enrollment in the trial. 
2. FiO2  0.40 and PEEP  8 cm 
FiO2 
.30 
.40 
.40 .40 
.40 
.40 
.40 
.40 
.50 
.50 .50 
.60 
.70 
.80 
.80 
.90 
1.00 1.00 
PEEP 
5 
5 
6 
8 
10 
12 
14 
16 
16 
18 
20 
20 
20 
20 
22 
22 
22 
24 


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3. Values of both PEEP and FiO2  values from previous day (comparing Reference 
Measurement values, section 6.3). 
4. Systolic arterial pressure  90 mm Hg without vasopressor support ( 5 mcg / kg / min 
dopamine will not be considered a vasopressor). 
Spontaneous breathing trial (SBT) procedure and assessment for unassisted breathing 
If criteria 1-4 above are met, first the neuromuscular blocking agent will need to be discontinued 
if the medication is still being infused. When the neuromuscular blocking agent has worn off and 
the patient is having spontaneous respirations, then initiate a trial of up to 120 minutes of 
spontaneous breathing with FIO2 < 0.5 using any of the following approaches: 
1. Pressure support < 5cm H2O, PEEP < 5cm H2O 
2. CPAP < 5 cm H2O  
3. T-piece 
4. Tracheostomy mask  
Monitor for tolerance using the following: 
1. SpO2  90% and / or PaO2  60 mmHg 
2. Mean spontaneous tidal volume  4 ml / kg PBW (if measured) 
3. Respiratory Rate  35 / min 
4. pH  7.30 (if measured) 
5. No respiratory distress (defined as 2 or more of the following): 
a. Heart rate ≥ 120% of the 0600 rate ( ≤ 5 min at > 120% may be tolerated) 
b. Marked use of accessory muscles 
c. Abdominal paradox 
d. Diaphoresis 
e. Marked subjective dyspnea. 
If any of the goals 1-5 are not met, revert to previous ventilator settings or to PS + 10 cm H2O 
with Positive End-expiratory Pressure and FiO2 = previous settings and reassess for weaning 
the next morning. 
The clinical team may decide to change mode of support during spontaneous breathing (PS = 5, 
CPAP, tracheostomy mask, or T-piece) at any time.  
Decision to remove ventilatory support 
For intubated patients, if tolerance criteria for spontaneous breathing trial (1-5 above) are met 
for at least 30 minutes, the clinical team may decide to extubate.  However, the spontaneous 
breathing trial can continue for up to120 minutes if tolerance remains in question. If any of 
criteria 1-5 are not met during unassisted breathing (or 120 minutes has passed without clear 
tolerance), then the ventilator settings that were in use before the attempt to wean will be 
restored and the patient will be reassessed for weaning (see section D.2) the following day. 


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 Definition of unassisted breathing 
a) Extubated with face mask, nasal prong oxygen, or room air, OR 
b) T-tube breathing, OR 
c) Tracheostomy mask breathing, OR 
d) CPAP  5 without PS or IMV assistance 
e) Use of CPAP or BIPAP solely for sleep apnea management 
f) Use of a high flow oxygen system 
Completion of ventilator procedures 
Patients will be considered to have completed the study ventilator procedures if any of the 
following conditions occur: 
a. 
Death 
b. 
Hospital discharge 
c. 
Alive 28 days after enrollment 
If a patient requires positive pressure ventilation after a period of unassisted breathing, the 
study ventilator procedures will resume unless the patient was discharged from the hospital or > 
28 days elapsed since enrollment. 
Removal from the ventilator management protocol 
Patients may be removed from the 6 ml / kg tidal volume ventilation requirement if they develop 
neurologic conditions where hypercapnia would be contraindicated (e.g., intracranial bleeding, 
GCS ≤ 8, cerebral edema, mass effect [midline shift on CT scan], papilledema, intracranial 
pressure monitoring, fixed pupils). 
 


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E    CONSERVATIVE FLUID MANAGEMENT APPROACH 
A modified conservative fluid protocol will be used based on the findings from FACTT that 
conservative fluid management increased ventilator free days.  This protocol is recommended 
for all enrolled patients, to be used until UAB or study day 7, whichever occurs first. 
1. Discontinue maintenance fluids. 
2. Continue medications and nutrition. 
3. Manage electrolytes and blood products per usual practice. 
4. For shock, use any combination of fluid boluses# and vasopressor(s) to achieve MAP ≥ 
60 mmHg as fast as possible. Wean vasopressors as quickly as tolerated beginning four 
hours after blood pressure has stabilized. 
5. Withhold diuretic therapy in renal failure § and until 12 hours after last fluid bolus or 
vasopressor given. 
This protocol is a simplified modification of the conservative protocol used in FACTT.  For 
patients without a CVC, no fluid gain over the first 7 study days is recommended once patients’ 
blood pressure has stabilized.  Stable blood pressure is defined as no requirement for either 
vasopressors or a fluid bolus to support blood pressure for 12 or more hours. 
§ Renal failure is defined as dialysis dependence, oliguria with serum creatinine > 3mg/dl, or oliguria 
with serum creatinine 0-3 with urinary indices indicative of acute renal failure. 
# Recommended fluid bolus= 15 mL / kg crystalloid (round to nearest 250 mL) or 1 Unit packed red 
cells or 25 grams albumin 
* Recommended Furosemide dosing = begin with 20 mg bolus or 3 mg / hr infusion or last known 
effective dose.  Double each subsequent dose until goal achieved (oliguria reversal or intravascular 
pressure target) or maximum infusion rate of 24 mg / hr or 160 mg bolus reached.  Do not exceed 
620 mg / day.  Also, if patient has heart failure, consider treatment with dobutamine. 
 
 
CVP 
(recommended) 
 
 
 
PAOP 
(optional) 
 
MAP > 60 mm Hg AND off vasopressors for > 12 hours 
Average urine output < 
0.5 ml/kg/hr 
Average urine output > 0.5 
ml/kg/hr 
>8 
> 12 
 
Furosemide* 
 
Reassess in 1 hour 
Furosemide* 
 
Reassess in 4 hours 
4-8 
8-12 
Give fluid bolus as fast as 
possible# 
 
Reassess in 1 hour 
 
< 4 
 
< 8 
No intervention 
Reassess in 4 hours 


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F    DE-IDENTIFIED DATA ELEMENTS FOR SCREENED, NON-ENROLLED 
SUBJECTS 
The following data elements will be collected on screened subjects who met the inclusion 
criteria but were not enrolled. 
 Did frontal CXR show bilateral infiltrates consistent with pulmonary edema? 
 Number of quadrants with opacities? 
 Is patient intubated? 
 PaO2 
 SpO2 
 FiO2 
 Was there evidence of left atrial hypertension? 
 Month of the year that patient met screening criteria (1-12). 
 Gender 
 Ethnicity 
 Age (if age >89, 89 will be entered for age) 
 Patient location (e.g. MICU, SICU, etc.) and if regularly screened 
 Reason(s) patient excluded from study. 
 If not excluded, not enrolled, why? 
 Lung injury category (e.g. sepsis, pneumonia) 
 If sepsis, site of infection 
 


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G    NEUROMUSCULAR AND LONG TERM OUTCOMES 
 
Phone Interviews for Survivors from All PETAL Study Sites 
We will perform phone interviews for vital status and the domains noted in Section 6.4. 
Centralized vs site-level administration of phone surveys will be determined by the PETAL 
Steering Committee.  
Interviews will be performed by basic research staff using detailed scripts appropriate for each 
survey instrument. Manuals of Operations will be developed for training, reference and quality 
assurance review.  
 
 
 


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H    DATA AND SAFETY MONITORING BOARD 
The principal role of the DSMB is to assure the safety of patients in the ROSE trial.  They will 
regularly monitor data from this trial, review and assess the performance of its operations, and 
make recommendations to the NHLBI with respect to: 
 Review of adverse events 
 Interim results of the study for evidence of efficacy or adverse events 
 Possible early termination of the trial because of early attainment of study objectives, 
safety concerns, or inadequate performance 
 Possible modifications in the clinical trial protocol 
 Performance of individual centers 
Two interim analyses will be conducted at approximately 33% and 67% target enrollment 
accrual. 
 
The NHLBI PETAL Network DSMB is appointed by the Director, NHLBI and makes 
recommendations to the NHLBI Director. The DSMB reviews all protocols for safety following 
review by an independent NHLBI Protocol Review Committee. The DSMB will consist of 
members with expertise in acute lung injury, emergency medicine, biostatistics, ethics, and 
clinical trials. An NHLBI staff member not associated with PETAL will serve as Executive 
Secretary. Appointment of all members is contingent upon the absence of any conflicts of 
interest. All the members of the DSMB are voting members. The Principal Investigator and the 
Medical Monitor of the CCC will be responsible for the preparation of all DSMB and adverse 
event reports and may review unblinded data. The DSMB will develop a charter and review the 
protocol and sample consent form during its first meeting. Subsequent DSMB meetings will be 
scheduled in accordance with the DSMB Charter with the assistance of the CCC. When 
appropriate, conference calls may be held in place of face-to-face meetings. Recommendations 
to end, modify, or continue the trial will be prepared by the DSMB executive secretary for review 
by Director, NHLBI. Recommendations for major changes, such as stopping, will be reviewed by 
the NHLBI Director and communicated immediately. Other recommendations will be reviewed 
by the NHLBI director and distributed in writing to the CCC, which will distribute to the PETAL 
steering committee with instructions for reporting to local IRBs when appropriate.  
Details of the NHLBI policies regarding DSMBs can be found at the following URL: 
http://www.nhlbi.nih.gov/funding/policies/dsmb_inst.htm   
 
The PETAL Network Steering Committee is comprised of the Principal Investigators and Co-
investigators of all the Clinical sites, the CCC, and the NHLBI Project Officer who represents the 
NHLBI.  All sites have two votes and the CCC has one.   
 
 


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I     AUDIT QUESTIONNAIRE 
The Alcohol Use Disorders Identification Test [80] 
The Alcohol Consumption Questionnaire is important to administer because there is a common 
association between alcohol abuse and ARDS[81].  It will be important to have this information 
for a subgroup analysis. Knowledge of alcohol abuse will also help the primary team better care 
for the patient and improve patient outcome, as there are alcohol specific disorders in critically ill 
patients that often are not diagnosed and therefore not treated effectively. This survey will not 
be completed on subjects less than 18 years of age. 
We will use the modified AUDIT questionnaire (first three questions) as this simplified version 
has good performance characteristics and is less time consuming. 


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J     CISATRACURIUM PACKAGE INSERT AND ACURASYS STUDY 
PUBLICATION 
NIMBEX (cisatracurium besylate) is a nondepolarizing skeletal muscle relaxant for intravenous 
administration. Compared to other neuromuscular blocking agents, it is intermediate in its onset 
and duration of action. Cisatracurium besylate is one of 10 isomers of atracurium besylate and 
constitutes approximately 15% of that mixture. Cisatracurium besylate is [1R-[1α,2α(1'R*,2'R*)]]-
2,2'-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-
1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate. The molecular 
formula of the cisatracurium parent bis-cation is C53H72N2O12 and the molecular weight is 
929.2. The molecular formula of cisatracurium as the besylate salt is C65H82N2O18S2 and the 
molecular weight is 1243.50.  
The full package insert and the ACURASYS study primary publication, which together will serve 
as the Investigator Brochure for this trial, can be found here: 
Cisatracurium package insert: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3db3b76c-3e5a-456e-46a8-
456fde1e6195 
ACURASYS study: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1005372 
Note: The mean measured body weights in ACURASYS (+/- SD) were 77 (+/-18 kg; range 
43 to 126 kg) in the placebo group and 78 (+/-19 kg; range 30 to 185 kg) in the 
cisatracurium group (reference 2a) 
 


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K     SOFA SCORING SYSTEM 
 
 
We define a clinically significant organ failure as a new SOFA score of ≥ 2. 
 
 


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L     COMMON RISK FACTORS FOR ARDS 
 
Direct 
Pneumonia 
Aspiration of gastric contents 
Inhalational injury 
Pulmonary contusion 
Drowning 
 
Indirect 
Non-pulmonary sepsis 
Major trauma 
Pancreatitis 
Severe burns 
Non-cardiogenic shock 
Drug overdose 
Multiple transfusions or transfusion associated acute lung injury (TRALI) 
 
Source: Supplementary Online Content, eTable 1. The ARDS Definition Task Force. Acute 
respiratory distress syndrome: the Berlin Definition. JAMA. doi:10.1001/jama.2012.5669. 
 
 


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L     ICU MOBILITY SCALE [20] 
Classification 
Definition 
0 
Nothing (lying in bed) 
Passively rolled or passively exercised by staff, but not actively moving 
1 
Sitting in bed, exercising in bed 
Any activity in bed including rolling, bridging, active exercises, cycle ergometry 
and active assisted exercises; not moving out of bed or over edge of bed 
2 
Passively moving to chair (no 
standing) 
Hoist, passive lift or slide transfer, to the chair, with no standing or sitting on the 
edge of the bed 
3 
Sitting over edge of bed 
May be assisted by staff, but involves actively sitting over the edge of the bed 
with some trunk control 
4 
Standing 
Weight bearing through the feet in the standing position, with or without 
assistance.  This may include use of a standing lifer device or tilt table. 
5 
Transferring bed to chair 
Able to step or shuffle through standing to the chair. This involves actively 
transferring the weight from one leg to the other to move to the chair.  If the 
patient has been stood with the assistance of a medical device, they must step to 
the chair (not included if the patient is wheeled in a standing lifter device).  
6 
Marching on spot (at bedside) 
Able to walk on the spot by lifting alternate feet (must be able to step at least 4 
times, twice on each foot), with or without assistance. 
7 
Walking with assistance of 2 or 
more people 
Walking away from bed/chair by at least 5 m (5 yards) assisted by 2 or more 
people 
8 
Walking with assistance of 1 
person 
Walking away from bed/chair by at least 5 m (5 yards) assisted by 1person 
9 
Walking independently with a 
gait aid  
Walking away from bed/chair by at least 5 m (5 yards) with a gait aid but no 
assistance from another person. In a wheelchair bound person, this activity 
involves wheeling the chair 5m (5 yards) away from the bed/chair. 
10 
Walking independently without a 
gait aid 
Walking away from bed/chair by at least 5 m (5 yards) without a gait aid, or 
assistance from another person. 
 
 


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SAP_001.pdf: 
 
Reevaluation Of Systemic Early neuromuscular blockade 
Statistical Analysis Plan 
 
ACRONYM: 
 
ROSE 
 
PROTOCOL CO-CHAIRS: DEREK C ANGUS, MD, MPH, FRCP 
 
 
PROFESSOR OF CRITICAL CARE MEDICINE 
 
 
DEPARTMENT OF CRITICAL CARE MEDICINE 
UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE 
 
       
                      
      APRIL 12, 2018 
     INVESTIGATOR SIGNATURE                                     DATE 
 
 
                    MARC MOSS, MD 
PROFESSOR OF MEDICINE 
DIVISION OF PULMONARY AND CRITICAL CARE MEDICINE 
DEPARTMENT OF MEDICINE 
UNIVERSITY OF COLORADO SCHOOL OF MEDICINE 
 
 
 
 
 
             ________________________                    _____________ 
     INVESTIGATOR SIGNATURE                                     DATE 
 
STUDY STATISTICIAN 
DAVID SCHOENFELD, PHD 
          PROFESSOR OF MEDICINE 
          DEPARTMENT OF BIOSTATISTICS 
 
                                                                                                  APRIL 12, 2018 
     INVESTIGATOR SIGNATURE                                   DATE 
 
 


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Table of Contents 
Introduction .................................................................................................................................................. 2 
1. Trial Summary ........................................................................................................................................... 2 
1.1 Background ......................................................................................................................................... 2 
1.2 Inclusion Criteria ................................................................................................................................. 2 
1.3 Exclusion Criteria ................................................................................................................................. 3 
1.4 Randomization and Study Initiation Time Window ............................................................................ 3 
1.5 Efficacy ................................................................................................................................................ 4 
1.6 Sample Size/Interim Monitoring ......................................................................................................... 4 
2. Data Analysis Plan ..................................................................................................................................... 4 
2.1 Study Population ................................................................................................................................. 4 
2.2 Primary Outcome ................................................................................................................................ 4 
2.3 Analysis Methods for: Secondary Outcomes, Descriptive Variables, Safety Outcomes, Patient 
Characteristics ........................................................................................................................................... 5 
2.4 On Study Variables .............................................................................................................................. 5 
2.5 Adverse Events .................................................................................................................................... 5 
2.6 Subgroup Analysis ............................................................................................................................... 5 
2.7 Missing Data ........................................................................................................................................ 6 
2.8 Long Term Follow Up Data .................................................................................................................. 6 
2.9 Treatment for Non-Compliance .......................................................................................................... 7 
2.10 Heterogeniety of Treatment Effects ................................................................................................. 7 
Appendix: ...................................................................................................................................................... 8 
Appendix A1: Outcome Variables ............................................................................................................. 8 
Appendix A2: Reference Measurements ................................................................................................ 10 
Appendix A3: Derived Outcome Variables .............................................................................................. 12 
References .................................................................................................................................................. 16 
 
 
 
 
 
 
 
 
 
 
 


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Introduction 
The following document is the Statistical Analysis Plan for the ROSE Study. It describes the  
study and the statistical methods used to analyze the primary and secondary outcomes in the 
study.  Appendix A is a list of all variables that will be analyzed in the study along with their 
classification, and analysis method.  Appendix B is the definition of all derived and composite 
variables, and the data imputation rules for all variables where imputation is used. 
1. Trial Summary 
1.1 Background 
In 2010, the ACURASYS trial reported early neuromuscular blockade (also called skeletal 
muscle relaxant or muscle relaxant) administration improved adjusted survival for moderate to 
severe ARDS in a 340 patient trial conducted in 20 French ICUs. While intriguing, this approach 
has not been widely adopted in the U.S., and key limitations exist. First, the trial was 
underpowered. Mortality benefit was noted only after statistical adjustment; crude 90d mortality 
did not differ. Control mortality was also lower than predicted (though higher than many recent 
ARDS trials) and the authors concluded “given the observed mortality in our placebo group, the 
current study was underpowered”. Second, the mechanism responsible for the improvement in 
outcome with neuromuscular blockade is unclear. One possible explanation is that 
neuromuscular blockade results in improvement in patient-ventilator asynchrony with 
subsequent reduction in ventilator-induced lung injury and inflammation. Third, assessment of a 
known side effect of the intervention, muscle paresis, has been criticized as inadequate. As a 
result of these concerns, the critical care community has collectively recommended another 
phase III clinical trial to definitively test the safety and efficacy of neuromuscular blockade in 
patients with ARDS.  
1.2 Inclusion Criteria 
1. Age > 18 years 
2. Presence of all of the following conditions for < 48 hours 
i. 
(I) PaO2/FiO2 < 150 with PEEP > 8 cm H2O.a,b,c  
OR, IF ABG NOT AVAILABLE  
SpO2/FiO2 ratio that is equivalent to a PaO2/FiO2 < 150 with PEEP > 8 cm H2O 
(Appendix A1), and a confirmatory SpO2/FiO2 ratio between 1-6 hours after the 
initial Sp02/Fi02 ratio determination.  c,d 
ii. 
Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules 
iii. 
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 (Appendix L) 
a, If altitude >1000m, then PaO2/FiO2 < 150 x (PB/760). 
b These inclusion criteria ensure a non-transient, established hypoxia that persists despite elevated 
PEEP and time. Initial, post-intubation, PEEP is typically < 8 cm H2O. 
c The qualifying PaO2/FiO2 or the SpO2/FiO2 must be from intubated patients receiving at least 8 
cm H2O PEEP.  
d. When hypoxia is documented using pulse oximetry, a confirmatory SpO2/FiO2 ratio is required 
to further establish persistent hypoxia. Qualifying SpO2/FiO2 must use SpO2 values less than or 
equal to 96% Qualifying SpO2 must be measured at least 10 minutes after any change to FiO2.  


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The 48-hour enrollment time window begins when criteria i-iii are met. Criteria may 
be met at either the Network or referring hospital. The first qualifying SpO2/FiO2 (not 
the confirmatory SpO2/FiO2) is used determine this time window. 
1.3 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 < 48 hours 
11. Decision to withhold life-sustaining treatment; except in those patients committed to 
full support except cardiopulmonary resuscitation 
12. Moribund patient not expected to survive 24 hours; if CPR provided, assess for 
moribund status  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. PaO2/FiO2 (if available) >200 after meeting inclusion criteria and before 
randomization Oxygenation may improve during the 48 hour enrollment window. This 
exclusion criterion ensures that patients with mild ARDS are not included in the 
study. 
21. Endotracheal ventilation for greater than 120 hours (5 days) 
22. Patient has completed lung transplant evaluation and has been officially listed for 
lung transplant by UNOS 
1.4 Randomization and Study Initiation Time Window 
All patients must be enrolled and randomized within 48 hours of meeting inclusion criteria. After 
randomization, the low tidal volume protocol must be initiated within two hours (if not already 
being used). In the intervention arm, deep sedation followed by neuromuscular blockade must 
be initiated within four hours of randomization.  


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1.5 Efficacy 
The primary outcome is all-cause mortality prior to discharge home before day 90. 
1. Secondary Outcomes: 
 
ICU Acquired Weakness 
 
IL-6 levels (plasma) 
 
Hospital mortality to day 28 
 
Ventilator free days to day 28 
 
Organ failure free days to day 28 
 
ICU-free days at day 28 
 
Hospital-free days at day 28 
 
Physiologic measures 
 
Long term outcome assessments 
 
Use of rescue procedures 
 
Paralysis recall, in-hospital 
 
Supraventricular tachycardia and new onset atrial fibrillation 
1.6 Sample Size/Interim Monitoring 
1. With a 35% mortality rate in the control arm and 27% mortality rate in the intervention 
arm, the maximum required total sample size is 1408 subjects. 
2. The principal analysis will be intent-to-treat, based upon randomization assignment. 
3. Trial progress will be evaluated by an independent Data and Safety Monitoring Board 
(DSMB) to determine if the study should stop for superiority of either Active or 
Control therapy. There will be two interim analyses and a final analyses conducted 
when approximately each successive 1/3 of the patients have been enrolled. 
2. Data Analysis Plan 
2.1 Study Population 
There is only one study population. All analyses will be by intention to treat 
2.2 Primary Outcome 
The primary outcome is intention to treat 90 day all cause in-hospital mortality, where in-hospital 
includes study hospital and LTAC.  Patients who are discharged home (defined as residence 
prior to admission) prior to day 90 will be assumed to be alive at day 90. If the study does not 
cross a stopping boundary all patients will be followed for 90 days and the data can be analyzed 
using Pearson’s chi-square test.  However, at each interim analysis it is necessary to take into 
account patients who are still in the hospital with less than 90 days of follow up. This will be 
accomplished using the Kaplan Meier day 90 mortality point estimates with all patients who are 
discharged home or still alive at day 90 censored at day 91, which is beyond the last possible 
day of death. The 90 mortality estimates in the two treatment groups will be compared by a Z-
test using Greenwood’s standard error [1].  
The number of interim looks and stopping boundaries are given in the protocol. At each interim 
look the stopping boundaries will be updated using SAS PROC SEQTEST (SAS Institute Inc., 


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Cary, NC, USA.) with the information time defined by the Cutler and Ederer effective sample 
size [2].  
The hypothesis regarding the primary outcome is a two-sided superiority hypothesis. The overall 
type one error is a two sided p-value of 0.05 corrected for the group sequential design as 
described in the protocol.  
2.3 Analysis Methods for: Secondary Outcomes, Descriptive Variables, Safety 
Outcomes, Patient Characteristics 
Continuous secondary outcomes will be compared between treatment groups using a t-test. 
Ordinal secondary outcomes (defined as outcomes with ordinal levels such as none, mild, 
moderate…) will be compared between groups using the Cochran-Mantel-Haenszel ANOVA 
(row mean score) test. Categorical secondary outcomes will be compared between treatment 
groups using a Chi-square or Fisher’s exact test as appropriate to the sparseness of the data.  
All tests will use a two sided p=0.05 significance level. There will be no correction for multiple 
comparison.  
2.4 On Study Variables 
Variables that are measured daily, such as fluid balance, will be compared between treatment 
groups on each study day that they are measured. 
2.5 Adverse Events 
Adverse events will be analyzed using weighted Poisson regression with non-serious events 
weighted by one and serious events weighted by two. Events rather than patients will be the unit 
of analysis. Adverse events will be grouped and analyzed separately by MeDRA system organ 
classes, and MedDRA preferred term. 
2.6 Subgroup Analysis 
Three statistical tests will be performed for each subgroup. The treatment difference in the 
subgroup, the treatment difference for patients not in the subgroup and a test for interaction of 
subgroup status and treatment. The following are the planned subgroup analysis: 
1. The primary outcome will be compared between treatment groups in the cohort of 
patients with pre-randomization PaO2/FIO2 < 120 and in the cohort of patients with pre-
randomization PaO2/FIO2 ≥ 120. 
2. Time from meeting ARDS severity criteria for study enrollment to randomization divided 
into two groups using the median value. 
3. We will do a subgroup analysis using routine use of NMB in the study hospital as a 
grouping criterion. We will rank hospitals in terms of the number of sole exclusions for 
prior NMB use divided by the hospital’s total enrollment. We will then form three roughly 
equal sized patient subgroups, based on the rank of their treating hospital. 
4. We will conduct the required subgroup analysis of groups defined by race, ethnicity and 
gender. 


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2.7 Missing Data 
Analysis is based on all available data with no imputation of missing data with a few rare 
exceptions which are noted in Appendix B.  All our proposed analyses are valid under Missing 
at Random(MAR) data. 
2.8 Long Term Follow Up Data 
Six month and one year survival, for each treatment group, will be calculated using a multistate 
model.  Patients will be classified in terms of the following states, 1-Study Hospital, 2-Other 
Hospital,3-Home 4-Dead, with possible transitions of 1-2, 1-3,1-4,2-3,2-4. The time duration of 
each transition that is known will be calculated.  Then this model will be used to estimate the 6 
and 12 month survival, and it’s standard error for each treatment group separately[3].  The test 
of a treatment effect will then be the difference in the survival estimates divided by the pooled 
standard error.  The method of estimation is based on the multiplication of probabilities. For 
instance, suppose a patient went home at 100 days but only has 120 follow up at the time of 
analysis or is lost to follow up at 120 days.  Then the probability of death for this patient is 
probability of a transition from 3 to 4, for a patient who has been home for 20 days.    
The primary analysis of continuous and ordinal follow up data on patient’s functional status will 
be a comparison of the distribution of these data using the methods described in the analysis 
methods section 2,3. The primary issue with this choice of analysis is that the treatment 
difference is difficult to interpret if there is a mortality difference. In that case we will conduct 
several sensitivity analyses described below. 
The problem is that we are measuring follow up variables, for instance the Euro QOL, denoted 
here as QOL, in some patients on the better treatment who would have died on the worse 
treatment. When there is a survival difference the simple comparison does not measure the 
potential harm or benefit of the intervention on QOL.  What we seek to estimate, is the survival 
average causal effect, defined as the difference in QOL among patients who would have 
survived both treatments.  We will assume that patients who would survive on the worse 
treatment will also survive on the better one.  In that case, the mean value of QOL on the worse 
treatment among patients who would have survived on both treatments is just the ordinary 
mean of QOL on that treatment.  
To estimate the mean value of QOL on the best treatment among patients who would have 
survived both treatments, we need to take a weighted mean of QOL with weights equal to the 
probability of survival on the worst treatment given the value of QOL on the best treatment.  
Unfortunately, these weights cannot be estimated, but one can look at the difference in QOL on 
the two treatments as a function of how the weights are assigned in a sensitivity analysis.  Note 
that our primary analysis assumes all these weights are equal. 
We propose three sensitivity analysis of these variables ascertained among survivors. The first 
assumes that all the patients with the worst values of QOL would have died on the worst 
treatment.  In terms of weights, all the weights are one except for the m worst QOL values 
where m is the difference of mortality rates on the two treatments.  This was suggested by 
Permutt, T. and Li, F [4]. 


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The second method is to assume weights of the form exp(b Y),  where Y is QOL, and then vary 
b, note that b can be interpreted as the relative effect on mortality per unit Y.  Finally, we can 
use weights based on patient covariates, using the model specified in the ALVEOLI Trial [5] to 
estimate the weights.  For the first two analysis significance, will be tested by calculating the 
standard error of each mean.  For the last, we can use the methods described by Hayden, 
Pauler and Schoenfeld [6]. In addition, in order to give a graphical representation of these data, 
one can used these methods to estimate the distribution, for instance the probability that Y<K in 
in the better treatment which is the weighted mean of the indicator functions I(Y<K) weighted by 
the same weights described above.  We will assume that if we are missing an observation for 
reasons other than death it is missing at random(MAR) if the proportion of patients missing in 
this way is high we will conduct a sensitivity analysis of the MAR approach.  
2.9 Treatment for Non-Compliance 
For the primary endpoint, and for secondary end points that are significantly affected by 
treatment assignment we will estimate the causal effect of the actual treatment given using an 
instrumental variable approach [7]. 
2.10 Heterogeniety of Treatment Effects 
We will use a model fit on the ARMA 6ml/kg data and previously published [5] to develop a risk 
score for each patient in the study. The variables used were age, APACHE, pplat, missing pplat, 
number of organ failures, hospital days prior to enrollment, and AADO2. Then as a statistical 
test we will fit a logistic model with terms for treatment, risk score and a treatment risk score 
interaction.  The significance of the interaction term will test for Heterogeneriety of Treatment 
Effects. In addition as a graphical display of the data we will divide the patients into 10 equal 
sized group by risk score and plot the mortality difference as a function of risk score group. 
 
 
 
 
 
 
 
 
 
 
 


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Appendix:  
Appendix A1: Outcome Variables 
 
Variable 
Category 
Scale 
Method 
All-cause mortality 
prior to discharge 
home before day 90 
Primary Outcome 
Binary 
Wald-test from 90 
day KM estimate 
ICU acquired 
weakness 
Secondary Outcome 
Binary 
Monte Carlo Fisher’s 
Exact Test 
IL-6 levels (plasma) 
Secondary Outcome 
Continuous 
T-test 
Hospital mortality to 
day 28  
Secondary Outcome 
Binary 
Chi-square Test 
Ventilator free days to 
day 28 
Secondary Outcome 
Continuous 
T-test 
Organ failure free 
days to day 28 
Secondary Outcome 
Continuous 
T-test 
ICU-free days at day 
28 
 
Secondary Outcome 
Continuous 
T-test 
Hospital-free days at 
day 28 
Secondary Outcome 
Continuous 
T-test 
Oxygenation Index 
on study days 1-4,7 
PaO2 / FiO2 ratio on 
study days 1-4, 7 
Level of PEEP on 
study days 1-4, 7 
Plateau pressure on 
study day 1-4, 7 
Development of 
pneumothorax 
through day 7 
 
Physiologic measure 
 
Continuous 
 
 
Continuous 
 
 
Continuous 
 
 
Continuous 
 
 
Binary 
T-test 
 
 
T-test 
 
 
T-test 
 
 
T-test 
 
 
Fisher’s Exact Test 
Disability: using Katz 
Activities of Daily 
Living (ADL)/Lawton 
Instrumental 
Activities of Daily 
Living Scale (IADL) 
Long term outcome 
assessments 
 
 
 
 
 
 
 
 
 
 
Binary 
 
 
 
 
 
 
 
Chi-square Test 
 
 


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plus two additional 
Nagi items 
 
Health-Related 
Quality of Life 
(including utilities): 
EuroQol (EQ-5D-5L)  
 
Self-rated health: 1 
standard item 
 
Pain-interference: 1 
standard item 
 
Post-traumatic 
Stress-like 
Symptoms: Post-
Traumatic Stress 
Symptoms (PTSS-
14) 
 
Cognitive function: 
Montreal Cognitive 
Assessment (MoCA-
Blind)  
 
Via proxy, the 
Alzheimer’s Disease 
8 (AD8) 
Subsequent return to 
work, hospital and 
ED use, and location 
of residence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continuous 
 
 
 
 
 
 
Continuous 
 
 
 
Continuous 
 
 
 
 
Binary (Part B Score 
>= 45) 
 
 
 
 
 
 
 
 
Continuous 
Binary (< 26) 
 
 
 
 
 
Continuous 
 
 
Categorical 
 
 
 
 
 
 
 
 
T-test 
 
 
 
 
 
 
T-test 
 
 
 
T-test 
 
 
 
 
Chi-square Test 
 
 
 
 
 
 
 
 
 
T-test 
Chi-square Test 
 
 
 
 
 
T-test 
 
 
Fisher’s Exact Test 
Use of rescue 
procedures 
Safety 
Binary 
Fisher’s Exact Test 


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Paralysis recall, in-
hospital 
 
Safety 
Binary 
Fisher’s Exact Test 
Supraventricular 
tachycardia (SVT) 
or new onset atrial 
fibrillation  
 
Safety 
Binary 
Fisher’s Exact Test 
 
 
Appendix A2: Reference Measurements 
 
Variable 
Category 
Scale 
Method 
Time and dose of loading 
dose 
 
nContinuous 
Descriptive 
Time of initiation of 
cisatracurium infusion 
 
Continuous 
Descriptive 
Reason and duration of 
infusion hold during first 48 
hours 
 
 
Binary>=48.5 hours  
Continuous  
Descriptive 
Total dose of cisatricurium 
infusion during first 96 
hours 
 
 
Continuous  
Descriptive 
Name and total dose of 
other NMB during first 96 
hours 
 
 
Dose, Continuous 
Descriptive 
Additional NMB 
administered after 96 
hours (yes/no) 
 
Binary 
Descriptive 
Name and total dose of 
any NMB used in the first 
96 hours after 
randomization 
(Control Arm) 
 
Binary (Yes/ No) 
Continuous (Total 
Dose) 
 
Descriptive 
Additional NMB 
administered after 96 
hours (yes/no) (Control 
Arm) 
 
 
Binary (Yes/ No) 
Continuous (Total 
Dose) 
 
Descriptive 


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If receiving positive 
pressure ventilation: 
Ventilator mode 
 
Categorical, Days 1-4 
& 7  
Monte Carlo Fisher’s 
Exact Test 
If receiving positive 
pressure ventilation: 
set rate  
actual rate  
minute ventilation 
tidal volume  
FiO2 
 PEEP  
I:E ratio, 
 plateau, peak, mean 
airway pressures 
set peak flow,  
set inspiratory time  
 
 
Continuous, Days 1-4 
& 7  
T-Test 
PaO2, PaCO2, pH, and 
SpO2 
 
 
Continuous, Days 1-4 
& 7  
T-Test 
Serum electrolytes and 
glucose 
 
 
Continuous, Days 1-4 
& 7  
T-Test 
Intravenous sedatives 
Intravenous opioids  
Enteral or intravenous 
corticosteroids  
 
Binary, Days 1-4 & 7  
Chi-Square Test 
Sedation score: If RASS < 
-1 (or Riker < 3, Ramsay > 
3), and sedation given, list 
reason given 
 
 
Reasons 
(Categorical) 
Scale Used 
(Categorical) 
Light/ Deep/ Agitation 
(Categorical) 
Mean score 
(Continuous) 
Chi-square Test 
Chi-square Test 
Chi-square Test 
T-test 
Was a sedation 
interruption performed? 
Y/N 
 
Binary Daily 
 
Chi-square Test 


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Fluid intake and 
output/CVP if available 
 
 
Continuous  
T-Test 
ICU Mobility Scale 
Safety 
Binary (Able to sit at 
edge of bed or 
greater) 
Fisher’s Exact Test 
Manual Muscle Testing 
Safety 
Continuous 
T-test 
 
 
Appendix A3: Derived Outcome Variables 
 
Primary Outcome 
The primary outcome is intention to treat 90 day all cause in-hospital mortality, where in-hospital 
includes study hospital and LTAC. Patients who are discharged home (defined as residence 
prior to admission) prior to day 90 will be assumed to be alive at day 90.  It may be necessary to 
account for patients who are still in the hospital with less than 90 days of follow up. This will be 
accomplished using the Kaplan Meier day 90 mortality point estimates with all patients who are 
discharged home or still alive at day 90 censored at day 91, which is beyond the last possible 
day of death. 
If a patient has no data entered for the primary outcome then a censoring date is determined 
from the maximum date or study day on the available ACTIVITY, SOFA, VENT, MMT, 
TERMINATION, ICU History, Study Initiation and Drug Dosage, Protocol Deviation, AE, and 
BRICE forms.   
ICU acquired weakness 
Patients will be defined as having ICU acquired weakness if their Medical Research Council 
(MRC) MMT score is < 48 (or mean MRC < 4 for each muscle group tested). 
Hospital mortality to day 28 
Death prior to discharge alive from study hospital will be counted as hospital mortality. Patients 
whose final status is unknown but who are known to be alive on study day 28 based on known 
event dates on the termination form will be counted as alive. Patients with insufficient follow up 
to determine this outcome will be treated as missing data. 
Ventilator free days to day 28 
Ventilator free days to day 28 are defined as the number of days from the time of initiating 
unassisted breathing to day 28 after randomization, assuming survival for at least two 
consecutive calendar days after initiating unassisted breathing and continued unassisted 
breathing to day 28. If a patient returns to assisted breathing and subsequently achieves 
unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted 
breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the 
purpose of a surgical procedure will not count against the VFD calculation. If a patient was 
receiving assisted breathing at day 27 or dies prior to day 28, VFDs will be zero. Patients 
transferred to another hospital or other health care facility will be followed to day 28 to assess 
this endpoint. 


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Organ failure free days to day 28 
Organ failure is defined as present on any date when the most abnormal vital signs or clinically 
available lab value meets the definition of clinically significant organ failure according to SOFA 
scores. Patients will be followed for development of organ failures to death, hospital discharge 
or study day 28, whichever comes first.  Each day a patient is alive and free of a given organ 
failure will be scored as a failure-free day. Any day that a patient is alive and free of all organ 
failures will represent days alive and free of all organ failure. 
 
We define a clinically significant organ failure as a new SOFA score of ≥ 2. 
We treat post-ICU SOFA as normal (i.e. defining organ dysfunction as abnormal SOFA in an 
ICU); post-ICU means getting out and staying out of ICU; patients are still at risk and have 
SOFA scores in intervals between ICU readmissions. 
Carry forward until home date, death date, last known date in ICU+1, or day29, whichever 
comes first; patient status decides organ failure free if both status information and SOFA data 
are available.  
We carry last observation forward for any missing data except baseline P/F.  Carry forward 
vasopressors yes/no if taking any vasopressors and missing y/n. Carry forward vasopressor 
doses if taking this drug and missing dose. 
If a patient has missing data at baseline, then the patient would have missing SOFA 
components, but the total will be the sum of available components scores instead of missing.  
Notes: LOCF carries forward each sofa variable rather than carrying forward the computed 
scores. 
ICU-free days at day 28 


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Patient will be followed until death, study hospital discharge or study 28, whichever comes first. 
Any day a patient is alive and out of ICU will be scored as an ICU-free day. There is no penalty 
for readmission. 
Hospital-free days at day 28 
Hospital free days are counted from hospital discharge through day 28. A patient who is 
discharged from the study hospital on day 28 is assigned one hospital free day. A patient who is 
discharged from the study hospital after day 28 is assigned zero hospital free days. A patient 
who dies prior to day 29 is assigned zero hospital free days. 
Paralysis recall, in-hospital 
Paralysis recall assessment will be monitored once during hospitalization in all patients, using a 
modified Brice questionnaire. Paralysis recall will be counted if a patient answered “Yes” to “Do 
you remember anything between going to sleep and waking up?” and "unable to move or 
breathe”. Paralysis recall can be indicated in both AE and Brice forms. We gather information 
from both places and treat missing as “NO” if a patient has an open BRICE form.  
Long Term Outcomes 
Disability: using Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities of Daily 
Living Scale (IADL) plus two additional Nagi items 
ADL/IADL assessments are administered at baseline, months 3, 6 and 12. 2 additional NAGI 
items were collected at months 3, 6, and 12. The total score is a summation of the all the times. 
Possible 8 maximum points at baseline and 10 maximum points at follow up. Any missing items 
are allotted 0 points. 
Health-Related Quality of Life (including utilities): EuroQol (EQ-5D-5L)  
EQ-5D-5L assessment is given to either the subject or the proxy at baseline, month 3, month 6 
and month 12. Scores are calculated by mapping the 5-digit code generated from the answers 
to the U.S. EQ-5D-5L lookup table. Any missing items will result in a missing score. 
Self-rated health: 1 standard item 
Assessed at months 3, 6, and 12 and only if the patient is available. 
Pain-interference: 1 standard item 
Assessed at months 3, 6, and 12 and only if the patient is available. 
Post-traumatic Stress-like Symptoms: Post-Traumatic Stress Symptoms (PTSS-14) 
Assessed at months 3, 6, and 12 by the subject or the proxy. Part A score was calculated as a 
sum of all the questions answered as “Yes”. The part B score was a sum of all the answers 
(rated from 1 to 7) with a maximum score ranging from 14 to 98.  
Cognitive function: Montreal Cognitive Assessment (MoCA-Blind)  
MoCA-blind is assessed at 3, 6 and 12 months post-randomization if the subject is available. 
The 22-point score for the MoCA-blind is scaled up to 30 points. If information regarding a high 
school degree (>12 years of education) is missing, assume subject has a high school degree. 


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The additional points allotted to <12 years of education is added after converting to the 30-point 
scale. If any question is incomplete, then the patient is not given a total MoCA score.  
Via proxy, the Alzheimer’s Disease 8 (AD8) 
AD8 is assessed at 3, 6, and 12 months through the proxy if the subject is unable to be 
contacted. Total score is a sum of all the AD8 items. Missing answers allotted 0 points. 
Subsequent return to work, hospital and ED use, and location of residence 
Collected at months 3, 6, and 12 from the subject or proxy survey (if subject is unavailable). 
Additional Derived Variables 
Barotrauma 
Barotrauma includes pneumothorax and pneumomediastinum, which can be indicated in both 
AE and Termination forms. We gather the information from both places and treat missing as 
“NO”. 
Intervention Arm: Total dose of cisatricurium infusion during first and second 48 hours 
Total dose was calculated from cisatricurium infusion duration times rate plus boluses plus 
additional doses. 
Intervention Arm: Total dose of other NMB during first and second 48 hours 
Total dose was calculated from infusion duration times rate plus boluses plus additional doses 
of any neuromuscular blocker. 
Control Arm: Total dose of any NMB used in the first and second 48 hours after randomization 
Total dose was calculated as the sum of all doses of any neuromuscular blocker. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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References 
 
 
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