Reevaluation Of Systemic Early Neuromuscular Blockade

Study Overview
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Brief Summary
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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
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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.

Official Title
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Reevaluation Of Systemic Early Neuromuscular Blockade

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Cisatracurium Besylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age > 18 years Presence of all of the following conditions for < 48 hours: i. PaO2/FiO2 < 150 with PEEP >/= 8 cm H2O OR, if ABG not available, SaO2/FiO2 ratio that is equivalent to a PaO2/FiO2 < 150 with PEEP >/= 8 cm H2O , and a confirmatory SaO2/FiO2 ratio that is again equivalent 1-6 hours later 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. Patients must be enrolled within 48 hours of meeting inclusion criteria. Exclusion Criteria: Lack of informed consent Continuous neuromuscular blockade at enrollment Known pregnancy Currently receiving ECMO therapy Chronic respiratory failure defined as PaCO2 > 60 mm Hg in the outpatient setting Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing Actual body weight exceeding 1 kg per centimeter of height Severe chronic liver disease defined as a Child-Pugh score of 12-15 (Appendix A2) Bone marrow transplantation within the last 1 year Expected duration of mechanical ventilation of < 48 hours Decision to withhold life-sustaining treatment; except in those patients committed to full support except cardiopulmonary resuscitation if an actual cardiac arrest occurs Moribund patient not expected to survive 24 hours; if CPR provided, assess for moribund status greater than 6 from CPR conclusion Diffuse alveolar hemorrhage from vasculitis Burns > 70% total body surface Unwillingness to utilize the ARDS Network 6 ml/kg IBW ventilation protocol Previous hypersensitivity or anaphylactic reaction to cisatracurium Neuromuscular conditions that may potentiate neuromuscular blockade and/or impair spontaneous ventilation (Appendix A2) Neurologic conditions undergoing treatment for intracranial hypertension Enrollment in an interventional ARDS trial with direct impact on neuromuscular blockade and PEEP >120 hours of mechanical ventilation P/F < 200 mmHg at the time of randomization (if available)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Early Neuromuscular Blockade (NMB)<br>Patients will receive cisatracurium besylate for the first 48 hours of the trial. | Drug: Cisatracurium Besylate<br>* 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.<br>* Other names: Nimbex;|
| No Intervention: Control: No Routine Early NMB<br>Use of non-study NMB will be discouraged. | |

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Ventilator Free Days to Day 28 | Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. | 28 days after randomization | 
| Mean Organ Failure Free Days to Day 28 | SOFA (Sepsis-related Organ Failure Assessment) was used to determine criteria for an organ failure free day. Scores were based on four of the six SOFA organ categories: Coagulation, Liver, Cardiovascular, and Renal. Each category was scored 0-4; 0 being normal functioning and 4 being the most abnormal. A patient was considered failure free on each day alive with SOFA scores below 2 for all four organ systems. Ref: Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996. 22(7): p. 707-10. | 28 days after randomization | 
| ICU Free Days to Day 28 | ICU free days is defined as the number of days between randomization and day 28 in which the patient is in the ICU (for any part of a day). | 28 days after randomization | 
| Mean Hospital Free Days to Days 28 | Hospital free days are days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days. | 28 days after randomization | 
| Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities. | 3 months after randomization | 
| EuroQol (EQ-5D-5L): Health Related Quality of Life | Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07 | 3 months after randomization | 
| PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported. | 6 months after randomization | 
| MoCA-Blind: Montreal Cognitive Assessment | How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater. | 3 months after randomization | 
| Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities. | 6 months after randomization | 
| Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities. | 12 months after randomization | 
| EuroQol (EQ-5D-5L): Health Related Quality of Life | Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07 | 6 months after randomization | 
| EuroQol (EQ-5D-5L): Health Related Quality of Life | Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07 | 12 months after randomization | 
| MoCA-Blind: Montreal Cognitive Assessment | How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater. | 6 months after randomization | 
| MoCA-Blind: Montreal Cognitive Assessment | How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater. | 12 months after randomization | 
| PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported. | 12 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cisatracurium, ARDS, neuromuscular blocker