Acute Respiratory Distress Syndrome
Conditions
Keywords
ARDS, neuromuscular blocker, cisatracurium
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.
Interventions
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \> 18 years 2. 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
1. Lack of informed consent 2. Continuous neuromuscular blockade at enrollment 3. Known pregnancy 4. Currently receiving ECMO therapy 5. Chronic respiratory failure defined as PaCO2 \> 60 mm Hg in the outpatient setting 6. Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing 7. Actual body weight exceeding 1 kg per centimeter of height 8. Severe chronic liver disease defined as a Child-Pugh score of 12-15 (Appendix A2) 9. Bone marrow transplantation within the last 1 year 10. Expected duration of mechanical ventilation of \< 48 hours 11. Decision to withhold life-sustaining treatment; except in those patients committed to full support except cardiopulmonary resuscitation if an actual cardiac arrest occurs 12. Moribund patient not expected to survive 24 hours; if CPR provided, assess for moribund status greater than 6 from CPR conclusion 13. Diffuse alveolar hemorrhage from vasculitis 14. Burns \> 70% total body surface 15. Unwillingness to utilize the ARDS Network 6 ml/kg IBW ventilation protocol 16. Previous hypersensitivity or anaphylactic reaction to cisatracurium 17. Neuromuscular conditions that may potentiate neuromuscular blockade and/or impair spontaneous ventilation (Appendix A2) 18. Neurologic conditions undergoing treatment for intracranial hypertension 19. Enrollment in an interventional ARDS trial with direct impact on neuromuscular blockade and PEEP 20. \>120 hours of mechanical ventilation 21. P/F \< 200 mmHg at the time of randomization (if available)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Mortality to Day 90 | 90 days after randomization | The percentage of subjects alive at study day 90. Those subjects discharged home prior to day 90 were counted as alive at day 90. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Organ Failure Free Days to Day 28 | 28 days after randomization | SOFA (Sepsis-related Organ Failure Assessment) was used to determine criteria for an organ failure free day. Scores were based on four of the six SOFA organ categories: Coagulation, Liver, Cardiovascular, and Renal. Each category was scored 0-4; 0 being normal functioning and 4 being the most abnormal. A patient was considered failure free on each day alive with SOFA scores below 2 for all four organ systems. Ref: Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996. 22(7): p. 707-10. |
| ICU Free Days to Day 28 | 28 days after randomization | ICU free days is defined as the number of days between randomization and day 28 in which the patient is in the ICU (for any part of a day). |
| Mean Hospital Free Days to Days 28 | 28 days after randomization | Hospital free days are days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days. |
| Mean Ventilator Free Days to Day 28 | 28 days after randomization | Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. |
| EuroQol (EQ-5D-5L): Health Related Quality of Life | 3 months after randomization | Using a standardized scale, do health reasons limit the person's ability to enjoy their life? Pooled estimates from patient survey and proxy survey were used. Utility index was computed from a lookup table according to EQ-5D-5L response profiles; utility index ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health), minimal clinically important difference (MCID) is 0.07 |
| PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | 6 months after randomization | Does the patient have symptoms of anxiety and stress from their ICU stay? PTSS-14 is only asked at month 6 and month 12 in patient survey; total score is rated from 14 to 98 and a higher score indicates having more post-traumatic stress syndrome related symptoms. Participants with scores greater than or equal to 45 were reported. |
| MoCA-Blind: Montreal Cognitive Assessment | 3 months after randomization | How clearly can patient think and recall things? MoCA-Blind is only asked in patient survey; total score is rated from 0 to 30 and a higher score indicates better cognitive performance. Normal range: 26 or greater. |
| Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 3 months after randomization | Assesses whether individual can living independently and assess a range of common functional activities, from walking and toileting to managing money and cooking meals. Data is a pooled estimates from patient survey and proxy survey. The total score is rated from 0 to 10 (MCID=1; 1 point=1 ADL); a higher score indicates having more difficulties in daily activities. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Early Neuromuscular Blockade (NMB) Patients will receive cisatracurium besylate for the first 48 hours of the trial.
cisatracurium besylate: Patients randomized to the early neuromuscular blockade arm will receive a cisatracurium besylate bolus of 15 mg, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients randomized to the control arm will receive no protocol specified neuromuscular blockade. | 501 |
| Control: No Routine Early NMB Use of non-study NMB will be discouraged. | 505 |
| Total | 1,006 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Early Neuromuscular Blockade (NMB) | Control: No Routine Early NMB | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 153 Participants | 147 Participants | 300 Participants |
| Age, Categorical Between 18 and 65 years | 348 Participants | 358 Participants | 706 Participants |
| Age, Continuous | 56.6 years STANDARD_DEVIATION 14.7 | 55.1 years STANDARD_DEVIATION 15.9 | 55.8 years STANDARD_DEVIATION 15.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 64 Participants | 54 Participants | 118 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 410 Participants | 421 Participants | 831 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants | 30 Participants | 57 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 10 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 79 Participants | 140 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 63 Participants | 69 Participants | 132 Participants |
| Race (NIH/OMB) White | 360 Participants | 343 Participants | 703 Participants |
| Region of Enrollment United States | 501 participants | 505 participants | 1006 participants |
| Sex: Female, Male Female | 210 Participants | 236 Participants | 446 Participants |
| Sex: Female, Male Male | 291 Participants | 269 Participants | 560 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 213 / 501 | 216 / 505 |
| other Total, other adverse events | 19 / 501 | 15 / 505 |
| serious Total, serious adverse events | 28 / 501 | 21 / 505 |
Outcome results
Primary
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.
Time frame: 90 days after randomization
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Hospital Mortality to Day 90 | Alive at Day 90 | 288 Participants |
| Early Neuromuscular Blockade (NMB) | Hospital Mortality to Day 90 | Dead Prior to Day 90 | 213 Participants |
| Control: No Routine Early NMB | Hospital Mortality to Day 90 | Alive at Day 90 | 289 Participants |
| Control: No Routine Early NMB | Hospital Mortality to Day 90 | Dead Prior to Day 90 | 216 Participants |
p-value: 0.9395% CI: [-6.4, 5.9]Wald test for the difference of two prop
Secondary
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
Time frame: 6 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Neuromuscular Blockade (NMB) | EuroQol (EQ-5D-5L): Health Related Quality of Life | 0.74 score on a scale |
| Control: No Routine Early NMB | EuroQol (EQ-5D-5L): Health Related Quality of Life | 0.79 score on a scale |
Secondary
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
Time frame: 3 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Neuromuscular Blockade (NMB) | EuroQol (EQ-5D-5L): Health Related Quality of Life | 0.66 score on a scale |
| Control: No Routine Early NMB | EuroQol (EQ-5D-5L): Health Related Quality of Life | 0.73 score on a scale |
Secondary
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
Time frame: 12 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Neuromuscular Blockade (NMB) | EuroQol (EQ-5D-5L): Health Related Quality of Life | 0.75 score on a scale |
| Control: No Routine Early NMB | EuroQol (EQ-5D-5L): Health Related Quality of Life | 0.77 score on a scale |
Secondary
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).
Time frame: 28 days after randomization
Population: The overall number of participants analyzed reflects the number of patients that had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | ICU Free Days to Day 28 | 9.0 days | Standard Deviation 9.4 |
| Control: No Routine Early NMB | ICU Free Days to Day 28 | 9.4 days | Standard Deviation 9.8 |
Secondary
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.
Time frame: 12 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 2.9 score on a scale | Standard Deviation 2.6 |
| Control: No Routine Early NMB | Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 2.4 score on a scale | Standard Deviation 2.3 |
Secondary
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.
Time frame: 3 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 3.3 score on a scale | Standard Deviation 2.7 |
| Control: No Routine Early NMB | Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 3.0 score on a scale | Standard Deviation 2.7 |
Secondary
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.
Time frame: 6 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 2.7 score on a scale | Standard Deviation 2.4 |
| Control: No Routine Early NMB | Katz Activities of Daily Living (ADL)/Lawton Instrumental Activities Of Daily Living Scale (IADL) | 2.7 score on a scale | Standard Deviation 2.4 |
Secondary
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.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Mean Hospital Free Days to Days 28 | 5.7 days | Standard Deviation 7.8 |
| Control: No Routine Early NMB | Mean Hospital Free Days to Days 28 | 5.9 days | Standard Deviation 8.1 |
Secondary
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.
Time frame: 28 days after randomization
Population: The overall number of participants analyzed reflects the number of patients that had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Mean Organ Failure Free Days to Day 28 | 12.4 days | Standard Deviation 11.3 |
| Control: No Routine Early NMB | Mean Organ Failure Free Days to Day 28 | 12.5 days | Standard Deviation 11.5 |
Secondary
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.
Time frame: 28 days after randomization
Population: The overall number of participants analyzed reflects the number of patients that had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | Mean Ventilator Free Days to Day 28 | 9.6 days | Standard Deviation 10.4 |
| Control: No Routine Early NMB | Mean Ventilator Free Days to Day 28 | 9.9 days | Standard Deviation 10.9 |
Secondary
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.
Time frame: 3 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | MoCA-Blind: Montreal Cognitive Assessment | 22.2 score on a scale | Standard Deviation 5.2 |
| Control: No Routine Early NMB | MoCA-Blind: Montreal Cognitive Assessment | 22.8 score on a scale | Standard Deviation 4.8 |
Secondary
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.
Time frame: 6 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | MoCA-Blind: Montreal Cognitive Assessment | 22.8 score on a scale | Standard Deviation 4.8 |
| Control: No Routine Early NMB | MoCA-Blind: Montreal Cognitive Assessment | 23.2 score on a scale | Standard Deviation 5.1 |
Secondary
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.
Time frame: 12 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Neuromuscular Blockade (NMB) | MoCA-Blind: Montreal Cognitive Assessment | 23.3 score on a scale | Standard Deviation 4.9 |
| Control: No Routine Early NMB | MoCA-Blind: Montreal Cognitive Assessment | 24.0 score on a scale | Standard Deviation 4.4 |
Secondary
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.
Time frame: 6 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Neuromuscular Blockade (NMB) | PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | 38 participants |
| Control: No Routine Early NMB | PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | 31 participants |
Secondary
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.
Time frame: 12 months after randomization
Population: The overall number of participants analyzed reflects the number of patients that were alive, able to be contacted, and had sufficient data to allow for calculation of the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Neuromuscular Blockade (NMB) | PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | 21 participants |
| Control: No Routine Early NMB | PTSS-14: Post-traumatic Stress-like Symptoms Scores >/= 45 | 38 participants |