Cardiac Arrest
Conditions
Keywords
Cardiac Arrest, NMB, Neuromuscular Blockade, Rocuronium
Brief summary
The main purpose of this study is to evaluate if neuromuscular blockade improves lactate clearance (and preliminary secondary clinical outcome measures) as compared to usual care in post-cardiac arrest patients undergoing targeted temperature management.
Detailed description
Out-of-hospital cardiac arrest (OHCA) occurs in more than 300,000 patients in the United States each year with an estimated mortality of greater than 90%. Unfortunately, we currently have little to offer in terms of treatment other than supportive care for the post-cardiac arrest patient. Neuromuscular blockade (NMB) is sometimes utilized in post-arrest patients particularly for the prevention of shivering. However, usage of NMB remains controversial and current American Heart Association (AHA) recommendations are to minimize utilization. Recent prospective randomized trials in patients with acute respiratory distress syndrome suggest a mortality benefit from NMB and an excellent safety profile. Furthermore, observational trials in both sepsis and post-cardiac arrest show that the use of NMB is associated with improved survival. Given this, we hypothesize that continuous NMB will be beneficial in post-arrest patients. In order to test this hypothesis, we propose a multi-center, randomized, open-label, phase II trial in post-CA patients comparing sustained NMB administration for 24 hours to standard of care after return of spontaenous circulation (ROSC). We will enroll adult, comatose OHCA patients with ROSC and will utilize an already existing clinical trials network for the completion of the study. Patients will be randomized to receive either rocuronium for 24 hours or to receive placebo with usual care. Previous data from our group has suggested that lactate levels in the post-arrest patient are a good surrogate marker for mortality. We have therefore chosen to utilize lactate levels at 24 hours as the primary endpoint for the current trial. Secondarily we will evaluate clinical endpoints including length of stay (LOS), in-hospital mortality, and good neurological outcome. We will perform a sub-study of inflammatory markers and oxygen consumption.
Interventions
DRUGRocuronium
Neuromuscular Blockade
DRUGNormal Saline
Normal Saline
Sponsors
University of Pittsburgh Medical Center
Brigham and Women's Hospital
University of Alabama at Birmingham
Beaumont Hospital
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult (≥ 18 years) * Cardiac arrest with sustained return of spontaneous circulation (ROSC) * Comatose (i.e., not following commands) following ROSC * Undergoing targeted temperature management (TTM) * Time of enrollment ≤ 6 hours from initiation of targeted temperature management * Serum Lactate ≥2
Exclusion criteria
* Pre-existing dementia, severe brain injury, or dependence on others for activities of daily living (i.e. a modified Rankin scale (mRS) score of 4 or higher) * Traumatic etiology of the cardiac arrest * Protected population (pregnant, prisoner)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lactate Over 24 Hours | 24 hours | Change in median serum lactate level between enrollment and 24-hours after the receipt of study drug. A negative number indicates that the lactate levels were lower at 24 hours compared to their level at receipt of study drug. |
| Change in Lactate Over 24 Hours: Effect Estimate | 24 hours | Interaction between allocated treatment and time: ratio of geometric mean differences over 24 hours in log lactate values between the two groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mechanical Ventilation Duration | Duration of hospitalization, limit 180 days | Mechanical Ventilation Duration in Hours |
| Survival | Duration of hospitalization, limit 180 days | In-hospital survival |
| Time ROSC to Target Temperature | Duration of hospitalization, limit 180 days | Time from return of spontaneous circulation to target temperature |
| Muscle Weakness Score | Duration of hospitalization, limit 180 days | Medical Research Council Scale : Measured for 6 muscle groups (3 in the upper limbs and 3 in the lower limbs). Maximum score is 30 (grade 5 for each group) and minimum is 0 (grade 0 for each group). If muscle group strength was not symmetric bilaterally, higher measurement used. Higher scores indicate better outcomes. Grade 5: Muscle contracts normally against full resistance. Grade 4: Muscle strength is reduced but muscle contraction can still move joint against resistance. Grade 3: Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner's resistance completely removed. Grade 2: Muscle can move only if the resistance of gravity is removed. As an example, the elbow can be fully flexed only if the arm is maintained in a horizontal plane. Grade 1: Only a trace or flicker of movement is seen or felt in the muscle or fasciculations are observed in the muscle. Grade 0: No movement is observed |
| Number of Participants With Rankin Score ≤3 | Duration of hospitalization, limit 180 days | Modified Rankin scale to assess neurological outcome at discharge. The scale ranges from 0 to 6, and is used for measuring the performance of daily activities. The score is as follows: * 0: No symptoms * 1: No significant disability (able to carry out all usual activities, despite some symptoms) * 2: Slight disability (able to look after own affairs without assistance, but unable to carry out all previous activities) * 3: Moderate disability (requires some help, but able to walk unassisted) * 4: Moderately severe disability (unable to attend to own bodily needs without assistance, and unable to walk unassisted) * 5: Severe disability (requires constant nursing care and attention, bedridden, incontinent) * 6: Dead. Higher cores represent worse outcomes. Good and bad neurological outcome will be defined as a score of 0-3 and 4-6 respectively. This outcome reports the number of patients with a good neurological outcome( modified Rankin score ≤ 3) |
| Length of Intensive Care Unit (ICU) Stay | Length of Stay Truncated at 28 Days | Length of stay in ICU |
Countries
United States
Participant flow
Recruitment details
Between December 2014 and May 2019, we recruited adult patients (aged ≥18 years) who experienced a cardiac arrest and subsequently had sustained ROSC (≥20 minutes) but remained unresponsive and were undergoing TTM between 32℃ and 36℃. We added an additional inclusion criterion of a minimum serum lactate level of ≥2mmol/L early in study enrollment.
Pre-assignment details
Of 818 patients assessed for eligibility, 83 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Rocuronium Patients will receive a bolus dose of 1 mg/kg, then a continuous I.V. infusion as per standard intensive care unit practice.
Of note, protocol allows for use of cistatracurium in place of rocuronium for either reasons of drug-shortage or clinical conditions (if institutional preferences for dose adjustment in liver or renal insufficiency arise).
Rocuronium: Neuromuscular Blockade | 37 |
| Usual Care Patients will receive 100 mL of normal saline over 5-10 minutes at the beginning of the study in addition to usual care.
Normal Saline: Normal Saline | 43 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | 2 patients in NMB arm and 1 in control arm had clinical changes that precluded drug administration | 2 | 1 |
Baseline characteristics
| Characteristic | Usual Care | Total | Rocuronium |
|---|---|---|---|
| Age, Continuous | 64 years | 65 years | 66 years |
| Arrest Characteristics: Arrest Etiology (n, % cardiac) | 30 Participants | 57 Participants | 27 Participants |
| Arrest Characteristics: Bystander Cardipulmonary Resuscitation (CPR) Provided (n, % yes) | 26 Participants | 50 Participants | 24 Participants |
| Arrest Characteristics: Estimated Low-Flow Time (minutes, median, IQR) | 2 minutes | 3 minutes | 4 minutes |
| Arrest Characteristics: Initial Rhythm (n, % Shockable) | 16 Participants | 33 Participants | 17 Participants |
| Arrest Characteristics: Location (n, % Out of Hospital Cardiac Arrest) | 40 Participants | 75 Participants | 35 Participants |
| Arrest Characteristics: Witnessed (n, % yes) | 26 Participants | 53 Participants | 27 Participants |
| Characteristics at Enrollment: Partial Pressure of Carbon Dioxide (pCO2) median, IQR | 40.0 mmHg | 41.5 mmHg | 41.5 mmHg |
| Characteristics at Enrollment: Partial Pressure of Oxygen (pO2) median, IQR | 161.0 mmHg | 132.5 mmHg | 100.0 mmHg |
| Characteristics at Enrollment: pH (median, IQR) | 7.3 pH | 7.3 pH | 7.3 pH |
| Characteristics at Enrollment: Shock Stratification (n, % shock) | 21 Participants | 40 Participants | 19 Participants |
| Characteristics at Enrollment: S-T Elevation Myocardial Infarction (STEMI) present (n, % yes) | 6 Participants | 10 Participants | 4 Participants |
| Characteristics at Enrollment: Target temperature (median, IQR) | 34 celsius | 35 celsius | 35 celsius |
| Characteristics at Enrollment: Time from ROSC to Study Drug (hours, median, IQR) | 6.3 hours | 6.5 hours | 7.5 hours |
| Past Medical History: Active Malignancy | 2 Participants | 5 Participants | 3 Participants |
| Past Medical History: Atrial Fibrillation | 9 Participants | 16 Participants | 7 Participants |
| Past Medical History: Chronic Pulmonary Disease | 9 Participants | 21 Participants | 12 Participants |
| Past Medical History: Congestive Heart Failure | 12 Participants | 21 Participants | 9 Participants |
| Past Medical History: Coronary Artery Disease | 9 Participants | 23 Participants | 14 Participants |
| Past Medical History: Kidney Disease | 14 Participants | 23 Participants | 9 Participants |
| Past Medical History: Liver Cirrhosis | 2 Participants | 3 Participants | 1 Participants |
| Past Medical History: Prior Cardiac Arrest | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race (n, % American Indian/Native Alaskan) | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race (n, % Asian) | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race (n, % Black/African-American) | 12 Participants | 19 Participants | 7 Participants |
| Race/Ethnicity, Customized Race (n, % Other) | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race (n, % Unknown/Not Reported) | 9 Participants | 15 Participants | 6 Participants |
| Race/Ethnicity, Customized Race (n, % White) | 22 Participants | 42 Participants | 20 Participants |
| Region of Enrollment United States | 43 participants | 80 participants | 37 participants |
| Sex: Female, Male Female | 14 Participants | 31 Participants | 17 Participants |
| Sex: Female, Male Male | 29 Participants | 49 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 37 | 29 / 43 |
| other Total, other adverse events | 0 / 37 | 0 / 43 |
| serious Total, serious adverse events | 0 / 37 | 0 / 43 |
Outcome results
Primary
Change in Lactate Over 24 Hours
Change in median serum lactate level between enrollment and 24-hours after the receipt of study drug. A negative number indicates that the lactate levels were lower at 24 hours compared to their level at receipt of study drug.
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rocuronium | Change in Lactate Over 24 Hours | -2.2 mmol/L |
| Usual Care | Change in Lactate Over 24 Hours | -2.3 mmol/L |
Primary
Change in Lactate Over 24 Hours: Effect Estimate
Interaction between allocated treatment and time: ratio of geometric mean differences over 24 hours in log lactate values between the two groups.
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rocuronium | Change in Lactate Over 24 Hours: Effect Estimate | 1.3 Ratio |
Secondary
Length of Intensive Care Unit (ICU) Stay
Length of stay in ICU
Time frame: Length of Stay Truncated at 28 Days
Population: ICU survivors row include only the 14 patients in each arm who survived to ICU discharge (n=14 in each arm).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rocuronium | Length of Intensive Care Unit (ICU) Stay | All patients | 6.0 days |
| Rocuronium | Length of Intensive Care Unit (ICU) Stay | ICU survivors | 9.0 days |
| Usual Care | Length of Intensive Care Unit (ICU) Stay | All patients | 4.0 days |
| Usual Care | Length of Intensive Care Unit (ICU) Stay | ICU survivors | 5.0 days |
Comparison: All patients analyzed (N = 37 in NMB and 43 in Usual Care)p-value: 0.0995% CI: [1, 1.9]Negative binomial regression
Comparison: ICU survivors alone analyzed (n = 14 in each arm)p-value: 0.3595% CI: [0.8, 2]Negative binomial regression
Secondary
Mechanical Ventilation Duration
Mechanical Ventilation Duration in Hours
Time frame: Duration of hospitalization, limit 180 days
Population: Includes all patients, and also patients surviving to discontinuation of mechanical ventilation (n=14 in each group). Two patients discharged from the hospital on mechanical ventilation have duration truncated at time of discharge and are considered survivors to extubation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rocuronium | Mechanical Ventilation Duration | All patients | 102.0 Hours |
| Rocuronium | Mechanical Ventilation Duration | Survivors to extubation | 126.3 Hours |
| Usual Care | Mechanical Ventilation Duration | All patients | 82.7 Hours |
| Usual Care | Mechanical Ventilation Duration | Survivors to extubation | 66.9 Hours |
Comparison: Anaysis for the full data (n= 37 in NMB and 43 in Control)p-value: 0.1895% CI: [0.9, 1.9]Regression, Linear
Comparison: Anaysis for the patients surviving to extubation (n= 14 in both groups)p-value: 0.3295% CI: [0.7, 2.9]Regression, Linear
Secondary
Muscle Weakness Score
Medical Research Council Scale : Measured for 6 muscle groups (3 in the upper limbs and 3 in the lower limbs). Maximum score is 30 (grade 5 for each group) and minimum is 0 (grade 0 for each group). If muscle group strength was not symmetric bilaterally, higher measurement used. Higher scores indicate better outcomes. Grade 5: Muscle contracts normally against full resistance. Grade 4: Muscle strength is reduced but muscle contraction can still move joint against resistance. Grade 3: Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner's resistance completely removed. Grade 2: Muscle can move only if the resistance of gravity is removed. As an example, the elbow can be fully flexed only if the arm is maintained in a horizontal plane. Grade 1: Only a trace or flicker of movement is seen or felt in the muscle or fasciculations are observed in the muscle. Grade 0: No movement is observed
Time frame: Duration of hospitalization, limit 180 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rocuronium | Muscle Weakness Score | 30 Points |
| Usual Care | Muscle Weakness Score | 30 Points |
Secondary
Number of Participants With Rankin Score ≤3
Modified Rankin scale to assess neurological outcome at discharge. The scale ranges from 0 to 6, and is used for measuring the performance of daily activities. The score is as follows: * 0: No symptoms * 1: No significant disability (able to carry out all usual activities, despite some symptoms) * 2: Slight disability (able to look after own affairs without assistance, but unable to carry out all previous activities) * 3: Moderate disability (requires some help, but able to walk unassisted) * 4: Moderately severe disability (unable to attend to own bodily needs without assistance, and unable to walk unassisted) * 5: Severe disability (requires constant nursing care and attention, bedridden, incontinent) * 6: Dead. Higher cores represent worse outcomes. Good and bad neurological outcome will be defined as a score of 0-3 and 4-6 respectively. This outcome reports the number of patients with a good neurological outcome( modified Rankin score ≤ 3)
Time frame: Duration of hospitalization, limit 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rocuronium | Number of Participants With Rankin Score ≤3 | 11 Participants |
| Usual Care | Number of Participants With Rankin Score ≤3 | 9 Participants |
p-value: 0.3595% CI: [0.6, 4.7]Regression, Logistic
Secondary
Survival
In-hospital survival
Time frame: Duration of hospitalization, limit 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rocuronium | Survival | 14 Participants |
| Usual Care | Survival | 14 Participants |
p-value: 0.6395% CI: [0.5, 3.3]Regression, Logistic
Secondary
Time ROSC to Target Temperature
Time from return of spontaneous circulation to target temperature
Time frame: Duration of hospitalization, limit 180 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rocuronium | Time ROSC to Target Temperature | 6.8 Hours |
| Usual Care | Time ROSC to Target Temperature | 8.3 Hours |
p-value: 0.8295% CI: [0.7, 1.4]Regression, Linear