Neuromuscular Blockade for Post-Cardiac Arrest Care

Study Overview
=================
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.

Official Title
-----------------
Neuromuscular Blockade for Post-Cardiac Arrest Care

Conditions
-----------------
Cardiac Arrest

Intervention / Treatment
-----------------
* Drug: Rocuronium
* Drug: Normal Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rocuronium<br>Patients will receive a bolus dose of 1 mg/kg, then a continuous intravenous (IV) 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). | Drug: Rocuronium<br>* Neuromuscular Blockade<br>|
| Placebo Comparator: Usual Care<br>Patients will receive 100 mL of normal saline over 5-10 minutes at the beginning of the study in addition to usual care. | Drug: Normal Saline<br>* Normal Saline<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 hours | 
| 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. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time ROSC to Target Temperature | Time from return of spontaneous circulation to target temperature | Duration of hospitalization, limit 180 days | 
| Length of Intensive Care Unit (ICU) Stay | Length of stay in ICU | Length of Stay Truncated at 28 Days | 
| Mechanical Ventilation Duration | Mechanical Ventilation Duration in Hours | Duration of hospitalization, limit 180 days | 
| Survival | In-hospital survival | Duration of hospitalization, limit 180 days | 
| 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) | Duration of hospitalization, limit 180 days | 
| 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 | Duration of hospitalization, limit 180 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiac Arrest, NMB, Neuromuscular Blockade, Rocuronium