Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients

Study Overview
=================
Brief Summary
-----------------
The primary objective of the Neuroprotect trial is to assess whether or not a new goal directed hemodynamic optimization strategy can reduce cerebral ischemia in post-cardiac arrest (CA) patients.

Detailed Description
-----------------
Unconscious patients admitted to the intensive care unit after being successfully resuscitated from cardiac arrest (CA) are at high risk for death, and neurological deficits are common among survivors. Nevertheless, the optimal hemodynamic strategy to ensure optimal cerebral perfusion and maximal outcome has not been studied by a randomized controlled trial. In the absence of good evidence, current post-CA guidelines are adapted from sepsis guidelines and recommend targeting a mean arterial pressure (MAP) above 65 mmHg (Peberdy ea, Circulation 2010). Importantly, post-CA patients have a large cerebral penumbra at risk for infarction when resuscitated to suboptimal MAP's. In a large subset of post-CA patients the lower threshold of cerebral autoregulation is shifted rightward and these patients might benefit from resuscitation to higher MAP's (Sundgreen ea, Stroke 2001) in order to ensure adequate cerebral oxygenation. Our research group previously showed that a MAP of 85-100mmHg results in optimal cerebral perfusion in post-CA patients (Ameloot ea, resuscitation 2015). Two retrospective and 2 prospective observational studies suggested an association between higher MAP's and better outcome in post-CA patients (Ameloot ea, resuscitation 2015). However, the value of these trials is limited by their observational design. The question remains as to whether patients with higher MAP's do have a better outcome due to more optimal cerebral perfusion and less cerebral damage or whether a higher MAP is merely a non-causal marker of more limited disease severity in these patients. In other words, the primary research question is whether we can reduce cerebral ischemia and improve prognosis of post-cardiac arrest survivors by targeting higher mean systemic blood pressures thereby optimizing cerebral perfusion during their stay in the intensive care unit. To answer this, we propose a multicenter interventional open label investigator driven randomized controlled trial to compare a goal-directed potentially neuro-protective hemodynamic optimization strategy with the current standard of care. Primary efficacy endpoints of the study will include extent of cerebral damage as assessed with diffusion weighted magnetic resonance imaging (DW-MRI), functional and neurocognitive testing, biomarkers of brain injury and survival rates. The final utilization goal of the Neuroprotect post-CA trial is to show that our adapted hemodynamic protocol reduces cerebral ischemia, and improves survival and functional outcome of post-cardiac arrest patients.

Official Title
-----------------
Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients: a Randomized Controlled Trial (the NEUROPROTECT Post-CA Trial)

Conditions
-----------------
Cerebral Ischemia, Cardiac Arrest

Intervention / Treatment
-----------------
* Other: Neuroprotective goal directed hemodynamic optimization
* Other: MAP > 65mmHg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Out-of-hospital CA of presumed cardiac cause irrespective of the presenting rhythm Unconsciousness (Glasgow coma scale < 8) at hospital admission Age ≥ 18 years Sustained return of spontaneous circulation (ROSC) (=when chest compressions have not been required for 20 consecutive minutes) Exclusion Criteria: Suspected or confirmed intracranial bleeding or stroke Known limitations in therapy or Do Not Resuscitate-order Known disease compromising 180 day survival Known pre-CA cerebral performance category 3-4 Previous stroke (TIA can be included) MRI incompatible cardiac or neurosurgical device Systolic blood pressure < 90 mmHg on norepinephrine > 1 mcg/kg/min). Open chest ECMO (extracorporeal membrane oxygenation) Pregnancy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neuroprotect<br>MAP between 85-100mmHg SVO2 between 65-75% | Other: Neuroprotective goal directed hemodynamic optimization<br> <br> |
| Active Comparator: Control<br>MAP>65mmHg | Other: MAP > 65mmHg<br>* MAP > 65mmHg<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diffusion weighted MRI | cerebral ischemia in post-cardiac arrest (CA) patients as quantified by the apparent diffusion coefficient (ADC) on diffusion weighted MRI (DW-MRI) to be performed at day 4- 5 post-CA using ADC scores in 11 pre-specified brain regions (frontal cortex, parietal cortex, temporal cortex, occipital cortex, precentral cortex, postcentral cortex, caudate nucleus, putamen, thalamus, cerebellum, pons). | day 4-5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| diffusion weighted MRI | o Percentage of voxels under a suggested ADC threshold of 0.650x10-3 mm2/s | day 4-5 | 
| Diffusion weighted MRI | o Whole brain median ADC score [mm2/s] | day 4-5 | 
| CPC | o Cerebral performance category 3-5 at 180 days post-CA | 180 days after admission | 
| The Short Form (36) Health Survey | o SF36 questionnaire at 180 days post-CA | 180 days after admission | 
| Neurocognitive testing | Neurocognitive testing at discharge from the hospital by the adult verbal learning test | discharge from the hospital (expected time frame 2-4 weeks after admission) | 
| Neurocognitive testing | Neurocognitive testing at discharge from the hospital by the digit span backwards test | discharge from the hospital (expected time frame 2-4 weeks after admission) | 
| Neurocognitive testing | Neurocognitive testing at discharge from the hospital by the red pencil test | discharge from the hospital (expected time frame 2-4 weeks after admission) | 
| Neurocognitive testing | Neurocognitive testing at discharge from the hospital by the Wechsler Memory Scale Revised test | discharge from the hospital (expected time frame 2-4 weeks after admission) | 
| Biomarkers | Neuron specific enolase (day 1-2-3-4-5) | day 1-2-3-4-5 | 
| Functional testing | Activities Daily Life (ADL) | Discharge from the hospital (expected time frame 2-4 weeks after admission) | 
| Functional testing | 6 minute walking distance (6MWD) at discharge from the hospital | Discharge from the hospital (expected time frame 2-4 weeks after admission) | 
| ICU parameters | lenght of stay in ICU [number of days] | At ICU discharge (expected time frame 1-2 weeks after admission) | 
| ICU parameters | Ventilator days [number of days] | At ICU discharge (expected time frame 1-2 weeks after admission) | 
| ICU parameters | tracheostomy performed (yes/no) | At ICU discharge (expected time frame 1-2 weeks after admission) | 
| Renal function | creatinine [mg/dl] | day 1-2-3-4-5 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
post cardiac arrest, hemodynamics