Study to Evaluate Esmolol (Brevibloc) to Manage Cardiac Function in Patients With Subarachnoid Hemorrhage

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the clinical effect of esmolol treatment on cardiac function and electrophysiology; to assess the effects of esmolol treatment on serum adrenergic and cardiac biomarkers; to explore the safety of esmolol treatment shortly after subarachnoid hemorrhage (SAH). Patients will be followed for a maximum of 1 month after the index SAH. The primary outcome will be change in systolic function - ejection fraction by Simpson's rule (baseline versus Day 7 +/- 2 after SAH).

Detailed Description
-----------------
Subarachnoid hemorrhage (SAH) remains one of the most devastating forms of stroke. Over 25% of all stroke related potential years of life lost are from SAH. Outcomes are adversely affected by secondary ischemia from cerebral vasospasm, along with cardiac complications. Trials performed in patients with SAH have demonstrated benefit after the administration of beta blockers - reducing mortality nearly in half; but concerns over diminishing cerebral perfusion inhibited the widespread adoption of this therapy. Our specific aims are as follows: 1. To evaluate the clinical effect of esmolol treatment on cardiac systolic and diastolic function, along with cardiac electrophysiology; 2. To assess the effects of esmolol treatment on serum adrenergic and cardiac biomarkers; 3. To explore the safety of esmolol shortly after SAH. The primary outcome will be change in systolic function - ejection fraction by Simpson's rule (baseline versus Day 7 +/- 2 after SAH).

Official Title
-----------------
Adrenergic Blockade After Subarachnoid Hemorrhage

Conditions
-----------------
Subarachnoid Hemorrhage

Intervention / Treatment
-----------------
* Drug: Esmolol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subarachnoid hemorrhage presumed to be the result of ruptured aneurysm Age 18 years old or greater Able to enroll within 24 hours of onset of symptoms Systolic blood pressure over 140 mm Hg OR administration of antihypertensives after presentation Exclusion Criteria: Withdrawal of life support imminent (within six hours) Known heart failure or cardiomyopathy AND ejection fraction 35% or below Prisoner or pregnant female Ongoing vasopressor administration to maintain SBP, or clinical suspicion of left ventricular failure Clinically important arrhythmias (history of cardiac arrest or ventricular arrhythmias), conduction abnormalities (Mobitz Type 2, 3rd degree AV block, or symptomatic Mobitz 1 without pacemaker), clinical cardiogenic shock, or overt clinical heart failure Active bronchospastic disease (ongoing bronchospasm after SAH presentation or current treatment with oral corticosteroids for asthma or obstructive lung disease) End stage renal disease

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: esmolol<br>Esmolol will be used preferentially to control hypertension. | Drug: Esmolol<br>* The initial esmolol infusion will be 50 mcg/kg/minute IV. This will be increased by 25 mcg/kg/minute every 15 minutes until one of the following situations is reached: Heart rate less than 70 bpm. Systolic blood pressure less than 120 mmHg Maximum dose of esmolol of 200 mcg/kg/minute is reached.<br>* Other names: Brevibloc;|
| No Intervention: Standard care<br>Standard care for SAH includes other hypertensives such as nicardipine. | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in high sensitivity troponin |  | Peak to nadir within 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean difference in time weighted average amount of cerebral perfusion pressure below 60 mmHg. |  | Measured for 4 days from index SAH | 
| Proportion experiencing serious adverse event: hypotension requiring vasopressor (excluding during anesthesia), neurological deterioration, serious bronchospasm, and in hospital case fatality. |  | Measured during index hospitalization or first 30 days from index SAH | 
| Disability (30 days +/-7). |  | 30 days from index SAH | 
| Change in serum norepinephrine level from peak to nadir |  | Baseline versus 4th day after index SAH | 
| Change in corrected QT interval |  | First week after presentation for index SAH | 
| Proportion with echocardiographic wall motion abnormalities at baseline and day 7 +- 2 |  | First week after presentation. | 
| Proportion with electrocardiographic abnormalities cumulative through day 7 |  | Baseline, and at first week after presentation. | 
| Proportion with depressed ejection fraction on initial echocardiogram 36 - 49% |  | Baseline (within 24 hours of presentation for index SAH) | 
| Proportion with life-threatening arrhythmias or cardiac arrest |  | Measured through end of index hospitalization (approximately 30 days maximum) | 
| Change in serum troponin and BNP levels from peak to nadir |  | baseline through end of hospitalization | 
| Proportion with abnormal 30-day echocardiogram |  | 30 days post index SAH | 
| Proportion with symptomatic cerebral vasospasm |  | baseline until end of hospitalization | 
| Proportion with radiographic cerebral vasospasm |  | baseline until end of hospitalization | 
| Change in systolic function - ejection fraction by Simpson's rule (baseline vs Day 7 +/- 2) |  | 5-7 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
subarachnoid hemorrhage, esmolol, cardiac function, cardiac electrophysiology