Esmolol to Control Adrenergic Storm in Septic Shock- ROLL-IN 2

Study Overview
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Brief Summary
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Septic shock is a common syndrome caused by the body's response to an infection. Septic shock is responsible for 10% of all ICU admissions and 30% of ICU deaths. Use of beta blocker medications may improve outcomes after septic shock. This pilot study evaluates protocols to infuse the beta blocker esmolol in patients with septic shock.

Detailed Description
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This is a prospective, single arm, feasibility study of esmolol infusion in septic shock. The objective is to evaluate the feasibility, adequacy, and efficiency of study protocols for a subsequent ECASSS study. This study (ECASSS-R2) extends observations made in an initial pilot, ECASSS-R.

Official Title
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Esmolol to Control Adrenergic Storm in Septic Shock- ROLL-IN 2

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Esmolol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Within 72 hours of admission to the ICU and septic shock (sepsis present at time of admission) a. Septic shock defined by SEPSIS-3 consensus criteria as i. Suspected or documented infection ii. Sequential Organ Failure Assessment (SOFA) score increased by at least 2 points over baseline iii. Lactate > 2mmol/L iv. Receiving vasopressors to treat hypotension after at least 20 ml/kg intravenous crystalloid volume expansion Receiving vasopressors through a central venous catheter for more than 60 minutes. Arterial catheter in place or expected to be placed imminently. Heart rate > 90/min while receiving vasopressors for more than 60 minutes. Adequately volume expanded, as manifest by any of the following, performed as part of routine clinical care (i.e., no study procedures will be performed before signed consent). If none of these measures are clinically available, the clinical attending must confirm that volume expansion is adequate. (After enrollment, a final safety check will confirm the adequacy of volume expansion.) Central venous pressure (CVP) > 15 mm Hg. Negative Passive-Leg Raise (PLR) maneuver (<10% increase in cardiac output after PLR). No cardiac output response (<10% increase) after rapid infusion (<5 min) of 250 ml of IV crystalloid (i.e., a graded volume expansion challenge [GVEC]). Inferior vena cava (IVC) plethora For patients who happen to be breathing passively (i.e., paralyzed or deeply sedated) on a positive pressure mechanical ventilator delivering at least 8 ml/kg tidal volumes and in normal sinus rhythm, stroke volume variability <13% (such patients are acknowledged to be uncommon; the protocol does not recommend or require the induction of passive breathing). Exclusion Criteria: Lack of informed consent. Currently receiving ExtraCorporeal Membrane Oxygenation (ECMO). Known pregnancy or nursing. Patient is a prisoner. Patient on hospice (or equivalent comfort care approach) at or before the time of enrollment. Known or current atrial fibrillation. Previously enrolled in the trial. Known allergy to esmolol or vehicle (see Appendix 2 for BREVIBLOC vehicle ingredients). Receipt of nodal blocking agents (see Appendix 3 for list of such agents) within three half lives Hemoglobin < 7 gm/dl. Cardiac arrest within 24 hours. Pulmonary hypertension (moderate or severe), from documented history of prior right heart catheterization or current evidence on transthoracic echocardiogram (TTE) of any of the following Mean Pulmonary Arterial Pressure (mPAP) ≥ 35mmHg (millimeters of mercury) Systolic Pulmonary Arterial Pressure (SPAP) ≥ 60mmHg (millimeters of mercury) Cardiovascular collapse, as manifested by inability to achieve a mean arterial pressure (MAP) of 65 mmHg with vasopressor therapy. Cardiogenic shock, as defined by any of the following Cardiac index ≤ 2.3 L/min/m2 Ejection fraction ≤ 30% ScvO2 ≤ 60% Current infusion of any dose of dobutamine, milrinone, or dopamine (if dopamine is being used for clinically diagnosed bradycardia or cardiogenic shock) Current infusion of epinephrine for clinically diagnosed cardiogenic shock Significant atrioventricular dysfunction Sick sinus syndrome PR interval > 200 msec Current evidence or prior history of Grade 2 or Grade 3 heart block Pacemaker or plans to place a pacemaker Pheochromocytoma or status asthmaticus Receiving clonidine, guanfacine, or moxonidine Worse than moderate aortic stenosis Known aortic stenosis, with any of (1) mean gradient ≥ 40 mmHg OR (2) maximum gradient ≥ 60mmHg OR (3) aortic valve area ≤ 1.0cm2 OR (4) aortic valve area index ≤ 0.85cm2/m2 body surface area. Worse than mild mitral stenosis Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean gradient ≥ 5 mmHg.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Esmolol<br>Intravenous esmolol will be administered as a continuous infusion according to protocol to control tachycardia with maximal infusion rates in the range of 10-40 mcg/kg/min. | Drug: Esmolol<br>* Esmolol hydrochloride infusion<br>* Other names: BREVIBLOC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Organ-failure-free days |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause hospital mortality |  | During hospitalization | 
| All-cause 28-day and 90-day mortality |  | 28 days and 90 days | 
| Peak serum high-sensitivity troponin |  | 24 hours | 
| Left ventricular (LV) longitudinal strain |  | 24 hours | 
| ICU-free days |  | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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esmolol, adrenergic storm, septic shock