Esmolol to Control Adrenergic Storm in Septic Shock- ROLL-IN 2 (ECASSS-R2)

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.

Study Overview

• Status: Unknown
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Esmolol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Utah
    • Murray, Utah, United States, 84107
      • Recruiting
      • Intermountain Medical Center
      • Contact: David P Tomer, MS; Phone Number: (801) 507-4694; Email: David.Tomer@imail.org
      • Principal Investigator: Samuel M Brown, MD MS
      • Sub-Investigator: Colin K Grissom, MD
      • Sub-Investigator: Michael J Lanspa, MD MS
      • Sub-Investigator: Emily Wilson, MS
      • Sub-Investigator: Ithan Peltan, MD
      • Sub-Investigator: Ellie Hirshberg, MD
      • Sub-Investigator: Peter Crossno, MD
      • Sub-Investigator: Vivian Lee, MD
      • Sub-Investigator: Sarah Beesley, MD
      • Sub-Investigator: Rebecca Burk, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years

2. 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

3. Receiving vasopressors through a central venous catheter for more than 60 minutes.
4. Arterial catheter in place or expected to be placed imminently.
5. Heart rate > 90/min while receiving vasopressors for more than 60 minutes.

6. 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.)

   1. Central venous pressure (CVP) > 15 mm Hg.
   2. Negative Passive-Leg Raise (PLR) maneuver (<10% increase in cardiac output after PLR).
   3. 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]).
   4. Inferior vena cava (IVC) plethora
   5. 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:

1. Lack of informed consent.
2. Currently receiving ExtraCorporeal Membrane Oxygenation (ECMO).
3. Known pregnancy or nursing.
4. Patient is a prisoner.
5. Patient on hospice (or equivalent comfort care approach) at or before the time of enrollment.
6. Known or current atrial fibrillation.
7. Previously enrolled in the trial.
8. Known allergy to esmolol or vehicle (see Appendix 2 for BREVIBLOC vehicle ingredients).
9. Receipt of nodal blocking agents (see Appendix 3 for list of such agents) within three half lives
10. Hemoglobin < 7 gm/dl.
11. Cardiac arrest within 24 hours.

12. 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)
13. Cardiovascular collapse, as manifested by inability to achieve a mean arterial pressure (MAP) of 65 mmHg with vasopressor therapy.

14. 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

15. 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
16. Pheochromocytoma or status asthmaticus
17. Receiving clonidine, guanfacine, or moxonidine

18. 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.

19. Worse than mild mitral stenosis

    • Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean gradient ≥ 5 mmHg.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Esmolol; 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; Esmolol hydrochloride infusion; Other Names: BREVIBLOC

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
ICU-free days	28 days
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

Collaborators and Investigators

• Sponsor: Samuel Brown
• Collaborators: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Samuel M Brown, MD MS, Intermountain Health Care, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2017
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: July 2, 2017
• First Submitted That Met QC Criteria: July 2, 2017
• First Posted (Actual): July 5, 2017

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 25, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: septic shock; esmolol; adrenergic storm
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic beta-1 Receptor Antagonists; Esmolol
• Other Study ID Numbers: 1050522

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: In order to protect patient privacy and comply with relevant regulations, identified data will be unavailable. Requests for deidentified data from qualified researchers with appropriate ethics board approvals and relevant data use agreements will be processed by the Intermountain Office of Research, officeofresearch@imail.org.
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No