Esmolol Infusion for Patients With Septic Shock and Persistent Tachycardia (ECASSS-R)

Esmolol to Control Adrenergic Storm in Septic Shock - Roll-in

This is a prospective, single arm, "roll-in" study of esmolol infusion for patients with septic shock with persistent tachycardia after adequate intravenous volume expansion. The study will evaluate the adequacy and efficiency of study protocols for the anticipated, main ECASSS study, which will have a separate entry in clinicaltrials.gov.

Study Overview

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

Detailed Description

PRIMARY OBJECTIVE:

To evaluate the adequacy and efficiency of study protocols for the anticipated, randomized, controlled ECASSS study. The primary clinical outcome is organ-failure free days at 28 days, with multiple secondary outcomes, including those relevant to function of and compliance with the study protocols.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Utah
    • Murray, Utah, United States, 84143
      • Intermountain Medical Center and Intermountain Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years

2. Within 48 hours of admission to the ICU and septic shock (sepsis present at time of admission)

   a. Septic shock defined by consensus criteria as i. At least two systemic inflammatory response syndrome (SIRS) criteria ii. Suspected or documented infection iii. 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. For patients who happen to be breathing passively on a positive pressure mechanical ventilator delivering at least 8 ml/kg tidal volumes and in normal sinus rhythm, stroke volume variability <10% (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 ECMO (extracorporeal membrane oxygenation).
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
9. Receipt of nodal blocking 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 TTE (transthoracic echocardiography) of any of the following

    • mPAP (mean pulmonary artery pressure) ≥ 35 mmHg
    • SPAP (systolic pulmonary artery pressure)≥ 60 mmHg
13. Cardiovascular collapse, as manifested by inability to achieve a MAP (mean arterial pressure) of 65 mmHg with vasopressor therapy.

14. Cardiogenic shock, as defined by any of the following

    • Cardiac index ≤ 2 L/min/m2
    • Ejection fraction ≤ 25%
    • ScvO2 ≤ 60%
    • Current infusion of any dose of dobutamine, milrinone, or dopamine
    • Current infusion of epinephrine for clinically diagnosed cardiogenic shock

15. Significant atrioventricular dysfunction

    • Sick sinus syndrome
    • PR interval (time from onset of P wave to start of QRS complex) > 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. Hemoglobin < 7 gm/dl
19. Cardiovascular collapse (failure to achieve MAP of 65mmHg)
20. Cardiac arrest within 24 hours

21. 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.

22. 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; Esmolol infusion, started without bolus, with slow upward titration to a maximum infusion rate is protocolized, with a target heart rate of 80-90/min	Drug: Esmolol; Esmolol infusion; Other Names: Brevibloc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Organ-failure-free Days	As of day 28, the number of calendar days on which the patient receives none of (a) vasopressor therapy, (b) mechanical ventilation, or (c) renal replacement therapy. If the patients dies on or before day 28, they have -1 organ-failure-free days. The resulting point-based score combines the probability of death and the number of days without organ failure. Score of -1 = Death before day 28 (Lowest Score). Score of 28 = Patient has been successful at going 28 without any vasopressor therapy/mechanical ventilation/renal replacement therapy (Highest Score)	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality		90 days
Peak Serum High-sensitivity Troponin	Measured after enrollment.	Troponin is measured on day 0 and day 1 (first day of esmolol infusion is day 0)
Left Ventricular Global Longitudinal Strain at 24 Hours		Day 1
Development of Heart Block		for duration of esmolol infusion, an expected average of 2 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Compliance With Final Safety Check		Day 0
Percentage Hourly Checks During Which Protocol Compliance Was Observed	For the esmolol titration protocol, each hour (the closest value of heart rate to the hour) during the esmolol infusion will be determined to be "in range" or "out of range," with 3bpm margin for compliance (i.e., heart rate 77 to 93bpm). The initiation and cessation of esmolol will also be included as a timepoint for evaluation of compliance. Protocol compliance is considered adequate where overall compliance on hourly checks is >80%.	for duration of esmolol infusion, an expected average of 2 days
Number of Participants With Intolerance to Esmolol Infusion at Any Given Rate	Patients who met a prespecified stop event for esmolol titration, suggesting intolerance to a given infusion rate. Per protocol, study drug titration: "The target heart rate is 85 bpm. Start study drug infusion at 20 mcg/kg/min, without bolus, if HR (heart rate) ≥ 100 bpm. If HR >90 bpm and <100 bpm, start study drug infusion at 10 mcg/kg/min, without bolus. Increase by 20 mcg/kg/min every 20 minutes as long as HR > 90 bpm, to a maximum dose of 100 mcg/kg/min. If HR < 80 bpm and > 70 bpm, decrease infusion rate by 10 mcg/kg/min; if HR ≤ 70 bpm and > 60 bpm, decrease infusion rate by 20 mcg/kg/min."	duration of esmolol infusion (~2 days)

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni A, D'Egidio A, D'Ippoliti F, Raffone C, Venditti M, Guarracino F, Girardis M, Tritapepe L, Pietropaoli P, Mebazaa A, Singer M. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013 Oct 23;310(16):1683-91. doi: 10.1001/jama.2013.278477.
• Rudiger A, Singer M. The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol. 2013 Mar 1;11(2):187-95.
• Novotny NM, Lahm T, Markel TA, Crisostomo PR, Wang M, Wang Y, Ray R, Tan J, Al-Azzawi D, Meldrum DR. beta-Blockers in sepsis: reexamining the evidence. Shock. 2009 Feb;31(2):113-9. doi: 10.1097/SHK.0b013e318180ffb6.
• Oberbeck R, Kobbe P. Beta-adrenergic antagonists: indications and potential immunomodulatory side effects in the critically ill. Curr Med Chem. 2009;16(9):1082-90. doi: 10.2174/092986709787581770.
• Brown SM, Beesley SJ, Lanspa MJ, Grissom CK, Wilson EL, Parikh SM, Sarge T, Talmor D, Banner-Goodspeed V, Novack V, Thompson BT, Shahul S; Esmolol to Control Adrenergic Storm in Septic Shock-ROLL-IN (ECASSS-R) study. Esmolol infusion in patients with septic shock and tachycardia: a prospective, single-arm, feasibility study. Pilot Feasibility Stud. 2018 Aug 3;4:132. doi: 10.1186/s40814-018-0321-5. eCollection 2018.

Helpful Links

• Esmolol infusion in patients with septic shock and tachycardia: a prospective, single-arm, feasibility study

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: July 14, 2016
• First Submitted That Met QC Criteria: July 19, 2016
• First Posted (Estimate): July 22, 2016

Study Record Updates

• Last Update Posted (Actual): January 9, 2019
• Last Update Submitted That Met QC Criteria: December 20, 2018
• Last Verified: December 1, 2018

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: 1050147

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO