Esmolol to Treat the Hemodynamic Effects of Septic Shock

The main purpose of this study is to determine the effects of controlling the heart rate of patients with septic shock using an intravenous medication called esmolol.

Study Overview

• Status: Terminated
• Conditions: Septic Shock; Tachycardia; Hypotension
• Intervention / Treatment: Other: Saline; Drug: Esmolol

Detailed Description

Septic shock is a leading cause of death around the world, with a mortality that often ranges 30-50% but in some locations may be even higher. Despite advances in critical care medicine over the last several decades, few therapeutic interventions have demonstrated mortality benefit in this population besides antimicrobial medications, intravenous fluids, and controlling the source of the infection; multiple agents which at one time showed promise have ultimately failed to deliver meaningful clinical benefit. As such, there is an ongoing need to identify therapeutic interventions which can modify the course of disease for these patients.

Septic shock is traditionally characterized by a hyperdynamic hemodynamic profile with a high cardiac output (CO) and low systemic vascular resistance (SVR) in association with excessive catecholamine stimulation. Tachycardia is a common finding in septic shock as an early compensatory mechanism to increase cardiac output in the setting of low SVR. Often tachycardia persists beyond the initial stages of septic shock, and has been associated with restricted diastolic ventricular filling, increased oxygen requirements, and tachycardia-induced cardiomyopathy, as well as myocardial depression, immunosuppression, and direct myocyte toxicity via calcium overload. Generally, clinical practice has been to avoid trying to control the tachycardic response for fear of worsening cardiac output and causing cardiovascular collapse. However, a recent single center randomized trial of the intravenous beta-1 adrenoreceptor antagonist esmolol demonstrated that control of heart rate to a more 'normal' range was safe, well-tolerated, and appeared beneficial, with a 30% reduction in mortality found in this trial.

While an intriguing concept with results that appear promising, further investigation among an ICU cohort in the United States is necessary before the administration of beta-blockade therapy to a patient in septic shock should be implemented in routine clinical practice. We hypothesize that the provision of esmolol to patients in vasopressor-dependent septic shock with tachycardia will lower the heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in need for vasopressor support. To test our hypothesis, we are conducting a Phase II randomized trial to determine if esmolol decreases vasopressor requirements (primary endpoint) and alters the inflammatory cascade as well as oxygen consumption in patients with septic shock (secondary endpoints).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center

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:

• Adult (≥ 18 years)
• Sepsis defined as suspected or confirmed infection with at least two systemic inflammatory response syndrome (SIRS) criteria
• Norepinephrine (minimum 0.1 mcg/kg/min) support to maintain a mean arterial pressure ≥ 65 mmHg despite appropriate volume resuscitation (as defined by the clinical team, however at least 30mL/kg intravenous fluid
• Heart rate ≥ 95 per minute for at least 2 hours prior to enrollment
• 6-24 hours since ICU admission

Exclusion Criteria:

• Intravenous β-blocker therapy prior to randomization
• Pronounced cardiac dysfunction (i.e. cardiac index [CI] ≤ 2.2 L/min/m2)
• Known significant valvular heart disease
• Research-protected populations (pregnant women, prisoners, intellectually disabled)
• Known "Do-not-resuscitate" or "do-not-intubate" order at the time of enrollment
• Infusion of epinephrine, dopamine, dobutamine or milrinone at time of enrollment
• Known allergy/sensitivity to esmolol or history of asthma/COPD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Esmolol infusion; Esmolol infusion for 24 hours. Esmolol will be titrated to a heart rate of 80 - 94 per minute, starting at 10mcg/kg/min and subsequently increasing every 20 minutes in increments of 10 mcg/kg/min (or slower at the discretion of the team) until target is achieved. The maximum allowed dose will be 300mcg/kg/min. Patients, irrespective of treatment group, will be managed at the discretion of the clinical team. BIDMC has internal guidelines for the management of septic shock which reflect the most recent 2012 Surviving Sepsis Campaign guidelines and are incorporated into the care of patients with septic shock in the ICUs	Drug: Esmolol; Other Names: Beta Blocker
Placebo Comparator: Standard care, Saline; Standard care (no esmolol). Patients, irrespective of treatment group, will be managed at the discretion of the clinical team. BIDMC has internal guidelines for the management of septic shock which reflect the most recent 2012 Surviving Sepsis Campaign guidelines and are incorporated into the care of patients with septic shock in the ICUs	Other: Saline; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for Vasopressor Support, Measured as Mean Norepinephrine Equivalent Dose (mcg/kg/Min), at 6hr Time Point	The primary endpoint will be mean norepinephrine equivalent dose (mcg/kg/min) at 6 hours after onset of study drug. For the vasopressor vasopressin, the dose of vasopressin was multiplied by 2.5 in order to create a norepinephrine equivalent dose. For the vasopressor phenylephrine, the dose of phenylephrine was divided by 10 in order to create a norepinephrine equivalent dose.	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Need for Vasopressor Support	While the primary endpoint will be mean norepinephrine dose at 6h, we will also measure mean vasopressor dose in groups at 12h and 24h.	12 and 24 hours
Heart Rates Between Groups	We will measure median heart rate at the 6 and 12h time points.	6 and 12 hours
Time to Shock Reversal	Time to shock reversal (cessation of all vasopressors for at least 12h).	Duration of hospitalization, limit 180 days
Lactate	Median percent change from baseline lactate measured at the 6, 12, and 24 hour time points after study initiation between groups. Percent change was calculated by subtracting the later lactate from the baseline lactate and dividing the difference by the baseline lactate (i.e. (baseline lactate - 6h lactate)/baseline lactate).	6, 12, and 24 hours
Oxygen Consumption (VO2)	To analyze the difference in oxygen consumption between groups at 12 hours, 24 hours and over time for patients who were on mechanical ventilation at enrollment, VO2 measurements were compared (standardized by bodyweight in kilograms) over time (recorded every minute from the time of study drug administration over a period of at least 24 hours) between groups using mixed linear model accounting for repeated measures. Using an unadjusted model, mean differences at 12 hours, 24 hours and for differences in the overall trend over time were tested.	12 and 24 hours
Interleukin-4	To characterize effects of esmolol on inflammatory markers in patients with vasopressor-dependent septic shock, we compared log-transformed values of interleukin-4 at 12 and 24 hours and over time between groups using mixed linear model accounting for repeated measures and adjusting for pre-intervention levels.	12 and 24 hours
Interleukin-6	To characterize effects of esmolol on inflammatory markers in patients with vasopressor-dependent septic shock, we compared log-transformed values of interleukin-6 at 12 and 24 hours and over time between groups using mixed linear model accounting for repeated measures and adjusting for pre-intervention levels.	12 and 24 hours
Interleukin-10	To characterize effects of esmolol on inflammatory markers in patients with vasopressor-dependent septic shock, we compared log-transformed values of interleukin-10 at 12 and 24 hours and over time between groups using mixed linear model accounting for repeated measures and adjusting for pre-intervention levels.	12 and 24 hours
TNF-alpha	To characterize effects of esmolol on inflammatory markers in patients with vasopressor-dependent septic shock, we compared log-transformed values of TNF-alpha at 12 and 24 hours and over time between groups using mixed linear model accounting for repeated measures and adjusting for pre-intervention levels.	12 and 24 hours
C-reactive Protein	To characterize effects of esmolol on inflammatory markers in patients with vasopressor-dependent septic shock, we compared log-transformed values of C-reactive protein at 12 and 24 hours and over time between groups using mixed linear model accounting for repeated measures and adjusting for pre-intervention levels.	12 and 24 hours

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: American Heart Association

Publications and helpful links

General Publications

• Cocchi MN, Dargin J, Chase M, Patel PV, Grossestreuer A, Balaji L, Liu X, Moskowitz A, Berg K, Donnino MW. Esmolol to Treat the Hemodynamic Effects of Septic Shock: A Randomized Controlled Trial. Shock. 2022 Apr 1;57(4):508-517. doi: 10.1097/SHK.0000000000001905.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): December 31, 2019

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: February 18, 2015
• First Posted (Estimate): February 24, 2015

Study Record Updates

• Last Update Posted (Actual): June 28, 2021
• Last Update Submitted That Met QC Criteria: June 24, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Hypotension; Septic Shock; Esmolol; Tachycardia
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Shock, Septic; Shock; Tachycardia; Hypotension; 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: 2014P000415; 15SDG22420010 (Other Grant/Funding Number: American Heart Association)