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Esmolol to Treat the Hemodynamic Effects of Septic Shock

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ClinicalTrials.gov Identifier: NCT02369900
Recruitment Status : Recruiting
First Posted : February 24, 2015
Last Update Posted : February 26, 2019
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Michael N. Cocchi, MD, Beth Israel Deaconess Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Septic Shock Hypotension Tachycardia Drug: Esmolol Other: Saline Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Esmolol to Treat the Hemodynamic Effects of Septic Shock
Study Start Date : March 2015
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

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 Name: 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 Name: Normal Saline




Primary Outcome Measures :
  1. Reduction in need for vasopressor support at 6hr time point [ Time Frame: 6 hours ]
    The primary endpoint will be improvement in the hemodynamic profile as measured by a decrease in the need for norepinephrine support. This will be defined as the difference in norepinephrine dose between groups at 6 hours after onset of study drug.


Secondary Outcome Measures :
  1. Overall reduction in need for vasopressor support [ Time Frame: 24 hours ]
    While the primary endpoint will be difference in norepinephrine dose at 6h, we will also measure the difference in vasopressor dose between groups at 12h and over time.

  2. Differences in heart rates between groups [ Time Frame: 12 hours ]
    We will also measure differences in heart rate at the 6 and 12h time points and over time.

  3. Time to shock reversal [ Time Frame: Duration of hospitalization, limit 180 days ]
    Time to shock reversal (cessation of all vasopressors for at least 12h).

  4. Lactate [ Time Frame: 24 hours ]
    Change in lactate over time between groups. Measured at the 0, 6, 12, 24 hour time points after study initiation.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02369900


Contacts
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Contact: Michael Cocchi, M.D. 617-754-2339 mcocchi@bidmc.harvard.edu
Contact: Varun Konanki, B.S 617-754-2881 vkonanki@bidmc.harvard.edu

Locations
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United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02115
Contact: Michael N Cocchi, MD    617-754-2388      
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
American Heart Association

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Responsible Party: Michael N. Cocchi, MD, Michael N Cocchi MD, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT02369900     History of Changes
Other Study ID Numbers: 2014P000415
15SDG22420010 ( Other Grant/Funding Number: American Heart Association )
First Posted: February 24, 2015    Key Record Dates
Last Update Posted: February 26, 2019
Last Verified: February 2019
Keywords provided by Michael N. Cocchi, MD, Beth Israel Deaconess Medical Center:
Esmolol
Septic Shock
Hypotension
Tachycardia
Additional relevant MeSH terms:
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Tachycardia
Shock, Septic
Hypotension
Shock
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Vascular Diseases
Cardiovascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Cardiac Conduction System Disease
Esmolol
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs