Esmolol to Treat the Hemodynamic Effects of Septic Shock

Phase 2

Terminated

Conditions: Septic Shock
Tachycardia
Hypotension

Interventions: Other: Saline
Drug: Esmolol

Registration Number: NCT02369900

Lead Sponsor: 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.

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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 40

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard care, Saline	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
Esmolol infusion	Esmolol	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

Primary Outcome Measures

Name	Time	Method
Need for Vasopressor Support, Measured as Mean Norepinephrine Equivalent Dose (mcg/kg/Min), at 6hr Time Point	6 hours	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.

Secondary Outcome Measures

Name	Time	Method
Time to Shock Reversal	Duration of hospitalization, limit 180 days	Time to shock reversal (cessation of all vasopressors for at least 12h).
Oxygen Consumption (VO2)	12 and 24 hours	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.
Interleukin-10	12 and 24 hours	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.
TNF-alpha	12 and 24 hours	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.
C-reactive Protein	12 and 24 hours	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.
Overall Need for Vasopressor Support	12 and 24 hours	While the primary endpoint will be mean norepinephrine dose at 6h, we will also measure mean vasopressor dose in groups at 12h and 24h.
Heart Rates Between Groups	6 and 12 hours	We will measure median heart rate at the 6 and 12h time points.
Lactate	6, 12, and 24 hours	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).
Interleukin-4	12 and 24 hours	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.
Interleukin-6	12 and 24 hours	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.