Esmolol to Treat the Hemodynamic Effects of Septic Shock

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02369900
• Collaborator: American Heart Association (Other)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 58
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 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: Mar 1, 2015
• Actual Primary Completion Date: Dec 31, 2019
• Actual Study Completion Date: Dec 31, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. Heart Rates Between Groups [6 and 12 hours]

   We will measure median heart rate at the 6 and 12h time points.

3. Time to Shock Reversal [Duration of hospitalization, limit 180 days]

   Time to shock reversal (cessation of all vasopressors for at least 12h).

4. 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).

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• American Heart Association

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 1, 2015
• Statistical Analysis Plan - Dec 3, 2020
• Informed Consent Form - Sep 14, 2020

More Information

Publications

None provided.

• Responsible Party: Michael N. Cocchi, MD, Michael N Cocchi MD, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT02369900
• Other Study ID Numbers: 2014P000415; 15SDG22420010
• First Posted: Feb 24, 2015
• Last Update Posted: Jun 28, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Michael N. Cocchi, MD, Michael N Cocchi MD, Beth Israel Deaconess Medical Center: Esmolol; Septic Shock; Hypotension; Tachycardia
• Additional relevant MeSH terms: Shock, Septic; Hypotension; Tachycardia; Shock; Esmolol

Study Results

Participant Flow

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Period Title: Overall Study
STARTED	18	22
COMPLETED	18	22
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Esmolol Infusion	Standard Care, Saline	Total
Arm/Group Description	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 Esmolol	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 Saline	Total of all reporting groups
Overall Participants	18	22	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 55.6%	14 63.6%	24 60%
>=65 years	8 44.4%	8 36.4%	16 40%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	64	62	63
Sex: Female, Male (Count of Participants)
Female	8 44.4%	9 40.9%	17 42.5%
Male	10 55.6%	13 59.1%	23 57.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.6%	0 0%	1 2.5%
Not Hispanic or Latino	13 72.2%	18 81.8%	31 77.5%
Unknown or Not Reported	4 22.2%	4 18.2%	8 20%
Region of Enrollment (participants) [Number]
United States	18 100%	22 100%	40 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
Mean (Standard Deviation) [mcg/kg/min]	0.30 (0.17)	0.21 (0.19)

2. Secondary Outcome

Title	Overall Need for Vasopressor Support
Description	While the primary endpoint will be mean norepinephrine dose at 6h, we will also measure mean vasopressor dose in groups at 12h and 24h.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
12 hours	0.31 (0.19)	0.17 (0.17)
24 hours	0.24 (0.19)	0.16 (0.17)

3. Secondary Outcome

Title	Heart Rates Between Groups
Description	We will measure median heart rate at the 6 and 12h time points.
Time Frame	6 and 12 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
6 hours	92	98
12 hours	89	96

4. Secondary Outcome

Title	Time to Shock Reversal
Description	Time to shock reversal (cessation of all vasopressors for at least 12h).
Time Frame	Duration of hospitalization, limit 180 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
Median (Inter-Quartile Range) [days]	3.9	2.5

5. Secondary Outcome

Title	Lactate
Description	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).
Time Frame	6, 12, and 24 hours

Outcome Measure Data

Analysis Population Description

One patient in the standard care group was missing lactate levels at 6, 12, and 24 hours and one patient in the standard care group was missing a lactate level at 24 hours.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	21
6 hours	16.7	0
12 hours	27.5	8.8
24 hours	30.4	19.1

6. Secondary Outcome

Title	Oxygen Consumption (VO2)
Description	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.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

Only patients on mechanical ventilation who were able to be attached to the VO2 machine and had data within the first 24 hours were included.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	6	9
12 hours	3.78	4.29
24 hours	4.13	4.83

7. Secondary Outcome

Title	Interleukin-4
Description	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.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

Blood was not able to be drawn from all patients at all time points.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
12 hours	0.027	0.023
24 hours	0.016	0.018

8. Secondary Outcome

Title	Interleukin-6
Description	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.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

Blood was not able to be drawn from all patients at all time points.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
12 hours	62.3	78.3
24 hours	54.4	39.0

9. Secondary Outcome

Title	Interleukin-10
Description	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.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

Blood was not able to be drawn from all patients at all time points.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
12 hours	3.5	5.4
24 hours	3.4	2.8

10. Secondary Outcome

Title	TNF-alpha
Description	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.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

Blood was not able to be drawn from all patients at all time points.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
12 hours	4.5	8.7
24 hours	4.4	7.5

11. Secondary Outcome

Title	C-reactive Protein
Description	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.
Time Frame	12 and 24 hours

Outcome Measure Data

Analysis Population Description

Blood was not able to be drawn from all patients.

Arm/Group Title	Esmolol Infusion	Standard Care, Saline
Arm/Group Description	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 Esmolol	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 Saline
Measure Participants	18	22
12 hours	140.5	170.2
24 hours	155.2	189.7

Adverse Events

Time Frame	24 hours
Arm/Group Title	Esmolol Infusion		Standard Care, Saline
Arm/Group Description	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 Esmolol		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 Saline
All Cause Mortality
	Esmolol Infusion		Standard Care, Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		8/22 (36.4%)
Serious Adverse Events
	Esmolol Infusion		Standard Care, Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/18 (22.2%)		0/22 (0%)
Cardiac disorders
Decrease in Cardiac Index	4/18 (22.2%)	4	0/22 (0%)	0
Abnormal Heart Rhythym	1/18 (5.6%)	1	0/22 (0%)	0
General disorders
PEA arrest	1/18 (5.6%)	1	0/22 (0%)	0
Other (Not Including Serious) Adverse Events
	Esmolol Infusion		Standard Care, Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)

Limitations/Caveats

The trial ended early due to slow enrollments and ending of funding before the target enrollment was reached. Many patients with septic shock were excluded because of the absence of tachycardia, or due to the presence of myocardial dysfunction. We did not collect echocardiographic data. Patients in the esmolol arm had differing exposures to esmolol, based on variable dosing and duration due to individual patient characteristics.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.