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

• Sponsor: Intermountain Health Care, Inc. (Other)
• Overall Status: Completed
• CT.gov ID: NCT02841241
• Collaborator: Beth Israel Deaconess Medical Center (Other)
• Enrollment: 7
• Location: 1
• Arm: 1
• Duration (Months): 11
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Septic Shock	Drug: Esmolol	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Esmolol to Control Adrenergic Storm in Septic Shock - Roll-in
• Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Organ-failure-free Days [Day 28]

   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)

Secondary Outcome Measures

1. All-cause Mortality [90 days]

2. Peak Serum High-sensitivity Troponin [Troponin is measured on day 0 and day 1 (first day of esmolol infusion is day 0)]

   Measured after enrollment.

3. Left Ventricular Global Longitudinal Strain at 24 Hours [Day 1]

4. Development of Heart Block [for duration of esmolol infusion, an expected average of 2 days]

Other Outcome Measures

1. Proportion of Compliance With Final Safety Check [Day 0]

2. Percentage Hourly Checks During Which Protocol Compliance Was Observed [for duration of esmolol infusion, an expected average of 2 days]

   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%.

3. Number of Participants With Intolerance to Esmolol Infusion at Any Given Rate [duration of esmolol infusion (~2 days)]

   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."

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Age ≥ 18 years

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

1. 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

1. Receiving vasopressors through a central venous catheter for more than 60 minutes.

2. Arterial catheter in place or expected to be placed imminently.

3. Heart rate > 90/min while receiving vasopressors for more than 60 minutes.

4. 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.)

5. Central venous pressure (CVP) > 15 mm Hg.

6. Negative Passive-Leg Raise (PLR) maneuver (<10% increase in cardiac output after PLR).

7. 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).

8. 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

1. Cardiovascular collapse, as manifested by inability to achieve a MAP (mean arterial pressure) of 65 mmHg with vasopressor therapy.

2. 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

1. 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

1. Pheochromocytoma or status asthmaticus

2. Receiving clonidine, guanfacine, or moxonidine

3. Hemoglobin < 7 gm/dl

4. Cardiovascular collapse (failure to achieve MAP of 65mmHg)

5. Cardiac arrest within 24 hours

6. 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.

1. Worse than mild mitral stenosis • Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean gradient ≥ 5 mmHg.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Intermountain Medical Center and Intermountain Clinics	Murray	Utah	United States	84143

Sponsors and Collaborators

• Intermountain Health Care, Inc.
• Beth Israel Deaconess Medical Center

Investigators

• Principal Investigator: Samuel Brown, MD,MS, Intermountain Health Care, Inc.

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Dec 16, 2016

More Information

Additional Information:

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

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.
• 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. Review.
• 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. Review.
• Rudiger A, Singer M. The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol. 2013 Mar 1;11(2):187-95. Review.

• Responsible Party: Intermountain Health Care, Inc.
• ClinicalTrials.gov Identifier: NCT02841241
• Other Study ID Numbers: 1050147
• First Posted: Jul 22, 2016
• Last Update Posted: Jan 9, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Intermountain Health Care, Inc.: esmolol; adrenergic storm; septic shock
• Additional relevant MeSH terms: Shock, Septic; Shock; Esmolol

Study Results

Participant Flow

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Overall Participants	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46 (19)
Sex: Female, Male (Count of Participants)
Female	5 71.4%
Male	2 28.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%
Not Hispanic or Latino	6 85.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	6 85.7%
More than one race	1 14.3%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%
Admission APACHE (Acute Physiologic Assessment and Chronic Health Evaluation) II (Units on a scale (0-100)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale (0-100)]	28 (8)

Outcome Measures

1. Primary Outcome

Title	Organ-failure-free Days
Description	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)
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Median (Inter-Quartile Range) [units on a scale]	26

2. Secondary Outcome

Title	All-cause Mortality
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Peak Serum High-sensitivity Troponin
Description	Measured after enrollment.
Time Frame	Troponin is measured on day 0 and day 1 (first day of esmolol infusion is day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Median (Inter-Quartile Range) [ng/ml]	0.14

4. Secondary Outcome

Title	Left Ventricular Global Longitudinal Strain at 24 Hours
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Median (Inter-Quartile Range) [Percentage of myocardial shortening (%)]	-15.8

5. Secondary Outcome

Title	Development of Heart Block
Time Frame	for duration of esmolol infusion, an expected average of 2 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Count of Participants [Participants]	0 0%

6. Other Pre-specified Outcome

Title	Proportion of Compliance With Final Safety Check
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Count of Participants [Participants]	7 100%

7. Other Pre-specified Outcome

Title	Percentage Hourly Checks During Which Protocol Compliance Was Observed
Description	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%.
Time Frame	for duration of esmolol infusion, an expected average of 2 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Mean (Standard Deviation) [Percentage of hourly checks]	98 (4.4)

8. Other Pre-specified Outcome

Title	Number of Participants With Intolerance to Esmolol Infusion at Any Given Rate
Description	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."
Time Frame	duration of esmolol infusion (~2 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
Measure Participants	7
Count of Participants [Participants]	3 42.9%

Adverse Events

Time Frame	Duration of esmolol infusion (approximately 2 days)
Arm/Group Title	Esmolol
Arm/Group Description	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 Esmolol: Esmolol infusion
All Cause Mortality
	Esmolol
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Serious Adverse Events
	Esmolol
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Esmolol
	Affected / at Risk (%)	# Events
Total	0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.