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| ID | Type | Description | Link |
|---|---|---|---|
| 15SDG22420010 | Other Grant/Funding Number | American Heart Association |
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Funding expired, low enrollments
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| Name | Class |
|---|---|
| American Heart Association | OTHER |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Esmolol infusion | Active Comparator | 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 |
|
| Standard care, Saline | Placebo Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Esmolol | Drug |
|
| |
| Saline |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35066509 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 Esmolol |
| FG001 | 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 Saline |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 Esmolol |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | mcg/kg/min | 6 hours |
|
24 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 Esmolol |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Decrease in Cardiac Index | Cardiac disorders | Systematic Assessment | During intervention, the patient's CI dropped below 2.1. The esmolol medication was stopped per protocol. |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michael N. Cocchi MD | Beth Israel Deaconess Medical Center | 617-754-2388 | mcocchi@bidmc.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 1, 2015 | May 28, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 3, 2020 | May 4, 2021 | SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 14, 2020 | May 4, 2021 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| D007022 | Hypotension |
| D013610 | Tachycardia |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
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| ID | Term |
|---|---|
| C036604 | esmolol |
| D000319 | Adrenergic beta-Antagonists |
| D012965 | Sodium Chloride |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D018674 | Adrenergic Antagonists |
| D018663 | Adrenergic Agents |
| D018377 | Neurotransmitter Agents |
| D045504 | Molecular Mechanisms of Pharmacological Action |
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| Other |
|
|
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 |
| BG001 | 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 Saline |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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 Saline |
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | mcg/kg/min | 12 and 24 hours |
|
|
|
| Secondary | Heart Rates Between Groups | We will measure median heart rate at the 6 and 12h time points. | Posted | Median | Inter-Quartile Range | beats per minutes | 6 and 12 hours |
|
|
|
| Secondary | Time to Shock Reversal | Time to shock reversal (cessation of all vasopressors for at least 12h). | Posted | Median | Inter-Quartile Range | days | Duration of hospitalization, limit 180 days |
|
|
|
| Secondary | 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). | 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. | Posted | Median | Inter-Quartile Range | percent change from baseline | 6, 12, and 24 hours |
|
|
|
| Secondary | 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. | 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. | Posted | Median | Inter-Quartile Range | mL/kg/min | 12 and 24 hours |
|
|
|
| Secondary | 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. | Blood was not able to be drawn from all patients at all time points. | Posted | Median | Inter-Quartile Range | pg/mL | 12 and 24 hours |
|
|
|
| Secondary | 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. | Blood was not able to be drawn from all patients at all time points. | Posted | Median | Inter-Quartile Range | pg/mL | 12 and 24 hours |
|
|
|
| Secondary | 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. | Blood was not able to be drawn from all patients at all time points. | Posted | Median | Inter-Quartile Range | pg/mL | 12 and 24 hours |
|
|
|
| Secondary | 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. | Blood was not able to be drawn from all patients at all time points. | Posted | Median | Inter-Quartile Range | pg/mL | 12 and 24 hours |
|
|
|
| Secondary | 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. | Blood was not able to be drawn from all patients. | Posted | Median | Inter-Quartile Range | pg/mL | 12 and 24 hours |
|
|
|
| 6 |
| 18 |
| 4 |
| 18 |
| 0 |
| 18 |
| EG001 | 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 Saline | 8 | 22 | 0 | 22 | 0 | 22 |
|
| Abnormal Heart Rhythym | Cardiac disorders | Systematic Assessment | Patient had incidents of supraventricular tachycardia. The clinical team decided to continue esmolol treatment as the event was deemed unrelated to study protocol. |
|
| PEA arrest | General disorders | Systematic Assessment | An enrolled subject experienced a brief PEA arrest during turning. The arrest was attributed to a kinked endotracheal tube during turning and unrelated to study protocol. |
|
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| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D000075224 | Cardiac Conduction System Disease |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D045505 | Physiological Effects of Drugs |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| 12 hours |
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| 24 hours |
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| 24 hours |
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| 24 hours |
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| 24 hours |
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| 24 hours |
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| 24 hours |
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