Hypotension, Septic Shock, Tachycardia
Conditions
Keywords
Esmolol, Septic Shock, Hypotension, Tachycardia
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).
Interventions
OTHERSaline
DRUGEsmolol
Sponsors
American Heart Association
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Heart Rates Between Groups | 6 and 12 hours | We will measure median heart rate at the 6 and 12h time points. |
| Time to Shock Reversal | Duration of hospitalization, limit 180 days | Time to shock reversal (cessation of all vasopressors for at least 12h). |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 18 |
| 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 | 22 |
| Total | 40 |
Baseline characteristics
| Characteristic | Esmolol Infusion | Standard Care, Saline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 8 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 14 Participants | 24 Participants |
| Age, Continuous | 64 years | 62 years | 63 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 18 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 18 participants | 22 participants | 40 participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 18 | 8 / 22 |
| other Total, other adverse events | 0 / 18 | 0 / 22 |
| serious Total, serious adverse events | 4 / 18 | 0 / 22 |
Outcome results
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.
Time frame: 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmolol Infusion | Need for Vasopressor Support, Measured as Mean Norepinephrine Equivalent Dose (mcg/kg/Min), at 6hr Time Point | 0.30 mcg/kg/min | Standard Deviation 0.17 |
| Standard Care, Saline | Need for Vasopressor Support, Measured as Mean Norepinephrine Equivalent Dose (mcg/kg/Min), at 6hr Time Point | 0.21 mcg/kg/min | Standard Deviation 0.19 |
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.
Time frame: 12 and 24 hours
Population: Blood was not able to be drawn from all patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | C-reactive Protein | 12 hours | 140.5 pg/mL |
| Esmolol Infusion | C-reactive Protein | 24 hours | 155.2 pg/mL |
| Standard Care, Saline | C-reactive Protein | 12 hours | 170.2 pg/mL |
| Standard Care, Saline | C-reactive Protein | 24 hours | 189.7 pg/mL |
Secondary
Heart Rates Between Groups
We will measure median heart rate at the 6 and 12h time points.
Time frame: 6 and 12 hours
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | Heart Rates Between Groups | 6 hours | 92 beats per minutes |
| Esmolol Infusion | Heart Rates Between Groups | 12 hours | 89 beats per minutes |
| Standard Care, Saline | Heart Rates Between Groups | 6 hours | 98 beats per minutes |
| Standard Care, Saline | Heart Rates Between Groups | 12 hours | 96 beats per minutes |
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.
Time frame: 12 and 24 hours
Population: Blood was not able to be drawn from all patients at all time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | Interleukin-10 | 12 hours | 3.5 pg/mL |
| Esmolol Infusion | Interleukin-10 | 24 hours | 3.4 pg/mL |
| Standard Care, Saline | Interleukin-10 | 12 hours | 5.4 pg/mL |
| Standard Care, Saline | Interleukin-10 | 24 hours | 2.8 pg/mL |
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.
Time frame: 12 and 24 hours
Population: Blood was not able to be drawn from all patients at all time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | Interleukin-4 | 12 hours | 0.027 pg/mL |
| Esmolol Infusion | Interleukin-4 | 24 hours | 0.016 pg/mL |
| Standard Care, Saline | Interleukin-4 | 12 hours | 0.023 pg/mL |
| Standard Care, Saline | Interleukin-4 | 24 hours | 0.018 pg/mL |
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.
Time frame: 12 and 24 hours
Population: Blood was not able to be drawn from all patients at all time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | Interleukin-6 | 12 hours | 62.3 pg/mL |
| Esmolol Infusion | Interleukin-6 | 24 hours | 54.4 pg/mL |
| Standard Care, Saline | Interleukin-6 | 12 hours | 78.3 pg/mL |
| Standard Care, Saline | Interleukin-6 | 24 hours | 39.0 pg/mL |
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).
Time frame: 6, 12, and 24 hours
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | Lactate | 12 hours | 27.5 percent change from baseline |
| Esmolol Infusion | Lactate | 6 hours | 16.7 percent change from baseline |
| Esmolol Infusion | Lactate | 24 hours | 30.4 percent change from baseline |
| Standard Care, Saline | Lactate | 12 hours | 8.8 percent change from baseline |
| Standard Care, Saline | Lactate | 6 hours | 0 percent change from baseline |
| Standard Care, Saline | Lactate | 24 hours | 19.1 percent change from baseline |
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.
Time frame: 12 and 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Esmolol Infusion | Overall Need for Vasopressor Support | 12 hours | 0.31 mcg/kg/min | Standard Deviation 0.19 |
| Esmolol Infusion | Overall Need for Vasopressor Support | 24 hours | 0.24 mcg/kg/min | Standard Deviation 0.19 |
| Standard Care, Saline | Overall Need for Vasopressor Support | 12 hours | 0.17 mcg/kg/min | Standard Deviation 0.17 |
| Standard Care, Saline | Overall Need for Vasopressor Support | 24 hours | 0.16 mcg/kg/min | Standard Deviation 0.17 |
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.
Time frame: 12 and 24 hours
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | Oxygen Consumption (VO2) | 12 hours | 3.78 mL/kg/min |
| Esmolol Infusion | Oxygen Consumption (VO2) | 24 hours | 4.13 mL/kg/min |
| Standard Care, Saline | Oxygen Consumption (VO2) | 12 hours | 4.29 mL/kg/min |
| Standard Care, Saline | Oxygen Consumption (VO2) | 24 hours | 4.83 mL/kg/min |
Secondary
Time to Shock Reversal
Time to shock reversal (cessation of all vasopressors for at least 12h).
Time frame: Duration of hospitalization, limit 180 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esmolol Infusion | Time to Shock Reversal | 3.9 days |
| Standard Care, Saline | Time to Shock Reversal | 2.5 days |
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.
Time frame: 12 and 24 hours
Population: Blood was not able to be drawn from all patients at all time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Esmolol Infusion | TNF-alpha | 12 hours | 4.5 pg/mL |
| Esmolol Infusion | TNF-alpha | 24 hours | 4.4 pg/mL |
| Standard Care, Saline | TNF-alpha | 12 hours | 8.7 pg/mL |
| Standard Care, Saline | TNF-alpha | 24 hours | 7.5 pg/mL |