Septic Shock
Conditions
Keywords
esmolol, adrenergic storm, septic shock
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.
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.
Interventions
DRUGEsmolol
Esmolol infusion
Sponsors
Beth Israel Deaconess Medical Center
Intermountain Health Care, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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) a. 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 3. Receiving vasopressors through a central venous catheter for more than 60 minutes. 4. Arterial catheter in place or expected to be placed imminently. 5. Heart rate \> 90/min while receiving vasopressors for more than 60 minutes. 6. 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.) 1. Central venous pressure (CVP) \> 15 mm Hg. 2. Negative Passive-Leg Raise (PLR) maneuver (\<10% increase in cardiac output after PLR). 3. 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). 4. 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 13. Cardiovascular collapse, as manifested by inability to achieve a MAP (mean arterial pressure) of 65 mmHg with vasopressor therapy. 14. 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 15. 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 16. Pheochromocytoma or status asthmaticus 17. Receiving clonidine, guanfacine, or moxonidine 18. Hemoglobin \< 7 gm/dl 19. Cardiovascular collapse (failure to achieve MAP of 65mmHg) 20. Cardiac arrest within 24 hours 21. 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. 22. Worse than mild mitral stenosis • Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean gradient ≥ 5 mmHg.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| All-cause Mortality | 90 days | — |
| Left Ventricular Global Longitudinal Strain at 24 Hours | Day 1 | — |
| Development of Heart Block | for duration of esmolol infusion, an expected average of 2 days | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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%. |
| Proportion of Compliance With Final Safety Check | Day 0 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Esmolol: Esmolol infusion | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Esmolol |
|---|---|
| Admission APACHE (Acute Physiologic Assessment and Chronic Health Evaluation) II | 28 Units on a scale (0-100) STANDARD_DEVIATION 8 |
| Age, Continuous | 46 years STANDARD_DEVIATION 19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Organ-failure-free Days
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esmolol | Organ-failure-free Days | 26 units on a scale |
Secondary
All-cause Mortality
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Esmolol | All-cause Mortality | 0 Participants |
Secondary
Development of Heart Block
Time frame: for duration of esmolol infusion, an expected average of 2 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Esmolol | Development of Heart Block | 0 Participants |
Secondary
Left Ventricular Global Longitudinal Strain at 24 Hours
Time frame: Day 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esmolol | Left Ventricular Global Longitudinal Strain at 24 Hours | -15.8 Percentage of myocardial shortening (%) |
Secondary
Peak Serum High-sensitivity Troponin
Measured after enrollment.
Time frame: Troponin is measured on day 0 and day 1 (first day of esmolol infusion is day 0)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esmolol | Peak Serum High-sensitivity Troponin | 0.14 ng/ml |
Other Pre-specified
Number of Participants With Intolerance to Esmolol Infusion at Any Given Rate
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Esmolol | Number of Participants With Intolerance to Esmolol Infusion at Any Given Rate | 3 Participants |
Other Pre-specified
Percentage Hourly Checks During Which Protocol Compliance Was Observed
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmolol | Percentage Hourly Checks During Which Protocol Compliance Was Observed | 98 Percentage of hourly checks | Standard Deviation 4.4 |
Other Pre-specified
Proportion of Compliance With Final Safety Check
Time frame: Day 0
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Esmolol | Proportion of Compliance With Final Safety Check | 7 Participants |