High-risk, Non-cardiovascular Surgeries
Conditions
Brief summary
The purpose of this study is to find out if Esmolol is a safe and effective alternative treatment compared to standard treatment using a long acting beta blocker drug, in controlling abnormal heart rate before, during and immediately after surgery.
Detailed description
The benefit versus risk of perioperative beta blockade therapy for adverse ischemic event risk reduction in high risk patients undergoing non-cardiac surgery has been recently challenged. In particular the PeriOperative Ischemia Study Evaluation (POISE trial) showed a cardio-protective effect only at the expense of a higher incidence of stroke and all-cause mortality . In that study death and stroke were significantly associated with an increase in hypotension and bradycardia. Long acting agents - aggressively administered to achieve heart rate (HR) control - appear to be associated with significant adverse outcomes (death, stroke) despite myocardial ischemia and infarction reduction. It is estimated that 20 percent of high risk patients come to surgery with chronic beta blocker oral therapy. The American Heart Association recommends continuation of beta blockers in this situation as beta-blocker withdrawal is associated with increased rate of perioperative myocardial infarction . Protocols optimizing the perioperative administration of beta-blockers in high-risk patients are therefore needed. Esmolol is a cardioselective beta-blocker with a short elimination half-life (t1/2 = 9.2 min) and no intrinsic sympathomimetic activity. Evidence has revealed that Esmolol, with its unique short half life can be quickly titrated to both achieve a target hemodynamic effect as well as reduce (or loose) its effect quickly in unstable situations thereby mitigates undesired hypotension and / or bradycardia. This study proposes to assess the Safety and Efficacy of dosing to target endpoints with Esmolol - an ultra short acting beta blocker - the day of surgery compared to standard long acting oral Metoprolol the day of surgery.
Interventions
DRUGEsmolol
Infusion will be started at 50 mcg/kg/min for 4 minutes and titrated in increments of 50 mcg/kg/min up to a maximum of 300mcg/kg/min (maintenance dose) to maintain a heart rate between 60 and 80 beats per minute (bpm) while maintaining a minimum systolic blood pressure (SBP) of 95 mmHg during the length of surgery and up to 12 hours post-operatively.
Sponsors
Baxter Healthcare Corporation
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
41 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males or Females 2. Age \> 40y/o 3. Scheduled high risk (ASA II-IV) non-cardiac surgery with anticipated 12 hour post-operative ICU care 4. Written informed consent 5. Patients on a stable chronic oral beta-blocker therapy 6. Revised Cardiac Risk Index 1(below) Cardiac Risk Index 1 or greater (below) * a history of coronary disease * a history of congestive heart failure * a history of treated diabetes * a history of cerebrovascular disease * a history of chronic renal failure
Exclusion criteria
1. Active bleeding 2. Untreated left main disease 3. Active cardiac condition (eg unstable angina pectoris, acute exacerbation of CHF, serious arrhythmias, symptomatic valve disease) 4. Preoperative positive troponin T 5. Contraindication for esmolol use 6. Previous allergy or intolerance to esmolol 7. Cancer with an expected life expectancy \< 6 months 8. Pregnancy or lactating or planning to become pregnant 9. Failure to provide informed consent, unable to understand or follow instructions. 10. History of drug allergy or idiosyncrasy to beta-adrenergic drugs 11. Recent history (within 1 year) of drug or alcohol abuse 12. Patients with a Pacemaker 13. Abnormal liver function Child-Pugh - B 14. Body Mass Index \> 45 15. Reactive airway disease (defined as a history of hospitalization with status asthmaticus within the past one year) 16. Surgery scheduled to begin after 2pm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Intraoperative Case Time With Heart Rate (HR) <60 or >80 Bpm | Start of surgery to end of surgery, an average duration of 245 minutes | Duration of intraoperative excursion (ie, time spent) outside Target HR range defined as 60 to 80 bpm during surgery, expressed as percent of case minutes. Vital signs are measured from start of surgery to end of surgery at 5 minute intervals or less. |
| Percentage of Postoperative First Three Hours With Heart Rate (HR) <60 or >80 Bpm | End of surgery to 3 hours | Duration of postoperative first three hours spent outside Target HR range defined as 60 to 80 bpm, expressed as percent of the total 3 hours. Vital signs are measured from end of surgery to 3 hours postoperatively at 5 minute intervals for the first hour and every 15 minutes thereafter. |
| Percentage of Postoperative Hours 4 to 12 With Heart Rate (HR) <60 or >80 Bpm. | Postoperative hours 4-12 | Duration of postoperative hours 4 to 12 spent outside Target HR range defined as 60 to 80 bpm, expressed as percent of the total 9 hours. Vital signs are measured during hours four and five at 30 minute intervals and once every hour for the next 7 hours, through 12 hours postoperatively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Intraoperative Case Time With Systolic Blood Pressure <95 mmHg | Start of surgery to end of surgery, an average duration of 245 minutes | Duration of intraoperative case time patient was not in the target window of SBP \> 95 mmHg, expressed as percent of total case minutes. SBP is measured from start of surgery to end of surgery at 5 minute intervals or less. |
| Percentage of Postoperative First Three Hours With Systolic Blood Pressure <95 mmHg | end of surgery to 3 hours | Duration of postoperative first three hours patient was not in the target window of SBP \> 95 mmHg, expressed as percent of the total 3 hours. SBP is measured from end of surgery to 3 hours postoperatively at 5 minute intervals for first hour and every 15 minutes thereafter. |
| Percentage of Postoperative Hours 4 to 12 With Systolic Blood Pressure <95 mmHg | Postoperative hours 4-12 | Duration of postoperative hours 4 to 12 patient was not in the target window of SBP \> 95 mmHg, expressed as percent of the total 9 hours. SBP was measured during hours four and five at 30 minute intervals and once every hour for the next 7 hours, through 12 hours postoperatively. |
Countries
United States
Participant flow
Recruitment details
76 subject signed consent. 58 subjects met all inclusion/exclusion criteria and were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| Long-Acting Beta Blocker Administer patient's routine oral long acting beta blocker on day of surgery (standard of care). | 31 |
| Esmolol Replace patient's routine oral long-acting beta blocker on day of surgery with a bolus of 500 mcg/kg at start of surgery, followed by a 4 minute infusion at 50 mcg/kg/min, titrating up to a maximum of 300mcg/kg/min to maintain heart rate and SBP within specified thresholds during the length of surgery and continuing through 12 hours post-operatively. | 28 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Long-Acting Beta Blocker | Esmolol | Total |
|---|---|---|---|
| Age, Customized 18 years and older | 31 participants | 28 participants | 59 participants |
| Region of Enrollment United States | 31 participants | 28 participants | 59 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 22 Participants | 21 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 31 | 19 / 28 |
| serious Total, serious adverse events | 2 / 31 | 2 / 28 |
Outcome results
Primary
Percentage of Intraoperative Case Time With Heart Rate (HR) <60 or >80 Bpm
Duration of intraoperative excursion (ie, time spent) outside Target HR range defined as 60 to 80 bpm during surgery, expressed as percent of case minutes. Vital signs are measured from start of surgery to end of surgery at 5 minute intervals or less.
Time frame: Start of surgery to end of surgery, an average duration of 245 minutes
Population: Three enrolled cases (1 in the oral long acting beta blocker group and 2 in the Esmolol infusion group) were excluded from calculations a priori because they received diltiazem, a calcium channel blocker which lowers heart rate, before the operation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long-Acting Beta Blocker | Percentage of Intraoperative Case Time With Heart Rate (HR) <60 or >80 Bpm | 39.2 percentage of case minutes |
| Esmolol | Percentage of Intraoperative Case Time With Heart Rate (HR) <60 or >80 Bpm | 37.3 percentage of case minutes |
Primary
Percentage of Postoperative First Three Hours With Heart Rate (HR) <60 or >80 Bpm
Duration of postoperative first three hours spent outside Target HR range defined as 60 to 80 bpm, expressed as percent of the total 3 hours. Vital signs are measured from end of surgery to 3 hours postoperatively at 5 minute intervals for the first hour and every 15 minutes thereafter.
Time frame: End of surgery to 3 hours
Population: Ten cases (7 in the oral long acting beta blocker group and 3 in the Esmolol infusion group) were missing some of the postoperative vital sign measurements, resulting in gaps too long for valid calculation of the postoperative outcomes only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long-Acting Beta Blocker | Percentage of Postoperative First Three Hours With Heart Rate (HR) <60 or >80 Bpm | 56.5 percentage of 3 hour interval |
| Esmolol | Percentage of Postoperative First Three Hours With Heart Rate (HR) <60 or >80 Bpm | 39.2 percentage of 3 hour interval |
Primary
Percentage of Postoperative Hours 4 to 12 With Heart Rate (HR) <60 or >80 Bpm.
Duration of postoperative hours 4 to 12 spent outside Target HR range defined as 60 to 80 bpm, expressed as percent of the total 9 hours. Vital signs are measured during hours four and five at 30 minute intervals and once every hour for the next 7 hours, through 12 hours postoperatively.
Time frame: Postoperative hours 4-12
Population: Specific vital sign measurements were available for calculation of outcomes during the final 9 hours postoperatively in 18 cases in the Long-Acting beta blocker group and in 16 cases in the Esmolol group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long-Acting Beta Blocker | Percentage of Postoperative Hours 4 to 12 With Heart Rate (HR) <60 or >80 Bpm. | 39.5 percentage of 8 hour interval |
| Esmolol | Percentage of Postoperative Hours 4 to 12 With Heart Rate (HR) <60 or >80 Bpm. | 37 percentage of 8 hour interval |
Secondary
Percentage of Intraoperative Case Time With Systolic Blood Pressure <95 mmHg
Duration of intraoperative case time patient was not in the target window of SBP \> 95 mmHg, expressed as percent of total case minutes. SBP is measured from start of surgery to end of surgery at 5 minute intervals or less.
Time frame: Start of surgery to end of surgery, an average duration of 245 minutes
Population: Three enrolled cases (1 in the oral long acting beta blocker group and 2 in the Esmolol infusion group) were excluded from calculations a priori because they received diltiazem, a calcium channel blocker which lowers heart rate, before the operation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long-Acting Beta Blocker | Percentage of Intraoperative Case Time With Systolic Blood Pressure <95 mmHg | 3.3 percentage of surgery minutes |
| Esmolol | Percentage of Intraoperative Case Time With Systolic Blood Pressure <95 mmHg | 3.1 percentage of surgery minutes |
Secondary
Percentage of Postoperative First Three Hours With Systolic Blood Pressure <95 mmHg
Duration of postoperative first three hours patient was not in the target window of SBP \> 95 mmHg, expressed as percent of the total 3 hours. SBP is measured from end of surgery to 3 hours postoperatively at 5 minute intervals for first hour and every 15 minutes thereafter.
Time frame: end of surgery to 3 hours
Population: Ten cases (7 in the oral long acting beta blocker group and 3 in the Esmolol infusion group) were missing some of the postoperative vital sign measurements, resulting in gaps too long for valid calculation of the postoperative outcomes only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long-Acting Beta Blocker | Percentage of Postoperative First Three Hours With Systolic Blood Pressure <95 mmHg | 0 percentage of 3 hour interval |
| Esmolol | Percentage of Postoperative First Three Hours With Systolic Blood Pressure <95 mmHg | 0 percentage of 3 hour interval |
Secondary
Percentage of Postoperative Hours 4 to 12 With Systolic Blood Pressure <95 mmHg
Duration of postoperative hours 4 to 12 patient was not in the target window of SBP \> 95 mmHg, expressed as percent of the total 9 hours. SBP was measured during hours four and five at 30 minute intervals and once every hour for the next 7 hours, through 12 hours postoperatively.
Time frame: Postoperative hours 4-12
Population: Specific vital sign measurements were available for calculation of outcomes during the final 9 hours postoperatively in 18 cases in the Long-Acting BB group and in 16 cases in the Esmolol group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Long-Acting Beta Blocker | Percentage of Postoperative Hours 4 to 12 With Systolic Blood Pressure <95 mmHg | 0 percentage of 8 hour interval |
| Esmolol | Percentage of Postoperative Hours 4 to 12 With Systolic Blood Pressure <95 mmHg | 6.8 percentage of 8 hour interval |