Coronary Artery Disease, Pain, Postoperative
Conditions
Keywords
Pain management, Anesthetic, local, Nerve blockade, Coronary Artery Bypass Surgery, Analgesics, opioid, Postoperative complications, Bupivacaine
Brief summary
Exparel is a new local analgesic (numbing medication) that is intended to be longer acting than currently available local analgesics. The purpose of this study is to determine whether use of Exparel to numb the nerves along the breastbone after open heart surgery, will decrease pain and pain medication use after surgery.
Detailed description
This is a Phase 2, single-institution, randomized, double-blind, parallel-group, placebo-controlled trial of patients undergoing a median sternotomy for primary cardiopulmonary bypass grafting (CABG) surgery. 78 subjects (39 per treatment arm) will be randomized in a 1:1 ratio to receive a single-dose, parasternal nerve block with either 266 mg Exparel or placebo (0.9% normal saline solution). The nerve blocks will be performed under direct visualization at the end of surgery, just prior to sternal closure.
Interventions
DRUGExparel
Patients in this group will receive 266 mg Exparel diluted with 0.9% normal saline to a total volume of 50 mL and administered via parasternal intercostal nerve block prior to sternal closure. Post-operatively, patients will receive IV fentanyl as needed in the ICU while still intubated. A fentanyl PCA pump will be set up post-extubation as soon as possible and prior to the patient leaving the ICU.
DRUGPlacebo
Patients in this group will receive 50 mL of 0.9% normal saline as a parasternal intercostal nerve block prior to sternal closure. Post-surgical pain management will be the same as for the Exparel group.
Sponsors
Peter A Knight
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥ 18 years old * non-emergent coronary artery bypass grafting surgery (on and off pump) * median sternotomy
Exclusion criteria
* Concomitant cardiac procedures (e.g. aortic valve repair/replacement, mitral valve repair/replacement, aortic root replacements). * Redo sternotomy. * \< 50 kg (Exparel® is currently only approved in patients \> 50 kg). * Pregnant or nursing * History of alcohol, narcotic or illicit drug abuse * Participation in another study evaluating investigational medications within the past 30 days * Taking narcotic analgesics within 3 days pre-operatively or perioperative stress-dose steroids. * Chronic non-cardiac pain (e.g. lower back pain, fibromyalgia) requiring narcotic analgesics. * Pre-operative mild liver insufficiency as defined by liver function tests \[(i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST)\] ≥ 1.5 times the upper limit of normal (ULN: ALT: 0-35 U/L, AST: 0-35 U/L, Alk Phos 35-105 U/L, Total bilirubin: 0-1.2 mg/dL) * Pre-operative mild renal insufficiency (Cr ≥ 1.5 mg/dL) * Allergy to amide-type anesthetics * Recurrent ventricular arrhythmias, low cardiac output requiring inotrope and/or intra-aortic balloon pump support, left ventricular ejection fraction \< 30% at time of pre-operative screening/evaluation. * Unable to provide informed consent or unable to understand how to use pain rating scales. * Inability to understand or operate the patient-controlled analgesia (PCA) machine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Cumulative Morphine Equivalent | Outcome was measured at 1,2,4,8,12,24,36,48,60, and 72 hours post intercostal nerve block. | The cumulative opioid requirement is reported as morphine equivalent. The total amount of narcotics required by the subjects in the Exparel group and placebo group were measured at 1,2,4,8,12,24,36,48,60, and 72 hours post-injection of Exparel or 0.9% normal saline. The amounts were analyzed and are reported as morphine equivalents. |
| Median Pain Levels | Outcome was measured at 1,2,4,8,12,24,36,48,60, and 72 hours post intercostal nerve block. | The pain scores of the subjects in the Exparel group and placebo group were measured at 1,2,4,8,12,24,36,48,60, and 72 hours post-injection of Exparel or 0.9% normal saline. The pain scores were reported on a scale of 0 - 10. 0 being no pain. 10 being the worst pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Bowel Movement (Days) | 35 days | Time to first bowel movement following surgery. |
| Time to Extubation (Hours) | 77 hours | Time to remove endotracheal tube following surgery. |
| Time to Return to Work or Daily Activities | 36 days | Time to return to work or daily activities following surgery will be assessed at postoperative clinic follow up or during a follow up telephone interview. |
| Hospital Length of Stay (Days) | 25 days | Duration of time spent in the hospital following surgery. |
| ICU Length of Stay (Hours) | 135 hours | Duration of time spent in the intensive care unit postoperatively. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exparel 266 mg Exparel, single-dose injection.
Exparel: Patients in this group will receive 266 mg Exparel diluted with 0.9% normal saline to a total volume of 50 mL and administered via parasternal intercostal nerve block prior to sternal closure.
Post-operatively, patients will receive IV fentanyl as needed in the ICU while still intubated. A fentanyl PCA pump will be set up post-extubation as soon as possible and prior to the patient leaving the ICU. | 38 |
| Placebo 0.9% Normal saline, single-dose injection.
Placebo: Patients in this group will receive 50 mL of 0.9% normal saline as a parasternal intercostal nerve block prior to sternal closure.
Post-surgical pain management will be the same as for the Exparel group. | 41 |
| Total | 79 |
Baseline characteristics
| Characteristic | Placebo | Total | Exparel |
|---|---|---|---|
| Age, Categorical Age Distribution <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Age Distribution >=65 years | 17 Participants | 39 Participants | 22 Participants |
| Age, Categorical Age Distribution Between 18 and 65 years | 24 Participants | 40 Participants | 16 Participants |
| Age, Continuous | 64 years STANDARD_DEVIATION 8.6 | 65 years STANDARD_DEVIATION 8.19 | 66 years STANDARD_DEVIATION 7.7 |
| BMI | 30.4 kg/m^2 STANDARD_DEVIATION 4.7 | 30.7 kg/m^2 STANDARD_DEVIATION 4.7 | 31 kg/m^2 STANDARD_DEVIATION 4.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 40 Participants | 78 Participants | 38 Participants |
| Region of Enrollment United States | 41 Participants | 79 Participants | 38 Participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 36 Participants | 67 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 41 |
| other Total, other adverse events | 38 / 38 | 40 / 41 |
| serious Total, serious adverse events | 4 / 38 | 10 / 41 |
Outcome results
Primary
Median Cumulative Morphine Equivalent
The cumulative opioid requirement is reported as morphine equivalent. The total amount of narcotics required by the subjects in the Exparel group and placebo group were measured at 1,2,4,8,12,24,36,48,60, and 72 hours post-injection of Exparel or 0.9% normal saline. The amounts were analyzed and are reported as morphine equivalents.
Time frame: Outcome was measured at 1,2,4,8,12,24,36,48,60, and 72 hours post intercostal nerve block.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Exparel | Median Cumulative Morphine Equivalent | 1 hour post injection | 0 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 2 hours post injection | 0 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 4 hours post injection | 5 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 8 hours post injection | 5 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 12 hours post injection | 13 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 24 hours post injection | 11.5 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 36 hours post injection | 8.5 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 48 hours post injection | 4.167 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 60 hours post injection | 4.167 Morphine Equivalents |
| Exparel | Median Cumulative Morphine Equivalent | 72 hours post injection | 2.5 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 48 hours post injection | 3.33 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 1 hour post injection | 2.5 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 24 hours post injection | 18 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 2 hours post injection | 5 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 72 hours post injection | 3.33 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 4 hours post injection | 8.4 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 36 hours post injection | 15 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 8 hours post injection | 6 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 60 hours post injection | 3.33 Morphine Equivalents |
| Placebo | Median Cumulative Morphine Equivalent | 12 hours post injection | 16 Morphine Equivalents |
Primary
Median Pain Levels
The pain scores of the subjects in the Exparel group and placebo group were measured at 1,2,4,8,12,24,36,48,60, and 72 hours post-injection of Exparel or 0.9% normal saline. The pain scores were reported on a scale of 0 - 10. 0 being no pain. 10 being the worst pain.
Time frame: Outcome was measured at 1,2,4,8,12,24,36,48,60, and 72 hours post intercostal nerve block.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Exparel | Median Pain Levels | 4 hours post injection | 0 units on a scale |
| Exparel | Median Pain Levels | 24 hours post injection | 2 units on a scale |
| Exparel | Median Pain Levels | 2 hours post injection | 0 units on a scale |
| Exparel | Median Pain Levels | 36 hours post injection | 2 units on a scale |
| Exparel | Median Pain Levels | 8 hours post injection | 0 units on a scale |
| Exparel | Median Pain Levels | 1 hour post injection | 0 units on a scale |
| Exparel | Median Pain Levels | 60 hours post injection | 0 units on a scale |
| Exparel | Median Pain Levels | 12 hours post injection | 1.5 units on a scale |
| Exparel | Median Pain Levels | 72 hours post injection | 1 units on a scale |
| Exparel | Median Pain Levels | 48 hours post injection | 1.5 units on a scale |
| Placebo | Median Pain Levels | 72 hours post injection | 0 units on a scale |
| Placebo | Median Pain Levels | 1 hour post injection | 0 units on a scale |
| Placebo | Median Pain Levels | 2 hours post injection | 0 units on a scale |
| Placebo | Median Pain Levels | 4 hours post injection | 0 units on a scale |
| Placebo | Median Pain Levels | 8 hours post injection | 2 units on a scale |
| Placebo | Median Pain Levels | 12 hours post injection | 2 units on a scale |
| Placebo | Median Pain Levels | 24 hours post injection | 4 units on a scale |
| Placebo | Median Pain Levels | 36 hours post injection | 2 units on a scale |
| Placebo | Median Pain Levels | 48 hours post injection | 2 units on a scale |
| Placebo | Median Pain Levels | 60 hours post injection | 0 units on a scale |
Secondary
Hospital Length of Stay (Days)
Duration of time spent in the hospital following surgery.
Time frame: 25 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exparel | Hospital Length of Stay (Days) | 5 Days |
| Placebo | Hospital Length of Stay (Days) | 5 Days |
Secondary
ICU Length of Stay (Hours)
Duration of time spent in the intensive care unit postoperatively.
Time frame: 135 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exparel | ICU Length of Stay (Hours) | 25 Hours |
| Placebo | ICU Length of Stay (Hours) | 22.8 Hours |
Secondary
Time to Extubation (Hours)
Time to remove endotracheal tube following surgery.
Time frame: 77 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exparel | Time to Extubation (Hours) | 6.8 Hours |
| Placebo | Time to Extubation (Hours) | 6.4 Hours |
Secondary
Time to First Bowel Movement (Days)
Time to first bowel movement following surgery.
Time frame: 35 days
Population: Data was not collected on 3 participants in the Exparel arm and 1 participant in the Placebo arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exparel | Time to First Bowel Movement (Days) | 2 Days |
| Placebo | Time to First Bowel Movement (Days) | 2 Days |
Secondary
Time to Return to Work or Daily Activities
Time to return to work or daily activities following surgery will be assessed at postoperative clinic follow up or during a follow up telephone interview.
Time frame: 36 days
Population: Data was not collected on 15 participants in the Exparel arm and 17 participant in the Placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exparel | Time to Return to Work or Daily Activities | 21.8 Days | Standard Deviation 6.9 |
| Placebo | Time to Return to Work or Daily Activities | 21.3 Days | Standard Deviation 7.7 |