Parasternal Nerve Block in Cardiac Patients

• Sponsor: Peter A Knight (Other)
• Overall Status: Completed
• CT.gov ID: NCT01826851
• Collaborator: (none)
• Enrollment: 79
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Pain, Postoperative	Drug: Exparel; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 79 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Parasternal Intercostal Nerve Block in Post-Cardiac Surgery Patients: A Randomized, Controlled Trial of Extended-release Liposomal Bupivacaine (Exparel) Versus Placebo
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exparel 266 mg Exparel, single-dose injection.	Drug: 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.; Other Names: SKY0402 Bupivacaine liposome extended-release injectable suspension
Placebo Comparator: Placebo 0.9% Normal saline, single-dose injection.	Drug: 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.; Other Names: Preservative-free normal saline

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. Time to Extubation (Hours) [77 hours]

   Time to remove endotracheal tube following surgery.

2. ICU Length of Stay (Hours) [135 hours]

   Duration of time spent in the intensive care unit postoperatively.

3. Time to First Bowel Movement (Days) [35 days]

   Time to first bowel movement following surgery.

4. Hospital Length of Stay (Days) [25 days]

   Duration of time spent in the hospital following surgery.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester Medical Center	Rochester	New York	United States	14642

Sponsors and Collaborators

• Peter A Knight

Investigators

• Principal Investigator: Peter A Knight, MD, University of Rochester

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 15, 2018

More Information

Publications

None provided.

• Responsible Party: Peter A Knight, Professor, Cardiac Surgery, University of Rochester
• ClinicalTrials.gov Identifier: NCT01826851
• Other Study ID Numbers: RSRB 00044181
• First Posted: Apr 9, 2013
• Last Update Posted: Aug 1, 2018
• Last Verified: Jul 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Peter A Knight, Professor, Cardiac Surgery, University of Rochester: Pain management; Anesthetic, local; Nerve blockade; Coronary Artery Bypass Surgery; Analgesics, opioid; Postoperative complications; Bupivacaine
• Additional relevant MeSH terms: Coronary Artery Disease; Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	38	41
COMPLETED	38	41
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Exparel	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	38	41	79
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 42.1%	24 58.5%	40 50.6%
>=65 years	22 57.9%	17 41.5%	39 49.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (7.7)	64 (8.6)	65 (8.19)
Sex: Female, Male (Count of Participants)
Female	7 18.4%	5 12.2%	12 15.2%
Male	31 81.6%	36 87.8%	67 84.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 2.4%	1 1.3%
White	38 100%	40 97.6%	78 98.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	38 100%	41 100%	79 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31 (4.8)	30.4 (4.7)	30.7 (4.7)

Outcome Measures

1. Primary Outcome

Title	Median Cumulative Morphine Equivalent
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	38	41
1 hour post injection	0	2.5
2 hours post injection	0	5
4 hours post injection	5	8.4
8 hours post injection	5	6
12 hours post injection	13	16
24 hours post injection	11.5	18
36 hours post injection	8.5	15
48 hours post injection	4.167	3.33
60 hours post injection	4.167	3.33
72 hours post injection	2.5	3.33

2. Primary Outcome

Title	Median Pain Levels
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	38	41
1 hour post injection	0	0
2 hours post injection	0	0
4 hours post injection	0	0
8 hours post injection	0	2
12 hours post injection	1.5	2
24 hours post injection	2	4
36 hours post injection	2	2
48 hours post injection	1.5	2
60 hours post injection	0	0
72 hours post injection	1	0

3. Secondary Outcome

Title	Time to Extubation (Hours)
Description	Time to remove endotracheal tube following surgery.
Time Frame	77 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	38	41
Median (Inter-Quartile Range) [Hours]	6.8	6.4

4. Secondary Outcome

Title	ICU Length of Stay (Hours)
Description	Duration of time spent in the intensive care unit postoperatively.
Time Frame	135 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	38	41
Median (Inter-Quartile Range) [Hours]	25	22.8

5. Secondary Outcome

Title	Time to First Bowel Movement (Days)
Description	Time to first bowel movement following surgery.
Time Frame	35 days

Outcome Measure Data

Analysis Population Description

Data was not collected on 3 participants in the Exparel arm and 1 participant in the Placebo arm.

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	35	40
Median (Inter-Quartile Range) [Days]	2	2

6. Secondary Outcome

Title	Hospital Length of Stay (Days)
Description	Duration of time spent in the hospital following surgery.
Time Frame	25 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	38	41
Median (Inter-Quartile Range) [Days]	5	5

7. Secondary Outcome

Title	Time to Return to Work or Daily Activities
Description	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

Outcome Measure Data

Analysis Population Description

Data was not collected on 15 participants in the Exparel arm and 17 participant in the Placebo arm.

Arm/Group Title	Exparel	Placebo
Arm/Group Description	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.	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.
Measure Participants	23	24
Mean (Standard Deviation) [Days]	21.8 (6.9)	21.3 (7.7)

Adverse Events

Time Frame	Adverse event data were collected at throughout a 72 hour post intercostal nerve block at 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours. Adverse event data was also collected at the time of follow-up, which occurred at 3-4 weeks post-operatively.
Arm/Group Title	Exparel		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Exparel		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/41 (0%)
Serious Adverse Events
	Exparel		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/38 (10.5%)		10/41 (24.4%)
Cardiac disorders
Myocardial infarction	0/38 (0%)	0	0/41 (0%)	0
New onset SVT or ventricular tachycardia	3/38 (7.9%)	3	6/41 (14.6%)	6
Heart Failure	0/38 (0%)	0	0/41 (0%)	0
New onset ventricular fibrillation	0/38 (0%)	0	2/41 (4.9%)	2
General disorders
Suspected bupivacaine toxicity	0/38 (0%)	0	0/41 (0%)	0
Readmission to ICU	0/38 (0%)	0	0/41 (0%)	0
Multiorgan failure	0/38 (0%)	0	0/41 (0%)	0
Infections and infestations
Sepsis	0/38 (0%)	0	0/41 (0%)	0
Mediastinitis	0/38 (0%)	0	0/41 (0%)	0
Nervous system disorders
Transient ischemic attack	0/38 (0%)	0	0/41 (0%)	0
Cerebral vascular accident with permanent deficits	1/38 (2.6%)	1	0/41 (0%)	0
Coma	0/38 (0%)	0	0/41 (0%)	0
Encephalopathy	0/38 (0%)	0	0/41 (0%)	0
Renal and urinary disorders
Renal failure requiring hemodialysis	0/38 (0%)	0	0/41 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/38 (0%)	0	2/41 (4.9%)	2
Surgical and medical procedures
Sternal wound dehiscence	0/38 (0%)	0	0/41 (0%)	0
Reoperation due to graft failure	0/38 (0%)	0	0/41 (0%)	0
Reoperation for bleeding	0/38 (0%)	0	0/41 (0%)	0
Phrenic nerve Injury	0/38 (0%)	0	0/41 (0%)	0
Vascular disorders
Deep venous thrombosis	0/38 (0%)	0	0/41 (0%)	0
Pulmonary embolism	0/38 (0%)	0	0/41 (0%)	0
Acute limb ischemia	0/38 (0%)	0	0/41 (0%)	0
Aortic dissection	0/38 (0%)	0	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Exparel		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/38 (100%)		40/41 (97.6%)
Cardiac disorders
Atrial Fibrillation	12/38 (31.6%)	12	13/41 (31.7%)	13
Bradycardia	6/38 (15.8%)		4/41 (9.8%)
Bundle Branch Block	9/38 (23.7%)		8/41 (19.5%)
First Degree AV Block	5/38 (13.2%)		7/41 (17.1%)
Premature Atrial Contraction	2/38 (5.3%)		0/41 (0%)
Palpitations	7/38 (18.4%)		5/41 (12.2%)
Prolonged QT Interval	8/38 (21.1%)		5/41 (12.2%)
Premature Ventricular Contraction	11/38 (28.9%)		11/41 (26.8%)
ST Changes	2/38 (5.3%)		6/41 (14.6%)
Sinus Tachycardia	9/38 (23.7%)		6/41 (14.6%)
Gastrointestinal disorders
Constipation	16/38 (42.1%)		20/41 (48.8%)
Diarrhea	7/38 (18.4%)		9/41 (22%)
Nausea	24/38 (63.2%)		18/41 (43.9%)
Vomiting	9/38 (23.7%)		0/41 (0%)
General disorders
Anxiety	9/38 (23.7%)		16/41 (39%)
Blurred Vision	3/38 (7.9%)		0/41 (0%)
Chills	3/38 (7.9%)		3/41 (7.3%)
Diaphoresis	14/38 (36.8%)		14/41 (34.1%)
Dizziness/Light headedness	18/38 (47.4%)		22/41 (53.7%)
Fever	2/38 (5.3%)		6/41 (14.6%)
Itching	3/38 (7.9%)		0/41 (0%)
Metallic Taste in Mouth	5/38 (13.2%)		7/41 (17.1%)
Restlessness	12/38 (31.6%)		15/41 (36.6%)
Musculoskeletal and connective tissue disorders
Generalized Weakness	17/38 (44.7%)		18/41 (43.9%)
Nervous system disorders
Headache	4/38 (10.5%)		7/41 (17.1%)
Miosis	0/38 (0%)		3/41 (7.3%)
Parasthesias	5/38 (13.2%)		13/41 (31.7%)
Somnolence	12/38 (31.6%)		12/41 (29.3%)
Tinnitis	6/38 (15.8%)		3/41 (7.3%)
Tremors	2/38 (5.3%)		0/41 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.