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| Name | Class |
|---|---|
| Foundation for Anesthesia Education and Research | OTHER |
| American Heart Association | OTHER |
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In this study, the investigators aim to determine whether injecting botulinum toxin into epicardial fat pads is efficacious and safe for decreasing postoperative atrial fibrillation (POAF) after cardiac surgery. The investigators will test the hypothesis that botulinum toxin injected into the epicardial fat pads reduces POAF and length of stay (LOS) without increasing adverse events. This will be a prospective randomized trial of 130 patients undergoing coronary artery bypass graft (CABG), valve surgery or CABG + valve surgery with cardiopulmonary bypass. Patients will be randomized to receive either botulinum toxin (50 units per fat pad, n=65) or normal saline/placebo (1 mL per fat pad, n=65) injected into epicardial fat pads. All patients will receive standardized anesthetic, surgical, and post-surgical care. The primary outcome in this study will be time to occurrence of in-hospital POAF. Based on previous work and a pilot trial showing a pronounced reduction (relative risk reduction 77%) in POAF after injecting botulinum into the epicardial fat pads, the investigators anticipate a significant reduction in the risk for POAF with epicardial botulinum in this cohort, which includes valve surgery patients.
Purpose of the study: A pilot study to determine whether injecting botulinum toxin into epicardial fat pads is efficacious and safe for decreasing postoperative atrial fibrillation (POAF) after cardiac surgery
Hypothesis to be tested: Botulinum toxin injected into the epicardial fat pads reduces POAF.
Design and Procedures: This will be a prospective randomized pilot trial of 130 patients undergoing coronary artery bypass graft (CABG), valve surgery or CABG + valve surgery via median sternotomy with cardiopulmonary bypass. Patients <50 years of age, with chronic atrial fibrillation, prior cardiac surgery, EF<25%, preoperative inotropic support, hepatic or renal failure, known sensitivity to botulinum toxin, debilitating neuromuscular disease, or those with a history of atrioventricular block will be excluded from the study. Prior to surgery, all patients will have baseline Mini-Mental State Examination (MMSE) and blood sampling from an indwelling arterial line or venipuncture for measurement of inflammatory and genomic markers. Half of the patients will be randomized to receive injection of epicardial botulinum toxin in addition to standard of care, as described below. The other half will receive epicardial injection of normal saline.
Institution of cardiopulmonary bypass will be performed according to the routine surgical protocol. After instituting CPB, botulinum toxin (or normal saline) injections will be performed by the surgeon. This dose was selected given the prior report of its effectiveness in preventing POAF after cardiac surgery in a small pilot study.(Pokushalov et al., 2014) After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. POAF, if it occurs, will be treated as per routine of care. POAF will be defined as any detectable atrial fibrillation before discharge that lasts >30 seconds. On postoperative day (POD) 4, a member of the study team will visit each patient to administer the MMSE and capture a 5-minute ECG with a Holter monitor. In addition, patients will be contacted monthly for 4 months and at one year after surgery for follow up, and medical records will be reviewed for evidence of readmissions, arrhythmias, or other adverse events.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Epicardial Botulinum | Experimental | After instituting cardiopulmonary bypass (CPB), botulinum toxin injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 50U (1mL) of botulinum toxin (OnabotulinumtoxinA, Botox®). After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. |
|
| Epicardial Placebo | Placebo Comparator | After instituting cardiopulmonary bypass (CPB), placebo (normal saline) injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 1mL of normal saline. After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Botulinum Toxin Type A | Drug | The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to In-hospital Post-operative Atrial Fibrillation (POAF) | Patients will be seen on a daily basis and the timing of POAF compared between groups. The occurrence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) and the time from surgery to the first and subsequent episodes of POAF recorded and compared between groups. POAF will be determined by ECG or telemetry. | From the time of ICU arrival until the time of first documented POAF, or discharge whichever came first, assessed up to 2 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With In-hospital POAF | Patients will be seen on a daily basis and the occurrence of POAF compared between groups. | The incidence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) |
| Length of Stay |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21659633 | Background | Oh S, Choi EK, Zhang Y, Mazgalev TN. Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation. Circ Arrhythm Electrophysiol. 2011 Aug;4(4):560-5. doi: 10.1161/CIRCEP.111.961854. Epub 2011 Jun 9. | |
| 25104535 | Background | Pokushalov E, Kozlov B, Romanov A, Strelnikov A, Bayramova S, Sergeevichev D, Bogachev-Prokophiev A, Zheleznev S, Shipulin V, Salakhutdinov N, Lomivorotov VV, Karaskov A, Po SS, Steinberg JS. Botulinum toxin injection in epicardial fat pads can prevent recurrences of atrial fibrillation after cardiac surgery: results of a randomized pilot study. J Am Coll Cardiol. 2014 Aug 12;64(6):628-9. doi: 10.1016/j.jacc.2014.04.062. No abstract available. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Epicardial Botulinum | After instituting cardiopulmonary bypass (CPB), botulinum toxin injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 50U (1mL) of botulinum toxin (OnabotulinumtoxinA, Botox®). After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Botulinum Toxin Type A: The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated. |
| FG001 | Epicardial Placebo | After instituting cardiopulmonary bypass (CPB), placebo (normal saline) injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 1mL of normal saline. After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Epicardial Botulinum | After instituting cardiopulmonary bypass (CPB), botulinum toxin injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 50U (1mL) of botulinum toxin (OnabotulinumtoxinA, Botox®). After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Botulinum Toxin Type A: The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to In-hospital Post-operative Atrial Fibrillation (POAF) | Patients will be seen on a daily basis and the timing of POAF compared between groups. The occurrence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) and the time from surgery to the first and subsequent episodes of POAF recorded and compared between groups. POAF will be determined by ECG or telemetry. | Posted | Mean | Standard Error | hours | From the time of ICU arrival until the time of first documented POAF, or discharge whichever came first, assessed up to 2 weeks |
|
Adverse events from the time of randomization through hospital discharge following study surgery.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Epicardial Botulinum | After instituting cardiopulmonary bypass (CPB), botulinum toxin injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 50U (1mL) of botulinum toxin (OnabotulinumtoxinA, Botox®). After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Botulinum Toxin Type A: The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial Dysrhythmia - Atrial Fibrillation | Cardiac disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial Dysrhythmia - Atrial Fibrillation | Cardiac disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Joseph P Mathew Professor of Anesthesiology and Chairman Department of Anesthesiology | Duke University Health System | 919-681-6646 | joseph.mathew@duke.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 23, 2018 | Sep 25, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001281 | Atrial Fibrillation |
| D011183 | Postoperative Complications |
| ID | Term |
|---|---|
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D019274 | Botulinum Toxins, Type A |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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| Placebo | Drug |
|
|
Total and ICU length of stay will be determined by examining medical records for the length of inpatient hospitalization, assessed over the entire study period (up to two years). ICU and hospital LOS will be recorded and compared between groups |
| ICU length of stay was measured from time of surgery to time of ICU discharge. Post-operative length of stay was measured from time of surgery to time of hospital discharge. |
| Number of Participants With Adverse Events | The total number of postoperative complications (including infectious, neurologic, and renal complications, as well as mortality) and the number of subjects with complications will be monitored and compared between groups. | Adverse events from the time of surgery through hospital discharge, up to 2 weeks |
| BG001 | Epicardial Placebo | After instituting cardiopulmonary bypass (CPB), placebo (normal saline) injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 1mL of normal saline. After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Placebo |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Epicardial Placebo | After instituting cardiopulmonary bypass (CPB), placebo (normal saline) injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 1mL of normal saline. After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Placebo |
|
|
|
| Secondary | Number of Participants With In-hospital POAF | Patients will be seen on a daily basis and the occurrence of POAF compared between groups. | Posted | Count of Participants | Participants | The incidence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) |
|
|
|
|
| Secondary | Length of Stay | Total and ICU length of stay will be determined by examining medical records for the length of inpatient hospitalization, assessed over the entire study period (up to two years). ICU and hospital LOS will be recorded and compared between groups | Posted | Median | Inter-Quartile Range | time in hours | ICU length of stay was measured from time of surgery to time of ICU discharge. Post-operative length of stay was measured from time of surgery to time of hospital discharge. |
|
|
|
|
| Secondary | Number of Participants With Adverse Events | The total number of postoperative complications (including infectious, neurologic, and renal complications, as well as mortality) and the number of subjects with complications will be monitored and compared between groups. | Posted | Count of Participants | Participants | Adverse events from the time of surgery through hospital discharge, up to 2 weeks |
|
|
|
|
| 1 |
| 63 |
| 27 |
| 63 |
| 10 |
| 63 |
| EG001 | Epicardial Placebo | After instituting cardiopulmonary bypass (CPB), placebo (normal saline) injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 1mL of normal saline. After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. Placebo | 1 | 67 | 30 | 67 | 14 | 67 |
| Acute Kidney Injury | Renal and urinary disorders | Non-systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Urinary Tract Infection | Renal and urinary disorders | Non-systematic Assessment |
|
| Heart Block | Cardiac disorders | Non-systematic Assessment |
|
| Hypotension | Cardiac disorders | Non-systematic Assessment |
|
| Ileus | Gastrointestinal disorders | Non-systematic Assessment |
|
| Reexploration For Bleeding | Surgical and medical procedures | Non-systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Left pneumothorax | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Oropharyngeal dysphagia | Nervous system disorders | Non-systematic Assessment |
|
| Pulmonary Edema | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Sternal Wound Infection | Infections and infestations | Non-systematic Assessment |
|
| Acute abdomen dilation | Gastrointestinal disorders | Non-systematic Assessment |
|
| Acute respiratory failure/hypoxia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Altered Mental Status | Nervous system disorders | Non-systematic Assessment |
|
| Bilateral Toe and Index finger ischemia. | Vascular disorders | Non-systematic Assessment |
|
| Colitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Dialysis | Renal and urinary disorders | Non-systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypovolemia | Cardiac disorders | Non-systematic Assessment |
|
| IABP placement | Cardiac disorders | Non-systematic Assessment |
|
| Nausea/Vomiting/Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
| Pacemaker Placement | Cardiac disorders | Non-systematic Assessment |
|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Reintubation | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Renal Insufficiency | Renal and urinary disorders | Non-systematic Assessment |
|
| Respiratory Distress | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Right sided weakness | Nervous system disorders | Non-systematic Assessment |
|
| Stroke | Nervous system disorders | Non-systematic Assessment |
|
| Urinary Incontinence leading to foley re-insertion | Renal and urinary disorders | Non-systematic Assessment |
|
| Ventricular Dysrhythmia - Ventricular Tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| junctional rhythm | Cardiac disorders | Non-systematic Assessment |
|
| post-op hemorrhage, back to OR for re-exploration | Surgical and medical procedures | Non-systematic Assessment |
|
| Post-op blood loss anemia requiring transfusions | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| prolonged hospitalization c/o coagulation. | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D006867 |
| Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| .51 |
| Other |