Clinical trial NCT00246740: Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting
Official title: Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting: A Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronary Artery Bypass Grafting
Cardiopulmonary Bypass
Reperfusion Injury
Keywords: Doxycycline
coronary artery bypass grafting
Lead sponsor: University of Alberta
Sponsor class: OTHER
First posted: 2005-10-30
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether doxycycline (Periostat) at a sub-antimicrobial dose will decrease reperfusion injury after coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB).

Detailed description: This proposal is for a randomized, placebo-controlled, double-blinded study of the use of doxycycline in patients requiring CABG surgery. Patients will be randomized 1:1 to receive either doxycycline or placebo.

This study will be conducted in a blinded manner. The pharmacy will randomize patients and will have the randomization code. The code will only be broken in the case of an emergency and the event will be fully documented.

In addition to standard care, patients will receive oral administration of 20 mg of doxycycline or placebo twice a day at least 2 days prior to surgery, on the day of surgery, and on postoperative days 1, 2, and 3.

Myocardial atrial biopsies will be taken at 2 time points during the CABG procedure: during cannulation of the right atrium and 10 minutes after cross-clamp release. Tissue will be analyzed for MMP-2 and -9 activity and TnI and MLC-1 levels.

A Swan-Ganz-Catheter will be placed in the pulmonary artery over 24 hours to measure hemodynamics (LVSWI).

A coronary sinus catheter will be placed under echocardiographic guidance prior to initiation of CPB (will be removed 20 minutes after cross-clamp release).

Patients will have an additional ECG on post-operative days 1 and 3.

Additional blood will be drawn to determine doxycycline plasma levels, MMP-2 and -9 activity, total gelatinolytic activity, and levels of troponin I and T products at the following time points: pre-induction, prior to initiation of CPB, 10 and 20 minutes following the release of the aortic cross clamp (arterial and venous) and 3, 6, 24 and 72 hours post aortic cross clamp removal (venous). Each of the above samples will require 6 mL of blood for a study total of 72 mL. At the time of each blood draw we will measure and record the hematocrit value.

Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Aged 18 through 80 years, inclusive
* Scheduled for primary CABG surgery with CPB

Exclusion Criteria:

* Females of childbearing potential
* Emergency CABG
* Previous sternotomy
* Planned simultaneous surgery (i.e. valve repair or carotid endarterectomy)
* Myocardial infarction within 48 hours
* Pre-operative atrial fibrillation
* Pre-operative ventricular pacing or left bundle branch block (LBBB)
* Known hypersensitivity to tetracycline class antibiotics
* Renal failure requiring dialysis

Primary outcomes:
measure: Left Ventricular Stroke Work Index (LVSWI)
timeFrame: Before surgery up to 24h of reperfusion
Secondary outcomes:
measure: Cardiac Matrix Metalloproteinase-9 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion
timeFrame: Before surgery and 10 minutes reperfusion after surgery
measure: Cardiac Matrix Metalloproteinase-2 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion
timeFrame: Before surgery and 10 minutes reperfusion after surgery
measure: Venous Plasma Cardiac Matrix Metalloproteinase-9 Activity Before and After Reperfusion
timeFrame: Before surgery and up to 72 h reperfusion after surgery
measure: Venous Plasma Cardiac Matrix Metalloproteinase-2 Activity Before and After Reperfusion
timeFrame: Before surgery and up to 72 h reperfusion after surgery
measure: Venous Plasma Concentration of Troponin-I
timeFrame: Before surgery and 10 minutes reperfusion after surgery
measure: Cleaved TroponinI/GAPDH Ratios in Right Atrial Biopsy
timeFrame: Before surgery and 10 minutes reperfusion after surgery
measure: Venous Plasma Concentration of C-reactive Protein
timeFrame: Before surgery and up to 72 h reperfusion after surgery
measure: Venous Plasma Concentration of IL-6
timeFrame: Before surgery and up to 72 h reperfusion after surgery
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
Study officials:
affiliation: Department of Anesthesiology and Pain Medicine, University of Alberta Hospital
name: Barry A Finegan, FFARCS FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schulze CJ, Castro MM, Kandasamy AD, Cena J, Bryden C, Wang SH, Koshal A, Tsuyuki RT, Finegan BA, Schulz R. Doxycycline reduces cardiac matrix metalloproteinase-2 activity but does not ameliorate myocardial dysfunction during reperfusion in coronary artery bypass patients undergoing cardiopulmonary bypass. Crit Care Med. 2013 Nov;41(11):2512-20. doi: 10.1097/CCM.0b013e318292373c.