Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We examined the capability of a novel therapeutic complement inhibitor to prevent pathological complement activation and tissue injury in patients undergoing CPB. METHODS AND RESULTS: A humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinase-MB release, P=0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (P<0. 05) in patients who received 1 or 2 mg/kg. CONCLUSIONS: A single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.

Transesophageal echocardiography and the perioperative management of valvular heart disease.

Transesophageal echocardiography (TEE) is an integral part of decision-making and monitoring in the perioperative period for patients undergoing valvular heart surgery. Multiplanar probes with improved pre- and intraoperative evaluation, eg, improved accuracy of estimation of mitral regurgitation jet size, have led to a more precise surgical approach. In the intensive care unit, TEE is proving invaluable in diagnosing occult causes of clinical instability that are usually surgically correctable. Advances in imaging technology with three- and four-dimensional TEE will facilitate preoperative decision-making, determine intraoperative approaches to valvular surgery, and provide earlier recognition of complications in the intensive care unit.

Quality assurance for intraoperative transesophageal echocardiography monitoring: a report of 846 procedures.

We evaluated our experience with 846 consecutive transesophageal echocardiography (TEE) intraoperative monitoring procedures performed between November 1989 and July 1991. TEE frequency was 36 +/- 11 per month (range 16-55) and represented 69.8% of cardiac valve surgery cases, 40.2% of coronary artery bypass graft cases, and 2.2% of total operative caseload. Major patient complications consisted of transient vocal cord paresis and ingestion of glutaraldehyde-disinfectant solution. Minor complications consisted of a chipped tooth (one case) and pharyngeal abrasions (three cases). The Quality Assurance (Q/A) Program evaluated both record keeping and quality of imaging, as judged by cardiologist echocardiographer reviewers. The percentage of completion for each Q/A indicator was as follows: medical record documentation, 88%; database form annotation, 94%; and provision of videotape recording, 91%. TEE database forms were analyzed further in terms of the percentage of fields completed. Completion scores were 73%. The following scoring system was utilized for videotape evaluation by the cardiologists: 1 = excellent; 2 = good; 3 = poor. The median grade for both two-dimensional echocardiography and color flow Doppler (CFD) examinations was 2. Poor quality images (grade 3) were present in 15.2% of two-dimensional echocardiography and 20.3% of color flow Doppler examinations, and disproportionately associated with 4/26 attendings. Supplemental audit of the cardiology reviewers performance demonstrated 569/846 videotapes showed no objective evidence of review. The cardiology reviewer forms of the remaining 277 videotapes were evaluated in terms of the percentage of fields completed. The completion score was 56%. These data suggest the need for formal Q/A for intraoperative TEE, both for anesthesiologists and reviewing cardiologists.