Michael L. Dewar

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.

Single-clamp technique does not protect against cerebrovascular accident in coronary artery bypass grafting

OBJECTIVES By potentially avoiding the embolic consequences of a side-biting aortic clamp, the single-clamp technique may decrease cerebrovascular accidents in coronary artery bypass grafting. However, this theoretical superiority in stroke prevention has not been conclusively demonstrated and use of this technique may lead to adverse myocardial effects due to longer cross-clamp times. In this study, we sought to determine if the single-clamp technique prevents postoperative stroke in clinical practice. METHODS Of 607 consecutive isolated coronary bypass operations completed over a 3 year period, 301 (50%) were performed by one surgeon using exclusively the single-clamp technique and 306 (50%) were performed by a second surgeon using exclusively the two-clamp technique. Postoperative adverse events were retrospectively compared between these two groups. RESULTS There were no differences between groups in terms of postoperative stroke (1.7% single-clamp vs. 2.0% two-clamp, P=0.78), hospital mortality (2.7% single-clamp vs. 1.6% two-clamp, P=0.38), or perioperative myocardial infarction (2.6% single-clamp vs. 0.7% two-clamp, P=0.052). The two-clamp technique was not a significant predictor of stroke by logistic regression analysis (P=0.72). CONCLUSIONS We conclude that there are no statistically significant differences between clamp techniques with regard to stroke prevention or myocardial protection. We find no compelling evidence for surgeons successfully utilizing one technique to change to the other.

Cognitive and functional status predictors of delirium and delirium severity after coronary artery bypass graft surgery: an interim analysis of the Neuropsychiatric Outcomes After Heart Surgery study.

BACKGROUND Cognitive and functional impairment increase risk for post-coronary artery bypass graft (CABG) surgery delirium (PCD), but how much impairment is necessary to increase PCD risk remains unclear. METHODS The Neuropsychiatric Outcomes After Heart Surgery (NOAHS) study is a prospective, observational cohort study of participants undergoing elective CABG surgery. Pre-operative cognitive and functional status based on Clinical Dementia Rating (CDR) scale and neuropsychological battery are assessed. We defined mild cognitive impairment (MCI) based on either (1) CDR global score 0.5 (CDR-MCI) or (2) performance 1.5 SD below population means on any cognitive domain on neurocognitive battery (MCI-NC). Delirium was assessed daily post-operative day 2 through discharge using the confusion assessment method (CAM) and delirium index (DI). We investigate whether MCI - either definition - predicts delirium or delirium severity. RESULTS So far we have assessed 102 participants (mean age 65.1 ± 9; male: 75%) for PCD. Twenty six participants (25%) have MCI-CDR; 38 (62% of those completing neurocognitive testing) met MCI-NC criteria. Fourteen participants (14%) developed PCD. After adjusting for age, sex, comorbidity, and education, MCI-CDR, MMSE, and Lawton IADL score predicted PCD on logistic regression (OR: 5.6, 0.6, and 1.5, respectively); MCI-NC did not (OR [95% CI]: 11.8 [0.9, 151.4]). Using similarly adjusted linear regression, MCI-CDR, MCI-NC, CDR sum of boxes, MMSE, and Lawton IADL score predicted delirium severity (adjusted R(2): 0.26, 0.13, 0.21, 0.18, and 0.32, respectively). CONCLUSIONS MCI predicts post-operative delirium and delirium severity, but MCI definition alters these relationships. Cognitive and functional impairment independently predict post-operative delirium and delirium severity.

Free radial artery grafts: surgical technique and results.

In the search for alternative conduits, the use of radial artery (RA) grafts has found renewed interest. This study sought to evaluate prospectively the perioperative morbidity, including the postoperative complications in the donor forearm, and mortality in the routine use of RA grafts in coronary artery bypass surgery. Data were obtained prospectively on 200 consecutive patients who underwent coronary revascularization using at least one RA graft from January 1995 to April 1997. The mean age of the patents was 61.9+/-10.5 years (mean+/-standard deviation [SD]). The RA was obtained from one forearm in 197 patients and both forearms in 3 patients. Two patients (1%) required exploration for donor site hematomas, 4 patients (2%) had temporary perioperative dysesthesias in the region of the lateral cutaneous nerve of the forearm, and none had donor site wound infection. Two patients (1%) had a myocardial infarction with electrocardiographic changes in the areas grafted by the RA in the immediate postoperative period, indicating graft failure. The two deaths in the series were due to comorbid factors. Our data suggest that the RA is a safe and suitable conduit for coronary revascularization, and it provides good clinical results. Long-term follow-up of these patients is necessary to confirm the patency of RA conduits. Free RA grafts have the potential for use in other areas of surgery where a conduit is necessary for revascularization procedures.

Anomalous left coronary artery from the main pulmonary trunk: Physiologic and clinical importance of its association with persistent ductus arteriosus

SummaryAnomalous left coronary artery (ALCA) from the pulmonary trunk presents in early infancy with a clinical picture of failure to thrive, congestive heart failure (CHF), anginalike episodes, and mitral insufficiency. These manifestations which are due to myocardial ischemia may change in the presence of an associated lesion. We present a case and review two previous reports of a patent ductus arteriosus (PDA) associated with this anomaly. Although signs and symptoms are not as clear due to the less impaired coronary perfusion and the presence of a PDA, the presence of mitral insufficiency should raise the possibility of an anomalous coronary artery and, therefore, a cardiac catheterization and angiocardiography are recommended in anticipation of reparative surgery.

Comparison of 180-degree and 360-degree skeletal muscle nerve cuff electrodes.

Use of skeletal muscle for cardiac augmentation is a promising technique for treatment of end-stage cardiac failure. An electrode woven through the latissimus dorsi that recruits nearby nerve fibers is commonly used to pace skeletal muscles both in clinical practice and in the laboratory. A proximally placed nerve cuff electrode offers potential advantages in improved recruitment of muscle fibers and low threshold for stimulation. We tested the effectiveness of a nerve cuff electrode passed directly about the proximal thoracodorsal nerve. Our report looks at the efficacy of nerve cuff electrode stimulation and compares electrical and histologic characteristics of a 180-degree wrap of the thoracodorsal nerve to a 360-degree wrap in dogs over 3 months. Threshold voltage at the commonly used pulse width of 200 microseconds was typically in the range of 400 to 600 mV for each electrode after 3 months. Statistical analysis revealed no significant difference (p < 0.05) in threshold voltage or current between the 180-degree and 360-degree nerve cuff electrode either at acute evaluation or after 3 months. Even contraction of latissimus dorsi was achieved with all implants. Adenosine triphosphatase staining revealed 100% conversion of type II to type I fibers in all stimulated muscles. Histologic examination of the thoracodorsal nerve and latissimus dorsi muscle revealed no abnormalities grossly or by light microscopy. Thus, a carefully applied nerve cuff electrode is an atraumatic, effective method for skeletal muscle stimulation. The 180-degree and 360-degree nerve cuff configurations are equally effective.

An unusual case of nonbacterial thrombotic (marantic) endocarditis

Nonbacterial thrombotic (marantic) endocarditis (NBTE) is a rare clinical condition manifest as various-sized cardiac valvular lesions ranging from microscopic aggregates of platelets to large vegetations of fibrin and platelets. It is difficult to diagnose NBTE before death. Despite significant advances in noninvasive diagnostic techniques, definitive diagnosis requires a tissue biopsy. We present an unusual case of NBTE with a large subvalvular mass invading the left ventricular posterior wall and papillary muscles and causing mitral stenosis. In this case, the final diagnosis was only made at the time of therapeutic surgical excision of the mass and mitral valve replacement.

Hemodynamic compromise from a right coronary artery pseudoaneurysm after remote stent placement

v a o T n c T t c C i s p f d a 62-year-old diabetic hypertensive female on chronic hemodialysis was admitted from the emergency epartment for progressive marked right-sided heart ailure, fatigue, fever, positive blood cultures for gramositive cocci, and a history of repeated vascular access hromboses with septic thrombophlebitis. She was tachyardic, tachypneic, and hypotensive. Chest x-ray was bnormal and a chest computed tomography (CT) scan as performed. The patient had suffered an acute inferior and right entricular myocardial infarction nearly 7 months earlier ith hypotension and bradyarrhythmias during an adission for Staphylococcus aureus septic thrombophlebitis. rimary angioplasty was performed. Because of a treendous thrombus burden an Angiojet was used, folowed by stenting of the proximal right coronary artery or residual stenosis and dissection. Chest CT demonstrated a 6 7 cm intrapericardial uid collection containing high-density contrast (Fig 1). ransesophageal echocardiography showed a pseudoanurysm surrounding the right coronary artery stent, ante-