Jane Fitch

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.

Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes

BACKGROUND:  Platelet (PLT) transfusions are administered in cardiac surgery to prevent or treat bleeding, despite appreciation of the risks of blood component transfusion. The current analysis investigates the hypothesis that PLT transfusion is associated with adverse outcomes associated with coronary artery bypass graft surgery (CABG).

The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery : A prospective randomized, double-blinded controlled, multi-center trial

We compared (a) the perioperative complications; (b) times to eligibility for, and actual time of the following: extubation, less intense monitoring, intensive care unit (ICU), and hospital discharge; and (c) resource utilization of nursing ratio for patients receiving either a typical fentanyl/isoflurane/propofol regimen or a remifentanil/isoflurane/propofol regimen for fast-track cardiac anesthesia in 304 adults by using a prospective randomized, double-blinded, double-dummy trial. There were no differences in demographic data, or perioperative mortality and morbidity between the two study groups. The mini-mental status examination at postoperative Days 1 to 3 were similar between the two groups. The eligible and actual times for extubation, less intense monitoring, ICU discharge, and hospital discharge were not significantly different. Further analyses revealed no differences in times for extubation and resource utilization after stratification by preoperative risk scores, age, and country. The nurse/patient ratio was similar between the remifentanil/isoflurane/propofol and fentanyl/isoflu-rane/propofol groups during the initial ICU phase and less intense monitoring phase. Increasing preoperative risk scores and older age (>70 yr) were associated with longer times until extubation (eligible), ICU discharge (eligible and actual), and hospital discharge (eligible and actual). Times until extubation (eligible and actual) and less intense monitoring (eligible) were significantly shorter in Canadian patients than United States’ patients. However, there was no difference in hospital length of stay in Canadian and United States’ patients. We conclude that both anesthesia techniques permit early and similar times until tracheal extubation, less intense monitoring, ICU and hospital discharge, and reduced resource utilization after coronary artery bypass graft surgery.

Amplification of the inflammatory response : Adhesion molecules associated with platelet/white cell responses

Cardiopulmonary bypass (CPB) causes leukocyte and platelet activation, resulting in upregulation of the adhesion receptor CD11b/CD18 on leukocytes and upregulation of P-selectin, the adhesion receptor that binds the activated platelet to polymorphonuclear neutrophils (PMNs) and monocytes. Our laboratory has studied the expression of activation-dependent adhesion receptors during in vivo CPB. Both PMN and monocyte CD11b were upregulated during CPB but with differing time courses. Peak PMN CD11b levels occurred at the end of the hypothermic phase of bypass, whereas monocyte CD11b levels increased steadily throughout the course of CPB, peaked at 2-4 h after CPB, and remained significantly elevated as late as 18-24 h post CPB. The percentage of P-selectin-positive platelets increased significantly during bypass, peaking around the end of bypass and remaining elevated in the early post-bypass period. The level then returned to normal by 18 h post-bypass. Monocyte-platelet binding paralleled the increase in P-selectin-positive platelets during bypass and similarly remained elevated in the post-bypass period. PMN-platelet binding also increased but peaked early during CPB. Upregulation of these adhesive receptors and formation of platelet-leukocyte conjugates may influence the prothrombotic activity of monocytes and the proinflammatory activity of PMNs in the post-CPB period. Our laboratory has developed an in vitro model of extracorporeal circulation, and recirculation of blood on this circuit results in significant activation of PMNs and monocyte CD11b expression, increasing progressively over time. Likewise, the percentage of P-selectin-positive platelets increased and was paralleled by the formation of leukocyte-platelet conjugates comparable to the pattern found in vivo. Generation of the complement fragments C5a and the C5b-9 membrane-attack complex may contribute to platelet P-selectin expression and formation of leukocyte-platelet conjugates during CPB. The in vitro model has been used to test the cellular effects of complement inhibition employing a monoclonal antibody that blocks cleavage of C5 into C5a and C5b to determine the role of early vs. late complement components in the cellular activation induced by CPB. Preliminary results demonstrate that blockage of the formation of C5a and the C5b-9 membrane-attack complex during simulated extracorporeal circulation effectively inhibits platelet and PMN activation and the formation of leukocyte-platelet conjugates.

Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation

OBJECTIVE Complement activation is induced by cardiopulmonary bypass, and previous work found that late complement components (C5a, C5b-9) contribute to neutrophil and platelet activation during bypass. In the present study, we blocked C5b-9 formation during extracorporeal recirculation of whole blood to assess whether the membrane attack complex was responsible for both platelet and leukocyte activation. METHODS In a simulated extracorporeal model that activates complement (C3a and sC5b-9), platelets (CD62P expression, leukocyte-platelet conjugate formation), and leukocytes (increased CD11b expression and neutrophil elastase), we examined an anti-human C8 monoclonal antibody that inhibits C5b-9 generation for its effects on cellular activation. RESULTS Anti-C8 significantly inhibited sC5b-9 formation but did not block C3a generation. Anti-C8 also significantly inhibited the increase in platelet CD62P and monocyte-platelet conjugate formation seen with control circulation. Moreover, compared with control circulation, in which the number of circulating platelets fell by 45%, addition of anti-C8 completely preserved platelet counts. In contrast to blockade of both C5a and sC5b-9 during simulated extracorporeal circulation, neutrophil activation was not inhibited by anti-C8. However, circulating neutrophil and monocyte counts were preserved by addition of anti-C8 to the extracorporeal circuit. CONCLUSIONS The membrane attack complex, C5b-9, is the major complement determinant of platelet activation during extracorporeal circulation, whereas C5b-9 blockade has little effect on neutrophil activation. These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit.

Preliminary Report of the Effects of Complement Suppression With Pexelizumab on Neurocognitive Decline After Coronary Artery Bypass Graft Surgery

Background and Purpose— Pharmacological modulation of complement activation recently has been postulated as a therapeutic target in the treatment of neurological injury. We hypothesized that pexelizumab, a humanized scFv monoclonal antibody directed against the C5 complement component, would limit deficits in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Methods— The Phase II Pexelizumab study was a 914-patient, double-blind, placebo-controlled, 65-center study of patients undergoing coronary artery bypass graft surgery. Patients were randomized to pexelizumab bolus, bolus plus infusion, or placebo. Neurological and neurocognitive functions were assessed as secondary endpoints at baseline and on postoperative days (POD) 4 and 30. Cognitive deficits were assessed with multivariable tests accounting for baseline cognition, age, diabetes, years of education, sex, elevated creatinine, history of myocardial infarction, neurological disorder or congestive heart failure, and cardiopulmonary bypass time. Results— Pexelizumab had no statistically significant effect on the primary composite endpoint or on overall cognition. When domain specific effects were examined, a decline of at least 10% in the visuo-spatial domain was observed on POD 4 in 56% of patients receiving placebo compared with 40% receiving pexelizumab by bolus and infusion (P=0.003). Similarly, on POD 30, a 10% decline was present in 21% of patients in the placebo group versus only 12% of the drug bolus plus infusion group (P=0.016). No differences were seen between treatment groups in any of the other domains. Conclusions— Pexelizumab administration for 24 hours perioperatively had no effect on global measures of cognition but may reduce dysfunction in the visuo-spatial domain.

Future of Anesthesiology Is Perioperative Medicine: A Call for Action

1192 June 2015 C urrently, the American healthcare system is undergoing significant changes in response to healthcare reform legislation such as the Affordable Care Act of 2010, as well as market forces and the ongoing maturation of the American healthcare industry. This evolution is consistent with the changes that have occurred in other industries such as agriculture, travel, and aviation. Over the past decades, anesthesiologists have continually expanded their focus from the operating rooms to postanesthesia care units, intensive care units, and pain medicine. In parallel to the expansion of the clinical footprint of our discipline, the core training curriculum of anesthesiology residency has changed significantly to now include many nonoperating room anesthesia rotations.1 This development is not unique to the united States, and many other countries such as the united Kingdom, France, Germany, and Australia have developed strategies to increase the role of anesthesiologists in perioperative medicine.1 In a recent editorial in the British Journal of Anaesthesia entitled Anaesthesiology and Perioperative Medicine around the World: Different names, Same Goals, some of us argue that “regardless of what the model is called around the globe, we have to embrace our expanded role as perioperative physicians as our main value proposition.”2 A proposal raised at the 2014 annual meeting of the Society of Academic Anesthesiology Associations (SAAA) is the impetus for this editorial, which was written by Chairs of Anesthesiology Departments who also serve as members of the executive committee of SAAA. The SAAA annual meeting was attended by 498 representatives of 124 academic anesthesiology departments (including chairs, program directors, and subspecialty fellowship directors who are the constituent members of this association). During a general session of the SAAA annual meeting, Dr. Kain, the first author of this editorial, proposed the motion to formally change the name of our specialty. There was healthy discussion on both sides of the issues, with active participation by department chairs, residency program directors, and fellowship program directors. After the discussion, an informal show of hands was overwhelmingly in favor of the proposal. After the meeting, a survey was sent to the SAAA general membership (n = 500) asking, “Do you approve or oppose a resolution to the American Society of Anesthesiologists (ASA) Board of Directors to change the name of our specialty to Anesthesiology and Perioperative Medicine (from Anesthesiology)?” There were a total of 189 responses (38%): 172 (91% of the respondents) were in favor and 17 opposed (9%). Although SAAA does represent the academic leadership of our specialty, any change in the name of our specialty will require consultation and approval by multiple stakeholders such as the American Society of Anesthesiologists (ASA), American Board of Anesthesiology and the Accreditation Council for Graduate Medical education (ACGMe). The chief aim of this editorial is to present a proposal and rationale for changing the name of our specialty from “Anesthesiology” to “Anesthesiology and Perioperative Medicine” and to advance the process of discussions among all these stakeholders. Over the past few decades, the specialty of anesthesiology has expanded its practice from being largely confined to the operating room to include perioperative medical practice in acute pain medicine, postoperative and intensive care Future of Anesthesiology Is Perioperative Medicine

Full-Dose Aprotinin Use in Coronary Artery Bypass Graft Surgery: An Analysis of Perioperative Pharmacotherapy and Patient Outcomes

BACKGROUND: Inappropriate activation of hemostasis and inflammation may contribute to postoperative morbidity and mortality. The serine protease inhibitor, aprotinin, has been shown to prevent tissue and organ injury in laboratory and animal studies. In this retrospective analysis, we evaluated the relationship of aprotinin therapy with organ dysfunction in humans undergoing coronary artery bypass graft surgery (CABG). METHODS: Data from prospective randomized, double-blind, placebo-controlled studies evaluating the safety and efficacy of full-dose aprotinin (2 million KIU load, 2 million KIU pump prime, and 0.5 million KIU/h continuous infusion) to reduce blood loss and transfusion requirements in patients undergoing CABG (placebo, n = 861; aprotinin, n = 862) were examined retrospectively. Primary end-points were death, adverse cerebrovascular outcome, myocardial infarction (MI), and pharmacological interventions (inotropic drugs, vasopressors, and antiarrhythmics). RESULTS: Univariate analysis showed that relative to placebo, full-dose aprotinin therapy was associated with significant effects on the incidence of adverse cerebrovascular outcome (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.19–0.93; P = 0.03) and use of inotropic drugs (OR 0.79, 95% CI 0.65–0.97; P = 0.02), vasopressors (OR 0.74, 95% CI 0.61–0.90; P < 0.01), and antiarrhythmics (OR 0.79, 95% CI 0.65–0.96; P = 0.02), but not death (OR = 1.00, 95% CI 0.54–1.85; P = 1.0) or MI (OR 0.92, 95% CI 0.64–1.31; P = 0.6). Multivariate analysis confirmed results of univariate analysis. CONCLUSIONS: This retrospective analysis of data collected from prospective, randomized, placebo-controlled studies in CABG shows that full-dose aprotinin use was associated with a lower risk of adverse cerebrovascular outcomes and a reduced need for use of vasoactive drugs; the risk of death and perioperative MI was not affected by aprotinin therapy.

Heparin management test versus activated coagulation time during cardiovascular surgery: Correlation with anti-Xa activity

OBJECTIVE To compare the abilities of the heparin management test (HMT) and the activated coagulation time (ACT) to provide a measurement of heparin effect in patients undergoing cardiac or peripheral vascular surgery. These measurements of heparin effect were also compared with measurements of heparin concentrations tested by anti-Xa activity. A secondary objective was to compare the performance of the noncitrated HMT with that of the citrated HMT. DESIGN A prospective study. SETTING A single-center study conducted in a university hospital. PARTICIPANTS After human investigation committee approval and informed consent were obtained, adult patients undergoing cardiac or peripheral vascular surgery were included in this study. INTERVENTIONS In both surgical groups, blood was sampled for ACT, HMT, and anti-Xa activity. Each HMT was performed on both noncitrated and citrated samples. MEASUREMENTS AND MAIN RESULTS As an indicator of heparin effect, the HMT had a strong correlation with the ACT (r = 0.899; p < 0.01). In addition, the HMT had a significantly stronger correlation with anti-Xa activity than the ACT (p < 0.01). The correlation obtained from the noncitrated samples was identical with that obtained from the citrated samples (r = 0.819; p < 0.001 for both groups). CONCLUSION The ability of the HMT and the ACT to measure heparin effect was similar. The HMT performed better than the ACT when using anti-Xa activity as a measure of heparin concentration. Noncitrated HMT results were similar to citrated HMT results, thus supporting the use of fresh whole blood for testing purposes.

Transesophageal echocardiography interpretation: A comparative analysis between cardiac anesthesiologists and primary echocardiographers

Diagnostic interpretation of intraoperative transesophageal echocardiography (TEE) examinations may vary, particularly when the echocardiographer is also the anesthesiologist. We therefore evaluated the concordance of TEE interpretation as part of a process of continuous quality improvement (CQI). Ten cardiac anesthesiologists participating in a CQI program conducted 154 comprehensive TEE examinations, each consisting of 16 major fields describing cardiac anatomy and function. These examinations were subsequently interpreted off-line by two primary echocardiographers (a radiologist and a cardiologist). Agreement was assessed using the &kgr; coefficient and percent agreement. Overall &kgr; and percent agreement were 0.58 and 83% for anesthesiologists versus radiologist, 0.57 and 80% for anesthesiologists versus cardiologist, and 0.60 and 82% for radiologist versus cardiologist. Anesthesiologists with longer than 5 yr of TEE experience had higher levels of agreement with the radiologist when assessing the aorta, right atrium, pulmonary vein flow, transmitral flow, and fractional area change. Cardiac anesthesiologists supported by a CQI program interpret TEE examinations at a level comparable with physicians whose primary practice is echocardiography. Thus, the anesthesiologist and the intraoperative echocardiographer need not be mutually exclusive.