DEPARTMENT OF ANESTHESIOLOGY ANNUAL REPORT

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An exciting development is the establishment of formal ties with Dr. Steve Eubanks in the Department of Surgery and the members of the US Surgical Endosurgical Research Center. Utilizing the different strengths of each group, collaborative projects will focus on understanding the physiologic responses to surgery, with a special emphasis upon the fetal effects of nonobstetric related maternal surgery during pregnancy. DEBRA A. SCHWINN, M.D. Director, Molecular Pharmacology Laboratory Professor of Anesthesiology, Pharmacology/Cancer Biology, and Surgery AREAS OF RESEARCH: Molecular Pharmacology and Genetics of Adrenergic Receptors Our laboratory combines molecular pharmacology approaches with translational human functional genomics. The laboratory is involved in studying mechanisms underlying regulation of adrenergic receptors (ARs) in health and disease. Over the last ten years, we (with help from several collaborators) initially described and determined mechanisms underlying acute myocardial βAR desensitization during cardiopulmonary bypass (a procedure required to provide oxygenated blood during heart surgery at most medical centers world-wide) (Circulation, 1991; 84:2559; Circulation, 1998; 98:II275; Anesthesiology, 1998; 89:602). Based on successful animal studies, we initiated a clinical interventional trial designed to prevent acute myocardial βAR desensitization during heart surgery. By enhancing myocardial βAR functioning after cardiopulmonary bypass, fewer inotropic drugs should be required during heart surgery, facilitating patient recovery with fewer side effects. In addition to studying βARs during heart surgery, the laboratory primarily focuses on regulation of α 1ARs in health and disease. Since these receptors are important in smooth muscle and the heart, diseases such as hypertension, myocardial hypertrophy, and benign prostate hypertrophy are our main focus. Three α 1AR subtypes exist (α 1a, α 1b, and α 1d); over the years we have been involved in cloning cDNAs encoding each of these subtypes from both animal and human sources (PNAS, 1988; 85:7159; J Biol Chem, 1990; 265:8183; J Biol Chem, 1991; 266:6365; JPET 1995; 272:134). Our laboratory recently demonstrated that α 1aARs are present and functional in human vasculature (particularly resistance vessels and coronary arteries) and are modified (increased, along with the α 1aARs) by age (Circulation, Dec 1999). In order to understand mechanisms underlying these changes, our laboratory is currently examining regulation of the human α 1aAR at transcriptional and protein levels (J Biol Chem, 1997; 272:28237). After identification of the α 1aAR in human prostate smooth muscle (J Urol, 1993; 150:546), we more recently examined a novel role of other α 1ARs (specifically the α 1dAR) in bladder hypertrophy associated with BPH (J Urol, 1998; 160:937). A new emphasis in the laboratory is the role of genetic variability on human cardiovascular disease. Specifically the role of naturally occurring single nucleotide polymorphisms (SNPs) and insertions/deletions of α 1-adrenergic receptors in hypertension is being investigated. This involves using classical genetic approaches, large scale genomic sequencing, SNP identification, and analysis for association with disease in highly phenotyped populations. It also includes investigating the biology of each SNP in terms of α 1AR signal transduction pathways. A broad spectrum of individuals interact and study in our laboratory (undergraduates, medical students, graduate students, postdoctoral fellows, LABORATORY PROGRAMS junior faculty, various collaborators), and wide ranging approaches are utilized (e.g. molecular biology, classical pharmacology, biochemistry, pharmacogenetics, and clinical trials). The goal of our laboratory is to examine clinically important questions using basic science approaches, with the final goal of ultimately taking answers back to the clinic. THOMAS F. SLAUGHTER, M.D. Assistant Professor of Anesthesiology AREAS OF RESEARCH: Perioperative Hemostasis and Thrombosis; Coagulation Factor XIII and Tissue Transglutaminase Both clinical and basic science investigations are currently in progress to define mechanisms of excessive bleeding and thrombosis in the perioperative period. Our clinical studies continue to focus on the role of the fibrinolytic system in perioperative abnormalities of hemostasis and thrombosis and to define pharmacologic approaches to alleviate fibrinolytic bleeding in the surgical patient. In addition, we are engaged in field trials to develop novel point-of-care assays of coagulation for use in the perioperative setting. Basic laboratory investigations continue to focus on tissue transglutaminase and factor XIII, members of an enzymatic gene superfamily essential for intermolecular stabilization. Recent evidence suggests that transglutaminases play an important regulatory role in the life cycle of the cell by modulating cell growth and angiogenesis. Our laboratory is specifically interested in the role of these enzymes in modulating the extracellular matrix and consequently the processes of thrombosis, angiogenesis, and atherosclerosis. Recent investigations have focused on mechanisms for the post-translational regulation of transglutaminase activity as well as the role of transglutaminases in fibrin stabilization. LABORATORY PROGRAMS 123
LABORATORY PROGRAMS JACQUES SOMMA, M.D., FRCP(C) Assistant Professor of Anesthesiology Director, Human Neurophysiology and Pharmacology Laboratory AREA OF RESEARCH: Phase I Studies The Human Pharmacology Laboratory is a fully equipped laboratory supported by a comprehensive team of professionals who have the skills required to efficiently design, perform and analyze data for Phase I studies. Faculty John C. Keifer, M.D. David B. MacLeod, M.B., B.S., FRCA Eugene W. Morretti, M.D. Kerri M. Robertson, M.D., FRCP(C) David R. Wright, M.B., Ch.B. Fellow Yung-Wei Hsu, M.D. Support Staff Jennifer K. Fier, Staff Assistant Aaron K. Harrison, B.S., Clinical Trial Research Associate Karen W. Ramsey RN, BSN, M.B.A., MHA, Non-Cardiac Clinical Research Coordinator The Facility The Human Pharmacology Laboratory is located on the fourth floor of the Orange Zone in Duke South. It is fully equipped with standard life support and exhaustive monitoring equipment, which includes: EKG, NIBP, arterial blood pressure, end tidal CO 2, pulse oximetry, nerve stimulator, Respitrace, Medoc computer-controlled thermode, 4 channels EEG, Bispectral Index and Evoked Potentials. All the data is collected on a powerful data acquisition system based on a LabView platform. The Human Pharmacology Laboratory is also equipped with Computer Controlled Infusion Pumps. It stands that Duke is the leader in the field and owns the patent for CACI (Computer Assisted Continuous Infusion). The laboratory 124 LABORATORY PROGRAMS can, actually, host up to two hundred subjects per year. The Service Provided The Human Pharmacology Laboratory offer a complete solution for phase I study including: • using existing preliminary data (animal or human) to perform simulations that will help designing the protocol. • recruiting and performing the trial • analyzing, modeling and publishing the results of the study. Designing the protocol Using existing preliminary data (animal or human) simulations are performed to help design the protocol. Simulations are made for the lowest and the highest expected Cl’s and V’s using a reasonable inter and intra-individual variability. Simulated experimental data are generated according to different potential protocols. The protocols are then tested for their ability to answer the clinically relevant question. Different scenarios are considered and the best protocol is selected. Simulations help design better cost-effective studies by optimizing the quality of the results as well as minimizing the number of subjects needed for Phase II studies. Performing the study The Human Pharmacology Laboratory is a state of the art facility operated by a skilled team of professionals that offer superior and timely service. Duke University's excellent reputation for research, as well as the large population of healthy young adults living in the area, are the two key factors for fast and efficient enrollment. Analyzing the data State-of-the-art tools, such as NONMEM, are used to analyze and model the data. NONMEM is a sophisticated and powerful software package designed to perform population analysis for pharmacokinetics and dynamics. Intra and inter-variability can be modeled simultaneously with NONMEM. One of the strength of NONMEM includes the ability to adequately model PK/PD data sets with very few data points per subjects. Providing an adequate number of subjects, data sets can be modeled with as little as three data points per subjects. Active Protocols Two protocols are currently active: “A Double Blind Randomized Study to Compare the Analgesia and Respiratory Effect of Dexmedetomidine and Remifentanil," and “Age Effect on the Interaction between Propofol and Remifentanil.” The Human Neurophysiology and Pharmacology Laboratory in 2001 There will be an expansion of the Human Neurophysiology and Pharmacology Laboratory in 2001 with the addition of Dr. Lucian Radu Radulescu and Dr. Luis Ignacio Cortínez. Dr. Radulescu is a trained anesthesiologist from Romania. Since 1995, Dr. Radulescu has acquired a strong background in clinical trials through working in Dr. Steven L. Shafer’s Pharmacology Laboratory at Stanford University, and at Roche Laboratory. Dr Radulescu will join the Human Neurophysiology and Pharmacology Laboratory as an Associate in Research. Dr Cortinez is a Chilean anesthesiologist with a strong interest in pharmacology and computer controlled infusions. He is anticipated to start a two-year clinical-research fellowship with us in summer 2001. Our Labview data acquisition system is a project in constant evolution. In 2001 and in the future years the Labview project will expand and evolve in a very powerful research tool that will integrate CACI and network capabilities in addition to its powerful data acquisition capabilities. The project will be programmed using MFC and the visual C++ tools for Labview. In the upcoming year the Human Neurophysiology and Pharmacology Laboratory will broaden its research activities and will offer its expertise and
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DEPARTMENT OF ANESTHESIOLOGY Duke U
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This issue is dedicated to the memo
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DUKE DEPARTMENT OF ANESTHESIOLOGY M
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FACULTY, RESIDENTS, FELLOWS, AND CR
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FACULTY Thomas E. Buchheit, M.D. Cl
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FACULTY Joel S. Goldberg, M.D. Assi
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FACULTY John C. Keifer, M.D. Associ
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FACULTY Joseph P. Mathew, M.D. Asso
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FACULTY Claude A. Piantadosi, M.D.
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FACULTY Mark Stafford-Smith, M.D.,
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FACULTY Christopher C. Young, M.D.,
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20 FACULTY DUKE UNIVERSITY HEALTH S
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AFFILIATED FACULTY Scott T. Howell,
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Edmond C. Bloch, M.B., Ch.B. Associ
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INTERNS Atilio Barbeito, M.D. Abiga
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RESIDENTS John D. Mitchell, M.D. CA
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RESIDENTS CA-3 Tarsha V. Garvin, M.
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Paula D. Alford, B.A., CRNA Beatric
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CRNA Deborah J. Ferrero-Conover, CR
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CRNA Carolyn C. Knoop, CRNA, MSN Da
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CRNA Kena B. Sigman, CRNA, MSN Tede
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40 DUKE ANESTHESIA FACULTY WHO BECA
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CLINICAL ACTIVITIES Infraclavicular
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CLINICAL ACTIVITIES CARDIOTHORACIC
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CLINICAL ACTIVITIES Goals for 2000
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CLINICAL ACTIVITIES Narda D. Crough
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CLINICAL ACTIVITIES returned home t
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CLINICAL ACTIVITIES GENERAL, VASCUL
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CLINICAL ACTIVITIES some of the ser
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CLINICAL ACTIVITIES years, has comb
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CLINICAL ACTIVITIES Molecular Biolo
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CLINICAL ACTIVITIES ORTHOPAEDICS, P
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CLINICAL ACTIVITIES OTOLARYNGOLOGY,
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CLINICAL ACTIVITIES PAIN MANAGEMENT
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CLINICAL ACTIVITIES therapy. This y
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CLINICAL ACTIVITIES Regional Anesth
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CLINICAL ACTIVITIES thesiology Pain
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