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Combining Propofol and Remifentanil Pharmacokinetic COMBINING PROPOFOL AND REMIFENTANIL PHARMACOKINETIC AND PHARMACODYNAMIC MODELS IN THE OPERATING ROOM: AN OBSERVATIONAL STUDY by Farrant Hiroshi Sakaguchi A thesis submitted to the faculty of The University of Utah in partial fulfillment of the requirements for the degree of Master of Science Department of Bioengineering The University of Utah December 2004 Copyright © Farrant Hiroshi Sakaguchi 2004 All Rights Reserved 2 Supervisory Committee Approval Form 3 Final Reading Approval Form 4 ABSTRACT Remifentanil and propofol are commonly used together for total intravenous anesthesia. Though their synergistic pharmacodynamic interaction has been characterized with surrogate measures in volunteers, the relationship of these surrogate measures to actual surgical stimuli has not been validated prospectively in the operating room. This study combines a set of propofol and remifentanil pharmacokinetic (PK) and pharmacodynamic (PD) models to estimate their PD interaction and predicts the resulting likelihood of sedation and analgesia intraoperatively. With IRB approval and informed consent, we studied 24 ASA physical status I, II, and III patients scheduled for laproscopic surgery receiving total intravenous anesthesia. Standard anesthetic practice was not altered for this study. Responses and non- responses to the intraoperative stimuli of laryngoscopy and skin incision were recorded. The predicted effect-site concentrations at these data points, and at the loss and return of responsiveness, were plotted on response-surface models for corresponding surrogate measures determined in volunteers. Patient observations were compared to pharmacodynamic predictions. Methods to reduce differences between the model predictions and observations in the patients are identified and discussed. The results of this study suggest that tracheal intubation, a surgical milestone, is more stimulating than the surrogate measure of laryngoscopy alone. The PK-PD combined models for a surrogate indicator of sedation (OAA/S < 2) predict loss of responsiveness (LOR) and recovery of responsiveness (ROR) for 35% and 87% of the patients above the 50% isobol, respectively. The data also suggest that propofol, rather than remifentanil, is the main contributor to responsiveness in these patients. Clinically, this may mean that a quick recovery of consciousness may be achieved while managing postoperative pain by maintaining opioid levels while propofol levels are reduced. v TABLE OF CONTENTS ABSTRACT..............................................................................................................................iv LIST OF FIGURES................................................................................................................. vii ACKNOWLEDGMENTS..................................................................................................... viii Chapter 1. INTRODUCTION...........................................................................................................1 Purpose of Study......................................................................................................1 Pharmacological Modeling......................................................................................2 Methods for Preliminary Study............................................................................. 10 Conclusion from Preliminary Study ..................................................................... 11 References...............................................................................................................13 2. OBSERVATIONAL STUDY.......................................................................................... 15 Introduction............................................................................................................15 Methods...................................................................................................................16 Results.....................................................................................................................24 Discussion...............................................................................................................32 References...............................................................................................................37 3. CONCLUSION .............................................................................................................40 Summary.................................................................................................................40 Comparison of Observational Studies and Clinical Studies ...............................40 Utility and Limitations of Clinical Pharmacological Modeling..........................41 Future Work............................................................................................................42 References...............................................................................................................43 LIST OF FIGURES Figure Page 1.1. Three compartment model with an effect-site. ...................................................3 1.2. Pharmacodynamic Emax models for sedation and laryngoscopy.....................5 1.3. Isobologram for three pharmacodynamic interactions ......................................6 1.4. Response surface models for surrogate measures from Kern et al....................9 2.1. Ceff values at loss of responsiveness on the sedation response surface (OAA/S<2)............................................................................................................27 2.2. Ceff values at recovery of responsiveness on the sedation response surface (OAA/S<2)............................................................................................................28 2.2 Ceff values at recovery of responsiveness on the sedation response surface 2.3 Ceff values at laryngoscopy followed by tracheal intubation on the response surface for laryngoscopy.....................................................................................29 2.4 Ceff values at the first skin incision on the response surface for shin algometry ...............................................................................................................................30 2.5 Ceff values at the first skin incision on the response surface for electrical tetany ...............................................................................................................................31 vii ACKNOWLEDGMENTS I would like to express appreciation to Dr. Dwayne Westenskow for his support and encouragement throughout this project. I am indebted to Dr. Steve Kern for his high expectations and trust in my abilities. I am grateful to Dr. Kenneth Horch for teaching me to think rationally and to expect more of myself while progressing in life. I appreciate Dr. Talmage Egan’s constant enthusiasm and clinical insights. I thank Noah Syroid for his support in the project, help and patience with my coding. I also acknowledge the support and help of numerous friends who have encouraged, helped, and at times, mocked me through this process. I thank my parents, Maisie and Douglas Sakaguchi, for their continual love, trust, support, encouragement, and teaching. I especially thank them for their examples of seeking after wisdom and excellence in every area of life while teaching what is of greatest value. I thank my God for being alive and for surrounding me with such fine mentors, colleagues, friends, and family. This research has been generously funded by the NIH Grant # 1 RO1 HL 64590 and by the NASA Rocky Mountain Space Consortium. Thank you to MedFusion for the use of the Medex 3010a continuous infusion pumps. We appreciate the support of Colin Corporation for the use of their Colin CBM-7000, a continuous, non-invasive blood pressure monitor. CHAPTER 1 INTRODUCTION Purpose of Study Pharmacodynamic studies are often used to characterize the concentration-effect relationship of a single drug. 1,2,3 Predicting the effect of two drugs that have a pharmacodynamic interaction is complex. As a result of this complexity, pharmacodynamic interaction studies are usually performed in volunteers in a controlled environment. 4,5,6,7,8,9 The most significant limitation of these volunteer studies is that responses to surrogate measures of surgical stimuli are used. The relationship between the stimulus induced by a surrogate measure, such as electrical tetany, and by a surgical measure, such as skin incision, remains unclear. A volunteer study also evaluates sedation differently than in the perioperative setting; a volunteer study often describes the depth of sedation using a graded scale such as the observer’s assessment of alertness/sedation (OAA/S). 4,10 In the operating room “unconsciousness” is simply observed when the patient is non-responsive to verbal commands. Additionally, the volunteer study rigorously controls the dosing regimen over wide concentration ranges and allows time for the plasma concentration to equilibrate with the effect-site concentration. 2 This study combines pharmacokinetic and pharmacodynamic models, comparing these predictions with observations in patients. The goal was to assess models developed in volunteers by Kern et al. 4,5 by pharmacodynamically relating surgical stimuli to surrogate measures. An observational study has several limitations. The first is that the dosing regimen is not strictly controlled, resulting in periods of non- steady-state kinetics and greater uncertainty with respect to drug concentrations
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