LEARNING ABOUT NEW ANESTHETICS USING A MODEL DRIVEN, FULL HUMAN SIMULATOR W. Bosseau Murray, MB ChB, FRCA, MD (Anaest),1 Michael L. Good, MD,2 Joachim S. Gravenstein, MD,2 Johannes H. van Oostrom, PhD,2 and W. Glover Bras¢eld 3

Murray WB, Good ML, Gravenstein JS, Oostrom JH, Bras¢eld W. Learning about new anesthetics using a model driven, full human simulator. J Clin Monit 2002; 17: 293^300

ABSTRACT. Objective. New pharmacological agents are introduced into medical practice at an ever-increasing pace. Teaching how to use new medications in the clinical setting presents educational challenges and puts patients at risk. Methods. Patients and clinical settings in which remifentanil might provide clinical advantages over existing anesthetics were identi¢ed. A simulator curriculum was developed to demonstrate the use of remifentanil in the sample cases. The simulation was designed to highlight the clinical advantages and potential side e¡ects of remifentanil. A screen displaying the concentrations of remifentanil in plasma and in the hypothetical e¡ector site was developed. A simulator was modi¢ed (addition of an infusion pump and a pharmacokinetic screen display) and transported to several cities in the U.S.A. An instructor guided small groups of anesthesiologists and anesthetists through a structured program that enabled participants to observe drug e¡ects in simulated patients. Results. There were 836 participants in the remifentanil program, which was o¡ered in 58 cities in the U.S.A. Surveys were completed by 574 anesthesiologists. There was a signi¢cant di¡erence in comfort level for using remifentanil after the session compared to before (Chi-square, p < 0.001.) The statement: ‘‘Clinical simulation experience is a means to learn about new agents like remifentanil’’ was rated as ‘‘excellent’’ by 81% and as ‘‘good’’ by 19% of participants. No participant found the experience to be ‘‘not useful.’’ Conclusions. Patient simulation is a novel method of introducing new drugs to the medical community and is perceived by anesthesia providers as a valuable addition to available teaching methods. KEY WORDS. Human simulators, education, continuing medical education, remifentanil, pharmacokinetics, pharmacodynamics.

INTRODUCTION

From the 1 Department of Anesthesiology, Pennsylvania State University College of Medicine, 2 Department of Anesthesiology, University of Florida, 3 M.E.T.I. (Medical Education Technologies, Inc.), Sarasota, FL, U.S.A. Received Dec 29, 2000, and in revised form Jun 16, 2002. Accepted for publication Aug 20, 2002. Address correspondence to W. Bosseau Murray, Pennsylvania State University College of Medicine, Department of Anesthesiology H-187, 500 University Ave, Hershey, PA 17033, U.S.A. E-mail: [email protected] Journal of Clinical Monitoring and Computing 17: 293^300, 2002. 2002 Kluwer Academic Publishers. Printed in the Netherlands.

New pharmacological agents are introduced into medical practice at an ever-increasing pace. Learning to use new medications while simultaneously caring for an anesthetized patient puts the patient at risk. The introduction of remifentanil (UltivaTM ) into clinical practice o¡ered an opportunity to examine the role of patient simulators in helping anesthesia practitioners learn about new anesthetic agents before administering the drug to patients in the clinical setting. Remifentanil is a short acting narcotic introduced in the United States in 1996 [1]. This anesthetic has several novel features, including high potency, rapid onset of intended action and unwanted side e¡ects, as well as rapid metabolism. Rapid o¡set of e¡ect (within 5 to 10 minutes) makes it essential that early postoperative analgesia be established as part of the anesthesia plan.

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Because of these characteristics, the United States Food and Drug Administration (FDA) advised the manufacturer (Glaxo Wellcome) to make a signi¢cant e¡ort to train new users of the drug prior to use on patients. As part of this educational e¡ort, the manufacturer recruited the help of clinical educators in anesthesiology and a patient simulator manufacturer to develop an educational program using patient simulation, and o¡ered a series of simulator sessions throughout the United States. This report describes the development and implementation of a simulator-based learning program for remifentanil, and the results of a survey completed by anesthesiologists and anesthetists before and after remifentanil training using patient simulation.

METHODS AND MATERIALS

Curriculum development Representatives of the drug manufacturer (Glaxo Wellcome, Research Triangle Park, NC), Human Patient Simulator (HPS) manufacturer, (M.E.T.I., Medical Education Technologies, Inc., Sarasota, FL), and clinical educators in anesthesiology worked collaboratively to develop a simulator-based learning curriculum for remifentanil, a short acting, synthetic narcotic. ^ ^

^

First, speci¢c learning objectives were established (see Table 1). Second, patients and clinical situations in which remifentanil might provide clinical advantages over existing anesthetics were identi¢ed (see Table 2 for an example). Third, simulation scenarios were developed to highlight the clinical advantages and potential side e¡ects of this new anesthetic drug (see Table 3 for a model). Apnea, sti¡ chest, hypotension, and bradycardia were identi¢ed as side e¡ects that anesthesia practitioners must be able to recognize and treat.

A consistent format (see Table 3) was used in all four simulation scenarios. This facilitated the rapid familiarization of the moderators with the educational program.

Simulator modi¢cations Commercially available patient simulators use an adult size mannequin that employs mathematical models of human physiology and pharmacology, and solid-state technology connected to standard monitoring instru-

Table 1. Learning objectives for the remifentanil simulator-based learning program Recognize unique pharmacokinetic/pharmacodynamic pro¢le of remifentanil: 1. Rapid onset of action (within 1 minute) for profound analgesia during intubation. 2. Steady-state concentrations within 5 to 10 minutes, allowing for precise control of anesthesia/analgesia and rapid response to titration. 3. The £exibility to administer higher opioid doses for superior control of intraoperative stress. 4. Rapid, predictable recovery from opioid e¡ects (within 5 to 10 minutes). 5. Rapid clearance with no opioid accumulation, regardless of dose or duration of infusion. 6. Consistent o¡set of action, regardless of gender, age, weight, or renal/hepatic status. 7. The imperative to balance the desired rapid onset of analgesic e¡ects in the post-anesthesia care unit with the dangerous potential of rapidly evolving, profound respiratory depression. Recognize potential side e¡ects and other special considerations: 1. Rapid o¡set of e¡ect (within 5 to 10 minutes) requires that early postoperative analgesia be established as part of the anesthesia plan. 2. IV tubing must be cleared after remifentanil is discontinued. 3. In monitored anesthesia care, it is not recommended that bolus doses of remifentanil be used simultaneously with a continuous infusion because of a high incidence of apnea and muscle rigidity. 4. The adverse events of respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity observed with remifentanil are characteristic of mu opioid pharmacodynamics.

ments. Thus, the simulator presents a realistic training environment for anesthesiologists, intensivists, and other acute care physicians (see Figure 1). For this project, the simulator was modi¢ed by developing software drivers to accept information from a syringe infusion pump connected via an RS-232 serial connection. This greatly enhanced the realism of the simulation environment by requiring participants to actually load a syringe and operate the controls of the infusion pump in order to administer remifentanil to the simulated patient. To further enhance the educational experience, a computer screen display was developed to show the instantaneous remifentanil infusion rate, blood plasma concentration, and a hypothetical e¡ector site concentration [2] plotted as a function of time (Figure 2). In addition, this display shows the concentrations at which analgesia and apnea would occur. The display computer

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Table 2. Mr Outta Joint, a patient with a dislocated shoulder who comes for reduction represents a case description for the remifentanil simulator-based learning program A 30-year-old, muscular, healthy man comes for reduction of a dislocated shoulder. He has eaten three hours ago, the dislocation occurred 30 minutes ago while he helped with the transport of a piano. Medical history, physical examination, and laboratory data reveal nothing of anesthetic signi¢cance except that he is overweight (225 lbs. at 50 900 = 102 Kg and 1.75 m) and the patient’s wife reports that he snores to the point of occasional brief moments of apnea during sleep. He does not smoke and drinks a few beers on weekends. Inspection of the airway suggests an easy intubation. He has been given 10 mg morphine IM for pain 45 minutes ago in the emergency room. The surgeon knows the patient, has treated him for a dislocated shoulder twice before, and says that the patient must be relaxed and that the procedure will take about 5 minutes (having worked with this surgeon, you believe the estimate). Vital signs: SpO2 97%, BP 135/80 mmHg, HR 80 bpm, RR 19 breaths/min. You plan to do a rapid sequence induction after denitrogenation. The drugs available to you include thiopental, propofol, succinylcholine, remifentanil, as well as nitrous oxide and oxygen. The usual emergency drugs are also available. An IV is running with Lactated Ringer’s 600 ml remaining in the 1000 ml bag. Minimal postoperative pain is anticipated. Other scenarios used in this project included that of an obese, hypertensive patient with a kidney stone, an inebriated obese, combative patient with a compound fracture of a femur, and a 75-year-old woman who requires a cataract operation under monitored anesthesia care. The experienced clinician will be able to incorporate many clinical challenges into these scenarios to demonstrate the advantages, limitations and potential side e¡ects of remifentanil. Indeed, many other scenarios can be devised to enrich the repertoire of simulated patients with challenging problems.

Fig. 2. Computer display screen showing the instantaneous remifentanil infusion rate, blood plasma concentration, and e¡ector site concentration plotted as a function of time.

receives its data from the HPS pharmacokinetic and pharmacodynamic (PK-PD) models of the simulator [3]. The PK-PD model is based on a multi-compartment model with rate constants that describe the kinetics, resulting in dose-response pro¢les. Dose-response pro¢les for over 60 di¡erent intravenous drugs and their e¡ect on the cardiovascular and respiratory systems have been de¢ned. A pro¢le for remifentanil was developed from data from the published studies. Plasma and e¡ector site concentrations from PK-PD model for remifentanil were communicated via an RS-232 connection to the display computer.

Program format

Fig. 1. Anesthesiology residents and faculty gather around a contemporary patient simulator to learn and practice the induction of general endotracheal anesthesia.

The modi¢ed Human Patient Simulator, anesthesia machine and monitors were transported to cities throughout the United States where anesthesiologists and anesthetists, in practice and in training, participated in the remifentanil simulator-based curriculum in open-ended learning sessions. The simulation sessions were structured with a physician moderator leading small groups of two to ten participants through the remifentanil scenarios. One or two participants assumed care of the patient while the remaining participants observed and o¡ered comments when problems, questions or unique clinical situations arose. The moderators leading each session o¡ered suggestions regarding clinical use of remifentanil and timely recognition and appropriate treatment of side e¡ects. The initial group of moderators attended a four-

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Table 3. Common structure of the clinical scenarios for the remifentanil simulator-based learning program Scenario state

Description of state events and transitions

Baseline

The simulator remains in this state until the plasma concentration of remifentanil exceeds 7 ng/ml (due to a large and rapid bolus or rapid infusion), or the instructor sequences manually to another state.

Stimulation

The instructor should select this state to coincide with patient stimulation, including laryngoscopy, nerve block, incision, or other surgical stimulation. In this state, the simulator checks the e¡ect site remifentanil concentration to determine if adequate analgesia has been achieved. A threshold concentration of 4 ng/ml is used for all scenarios except eye surgery, which uses a threshold of 1 ng/ml. If the remifentanil e¡ector site concentration is less than the threshold concentration, a small bolus of epinephrine is automatically released, which causes ‘‘break through’’ increases in heart rate and blood pressure.

Adequate analgesia

The state simply signi¢es that a su⁄cient e¡ector site concentration of remifentanil is present to produce adequate analgesia. The simulator returns to the Baseline state after 20 seconds.

Inadequate analgesia

A bolus of 25 mg epinephrine is automatically related, which causes ‘‘break through’’ increases in heart rate and blood pressure. The simulator returns to the Baseline state after 20 seconds.

Sti¡ chest

Ventilatory compliance decreases signi¢cantly in this state, creating the so-called ‘‘sti¡ chest’’ syndrome. The ‘‘sti¡ chest’’ develops over one minute; with positive pressure ventilation, airway pressures of 70 cmH2 O are observed with normal tidal volumes of 10 ml per kg. Plasma concentrations of any muscle relaxant, thiopental, propofol, or midazolam will prevent or cause resolution of the ‘‘sti¡ chest.’’ (Note: Any time the participant gives a large, rapid IV bolus of remifentanil, the instructor should consider manually sequencing to this ‘‘sti¡ chest’’ state.)

Normal ventilator compliance

‘‘Sti¡ chest’’ syndrome is corrected in this state following administration of any muscle relaxant, thiopental, propofol, or midazolam. The simulator remains in this state until plasma concentration falls below 7 ng/ml, at which time control returns to the Baseline state.

Unintended bolus

Contrary to recommendations, we let the remifentanil infusion enter the IV tubing at one of the ports NOT close to the patient. We also let the IV bag on that infusion be empty or nearly so. In the patient under MAC (or with a patient awakening from general anesthesia) we can demonstrate the unintended administration of a bolus of remifentanil when the IV bag is changed as follows: (a) remifentanil infusion is running in IV with an almost empty bag, (b) IV stops, being empty, (c) continue running remifentanil infusion pump for a couple of minutes, (d) the patient is responsive and breathing spontaneously; stop remifentanil (the tail-end of which now resides in the tubing between the infusion pump and IV catheter, (e) now change IV bag and let it begin to run, (f) patient now gets an unintended bolus of remifentanil and stops breathing. This demonstration can best be shown with the patient under MAC. It can also be activated if there is enough time and if the patient is breathing spontaneously after a general anesthetic involving a remifentanil infusion.

hour training session with the curriculum developers. This session included study of a comprehensive syllabus as well as hands-on practice with the patient simulator. Subsequent moderators observed actual sessions as onthe-job training following study of the syllabus. Each simulation scenario began with a ‘‘baseline’’ state, allowing the participant to gain familiarization with the patient simulator and simulated clinical environment, and to initiate anesthetic management. Clinical responses to remifentanil infusion and other intravenous and inhaled anesthetic agents were automatically calculated and controlled by the simulator’s pharmacokinetic and pharmacodynamic modules. In addition, when the plasma levels of remifentanil increased above 7 ng/dl

and no hypnotic or muscle relaxant agents had been previously administered, the scenario automatically sequenced to the ‘‘sti¡ chest’’ state (Table 3). At any point during the simulation, the session moderator could assess the dynamic balance between patient stimulation (e.g., laryngoscopy or surgical incision) and analgesic levels from remifentanil by sequencing to the ‘‘stimulation’’ state. This ‘‘stimulation’’ state was designed to demonstrate the e¡ects of inadequate analgesia. An e¡ector site concentration of 4 ng/dl was selected to di¡erentiate between an ‘‘adequate’’ and an ‘‘inadequate’’ analgesic state [4]. In the case of an ‘‘inadequate’’ state, the scenario simulated ‘‘light anesthesia’’ by the automated intravenous bolus administration of 25 mg epinephrine.

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Questionnaire Participants completed questionnaires before and after the simulator-based training (see Appendix). The questionnaires identi¢ed prior exposure to a patient simulator and to remifentanil, the comfort level of the anesthesiologists towards using remifentanil, and perception changes regarding remifentanil after participation in the training session. Free text comments were invited. As the remifentanil training program progressed over many months, an increasing number of participants reported having already used remifentanil in their clinical practice. To determine if using remifentanil prior to the simulator exercise in£uenced the participants’ perception about the drug, the ‘‘perception change’’ question responses were separated for the ¢rst 100 participants and compared to the remaining participants. Survey responses completed before and after simulator training were compared using Chi-square analysis, with p < 0.05 considered statistically signi¢cant.

RESULTS There were 836 participants in the remifentanil program, which was o¡ered in 58 cities in the U.S.A. in 1996 and 1997. Surveys were completed and returned by 574 anesthesiologists (68.6% response rate). All respondents did not complete all questions; thus result totals do not always add up to the total number of questionnaires returned. The majority of attendees (459, 79.9%) had no prior exposure or experience with a full human patient simulator. Remifentanil was available at 36% of the participants’ hospitals, available on trial basis at 18%, under review in 19%, and not available to 23%. There was a signi¢cant di¡erence in comfort level for using remifentanil after the session compared to before (Chi-square 328.89, DF 3, p < 0.001). The question posed before the simulation was: ‘‘How would you rate your comfort level using remifentanil in your practice?’’ And the post-test request: ‘‘Please rate your comfort level with using remifentanil practice now that you have participated in a remifentanil simulation.’’ The ‘‘Clinical simulation experience is a means to learn about new agents like remifentanil’’ statement was rated as ‘‘excellent’’ by 81% and as ‘‘good’’ by 19% of participants. No participant found the experience to be ‘‘not useful.’’ The majority of trainees (73%) gave a positive answer to the question: ‘‘Did the perception of remifentanil change in any way as a result of your experience with the simulator?’’ (Chi-square 55.21, DF = 1, p < 0.001). When comparing the ¢rst 100 participants to the last 409 participants, the percentage of participants report-

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ing a perception change toward remifentanil decreased from 83% to 70%, a statistically signi¢cant di¡erence (p = 0.01). The participants found the visualization of blood and e¡ector site concentrations of particular value, especially in correlation with the rapid onset and o¡set of both desired and side e¡ects. The real-time nature of the experience was deemed by participants to enhance their ability to use remifentanil in a safe manner.

DISCUSSION Rapid advances in medical technology and pharmacology present unique challenges for clinicians in practice. Once leaving the formal training setting, it is di⁄cult for the clinician in practice to gain pro¢ciency with new devices, to perform new procedures, and to experience the clinical pharmacology of new drugs. Some question the safety, e⁄ciency, and e¡ectiveness of learning new skills while simultaneously caring for patients [5, 6]. Recent cognitive science studies [7] indicate bene¢ts due to an association between the learning environment and the information retrieving environment. This concept may be applicable to the medical environment. An increase in the similarities between ‘‘the environment during learning’’ and the clinical (‘‘retrieving’’) environment may improve the e⁄ciency and amount of information retrievable (recalled) by the physician in the clinical environment. This has important implications for the simulated learning environment versus traditional lecture formats. Human patient simulators o¡er a unique learning opportunity. New equipment can be tried, new procedures rehearsed, and new drugs administered for the ¢rst time without risk to real patients. The learner can focus on the new concepts without endangering patients. Furthermore, simulators let the learner ‘‘look inside’’ the patient and examine parameters and variables that cannot be observed in real patients. For example, with a patient simulator, arterial blood gas values can be made continuously available for inspection. Similarly, the blood levels and e¡ector site concentrations of speci¢c drugs can be calculated and plotted in real time on a computer screen following injection into the simulated patient, as was done in this project (see Figure 2). The e¡ector site concentrations can be related the clinical e¡ects to be expected. There was a signi¢cant increase in provider comfort level using remifentanil following simulator training. This was due primarily to a conversion from those who were either ‘‘neutral’’ or ‘‘unclear’’ initially becoming

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‘‘somewhat’’ or ‘‘very’’ comfortable using remifentanil following the simulator-based program. The percentage who were ‘‘very comfortable’’ before and after training remained fairly constant at 14% and 15%, respectively. This suggests that for those who were already comfortable using remifentanil, there was a perception that the simulator-based training did not further enhance their comfort levels. However, for those who were not comfortable using remifentanil initially, the simulator training signi¢cantly increased their comfort level. Experience with the use of remifentanil in real patients can be expected to a¡ect the participants’ perception of the drug and of the simulation exercise. However, because the medical experience with real patients cannot be structured to optimize education, those participants with early remifentanil usage still reported a 70% positive ¢rst response to the ‘‘perception change’’ question. During the course of the program, we continuously improved operational aspects of the program. Initially, participants arrived at staggered intervals, straggling in throughout the course of the program. This interrupted the £ow of the demonstration, often requiring the moderator to go back and repeat points previously covered with the other participants. Utilizing company representatives or a second moderator to ‘‘entertain’’ late comers and prevent them from disrupting the simulation session in progress successfully resolved this problem. For future simulator-based programs of this type, we suggest participants be given a speci¢c time to report to the simulator. Many participants spent an inordinate amount of time familiarizing themselves with operation of medical equipment they do not use in their own local clinical practices. Particularly problematic in this program focusing on the intravenous infusion of a new anesthetic was the intravenous infusion pump. There are many di¡erent types and models of intravenous infusion pumps in use clinically throughout the country, yet only a single brand was used in these educational sessions. Because the moderator often had to operate the unfamiliar syringe pump for the participants, this detracted from the hands-on nature of the simulations. In the future, program developers should survey and determine the speci¢c makes and models of machines, monitors, and other medical devices and supplies that are used by the local participants. The simulation sessions were highly interactive, and participants asked many ‘‘what if’’ questions (for example, ‘‘Last week I did a case with remifentanil and we used a certain infusion rate. Can we use the equipment to simulate the blood levels and e¡ector site concentra-

tions at surgical incision, and the end of the case?’’) The dynamic nature of the patient simulator allowed the instructor to address these with real time demonstrations. Participants found the visualization of blood and e¡ector site levels of particular value, especially the demonstration of the rapid onset and o¡set of both desired and side e¡ects. Furthermore, numerous participants reported that after using the graphic displays during the simulated remifentanil cases, they for the ¢rst time ‘‘really understood’’ the pharmacological concept of the ‘‘e¡ector site.’’ Without elaboration, the e¡ector site was understood to represent di¡erent nervous cells responsible for analgesia and for control of ventilation, heart rate and blood pressure. The real-time nature of the exposure was deemed by participants to enhance their ability to use remifentanil in a safe fashion (see Appendix 3 for Free text comments). There are limitations with assessment of this simulator-based learning program. Survey bias may have been an issue because the company collecting the surveys funded the program and provided refreshments. However, because elements of the survey were collected before and after the simulation exercise, participants served as their own controls, minimizing the e¡ect of that bias. Further, the fact that later participants in the program who had used remifentanil in the clinical practice reported a lower rate of perception change would also suggest that signi¢cant survey bias was not present.

CONCLUSION Patient simulation is a novel method of introducing new drugs to the medical community and is perceived by anesthesia providers as a valuable addition to the available teaching methods. APPENDIX 1. PRE-SIMULATION PARTICIPANT QUESTIONNAIRE 1. Have you worked with a patient simulator before? { Yes { No 2. How would you rate your comfort level using remifentanil in your practice? { Very comfortable, I’m currently using remifentanil { Somewhat comfortable, I’m familiar with it but have not yet used remifentanil { Neutral, I’d like more information about remifentanil { Unclear, I’m unsure how remifentanil ‘‘¢ts in’’

Murray et al: SimulationTraining for Remifentanil

3. Is remifentanil available at the hospital or surgical center where you practice? { Yes, readily available { Yes, but on a trial basis { Not yet, but under review { Unavailable APPENDIX 2. POST-SIMULATION PARTICIPANT QUESTIONNAIRE 1. How would you rate the clinical simulation as a means to learn about new agents like remifentanil? { Excellent { Good { Neutral { Not useful 2. Please rate your comfort level with using remifentanil in your practice, now that you’ve participated in the remifentanil simulation { Very comfortable { More comfortable than before { Neutral { I’d like more information

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Related to the simulator experience ^ now willing to go ahead and use the drug ^ I expected these results from reading but was impressed with the reality of the simulation ^ I’m impressed ^ really helps to have a better sense of clinical timing ^ very informative to see pharmacokinetics of the drug similar to real clinical scenarios ^ I really knew very little about it until this experience Related to learning with the simulator ^ great teaching tool for medical students and residents ^ better understanding ^ the simulator experience greatly enhances learning as opposed to pure lecture format ^ easier to see how fast drugs go on-board and how fast to expect them to diminish ^ pharmacodynamics/kinetics curves excellent † would like to see other drugs represented ^ good way to learn how quickly this drug acts ^ it was good to see the di¡erent responses without worrying about patient damage

CONFLICT OF INTEREST STATEMENT

3. Did your perception of remifentanil change in any way as a result of your experience with the simulator? { Yes { No If yes, please describe:

Dr Gravenstein and Dr Good are co-inventors of the Human Patient Simulator. Drs Good, Gravenstein and Murray received honoraria from M.E.T.I. for serving as facilitators for development and training programs. Mr Bras¢eld is an employee of M.E.T.I.

4. What advantages does remifentanil o¡er over agents you currently use?

This paper was presented in part at the ASA Annual Meeting in Orlando, FL in October 1998.

5. Please give us any suggestions on how educational opportunities like this simulation exercise can further meet your needs.

REFERENCES

APPENDIX 3. FREE TEXT COMMENTS Related to the simulator per se’ ^ simulator builds familiarity and increases comfort level ^ visual demonstration of e¡ects ^ the graphs and the simulator made it so much simpler to visualize ^ excellent hands-on experience ^ I expected these results from reading but was impressed with reality of simulation

1. Hug CC. Remifentanil ^ safety issues with a new opioid drug. Anesthesia Patient Safety Foundation Newsletter 1996; 11 (3): 31^32 2. Westmoreland CL, Hoke JF, Sebel PS, Hug CC Jr, Muir KT. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291). in patients undergoing elective inpatient surgery. Anesthesiology 1993; 79 (5): 893^903 3. Van Meurs WL, Nikkelen E, Good ML. Pharmacokineticpharmacodynamic model for educational simulations. IEEE Trans Biomed Eng 1998; 45 (5): 582^90 4. Glass PSA, Hardman D, Kamiyama Y, Quill TJ, Marton G, Donn KH, Grosse CM, Hermann D. Preliminary pharmacokinetics and pharmacodynamics of an ultrashort-acting opioid: Remifentanil (GI 87084B). Anesth Analg 1993; 77: 1031^1040

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5. Murray WB, Shelley KH, Schneider AJL. Education for practical anesthesia (Editorial Comment). Current Opinion in Anesthesia 1994; 7: 471^472 6. Allen G, Murray WB. Teaching airway management skills. Anesthesiology 1996; 85 (2): 437^439 7. Schacter DL. The psychology of memory. In: Ledoux J, Hirst W, eds. Mind and brain: Dialogues in cognitive neuroscience. Cambridge U.K.: Cambridge University Press, 1990