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Ambulatory Anesthesiology Section Editor: Peter S. A. Glass

A Randomized, Controlled, Double-Blind Trial of Patient-Controlled Sedation with Propofol/Remifentanil Versus Midazolam/Fentanyl for Colonoscopy Jeff E. Mandel, MD, MS* Jonathan W. Tanner, MD, PhD* Gary R. Lichtenstein, MD† David C. Metz, MD† David A. Katzka, MD† Gregory G. Ginsberg, MD† Michael L. Kochman, MD†

BACKGROUND: Patient-controlled sedation (PCS) with propofol has been advocated as a method for dealing with the narrow therapeutic window for moderate sedation, but previous studies have methodologic limitations. We hypothesized that, by using remifentanil in conjunction with propofol and using PCS in both arms of the study, we could demonstrate marked improvements in facility use compared with fentanyl plus midazolam. METHODS: Fifty patients undergoing elective colonoscopy were randomized (with concealed allocation) to midazolam/fentanyl (group MF) or propofol/remifentanil (group PR) administered via PCS. Time intervals for sedation and recovery, perceptions by patient, nurse, and gastroenterologist, and need for anesthesiologist intervention were assessed. RESULTS: Group PR patients were sedated and recovered significantly more rapidly than did group MF (P ⬍ 0.0001). In the group PR, recovery room time was actually shorter than procedure room time. Patient, nurse, and gastroenterologist perceptions were equivalent between the groups. Two patients in group PR required anesthesiologist intervention for arterial desaturation exceeding the primary safety end point. CONCLUSIONS: PCS with propofol/remifentanil yields superior facility throughput compared with midazolam/fentanyl when used in an appropriate care setting. (Anesth Analg 2008;106:434 –9)


olorectal cancer is the second most common cause of cancer-related mortality in the United States, accounting for 55,000 deaths annually.1 Use of colonoscopy for screening has been advocated as an effective means for reducing deaths from colon cancer. An estimated 14.5 million colonoscopies were performed in the United States in 2002.2 In the United States, colonoscopy is considered to be sufficiently uncomfortable as to require sedation. Sedation is not without risks, and complications attributable to sedation may exceed technical complications by a factor of 10.3 Sedation with propofol has been advocated as an alternative to the more commonly used combination of midazolam and narcotic sedation. Propofol is associated with faster onset and offset of sedation and

From the Departments of *Anesthesiology and Critical Care, and †Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Accepted for publication September 19, 2007. Reprints will not be available from the author. Address correspondence to Jeff E. Mandel, MD, MS, Department of Anesthesiology and Critical Care, 780 B Dulles Building, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. Address e-mail to Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/01.ane.0000297300.33441.32


higher patient satisfaction, but may require resuscitation maneuvers more often than conventional sedation. Patient-controlled sedation (PCS) has been advocated to improve titration of sedation with propofol. The approach taken in previous studies of PCS is to attempt to minimize the respiratory and hemodynamic side effects of propofol, whereas the current study attempts to maximize the time savings associated with propofol sedation by the addition of significant doses of remifentanil and use of an anesthesiologist for rescue when needed. We used PCS in both arms of the study to avoid bias in the dosage of midazolam and fentanyl, and evaluated the equivalence of sedation by assessment of blinded participants. Our hypothesis was that the combination of propofol and remifentanil would significantly reduce the time to sedation and ambulation without assistance when compared with midazolam and fentanyl at equivalent levels of patient, nurse, and gastroenterologist satisfaction.

METHODS The protocol was approved by the IRB of the University of Pennsylvania School of Medicine. Fifty patients scheduled for elective outpatient colonoscopy with conscious sedation were recruited from the practices of the gastroenterologist investigators. Patients known to have failed sedation with conventional drugs or to have significant comorbidity were not Vol. 106, No. 2, February 2008

Table 1. Medication Regimens Group midazolam/fentanyl (MF) Drug content in syringe Concentrations Volume in syringe Initial bolus Demand dose Lockout

Fentanyl 250 ␮g Midazolam 10 mg Saline 5 mL Fentanyl 12.5 ␮g/mL Midazolam 0.5 mg/mL 20 mL 4 mL 1 mL 1 min

explicitly excluded from participation. After recruitment, patients were randomized to one of two groups by sequentially numbered envelopes. The anesthesiologist prepared a 60-mL syringe loaded with the mixture of study drugs and programmed a Graseby 3300 syringe pump (Marcal Medical, Millersville, MD) as shown in Table 1. The midazolam-fentanyl mixture was prepared by combining 10 mL of midazolam (1 mg/mL), 5 mL of fentanyl (50 ␮g/mL), and 5 mL of saline. An initial bolus of 4 mL and demand dose of 1 mL with 1 min lockout were programmed. The propofol-remifentanil mixture was prepared by dissolving 1 mg remifentanil in 2.5 mL of propofol (10 mg/mL) and adding 1 mL of this mixture to 39 mL of propofol. The admixture was performed immediately before initiation of the study; no evidence of deemulsification of propofol was noted. An initial bolus of 2.5 mL and demand dose of 0.75 mL with a zero lockout were programmed. The actual lockout for group propofol-remifentanil (PR) was dependent on bolus and syringe size; for the 60-mL syringe with 0.75-mL bolus, this was approximately 13 s. The infusion pump was connected to a pigtail adapter placed at the hub of the IV catheter with a dead-space of ⬍0.1 mL. An infusion set with a check valve was used to avoid retrograde flow. The carrier fluid was observed to assure continuous infusion without obstruction. All patients were monitored according to standard practice in our institution, with continuous pulse oximetry, electrocardiogram, and noninvasive arterial blood pressure measured at 5-min intervals, and oxygen 2 L/min was administered by nasal cannula. An Advanced Cardiac Life Support certified nurse was present throughout the procedure, with primary responsibility for record keeping and patient safety. The nurse was permitted to undertake normal measures to deal with desaturation, including verbal stimulation and chin lift. Patients were instructed to press the button as often as they felt the need to do so, as there was a lockout to limit the amount of medication and an anesthesiologist to intervene. Nurses were instructed to respond to the question “should I press the button” with the answer “If you want to press the button, do so.” Patients were instructed that after the procedure, we wanted to see how quickly they could ambulate, and Vol. 106, No. 2, February 2008

Group propofol/remifentanil (PR) Remifentanil 400 ␮g Propofol 400 mg Remifentanil 10 ␮g/mL Propofol 10 mg/mL 40 mL 2.5 mL 0.75 mL 13 s

that a research assistant would be with them to assess this. Blinding was achieved by covering the clear Lexan™ shell of the pump with opaque labels, and shrouding the microbore infusion tubing with opaque plastic sheathing used for chemotherapeutic infusions. The gastroenterologist, nurse, and patient were unaware of the lockout period. The anesthesiologist was blinded before allocation, but was aware of the treatment regimen while present to intervene for adverse events. Safety end points included arterial desaturation ⬍85% for more than 60 s, hypotension ⬍90 mm Hg systolic or 20% decrease from baseline persisting on repeat determination 1 min later, or inability to tolerate the procedure. Times were recorded using a synchronized time source for the following events: initiation of sedation, insertion of the colonoscope, cecal intubation, removal of colonoscope, clearance for transportation to postanesthesia care unit (PACU), and ability to walk without assistance. Initiation of sedation was the time at which the pump was activated to administer the initial loading dose. Insertion of the colonoscope was determined by the gastroenterologist based on clinical assessment of patient readiness. Cecal intubation and removal of colonoscope were announced by the gastroenterologist. Clearance for transportation was determined by the endoscopy suite nurse. Assessment of readiness to ambulate was made by a blinded observer who remained with the patient for the duration of the PACU stay. The observer was instructed that the patients were required to be able to walk as if they were leaving the PACU unescorted. The intent of the selection of time points was to closely resemble the normal clinical workflow. The collected times were used to derive the following intervals: Procedure time ⫽ Colonoscope out–Colonoscope in Time to Sedation ⫽ Colonoscope in–Initiate sedation Time to Recovery ⫽ Ambulation–Colonoscope out Procedure room time ⫽ Transport–Initiate sedation PACU time ⫽ Ambulation–Transport Satisfaction of gastroenterologist, nurse, and patient were obtained by a 7-point Likert scale. The gastroenterologist and nurse were asked to evaluate two statements: “The patient was adequately sedated” © 2008 International Anesthesia Research Society


Table 2. Group Comparison Group midazolam/fentanyl (MF) (24)

Group propofol/remifentanil (PR) (25)

57.7 ⫾ 10.8 28.1 ⫾ 6.0 11/13 1 10 13 21 ⫾ 12.3

60.5 ⫾ 9.6 28.6 ⫾ 5.9 13/12 2 10 13 19 ⫾ 9.9

Age (mean ⫾ sd) Body mass index (kg/m2) (mean ⫾ sd) Gender (male/female) ASA III Polypectomies Position change Procedure duration (min) (mean ⫾ sd)

(statement 1) and “The patient was safe” (statement 2). Patients were asked to evaluate three statements: “I felt comfortable with controlling my own sedation” (statement 3), “I was comfortable throughout the procedure” (statement 4), and “I would have this anesthetic again, and encourage others to do so” (statement 5).

Statistics A sample size estimate was calculated by using previously published data comparing PCS propofol/ alfentanil to conventional sedation.4 A study comprised of 20 patients per group, and a P ⫽ 0.05 was determined to have a 95% power. We sought approval for 25 patients per group to insure against incomplete studies due to adverse events and procedures aborted due to inadequate bowel preparation. Patients were randomly allocated to two groups of 25 by the randperm function of MATLAB (The Mathworks, Natick, MA). A blocking of 10 and 40 was used to permit safety review after the first 10 cases. Times were compared by two-sided Student’s t-test for two samples assuming equal variance, as were demographic data such as age and body mass index (BMI), and presented as mean ⫾ sd. Comparison of satisfaction scores was performed by ordered logit regression for group, gender, age, height, weight, and BMI. Linear regression of sedation and ambulation times was performed to examine possible confounding by gender, age, height, weight, BMI, and gastroenterologist. All statistics were performed with STATA 8 (Stata Corp, TX).

RESULTS Forty-nine patients completed the study; one patient was excluded for noncompliance with bowel preparation. The groups were equivalent for age, BMI, gender, and number of ASA III patients. There were no significant differences between groups in the number of polypectomies, the number of patients requiring position change to achieve cecal intubation, and in overall procedure time (exclusive of time to sedation). These values are summarized in Table 2. Patients in group midazolam-fentanyl (MF) consumed 6.4 ⫾ 2 mg midazolam and 161 ⫾ 49 ␮g fentanyl (mean ⫾ sd). Patients in group PR consumed 115 ⫾ 42 mg propofol and 115 ⫾ 42 ␮g remifentanil. 436

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Figure 1. Times to sedation and ambulation and time spent in the procedure room and recovery room. Group propofol/ remifentanil (PR); group midazolam/fentanyl (MF).

Times to sedation and ambulation and time spent in the procedure room and recovery room are summarized in Figure 1. Patients in group MF required significantly more time to achieve sedation—7.6 ⫾ 3.6 min vs 3.4 ⫾ 1.3 min in group PR. Time to ambulation without assistance was also longer in group MF—36.4 ⫾ 5.3 min vs 9.2 ⫾ 4.0 min. Recovery room time was longer in group MF—32 ⫾ 25 min vs 4.9 ⫾ 4.3 min. These differences were significant at P ⬍ 0.0001. Age, gender, height, weight, BMI, and gastroenterologist were not confounders for these intervals. Procedure room time was not significantly different between groups. Of interest, recovery room time was appreciably shorter than procedure room time for group PR. Agreement with statements 1 and 2 by nurses and gastroenterologists and statements 3, 4, and 5 by patients were analyzed by ordered logit regression. No correlation was found between ratings and group, gender, age, height, weight, or BMI. Of the 343 responses, only 14 ratings were lower than neutral. ANESTHESIA & ANALGESIA

More group PR patients had low safety ratings, more group MF patients had low satisfaction ratings. The study was not designed to detect differences in the rate of cardiopulmonary complications, but end points for anesthesiologist intervention were required for study approval. There were no significant differences in hemodynamic safety end points (two in group PR, one in group MF). In group PR, two patients required intervention by the anesthesiologist, in both cases, two breaths of 100% oxygen via a Mapleson circuit and facemask. Both of these episodes occurred shortly after cecal intubation, when stimulation diminished markedly, and both patients were awake and responsive to verbal commands within 60 s of the intervention. No patients in group MF required intervention. There were no technical complications of colonoscopy, and all patients completed colonoscopy without non-PCS sedation. The success of blinding could not be assessed with complete certainty. Although gastroenterologists and nurses would periodically express opinions as to which arm the patient was in, the only primary data collection point subject to observer bias was colonoscope insertion time, which generally preceded the time at which the gastroenterologist would have any opinion on the form of sedation. Patients uniformly failed to express an opinion as to the arm of the study into which they perceived to be allocated.

DISCUSSION The practice of sedation for procedures such as colonoscopy exposes the patient to risk of morbidity and mortality, and appropriate safeguards for patient safety must be preserved. Economic pressure to deliver care under cost constraints has led to calls for changes in Food and Drug Administration labeling on drugs such as propofol to permit their use in settings other than the traditional anesthesia care model.5 Although involvement of anesthesia providers in colonoscopy has been demonstrated to reduce sedationrelated adverse events,6 concern related to the costs of such sedation practices led the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy to state their position that “the routine assistance of an anesthesiologist/anesthetist for average risk patients undergoing standard upper and lower endoscopic procedures is not warranted.�7 Current trends suggest a reduction in reimbursement for anesthesia-directed procedural sedation8 at a time when many anesthesia departments are unable to provide coverage for the current volume of procedural sedation.9 A demonstration that anesthesiologist involvement in sedation practices might increase facility efficiency and reduce overall cost of care would be useful information in guiding policy on an important public health issue. The use of propofol by nonanesthesiologists has been reported in numerous prospective studies, and has been Vol. 106, No. 2, February 2008

associated with significantly shorter time to sedation and recovery with higher patient satisfaction.10 The narrow therapeutic window for moderate sedation with propofol has prompted use of PCS to avoid unintended general anesthesia. In patients randomized to propofol-alfentanil PCS or midazolampethidine, the rate of over-sedation was lower with PCS, time to discharge was shorter, and all patients expressed satisfaction with their care.4 These results have been confirmed in other reports.11,12 PCS with midazolam has been compared with PCS with propofol in patients undergoing third molar extraction13 and cataract extraction.14 Patient satisfaction was equivalent, but recovery time was shorter with propofol. The limitations of previous studies include the management of narcotics and lack of concealed allocation. Fentanyl and demerol have been given at the discretion of the physician, and alfentanil doses given in conjunction with propofol fall short of those necessary to reduce propofol requirements. Pharmacokinetic simulation of recovery time from infusions of propofol and alfentanil has demonstrated that the fastest recovery is achieved using the lowest feasible dose of propofol relative to alfentanil, and lack of sensitivity of wakeup time to infusion duration when remifentanil is used as the narcotic.15 We used fixed ratios of narcotic and sedative to permit a single syringe to be used in each arm of the study, eliminating the need for discretionary narcotic use and facilitating concealed allocation. The ratio of remifentanil to propofol was high enough to expect a propofolsparing effect, but the optimality of the ratio was not assessed. The primary end points in this study were time intervals. Time to sedation and time to recovery were significantly shorter in group PR, and differences were more striking than those reported in previous efforts. Ambulation time was shorter than procedure time, which might permit reduced PACU staffing ratios from the current recommendations of 3 or 4 PACU slots per endoscopy suite.16 The magnitude of the cost savings with such an approach is currently unknown. Perceptions were a secondary end point in the study. There were minor differences in perceptions between groups, and between nurses and gastroenterologists, but no significant differences were found. Patient satisfaction was typically high. There was one patient in group MF who was dissatisfied with the process of controlling his or her own sedation, whereas all other patients were accepting. The extent to which this result can be extended to a wider population is unclear. Satisfaction with patientcontrolled analgesia has been demonstrated to be affected by the psychological test locus of control.17 PCS applied as the sole option for sedation would likely result in lower satisfaction scores. The doses of midazolam and fentanyl exceeded those typically administered by the same gastroenterologists during routine conscious sedation. The doses Š 2008 International Anesthesia Research Society


we report for propofol are comparable with those reported by Bright et al.4 using PCS propofol/alfentanil, and approximately half that reported by Sipe et al.10 using nurse-administered propofol sedation. The primary safety end point was arterial desaturation below 85% for 60 s. Although 90% saturation is an often-used criterion for significant desaturation during sedation, there appears to be no validation of this cutoff. Moller et al.,18 in an observational study of 296 patients, noted episodes of desaturation between 86% and 90% in 53% of patients that were undetected by anesthesiologists in 70% of cases, and when detected, were discovered on average after 70 s. Severinghaus et al.19 subjected 50 volunteers to deliberate hypoxia intended to yield arterial saturation of 55% for 30 – 45 s without deleterious effects. Thus, the safety end point seemed only slightly below a level that most anesthesiologists would fail to detect by clinical signs, and significantly above levels intentionally produced by Severinghaus et al. The primary safety end point was intended to mimic a process in which the nurse would initiate a response to desaturation with backup from an anesthesiologist in a nearby location. Desaturation requiring supplemental oxygen is a relatively common occurrence in colonoscopy; a prospective study of 3196 patients noted an incidence of 4.4%.20 The combination of propofol and remifentanil has been demonstrated to yield significant respiratory depression.21 This propensity for respiratory adverse events was seen in this study; in two patients in group PR, the anesthesiologist intervened due to the safety end point. In both instances, the desaturation occurred immediately subsequent to cecal intubation and resolved promptly without heroic measures. We conclude that the presence of an anesthesiologist was beneficial. The frequency of intervention was entirely a function of the specified end point. The recovery from respiratory depression with the propofolremifentanil mixture is rapid. Had a lower saturation threshold been chosen, or a longer time, or had patients been administered oxygen, the rate of intervention may have been different, perhaps zero. The primary safety end point was not intended to measure respiratory depression but, rather, the ability of patients to recover from transient desaturation through low-skill interventions by Advanced Cardiac Life Support certified nurses. Clinicians would not normally elect to defer intervention during desaturation for 60 s. We cannot recommend this form of sedation to those not prepared to administer resuscitative measures promptly, and do not suggest that the methods used in this study are standard clinical practice. The applicability of this form of sedation to other endoscopic procedures, or sedation in general, is unknown. An efficient sedation protocol could significantly improve treatment applicability by increased 438

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throughput in procedure rooms, greater patient acceptance, and decreased PACU costs. The extent to which PCS with anesthesiologist rescue can form the basis of a safe, cost-effective alternative to a two-tiered system of conscious sedation by nurses and deep sedation in a monitored anesthesia care model will require further study. ACKNOWLEDGMENTS E. Andrew Ochroch, MD, MPH, assisted in statistical analysis. Bhavisha Dhillon, RN, Laura Chang, BS, and Min Wang, BA, assisted in postprocedure assessment. Dr. Mandel acknowledges honoraria for lectures from Abbott Laboratories. REFERENCES 1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15–36 2. Seeff LC, Richards TB, Shapiro JA, Nadel MR, Manninen DL, Given LS, Dong FB, Winges LD, McKenna MT. How many endoscopies are performed for colorectal cancer screening? Results from CDC’s survey of endoscopic capacity. Gastroenterology 2004;127:1670 –7 3. Sieg A, Hachmoeller-Eisenbach U, Eisenbach T. Prospective evaluation of complications in outpatient GI endoscopy: a survey among German gastroenterologists. Gastrointest Endosc 2001;53:620 –7 4. Bright E, Roseveare C, Dalgleish D, Kimble J, Elliott J, Shepherd H. Patient-controlled sedation for colonoscopy: a randomized trial comparing patient-controlled administration of propofol and alfentanil with physician-administered midazolam and pethidine. Endoscopy 2003;35:683–7 5. Rex DK. Review article: moderate sedation for endoscopy: sedation regimens for non-anaesthesiologists. Aliment Pharmacol Ther 2006;24:163–71 6. Vargo JJ, Holub JL, Faigel DO, Lieberman DA, Eisen GM. Risk factors for cardiopulmonary events during propofol-mediated upper endoscopy and colonoscopy. Aliment Pharmacol Ther 2006;24:955– 63 7. Rex DK. Three challenges: propofol, colonoscopy by undertrained physicians, and CT colonography. Am J Gastroenterol 2005;100:510 –3 8. Hannenberg AA. Payment for procedural sedation. Curr Opin Anaesthesiol 2004;17:171– 6 9. Lalwani K. Demographics and trends in nonoperating-room anesthesia. Curr Opin Anaesthesiol 2006;19:430 –5 10. Sipe BW, Rex DK, Latinovich D, Overley C, Kinser K, Bratcher L, Kareken D. Propofol versus midazolam/meperidine for outpatient colonoscopy: administration by nurses supervised by endoscopists. Gastrointest Endosc 2002;55:815–25 11. Heuss LT, Drewe J, Schnieper P, Tapparelli CB, Pflimlin E, Beglinger C. Patient-controlled versus nurse-administered sedation with propofol during colonoscopy. A prospective randomized trial. Am J Gastroenterol 2004;99:511– 8 12. Lee DW, Chan AC, Sze TS, Ko CW, Poon CM, Chan KC, Sin KS, Chung SC. Patient-controlled sedation versus intravenous sedation for colonoscopy in elderly patients: a prospective randomized controlled trial. Gastrointest Endosc 2002;56:629 –32 13. Rudkin GE, Osborne GA, Finn BP, Jarvis DA, Vickers D. Intra-operative patient-controlled sedation. Comparison of patient-controlled propofol with patient-controlled midazolam. Anaesthesia 1992;47:376 – 81 14. Pac-Soo CK, Deacock S, Lockwood G, Carr C, Whitwam JG. Patient-controlled sedation for cataract surgery using peribulbar block. Br J Anaesth 1996;77:370 – 4 15. Vuyk J, Mertens MJ, Olofsen E, Burm AG, Bovill JG. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology 1997;87:1549 – 62 16. Marcus SN. Efficiency in endoscopy centers. Gastrointest Endosc 2006;64:765–7


17. Johnson LR, Magnani B, Chan V, Ferrante FM. Modifiers of patient-controlled analgesia efficacy. I. Locus of control. Pain 1989;39:17–22 18. Moller JT, Johannessen NW, Berg H, Espersen K, Larsen LE. Hypoxaemia during anaesthesia—an observer study. Br J Anaesth 1991;66:437– 44 19. Severinghaus JW, Naifeh KH, Koh SO. Errors in 14 pulse oximeters during profound hypoxia. J Clin Monit 1989; 5:72– 81

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20. Nelson DB, McQuaid KR, Bond JH, Lieberman DA, Weiss DG, Johnston TK. Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc 2002; 55:307–14 21. Nieuwenhuijs DJ, Olofsen E, Romberg RR, Sarton E, Ward D, Englbers F, Vuyk J, Mooren R, Teppema LJ, Dahan A. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology 2003;98:312–22

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Midazolam vs Propofol Colonoscopy