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The comparison of midazolam and topical lidocaine spray versus the combination of midazolam, meperidine, and topical lidocaine spray to sedate patients for upper endoscopy
The comparison of midazolam and topical lidocaine spray versus the combination of midazolam, meperidine, and topical lidocaine spray to sedate patients for upper endoscopy Louis LaLuna, MD, Melvin L. Allen, PhD, Anthony J. DiMarino, Jr, MD Philadelphia, Pennsylvania
Background: Whether an opiate-benzodiazepine combination is superior to benzodiazepine alone for sedation in upper endoscopy is controversial. The purpose of this study was to compare the effectiveness of intravenous midazolam alone versus the combination of intravenous midazolam and intravenous meperidine for the sedation of patients undergoing upper endoscopy. Methods: One hundred seven patients scheduled for outpatient diagnostic esophagogastroduodenoscopy were randomly assigned to receive 50 mg intravenous meperidine (53 of 107) or placebo (54 of 107). All patients received topical lidocaine spray and as much midazolam as the endoscopist thought the patient needed. Patients and endoscopists were blinded as to assignment. Data collected included intubation time (seconds), procedure time (minutes), pulse, blood pressure, complications, and the need for reversal agents. The endoscopist evaluated the quality of sedation immediately after the procedure (1 = excellent, 2 = good, 3 = fair, and 4 = poor). The patient evaluated the procedure the next day by phone (1 = no discomfort or did not remember, 2 = slightly uncomfortable, 3 = extremely uncomfortable, and 4 = unacceptable). Patients were also asked whether they would agree to another esophagogastroduodenoscopy if their doctor thought it was medically necessary. Results: The intubation time, procedure time and blood pressure were not significantly different between the 2 groups. In comparing the meperidine group versus placebo group, the highest pulse (82.3 vs. 93.7, p = 0.0010), lowest pulse (67.2 vs. 72.3, p = 0.0194) and amount of midazolam used (4.0 vs. 4.8 mg, p = 0.0185 or 0.53 vs. 0.67 mg/kg, p = 0.0083) were significantly different by using a t test analysis. Patient evaluations comparing meperidine versus placebo showed responses of 1 (52 vs. 49), 2 (1 vs. 3), 3 (0 vs. 2) and 4 (0 vs. 0), which were not significantly different. The endoscopists’ evaluation comparing meperidine versus placebo gave responses of excellent (44 vs. 27), good (6 vs. 22), fair (3 vs. 5) and poor (0 vs. 0), which were highly significantly different (p < 0.001) by using chi-square statistical techniques. Conclusion: The addition of meperidine to midazolam in sedating patients undergoing upper endoscopy adds no benefit from the patient viewpoint, whereas endoscopists favored the use of both medications. (Gastrointest Endosc 2001;53:289-93.)
Diagnostic EGD is considered a safe and painless procedure. However, when performed without sedation it often induces intolerable gagging and patients often perceive it as unpleasant.1,2 Conscious sedation is the term used for the administration of medication during an EGD to prevent gagging and relax Received March 23, 2000. For revision May 4, 2000. Accepted July 6, 2000. From the Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Presented in part at the 1998 ASGE Annual Meeting, New Orleans, Louisiana. Reprint requests: Anthony J. DiMarino, Jr., MD, Thomas Jefferson University Hospital, Division of Gastroenterology and Hepatology, Suite 480, Philadelphia, PA 19107. Copyright © 2001 by the American Society for Gastrointestinal Endoscopy 0016-5107/2001/$35.00 + 0 37/1/112192 doi:10.1067/mge.2001.112192 VOLUME 53, NO. 3, 2001
the patient, thus allowing a complete and painless procedure. To achieve adequate sedation American GI endoscopists typically use a combination of midazolam and meperidine.3 Although this combination provides excellent sedation, it may be associated with an increased risk of adverse cardiopulmonary events.1,2,4-10 Current guidelines recommend that the lowest possible dose of medication needed to achieve adequate patient comfort be used.11 Topical anesthesia increases patient acceptance and tolerance and rarely induces significant alterations in cardiorespiratory parameters.6,12,13 Our study was designed to evaluate whether the additional administration of meperidine to patients receiving midazolam and topical lidocaine spray improves patient tolerance or physician rating of the adequacy of sedation in patients undergoing diagnostic EGD. GASTROINTESTINAL ENDOSCOPY
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Midazolam vs midazolam plus meperidine sedation: EGD
Table 1. Demographic, temporal, cardiovascular, and dosage measures in the 2 study groups Group 1 (midazolam, topical lidocaine spray, meperidine)
Group 2 (midazolam, topical lidocaine spray, placebo)
53 54.3 ± 12.5 (30-81) 28 25 28 7.2 ± 5.9 6.6 ± 4.5 82.3 ± 13.7 67.2 ± 9.4 120.5 ± 25.6 90.7 ± 14.9 4.0 ± 1.4 0.053 ± 0.020
54 55.7 ± 14.8 (20-81) 28 26 22 8.1 ± 10.0 6.1 ± 3.0 93.7 ± 19.8 72.3 ± 12.5 126.7 ± 23.2 94.1 ± 15.1 4.8 ± 1.7 0.066 ± 0.029
No. of patients (107) Age (yr) (range) Men (56) Women (51) Previous EGD Intubation time (sec) Procedure time (min) Highest pulse Lowest pulse Lowest systolic blood pressure (mm Hg) Lowest mean arterial pressure (mm Hg) Midazolam (mg) Midazolam (mg/kg)
p Value NS
NS NS NS 0.0010 0.0194 NS NS 0.0185 0.0083
NS, Not significant.
PATIENTS AND METHODS One hundred seven patients (51 women, 56 men; mean age: 55 years; age range: 20 to 81 years) scheduled for outpatient diagnostic EGD participated in the study. Patients were recruited from a university gastroenterology practice and a university satellite community office setting. Indications for EGD included intractable nausea, unexplained abdominal pain, dysphagia, hoarseness, unexplained weight loss, suspected gastric carcinoma, or unexplained hemoccult positive stool. Exclusion criteria included age younger than 18 years; inability to understand the written consent; pregnancy; emergent endoscopic procedures; patients with known allergies to benzodiazepines, opiates or lidocaine spray; chronic daily use of benzodiazepines or opiates; or consumption of 2 or more alcoholic beverages more than 3 times per week. In addition, patients for whom therapeutic interventions were known to be required in conjunction with their EGD were excluded. Other exclusion criteria included the known presence of an esophageal stricture requiring dilation, and an anticipated need for esophageal variceal banding or injection sclerotherapy, stent placement, argon plasma coagulation, or laser therapy. All eligible patients scheduled for a diagnostic EGD were asked to participate in the study. Each patient gave informed written consent. The study was approved by the Institutional Review Board of our university and was conducted from April to November, 1997. Medications in this study included midazolam (Versed; Roche Pharma, Inc., Nutley, N.J.), meperidine (Demerol; Abbott Laboratories, Abbott Park, Ill.), normal saline for injection, and a 10% lidocaine spray (Xylocaine; Astra, King of Prussia, Pa.). A study coordinator prepared all syringes. Syringes were labeled with a study number only and all medications and syringes were identical in appearance. All patients received 4 squirts of topical spray. All patients then received 1 mg midazolam intravenously in conjunction with either intravenous meperidine or placebo, as determined by a prior coin toss. If a patient was assigned to receive intravenous meperidine, it was administered as 0.5 mL of a 50 mg/mL concentration of meperidine given 2 minutes after the 1 mg of intra290
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venous midazolam had been administered. If a patient had been assigned to the placebo arm of the trial, it was administered as 0.5 mL of normal saline solution given 2 minutes after the 1 mg of midazolam had been administered. Two minutes after the initial injection of either intravenous meperidine or placebo (normal saline solution), a second dose of 25 mg of intravenous meperidine or normal saline solution was then administered. Further doses of midazolam were administered to achieve adequate sedation of the patient as determined by the endoscopist. The endoscopist administered topical lidocaine spray and all sedative medications. The patients, nurses, and endoscopists were blinded as to whether the patient received meperidine or placebo. All procedures were performed by attending gastroenterologists at our institution without the assistance of fellows. The 8 endoscopists participating in the study had an average of 11 years of endoscopic experience. Four endoscopists each performed procedures on 16 or more of the patients. Data were recorded continuously by a nurse, unaware of treatment assignment, during each endoscopic procedure and included intubation time (in seconds from insertion of the endoscope into the patient’s mouth until passage through the cricopharyngeus), procedure time (number of minutes the endoscope was inserted), pulse and blood pressure. Pulse and blood pressure were monitored every 3 minutes and automatically recorded by using Criticare Monitors (Model No. 507EP and two Model No. 506; Criticare Systems, Inc., Waukesha, N.J.). The endoscopist recorded the presence or absence of cardiopulmonary complications, the need for reversal agents, whether retching interfered with the procedure (his/her determination), whether it was necessary to terminate the procedure prematurely, and the effectiveness of sedation (1 = excellent, 2 = good, 3 = fair, 4 = poor). The patient’s evaluation of the procedure was obtained the following day by telephone (1 = no discomfort or did not remember, 2 = slightly uncomfortable, 3 = extremely uncomfortable, 4 = unacceptable). The patient was also asked whether he/she would agree to another EGD if their doctor thought it was medically necessary. VOLUME 53, NO. 3, 2001
Midazolam vs midazolam plus meperidine sedation: EGD
Table 2. Endoscopist evaluation of patient sedation Group 1 (midazolam, topical lidocaine spray, meperidine) Excellent Good Fair Poor
Table 3. Patient evaluation of the endoscopy Group 1 (midazolam, Group 2 (midazolam, topical lidocaine topical lidocaine spray, meperidine) spray, placebo)
Group 2 (midazolam, topical lidocaine spray, placebo)
44 6 3 0
27 22 5 0
These data were not affected by gender. p < 0.001.
Continuous variables were analyzed by using the Cochran test and categorical variables were analyzed by using chi-square. The α level required to reject the null hypothesis was 0.05. No adjustment was made to p values for having 2 endpoints. A Bonferroni correction would double the p values, which in this case has no effect on conclusions. The analyses were performed with computer software (SAS/STAT user’s guide, 6.03 ed., 1988; SAS Institute, Inc., Cary, N.C.). All endoscopic procedures were performed with a standard upper GI endoscope with an insertion tube diameter of 10.5 mm (GIFQ140; Olympus America, Inc., Melville, N.Y.).
RESULTS The 107 patients studied were randomized by coin toss to 53 in the meperidine group and 54 in the placebo group. There was no difference between the 2 groups with regard to indications for endoscopy, intubation time, procedure time, lowest systolic blood pressure and lowest mean arterial pressure (p > 0.05). The differences in the highest and lowest pulse were statistically different but clinically irrelevant. The mean and standard deviation for the amount of midazolam used in the meperidine group was 4.0 ± 1.42 mg (range 1 to 8 mg) and in the placebo group was 4.8 ± 1.74 mg (range 1 to 10 mg, p = 0.0185, Table 1). The mean and standard deviation for the amount of midazolam by weight used in the meperidine group was 0.53 ± 0.021 mg/kg (range 0.14 to 0.110 mg/kg) and in the placebo group was 0.066 ± 0.29 mg/kg (range 0.22 to 0.162 mg/kg, p = 0.0083, Table 1). There was no cardiopulmonary complications, need for reversal agents or early termination of the procedure in either group. Retching interfering with the procedure as determined by the endoscopist was noted in 4 of the 53 patients in the meperidine group (7.6%) and in 15 of the 54 patients in the placebo group (27.8%) with a p value of 0.006. All but 1 patient (from the placebo group) was willing to undergo EGD again in the future, which was not statistically significant. The 2 primary outcomes measured were the endoscopists’ evaluation of the effectiveness of the sedation and the patients’ evaluation of the procedure. Table 2 shows the results of the endoscopists’ VOLUME 53, NO. 3, 2001
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No discomfort Slight discomfort Extremely uncomfortable Unacceptable
52 1 0 0
49 3 2 0
p = 0.097.
evaluation. The difference between the 2 groups was statistically significant with p < 0.001. Table 3 shows the results of the patients’ evaluation; there was not a statistically significant difference between the 2 study groups. DISCUSSION Methods of obtaining conscious sedation for EGD vary throughout the world. The spectrum ranges from no sedation4,12,14 to the combined use of benzodiazepines and opioids.1,3 American endoscopists typically use midazolam and meperidine.3 Although this combination provides excellent sedation, it may be associated with an increased risk of adverse cardiopulmonary events.1,2,4-10 These account for more than 60% of the mortality and 50% of the morbidity associated with EGD.1 The American Society for Gastrointestinal Endoscopy (ASGE)/United States Food and Drug Administration collaborative study demonstrated that 94% of the cardiorespiratory events reported were associated with the administration of a narcotic agent.3 Patients who are elderly or who have comorbid serious illnesses, including cardiovascular, pulmonary, renal, hepatic, metabolic and neurologic disorders, and morbid obesity, may be at increased risk for complications due to the administration of sedative drugs.3,11,15,16 Guidelines from the ASGE were devised to decrease complications during endoscopic procedures. They include a medical history, continuous venous access, use of minimum doses of benzodiazepines and opiates (with the availability of their antagonists), continuous monitoring of vital signs from presedation through postprocedure observation, pulse oximetry and selective electrocardiography monitoring, use of supplemental oxygen when indicated, the availability of resuscitation equipment and adequate training of personnel in resuscitation procedures and a dedicated staff for recovery monitoring for all patients.11,17 Rey17 and Quine et al.18 demonstrated that deviating from these recommendations may result in increased morbidity and mortality. No complications were encountered in our study. The lack of a complication may be partially due to the fact that therapeutic and emergent cases were excluded. GASTROINTESTINAL ENDOSCOPY
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Prior studies have attempted to assess the extent of conscious sedation necessary for patients undergoing an EGD. Some studies have demonstrated the ability of patients to tolerate an EGD without sedation4,12,14; however, these either did not include control subjects or still demonstrated a benefit with sedation. Most studies suggest that patient tolerance and willingness to undergo the procedure in the future increase when sedatives are used.5,8,19 The role of topical anesthesia in EGD remains controversial,20,21 but 3 studies have shown that topical lidocaine spray increased patient acceptance and tolerance as assessed by patient and endoscopist.12,13,22 Froehlich et al.6 showed that low dose midazolam (35 µg/kg) and lidocaine spray have an additive beneficial effect on patient tolerance and rarely induce significant alterations in cardiorespiratory parameters. Diab et al.23 compared sedation with midazolam alone to the combination of midazolam and meperidine for an EGD. This study demonstrated an improved ability of patients to tolerate an EGD from the endoscopist’s standpoint when patients were given both midazolam and meperidine. However, the endoscopist’s assessment of the quality of sedation was subjective because no consistent or standardized grading scale was acceptable among the various physicians. There was no difference in the degree of amnesia or the willingness of patients to undergo another EGD in the future. Patients in this study did not receive a topical anesthetic. The reasons the endoscopists gave for a “poor” rating included difficulty with intubation, the presence of retching and premature termination of the procedure. All of these problems might be mitigated with the use of topical lidocaine spray. Our study was similar in design to that of Diab et al. except for the addition of topical lidocaine spray for all patients undergoing EGD. Our results show that meperidine did not improve patient satisfaction with sedation and most patients were not able to remember the procedure. All patients except 1 were willing to undergo an endoscopy again if indicated. The endoscopists in our study did rate the combination of midazolam plus meperidine as superior to midazolam alone with respect to ease of performance of the examination. In addition, they were unable to accurately identify which patients received meperidine and which placebo. There was a statistically significant decrease in the amount of retching during the procedure when meperidine was used. It was not necessary to terminate a procedure prematurely in either group. An analysis of data for patients older than 65 years revealed no statistical difference between the 2 groups with respect to 292
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Midazolam vs midazolam plus meperidine sedation: EGD
physician satisfaction with sedation. However, in this age range there were only 8 patients in the placebo group and 18 in the meperidine group. This small sample size did not allow statistical analysis and this issue was not specifically addressed by this study. It is mentioned only as an area for possible further study. The difference in the mean amount of midazolam used between the 2 groups was 0.8 mg. On a weight basis, the difference was only 0.013 mg/kg. Although this difference is statistically significant, it may not be clinically or financially meaningful. With respect to the cost differential between 50 mg of meperidine and 1 additional mg of midazolam, meperidine would currently be less expensive. The price of midazolam may change as this drug comes off patent and generic formulations become available, which may lessen this cost differential. In addition, depending on how midazolam is prepared (multidose vial, 2 mg aliquots or 5 mg aliquots) it may be necessary to discard some unused midazolam after each procedure, which would further complicate a cost analysis. Interestingly, patients who had undergone a previous EGD with both midazolam and meperidine who received only midazolam in our study reported less discomfort than that experienced as a result of their previous EGD. It is possible that these patients received more midazolam when the drug was given alone, thereby leading to an increased amnesiac effect. Alternatively, a decrease in anxiety as a result of familiarity with the procedure may account for the difference. In summary, patients found that the combination of intravenous midazolam and topical lidocaine spray provides adequate comfort and tolerance of a diagnostic EGD and were willing to undergo another EGD, if necessary, with this same sedation. Physicians found the addition of intravenous meperidine decreased patient retching and improved the quality of sedation. Intubation time and procedure time were similar, as was the safety profile for both groups. REFERENCES 1. Bell GD. Review article: premedication and intravenous sedation for upper gastrointestinal endoscopy. Aliment Pharmacol Ther 1990;4:103-22. 2. Lauven PM. Pharmacology of drugs for conscious sedation. Scand J Gastroenterol 1990;25:1-6. 3. Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/US Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991;37:421-7. 4. Porro GB, Lazzaroni M. Premedication for upper gastrointestinal endoscopy: still a matter for debate? Endoscopy 1991;23:32-6. 5. McCloy RF, Pearson RC. Which agent and how to deliver it. Scand J Gastroenterol 1990;25:7-11. VOLUME 53, NO. 3, 2001
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6. Froehlich F, Schwizer W, Thorens J, Kohler M, Gonvers JJ, Fried M. Conscious sedation for gastroscopy: patient tolerance and cardiorespiratory parameters. Gastroenterology 1995;108:697-704. 7. Chokhavatia S, Nguyen L, Williams R, Kao J, Heavner JE. Sedation and analgesia for gastrointestinal endoscopy. Am J Gastroenterol 1993;68:393-6. 8. Nagengast FM. Sedation and monitoring in gastrointestinal endoscopy. Scand J Gastroenterol 1993;28:28-32. 9. Daneshmend TK, Bell GD, Logan RFA. Sedation for upper gastrointestinal endoscopy: results of a nationwide survey. Gut 1991;32:12-5. 10. Aker J. Review of current research on midazolam and diazepam for endoscopic premedication. Soc Gastroenterol Nurs 1990;13:24S-8S. 11. The ASGE Standard of Practice Committee. Sedation and monitoring of patients undergoing gastrointestinal procedures. Gastrointest Endosc 1995;42:626-9. 12. Archimandritis A, Tjivras M, Tryphonos M, Delikaris P, Diamantis T. Is premedication necessary in diagnostic endoscopy of the upper gastrointestinal tract? [letter]. Endoscopy 1991;23:240. 13. Leitch DG, Wicks J, El Beshir OA, Ali SAM, Chaudhury BK. Topical anesthesia with 50 mg of lidocaine spray facilitates upper gastrointestinal endoscopy. Gastrointest Endosc 1993; 39:384-7. 14. Al-Atrakchi HA. Upper gastrointestinal endoscopy without sedation: a prospective study of 2000 examinations. Gastrointest Endosc 1989;35:79-81.
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15. Lieberman DA, Wueker CK, Katon RM. Cardiopulmonary risk of esophagogastroduodenoscopy: role of endoscope diameter and systemic sedation. Gastroenterology 1985;88:468-72. 16. Bell GD, Spickett GP, Reeve PA, Morden A, Logan RF. Intravenous midazolam for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient. Br J Clin Pharmacol 1987;23:241-3. 17. Rey JF. Sedation for upper gastrointestinal endoscopy: as much as possible, or without? Endoscopy 1996;28:308-9. 18. Quine MA, Bell GD, Charlton JE, Devlin HB, Hopkins A. Prospective audit of upper gastrointestinal endoscopy in two regions of England. Gut 1995;36:462-7. 19. Thompson DG, Evans SJ, Murray RS, Lennard-Jones JE, Cowan RE, Wright JT. Patients appreciate premedication for endoscopy. Lancet 1980;30:469-70. 20. Chuah SY, Crowson CP, Dronfield MW. Topical anesthesia in upper gastrointestinal endoscopy. Br Med J 1991;303:695. 21. Cantor DS, Baldridge ET. Premedication with meperidine and diazepam for upper gastrointestinal endoscopy precludes the need for topical anesthesia. Gastrointest Endosc 1986; 32:339-41. 22. Campo R, Brullet E, Montserrat A, Calvet X, Rivero E, Brotons C. Topical pharyngeal anesthesia improves tolerance of upper gastrointestinal endoscopy: a randomized doubleblind study. Endoscopy 1995;27:659-64. 23. Diab FH, King PD, Barthel JS, Marshall JB. Efficacy and safety of combined meperidine and midazolam for EGD sedation compared with midazolam alone. Am J Gastroenterol 1996;91:1120-5.
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Background: Whether an opiate-benzodiazepine combination is superior to benzodiazepine alone for sedation in upper endoscopy is controversial. The purpose of this study was to compare the effectiveness of intravenous midazolam alone versus the combination of intravenous midazolam and intravenous meperidine for the sedation of patients undergoing upper endoscopy. Methods: One hundred seven patients scheduled for outpatient diagnostic esophagogastroduodenoscopy were randomly assigned to receive 50 mg intravenous meperidine (53 of 107) or placebo (54 of 107). All patients received topical lidocaine spray and as much midazolam as the endoscopist thought the patient needed. Patients and endoscopists were blinded as to assignment. Data collected included intubation time (seconds), procedure time (minutes), pulse, blood pressure, complications, and the need for reversal agents. The endoscopist evaluated the quality of sedation immediately after the procedure (1 = excellent, 2 = good, 3 = fair, and 4 = poor). The patient evaluated the procedure the next day by phone (1 = no discomfort or did not remember, 2 = slightly uncomfortable, 3 = extremely uncomfortable, and 4 = unacceptable). Patients were also asked whether they would agree to another esophagogastroduodenoscopy if their doctor thought it was medically necessary. Results: The intubation time, procedure time and blood pressure were not significantly different between the 2 groups. In comparing the meperidine group versus placebo group, the highest pulse (82.3 vs. 93.7, p = 0.0010), lowest pulse (67.2 vs. 72.3, p = 0.0194) and amount of midazolam used (4.0 vs. 4.8 mg, p = 0.0185 or 0.53 vs. 0.67 mg/kg, p = 0.0083) were significantly different by using a t test analysis. Patient evaluations comparing meperidine versus placebo showed responses of 1 (52 vs. 49), 2 (1 vs. 3), 3 (0 vs. 2) and 4 (0 vs. 0), which were not significantly different. The endoscopists’ evaluation comparing meperidine versus placebo gave responses of excellent (44 vs. 27), good (6 vs. 22), fair (3 vs. 5) and poor (0 vs. 0), which were highly significantly different (p < 0.001) by using chi-square statistical techniques. Conclusion: The addition of meperidine to midazolam in sedating patients undergoing upper endoscopy adds no benefit from the patient viewpoint, whereas endoscopists favored the use of both medications. (Gastrointest Endosc 2001;53:289-93.)
Diagnostic EGD is considered a safe and painless procedure. However, when performed without sedation it often induces intolerable gagging and patients often perceive it as unpleasant.1,2 Conscious sedation is the term used for the administration of medication during an EGD to prevent gagging and relax Received March 23, 2000. For revision May 4, 2000. Accepted July 6, 2000. From the Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Presented in part at the 1998 ASGE Annual Meeting, New Orleans, Louisiana. Reprint requests: Anthony J. DiMarino, Jr., MD, Thomas Jefferson University Hospital, Division of Gastroenterology and Hepatology, Suite 480, Philadelphia, PA 19107. Copyright © 2001 by the American Society for Gastrointestinal Endoscopy 0016-5107/2001/$35.00 + 0 37/1/112192 doi:10.1067/mge.2001.112192 VOLUME 53, NO. 3, 2001
the patient, thus allowing a complete and painless procedure. To achieve adequate sedation American GI endoscopists typically use a combination of midazolam and meperidine.3 Although this combination provides excellent sedation, it may be associated with an increased risk of adverse cardiopulmonary events.1,2,4-10 Current guidelines recommend that the lowest possible dose of medication needed to achieve adequate patient comfort be used.11 Topical anesthesia increases patient acceptance and tolerance and rarely induces significant alterations in cardiorespiratory parameters.6,12,13 Our study was designed to evaluate whether the additional administration of meperidine to patients receiving midazolam and topical lidocaine spray improves patient tolerance or physician rating of the adequacy of sedation in patients undergoing diagnostic EGD. GASTROINTESTINAL ENDOSCOPY
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Table 1. Demographic, temporal, cardiovascular, and dosage measures in the 2 study groups Group 1 (midazolam, topical lidocaine spray, meperidine)
Group 2 (midazolam, topical lidocaine spray, placebo)
53 54.3 ± 12.5 (30-81) 28 25 28 7.2 ± 5.9 6.6 ± 4.5 82.3 ± 13.7 67.2 ± 9.4 120.5 ± 25.6 90.7 ± 14.9 4.0 ± 1.4 0.053 ± 0.020
54 55.7 ± 14.8 (20-81) 28 26 22 8.1 ± 10.0 6.1 ± 3.0 93.7 ± 19.8 72.3 ± 12.5 126.7 ± 23.2 94.1 ± 15.1 4.8 ± 1.7 0.066 ± 0.029
No. of patients (107) Age (yr) (range) Men (56) Women (51) Previous EGD Intubation time (sec) Procedure time (min) Highest pulse Lowest pulse Lowest systolic blood pressure (mm Hg) Lowest mean arterial pressure (mm Hg) Midazolam (mg) Midazolam (mg/kg)
p Value NS
NS NS NS 0.0010 0.0194 NS NS 0.0185 0.0083
NS, Not significant.
PATIENTS AND METHODS One hundred seven patients (51 women, 56 men; mean age: 55 years; age range: 20 to 81 years) scheduled for outpatient diagnostic EGD participated in the study. Patients were recruited from a university gastroenterology practice and a university satellite community office setting. Indications for EGD included intractable nausea, unexplained abdominal pain, dysphagia, hoarseness, unexplained weight loss, suspected gastric carcinoma, or unexplained hemoccult positive stool. Exclusion criteria included age younger than 18 years; inability to understand the written consent; pregnancy; emergent endoscopic procedures; patients with known allergies to benzodiazepines, opiates or lidocaine spray; chronic daily use of benzodiazepines or opiates; or consumption of 2 or more alcoholic beverages more than 3 times per week. In addition, patients for whom therapeutic interventions were known to be required in conjunction with their EGD were excluded. Other exclusion criteria included the known presence of an esophageal stricture requiring dilation, and an anticipated need for esophageal variceal banding or injection sclerotherapy, stent placement, argon plasma coagulation, or laser therapy. All eligible patients scheduled for a diagnostic EGD were asked to participate in the study. Each patient gave informed written consent. The study was approved by the Institutional Review Board of our university and was conducted from April to November, 1997. Medications in this study included midazolam (Versed; Roche Pharma, Inc., Nutley, N.J.), meperidine (Demerol; Abbott Laboratories, Abbott Park, Ill.), normal saline for injection, and a 10% lidocaine spray (Xylocaine; Astra, King of Prussia, Pa.). A study coordinator prepared all syringes. Syringes were labeled with a study number only and all medications and syringes were identical in appearance. All patients received 4 squirts of topical spray. All patients then received 1 mg midazolam intravenously in conjunction with either intravenous meperidine or placebo, as determined by a prior coin toss. If a patient was assigned to receive intravenous meperidine, it was administered as 0.5 mL of a 50 mg/mL concentration of meperidine given 2 minutes after the 1 mg of intra290
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venous midazolam had been administered. If a patient had been assigned to the placebo arm of the trial, it was administered as 0.5 mL of normal saline solution given 2 minutes after the 1 mg of midazolam had been administered. Two minutes after the initial injection of either intravenous meperidine or placebo (normal saline solution), a second dose of 25 mg of intravenous meperidine or normal saline solution was then administered. Further doses of midazolam were administered to achieve adequate sedation of the patient as determined by the endoscopist. The endoscopist administered topical lidocaine spray and all sedative medications. The patients, nurses, and endoscopists were blinded as to whether the patient received meperidine or placebo. All procedures were performed by attending gastroenterologists at our institution without the assistance of fellows. The 8 endoscopists participating in the study had an average of 11 years of endoscopic experience. Four endoscopists each performed procedures on 16 or more of the patients. Data were recorded continuously by a nurse, unaware of treatment assignment, during each endoscopic procedure and included intubation time (in seconds from insertion of the endoscope into the patient’s mouth until passage through the cricopharyngeus), procedure time (number of minutes the endoscope was inserted), pulse and blood pressure. Pulse and blood pressure were monitored every 3 minutes and automatically recorded by using Criticare Monitors (Model No. 507EP and two Model No. 506; Criticare Systems, Inc., Waukesha, N.J.). The endoscopist recorded the presence or absence of cardiopulmonary complications, the need for reversal agents, whether retching interfered with the procedure (his/her determination), whether it was necessary to terminate the procedure prematurely, and the effectiveness of sedation (1 = excellent, 2 = good, 3 = fair, 4 = poor). The patient’s evaluation of the procedure was obtained the following day by telephone (1 = no discomfort or did not remember, 2 = slightly uncomfortable, 3 = extremely uncomfortable, 4 = unacceptable). The patient was also asked whether he/she would agree to another EGD if their doctor thought it was medically necessary. VOLUME 53, NO. 3, 2001
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Table 2. Endoscopist evaluation of patient sedation Group 1 (midazolam, topical lidocaine spray, meperidine) Excellent Good Fair Poor
Table 3. Patient evaluation of the endoscopy Group 1 (midazolam, Group 2 (midazolam, topical lidocaine topical lidocaine spray, meperidine) spray, placebo)
Group 2 (midazolam, topical lidocaine spray, placebo)
44 6 3 0
27 22 5 0
These data were not affected by gender. p < 0.001.
Continuous variables were analyzed by using the Cochran test and categorical variables were analyzed by using chi-square. The α level required to reject the null hypothesis was 0.05. No adjustment was made to p values for having 2 endpoints. A Bonferroni correction would double the p values, which in this case has no effect on conclusions. The analyses were performed with computer software (SAS/STAT user’s guide, 6.03 ed., 1988; SAS Institute, Inc., Cary, N.C.). All endoscopic procedures were performed with a standard upper GI endoscope with an insertion tube diameter of 10.5 mm (GIFQ140; Olympus America, Inc., Melville, N.Y.).
RESULTS The 107 patients studied were randomized by coin toss to 53 in the meperidine group and 54 in the placebo group. There was no difference between the 2 groups with regard to indications for endoscopy, intubation time, procedure time, lowest systolic blood pressure and lowest mean arterial pressure (p > 0.05). The differences in the highest and lowest pulse were statistically different but clinically irrelevant. The mean and standard deviation for the amount of midazolam used in the meperidine group was 4.0 ± 1.42 mg (range 1 to 8 mg) and in the placebo group was 4.8 ± 1.74 mg (range 1 to 10 mg, p = 0.0185, Table 1). The mean and standard deviation for the amount of midazolam by weight used in the meperidine group was 0.53 ± 0.021 mg/kg (range 0.14 to 0.110 mg/kg) and in the placebo group was 0.066 ± 0.29 mg/kg (range 0.22 to 0.162 mg/kg, p = 0.0083, Table 1). There was no cardiopulmonary complications, need for reversal agents or early termination of the procedure in either group. Retching interfering with the procedure as determined by the endoscopist was noted in 4 of the 53 patients in the meperidine group (7.6%) and in 15 of the 54 patients in the placebo group (27.8%) with a p value of 0.006. All but 1 patient (from the placebo group) was willing to undergo EGD again in the future, which was not statistically significant. The 2 primary outcomes measured were the endoscopists’ evaluation of the effectiveness of the sedation and the patients’ evaluation of the procedure. Table 2 shows the results of the endoscopists’ VOLUME 53, NO. 3, 2001
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No discomfort Slight discomfort Extremely uncomfortable Unacceptable
52 1 0 0
49 3 2 0
p = 0.097.
evaluation. The difference between the 2 groups was statistically significant with p < 0.001. Table 3 shows the results of the patients’ evaluation; there was not a statistically significant difference between the 2 study groups. DISCUSSION Methods of obtaining conscious sedation for EGD vary throughout the world. The spectrum ranges from no sedation4,12,14 to the combined use of benzodiazepines and opioids.1,3 American endoscopists typically use midazolam and meperidine.3 Although this combination provides excellent sedation, it may be associated with an increased risk of adverse cardiopulmonary events.1,2,4-10 These account for more than 60% of the mortality and 50% of the morbidity associated with EGD.1 The American Society for Gastrointestinal Endoscopy (ASGE)/United States Food and Drug Administration collaborative study demonstrated that 94% of the cardiorespiratory events reported were associated with the administration of a narcotic agent.3 Patients who are elderly or who have comorbid serious illnesses, including cardiovascular, pulmonary, renal, hepatic, metabolic and neurologic disorders, and morbid obesity, may be at increased risk for complications due to the administration of sedative drugs.3,11,15,16 Guidelines from the ASGE were devised to decrease complications during endoscopic procedures. They include a medical history, continuous venous access, use of minimum doses of benzodiazepines and opiates (with the availability of their antagonists), continuous monitoring of vital signs from presedation through postprocedure observation, pulse oximetry and selective electrocardiography monitoring, use of supplemental oxygen when indicated, the availability of resuscitation equipment and adequate training of personnel in resuscitation procedures and a dedicated staff for recovery monitoring for all patients.11,17 Rey17 and Quine et al.18 demonstrated that deviating from these recommendations may result in increased morbidity and mortality. No complications were encountered in our study. The lack of a complication may be partially due to the fact that therapeutic and emergent cases were excluded. GASTROINTESTINAL ENDOSCOPY
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Prior studies have attempted to assess the extent of conscious sedation necessary for patients undergoing an EGD. Some studies have demonstrated the ability of patients to tolerate an EGD without sedation4,12,14; however, these either did not include control subjects or still demonstrated a benefit with sedation. Most studies suggest that patient tolerance and willingness to undergo the procedure in the future increase when sedatives are used.5,8,19 The role of topical anesthesia in EGD remains controversial,20,21 but 3 studies have shown that topical lidocaine spray increased patient acceptance and tolerance as assessed by patient and endoscopist.12,13,22 Froehlich et al.6 showed that low dose midazolam (35 µg/kg) and lidocaine spray have an additive beneficial effect on patient tolerance and rarely induce significant alterations in cardiorespiratory parameters. Diab et al.23 compared sedation with midazolam alone to the combination of midazolam and meperidine for an EGD. This study demonstrated an improved ability of patients to tolerate an EGD from the endoscopist’s standpoint when patients were given both midazolam and meperidine. However, the endoscopist’s assessment of the quality of sedation was subjective because no consistent or standardized grading scale was acceptable among the various physicians. There was no difference in the degree of amnesia or the willingness of patients to undergo another EGD in the future. Patients in this study did not receive a topical anesthetic. The reasons the endoscopists gave for a “poor” rating included difficulty with intubation, the presence of retching and premature termination of the procedure. All of these problems might be mitigated with the use of topical lidocaine spray. Our study was similar in design to that of Diab et al. except for the addition of topical lidocaine spray for all patients undergoing EGD. Our results show that meperidine did not improve patient satisfaction with sedation and most patients were not able to remember the procedure. All patients except 1 were willing to undergo an endoscopy again if indicated. The endoscopists in our study did rate the combination of midazolam plus meperidine as superior to midazolam alone with respect to ease of performance of the examination. In addition, they were unable to accurately identify which patients received meperidine and which placebo. There was a statistically significant decrease in the amount of retching during the procedure when meperidine was used. It was not necessary to terminate a procedure prematurely in either group. An analysis of data for patients older than 65 years revealed no statistical difference between the 2 groups with respect to 292
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physician satisfaction with sedation. However, in this age range there were only 8 patients in the placebo group and 18 in the meperidine group. This small sample size did not allow statistical analysis and this issue was not specifically addressed by this study. It is mentioned only as an area for possible further study. The difference in the mean amount of midazolam used between the 2 groups was 0.8 mg. On a weight basis, the difference was only 0.013 mg/kg. Although this difference is statistically significant, it may not be clinically or financially meaningful. With respect to the cost differential between 50 mg of meperidine and 1 additional mg of midazolam, meperidine would currently be less expensive. The price of midazolam may change as this drug comes off patent and generic formulations become available, which may lessen this cost differential. In addition, depending on how midazolam is prepared (multidose vial, 2 mg aliquots or 5 mg aliquots) it may be necessary to discard some unused midazolam after each procedure, which would further complicate a cost analysis. Interestingly, patients who had undergone a previous EGD with both midazolam and meperidine who received only midazolam in our study reported less discomfort than that experienced as a result of their previous EGD. It is possible that these patients received more midazolam when the drug was given alone, thereby leading to an increased amnesiac effect. Alternatively, a decrease in anxiety as a result of familiarity with the procedure may account for the difference. In summary, patients found that the combination of intravenous midazolam and topical lidocaine spray provides adequate comfort and tolerance of a diagnostic EGD and were willing to undergo another EGD, if necessary, with this same sedation. Physicians found the addition of intravenous meperidine decreased patient retching and improved the quality of sedation. Intubation time and procedure time were similar, as was the safety profile for both groups. REFERENCES 1. Bell GD. Review article: premedication and intravenous sedation for upper gastrointestinal endoscopy. Aliment Pharmacol Ther 1990;4:103-22. 2. Lauven PM. Pharmacology of drugs for conscious sedation. Scand J Gastroenterol 1990;25:1-6. 3. Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/US Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991;37:421-7. 4. Porro GB, Lazzaroni M. Premedication for upper gastrointestinal endoscopy: still a matter for debate? Endoscopy 1991;23:32-6. 5. McCloy RF, Pearson RC. Which agent and how to deliver it. Scand J Gastroenterol 1990;25:7-11. VOLUME 53, NO. 3, 2001
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6. Froehlich F, Schwizer W, Thorens J, Kohler M, Gonvers JJ, Fried M. Conscious sedation for gastroscopy: patient tolerance and cardiorespiratory parameters. Gastroenterology 1995;108:697-704. 7. Chokhavatia S, Nguyen L, Williams R, Kao J, Heavner JE. Sedation and analgesia for gastrointestinal endoscopy. Am J Gastroenterol 1993;68:393-6. 8. Nagengast FM. Sedation and monitoring in gastrointestinal endoscopy. Scand J Gastroenterol 1993;28:28-32. 9. Daneshmend TK, Bell GD, Logan RFA. Sedation for upper gastrointestinal endoscopy: results of a nationwide survey. Gut 1991;32:12-5. 10. Aker J. Review of current research on midazolam and diazepam for endoscopic premedication. Soc Gastroenterol Nurs 1990;13:24S-8S. 11. The ASGE Standard of Practice Committee. Sedation and monitoring of patients undergoing gastrointestinal procedures. Gastrointest Endosc 1995;42:626-9. 12. Archimandritis A, Tjivras M, Tryphonos M, Delikaris P, Diamantis T. Is premedication necessary in diagnostic endoscopy of the upper gastrointestinal tract? [letter]. Endoscopy 1991;23:240. 13. Leitch DG, Wicks J, El Beshir OA, Ali SAM, Chaudhury BK. Topical anesthesia with 50 mg of lidocaine spray facilitates upper gastrointestinal endoscopy. Gastrointest Endosc 1993; 39:384-7. 14. Al-Atrakchi HA. Upper gastrointestinal endoscopy without sedation: a prospective study of 2000 examinations. Gastrointest Endosc 1989;35:79-81.
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15. Lieberman DA, Wueker CK, Katon RM. Cardiopulmonary risk of esophagogastroduodenoscopy: role of endoscope diameter and systemic sedation. Gastroenterology 1985;88:468-72. 16. Bell GD, Spickett GP, Reeve PA, Morden A, Logan RF. Intravenous midazolam for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient. Br J Clin Pharmacol 1987;23:241-3. 17. Rey JF. Sedation for upper gastrointestinal endoscopy: as much as possible, or without? Endoscopy 1996;28:308-9. 18. Quine MA, Bell GD, Charlton JE, Devlin HB, Hopkins A. Prospective audit of upper gastrointestinal endoscopy in two regions of England. Gut 1995;36:462-7. 19. Thompson DG, Evans SJ, Murray RS, Lennard-Jones JE, Cowan RE, Wright JT. Patients appreciate premedication for endoscopy. Lancet 1980;30:469-70. 20. Chuah SY, Crowson CP, Dronfield MW. Topical anesthesia in upper gastrointestinal endoscopy. Br Med J 1991;303:695. 21. Cantor DS, Baldridge ET. Premedication with meperidine and diazepam for upper gastrointestinal endoscopy precludes the need for topical anesthesia. Gastrointest Endosc 1986; 32:339-41. 22. Campo R, Brullet E, Montserrat A, Calvet X, Rivero E, Brotons C. Topical pharyngeal anesthesia improves tolerance of upper gastrointestinal endoscopy: a randomized doubleblind study. Endoscopy 1995;27:659-64. 23. Diab FH, King PD, Barthel JS, Marshall JB. Efficacy and safety of combined meperidine and midazolam for EGD sedation compared with midazolam alone. Am J Gastroenterol 1996;91:1120-5.
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