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Fentanyl-midazolam-flumazenil anesthesia for induced abortion
Int. J. Gynecol. O&et., 1989.30: 69-72 International Federation of Gynecology and Obstetrics
Fentanyl-midazolam-flumazenil abortion
69
anesthesia for induced
0. Hamar, Gy. GaramvGlgyi and A. K&m&n Second Obstetrics and Gynecological Clinic. Semmelwek University Medicai School, Budapt
(Hungary)
(Recdved May 18th. 1988) (Revised and accepted October 5th, 1988)
Abstract A new anesthetic method (fentanyl-midazolam-flumazenil) was compared with a previously administered anesthetic regimen (pethidine-diazepam-ketamine) in two groups of 25 women, each of whom underwent termination of pregnancy. No significant difference was found between the two groups in quality of anesthesia. Recovery was assessed by means of the Aldrete score and a visual analog scale. The recovery time was significantly shorter in patients who received the fentanyl-midazolam-flumazenil.
Keywords: Hypnotics; Benzodiazepines-midazolam; Antagonist; Benzodiazepine antagonist-flumazenil; Anesthesia; Outpatient anesthesia. Introduction Termination of pregnancy within the first 12 weeks by suction curettage with the patient under general anesthesia is a common ambulatory procedure in gynecologic clinics throughout the world. This operation often is considered “minor” and the length of the
patient’s hospitalization depends mainly on recovery from the anesthetic agents used. should Ideally, the anesthetic technique include a rapid, smooth induction and the maintenance of an appropriate level of anesthesia without excessive blood loss or risk of cardiorespiratory instability. Recovery should be rapid, and complications such as nausea, vomiting and anaphylactic reactions, should be rare or non-existent [ 111. Studies of intravenous anesthetic techniques for short surgical procedures often have compared midazolam with thiopental or methohexital [3,9,11]. Midazolam, a shortacting water-soluble benzodiazepine, is being used increasingly for anesthesia in patients undergoing various types of outpatient surgical procedures. Midazolam has minimal cardiovascular effects, even in patients with previously compromised coronary perfusion. A further and important clinical advantage of this i.v. induction agent is its amnestic effect Flumazenil,’ an imidazobenzomw. diazepine, is a benzodiazepine antagonist that specifically blocks the central effects of agents acting through the benzodiazepine receptor by competitive inhibition [6,8]. In the present study, we evaluated recovery after fentanyl-midazolam-flumazenil anesthesia [ 121 compared to pethidine-diazepamketamine anesthesia and attempted to Clinical and Clinical Research
0 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
70
Hamar et al.
determine whether the new method (fentanylmidazolam-flumazenil) is suitable for use in outpatient abortions. Previously, pethidinediazepam-ketamine anesthesia was used in our department for anesthesia in 10,803 cases of abortion. Methods Fifty consecutive patients (ASA l-2) with a gestation of less than 12 weeks underwent Individuals with neurological abortion. diseases, known allergy to benzodiazepine or who were receiving treatment with psychotropic drugs were not studied. The study was conducted in accordance with the Helsinki II Declaration. Patients were randomly assigned to two groups in order to receive pethidinediazepam-ketamine (ketamine group), or fentanyl-midazolam-flumazenil (midazolam group). One hour before surgery, the patients were premeditated orally with diazepam 5 mg. In the ketamine group, anesthesia was induced with diazepam 0.15 mg/kg intravenously, together with pethidine 1 mg/kg. After this, ketamine (1.0 mg/kg) was administered. If necessary, supplementary doses of ketamine 0.25 mg/kg were injected. In the midazolam group, anesthesia was induced with midazolam, 0.3 mg/kg intravenously, together with fentanyl 2.5 pg/kg, max. 0.15 mg. A further dose of midazolam (0.15 mg/ kg) was administered if the eyelash reflex was still present 3 min after the initial dose. Where necessary, supplementary doses of midazolam (0.15 mg/kg) or fentanyl(1 pg/kg, max. 0.05 mg), or both, were injected. Immediately after termination of anesthesia patients received flumazenil(0.4 mg i.v.) within 60 s. The patients breathed spontaneously. Oxygen, nitrous oxide or other inhalation anesthetic agents were not administered. Postoperatively, the patients remained in the operating theatre for 10 min and were then transferred to the recovery room. The overall quality of anesthesia was graded on a 10 cm visual analog scale (very Int J Gynecol Obstet30
good-excellent = 10; poor = 0) by the obstetrician at the end of intervention. The obstetricians were unaware of the type of anesthesia used. Recovery was assessed by means of the postanesthesia recovery score described by Aldrete [I]. The postanesthesia subjective level of sedation was also measured by a 10 cm visual analog scale (quite alert = 0; extremely tired = 10); after the patient was awake and cooperating well, she marked her evaluation [7]. Blood gas analysis was performed in all cases before induction of anesthesia and 90 and 180 min after surgery. Blood pressure and heart and respiratory rate were measured every 15 min. All patients were visited postoperatively by one of the anesthetists before they were discharged. Patients were asked if the same type of recovery would be acceptable on a future occasion. Statistical analysis was carried out using Student’s t-test. Values of P < 0.05 were considered statistically significant. All patients were discharged by 6 h after surgery. Results The main findings of the study are summarized in Table I. Recovery time was significantly shorter in those patients who received midazolam.
Table 1.
Comparison of the two study groups. The values aremean f S.D.
No. patients Age Weight (kg) Height (cm) Duration of anesthesia (min) Assessment score (cm) Recovery time (minp * Indicates statistically groups P-C 0.05.
Ketamine group
Midazolam group
25 24.2 + 9.8 59.8 + 15.2 165.4 + 25.3 11.9 f 9.2
25 25.6 + 61.4 j, 164.2 f 13.1 f
10.1 16.3 26.8 10.1
7.7 f 2.1 31.2 & 6.8
7.6 + 4.5 +
2.3 0.5
significant
differences
between the
Anesthesia for induced abortion Table II.
71
Total dose (mg) requirements of anesthetic agents; median (range).
Ketamine group Pethidine Diazepam Ketamine
Midaaolam group 55.3 (25.0-75.0) 15.2(10.0-20.0) 65.3 (50.0-87.5)
Fentanyl Midazolam Flumazenil
0.125 (0.1-0.15) 25.5 (22.5-40.0) 0.4
Table III. The postanesthetic recovery of the patients measured with Aldrete scoring system. The time is the time from administration of the antagonist to the end of surgery. 5 min’ Ketamine
10 min’ Midazolam
40min
Ketamine
Midazolam
Ketamine
Midazolam
Activity Respiration Circulation Consciousness Color
0 1.08 2 0.6 1.92
2 2 2 2 2
0.02 2 2 1.12 2
2 2 2 2 2
2 2 2 2 2
2 2 2 2 2
Total score
5.60
10
7.14
10
10
10
*Indicates statistically significant differences between the groups P< 0.05.
Dosage requirements for anesthetic agents are shown in Table II. The postanesthetic recovery score also documented more rapid recovery in the midazolam group. The difference between the two study groups was significant at 5 min and 10 min after surgery (Table III). The results of subjective expressions of postoperative sedation (measured by the visual analogue scale) are summarized in Fig. 1. In the midazolam group, every patient was awake 5 min after termination of anesthesia. In the ketamine group, however, the prolonged recovery time delayed the examination until 40 min after termination of anesthesia. Thus, the difference between the two groups is significant at 40 min after surgery, but at 90 min and 180 min the difference did not reach statistical significance. Respectively, 92% of the midazolam group and 64% of the ketamine group were willing to have the same type of recovery for a future operation. In the ketamine group, 36% of the patients complained of unpleasant dreams. No significant differences between the groups
occurred in blood gas values, blood pressure, and heart and respiratory rates. All values were within normal limits. No serious complications were noted during the study. In each group, only two patients vomited slightly. In neither group was there any complaint of awareness during anesthesia.
*
I i I
“Lb. 0
’ 6
10
20
40
*
so
180
tlmin)
Fig. 1. Postanesthetic sedation on a 10 cm visual analog scale (VAS). 0, Values of ketamin group; 0, values from midazolam group. Median (interquartile range). *indicates statistically significant differences between the groups P< 0.05. Clinical and Clinical Research
12
Hamar et al.
Discussion An ideal intravenous anesthetic agent for outpatient anesthesia should have a fast onset and short duration of action. It should be rapidly metabolized into pharmacologically inactive and nontoxic metabolites. There should be no accumulation after repeated doses. Cardiorespiratory stability, good local tissue tolerance, and lack of allergic phenomena should be assured. Midazolam fulfills some of these criteria [2,4,11]. The recovery time is shorter after fentanylmidazolam-flumazenil anesthesia than after pethidine-diazepam-ketamine anesthesia, but the differences of subjective sedation values at 90 min and 180 min are not significant. In the ketamine group, 36% of the patients complained of unpleasant dreams. The recovery of the midazolam group was more comfortable. The results of our study demonstrate that fentanyl-midazolam-flumazenil anesthesia is suitable for anesthesia in patients undergoing abortion. References
3
4
5 6
I
8
Crawford ME, Carl P, Andersen RS, Mikkelsen BO.: Comparison between midazolam and thiopentone based balanced anesthesia for day-case surgery. Br J Anaesth 56: 165, 1984. Dundee JW, Samuel JC, Toner W, Howard PJ: Midazolam: a water soluble benzodiazepine. Studies in volunteers. Anaesthesia 54: 507,198O. Dundee JW, Wilson DB: Amnesic action of midazolam. Anaesthesia 35: 459,198O. Hunkeler W, Mohler H, Pieri L, Pole P, Bonetti EP, Cumin R, Schaffer R, Haefely W: Selective antagonist of benzodiazepines. Nature 290: 514,198l. Manner T, Kanto J, Salonen M: Use of simple test to determine the residual effects of the analgesic component of balanced anesthesia. Br J Anaesth 59: 978,1987. Miihler H, Burhard WP, Keller HH, Richards JG, Haefely W: Benzodiazepine antagonist RO 15-1788: binding characteristics and interaction with drug induced changes in dopamine-turnover and cerebellar CGHP levels. J Neurochem37: 714,198l. Reves JG, Vinik R, Hirschfield RM, Holcomb C. Strong S: Midazolam compared with thiopentone as a hypnotic component in balanced anesthesia: a randomized double blind study. Can Anaesth Sot J 26: 42, 1979. Schulte-Sasse V, Hess W, Tamow J: Haemodynamic responses to induction of anesthesia using midazolam in cardiac surgical patients. Br J Anaesth 54: 1053, 1982. Verma R, Ramasubramanian R, Sachar RM: Anesthesia for termination of pregnancy: midazolam compared with methohexital. Anesth Analg 64: 792, 1985. Wolff J, Carl P, Clausen TG, Mikkelsen BO: RO 15-1788 for postoperative recovery. Anaesthesia 41: 1001,1986.
Address for reprints: 1 2
Aldrete JA, Kroulik D: A postanesthetic recovery score. Anesth Analg 49: 924, 1970. Avram MJ, Fragen RJ, Caldwell NJ: Midazolam kinetics in women of two age groups. Clin Pharmacol Ther 34: 5051983.
Int JGynecol Obstet 30
Ott6 Hnmar Second Obstetrics and Gynecological Clinic Semmelweis University Medical School 1082 Budapest, hi 6178/a Hungary
Fentanyl-midazolam-flumazenil abortion
69
anesthesia for induced
0. Hamar, Gy. GaramvGlgyi and A. K&m&n Second Obstetrics and Gynecological Clinic. Semmelwek University Medicai School, Budapt
(Hungary)
(Recdved May 18th. 1988) (Revised and accepted October 5th, 1988)
Abstract A new anesthetic method (fentanyl-midazolam-flumazenil) was compared with a previously administered anesthetic regimen (pethidine-diazepam-ketamine) in two groups of 25 women, each of whom underwent termination of pregnancy. No significant difference was found between the two groups in quality of anesthesia. Recovery was assessed by means of the Aldrete score and a visual analog scale. The recovery time was significantly shorter in patients who received the fentanyl-midazolam-flumazenil.
Keywords: Hypnotics; Benzodiazepines-midazolam; Antagonist; Benzodiazepine antagonist-flumazenil; Anesthesia; Outpatient anesthesia. Introduction Termination of pregnancy within the first 12 weeks by suction curettage with the patient under general anesthesia is a common ambulatory procedure in gynecologic clinics throughout the world. This operation often is considered “minor” and the length of the
patient’s hospitalization depends mainly on recovery from the anesthetic agents used. should Ideally, the anesthetic technique include a rapid, smooth induction and the maintenance of an appropriate level of anesthesia without excessive blood loss or risk of cardiorespiratory instability. Recovery should be rapid, and complications such as nausea, vomiting and anaphylactic reactions, should be rare or non-existent [ 111. Studies of intravenous anesthetic techniques for short surgical procedures often have compared midazolam with thiopental or methohexital [3,9,11]. Midazolam, a shortacting water-soluble benzodiazepine, is being used increasingly for anesthesia in patients undergoing various types of outpatient surgical procedures. Midazolam has minimal cardiovascular effects, even in patients with previously compromised coronary perfusion. A further and important clinical advantage of this i.v. induction agent is its amnestic effect Flumazenil,’ an imidazobenzomw. diazepine, is a benzodiazepine antagonist that specifically blocks the central effects of agents acting through the benzodiazepine receptor by competitive inhibition [6,8]. In the present study, we evaluated recovery after fentanyl-midazolam-flumazenil anesthesia [ 121 compared to pethidine-diazepamketamine anesthesia and attempted to Clinical and Clinical Research
0 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
70
Hamar et al.
determine whether the new method (fentanylmidazolam-flumazenil) is suitable for use in outpatient abortions. Previously, pethidinediazepam-ketamine anesthesia was used in our department for anesthesia in 10,803 cases of abortion. Methods Fifty consecutive patients (ASA l-2) with a gestation of less than 12 weeks underwent Individuals with neurological abortion. diseases, known allergy to benzodiazepine or who were receiving treatment with psychotropic drugs were not studied. The study was conducted in accordance with the Helsinki II Declaration. Patients were randomly assigned to two groups in order to receive pethidinediazepam-ketamine (ketamine group), or fentanyl-midazolam-flumazenil (midazolam group). One hour before surgery, the patients were premeditated orally with diazepam 5 mg. In the ketamine group, anesthesia was induced with diazepam 0.15 mg/kg intravenously, together with pethidine 1 mg/kg. After this, ketamine (1.0 mg/kg) was administered. If necessary, supplementary doses of ketamine 0.25 mg/kg were injected. In the midazolam group, anesthesia was induced with midazolam, 0.3 mg/kg intravenously, together with fentanyl 2.5 pg/kg, max. 0.15 mg. A further dose of midazolam (0.15 mg/ kg) was administered if the eyelash reflex was still present 3 min after the initial dose. Where necessary, supplementary doses of midazolam (0.15 mg/kg) or fentanyl(1 pg/kg, max. 0.05 mg), or both, were injected. Immediately after termination of anesthesia patients received flumazenil(0.4 mg i.v.) within 60 s. The patients breathed spontaneously. Oxygen, nitrous oxide or other inhalation anesthetic agents were not administered. Postoperatively, the patients remained in the operating theatre for 10 min and were then transferred to the recovery room. The overall quality of anesthesia was graded on a 10 cm visual analog scale (very Int J Gynecol Obstet30
good-excellent = 10; poor = 0) by the obstetrician at the end of intervention. The obstetricians were unaware of the type of anesthesia used. Recovery was assessed by means of the postanesthesia recovery score described by Aldrete [I]. The postanesthesia subjective level of sedation was also measured by a 10 cm visual analog scale (quite alert = 0; extremely tired = 10); after the patient was awake and cooperating well, she marked her evaluation [7]. Blood gas analysis was performed in all cases before induction of anesthesia and 90 and 180 min after surgery. Blood pressure and heart and respiratory rate were measured every 15 min. All patients were visited postoperatively by one of the anesthetists before they were discharged. Patients were asked if the same type of recovery would be acceptable on a future occasion. Statistical analysis was carried out using Student’s t-test. Values of P < 0.05 were considered statistically significant. All patients were discharged by 6 h after surgery. Results The main findings of the study are summarized in Table I. Recovery time was significantly shorter in those patients who received midazolam.
Table 1.
Comparison of the two study groups. The values aremean f S.D.
No. patients Age Weight (kg) Height (cm) Duration of anesthesia (min) Assessment score (cm) Recovery time (minp * Indicates statistically groups P-C 0.05.
Ketamine group
Midazolam group
25 24.2 + 9.8 59.8 + 15.2 165.4 + 25.3 11.9 f 9.2
25 25.6 + 61.4 j, 164.2 f 13.1 f
10.1 16.3 26.8 10.1
7.7 f 2.1 31.2 & 6.8
7.6 + 4.5 +
2.3 0.5
significant
differences
between the
Anesthesia for induced abortion Table II.
71
Total dose (mg) requirements of anesthetic agents; median (range).
Ketamine group Pethidine Diazepam Ketamine
Midaaolam group 55.3 (25.0-75.0) 15.2(10.0-20.0) 65.3 (50.0-87.5)
Fentanyl Midazolam Flumazenil
0.125 (0.1-0.15) 25.5 (22.5-40.0) 0.4
Table III. The postanesthetic recovery of the patients measured with Aldrete scoring system. The time is the time from administration of the antagonist to the end of surgery. 5 min’ Ketamine
10 min’ Midazolam
40min
Ketamine
Midazolam
Ketamine
Midazolam
Activity Respiration Circulation Consciousness Color
0 1.08 2 0.6 1.92
2 2 2 2 2
0.02 2 2 1.12 2
2 2 2 2 2
2 2 2 2 2
2 2 2 2 2
Total score
5.60
10
7.14
10
10
10
*Indicates statistically significant differences between the groups P< 0.05.
Dosage requirements for anesthetic agents are shown in Table II. The postanesthetic recovery score also documented more rapid recovery in the midazolam group. The difference between the two study groups was significant at 5 min and 10 min after surgery (Table III). The results of subjective expressions of postoperative sedation (measured by the visual analogue scale) are summarized in Fig. 1. In the midazolam group, every patient was awake 5 min after termination of anesthesia. In the ketamine group, however, the prolonged recovery time delayed the examination until 40 min after termination of anesthesia. Thus, the difference between the two groups is significant at 40 min after surgery, but at 90 min and 180 min the difference did not reach statistical significance. Respectively, 92% of the midazolam group and 64% of the ketamine group were willing to have the same type of recovery for a future operation. In the ketamine group, 36% of the patients complained of unpleasant dreams. No significant differences between the groups
occurred in blood gas values, blood pressure, and heart and respiratory rates. All values were within normal limits. No serious complications were noted during the study. In each group, only two patients vomited slightly. In neither group was there any complaint of awareness during anesthesia.
*
I i I
“Lb. 0
’ 6
10
20
40
*
so
180
tlmin)
Fig. 1. Postanesthetic sedation on a 10 cm visual analog scale (VAS). 0, Values of ketamin group; 0, values from midazolam group. Median (interquartile range). *indicates statistically significant differences between the groups P< 0.05. Clinical and Clinical Research
12
Hamar et al.
Discussion An ideal intravenous anesthetic agent for outpatient anesthesia should have a fast onset and short duration of action. It should be rapidly metabolized into pharmacologically inactive and nontoxic metabolites. There should be no accumulation after repeated doses. Cardiorespiratory stability, good local tissue tolerance, and lack of allergic phenomena should be assured. Midazolam fulfills some of these criteria [2,4,11]. The recovery time is shorter after fentanylmidazolam-flumazenil anesthesia than after pethidine-diazepam-ketamine anesthesia, but the differences of subjective sedation values at 90 min and 180 min are not significant. In the ketamine group, 36% of the patients complained of unpleasant dreams. The recovery of the midazolam group was more comfortable. The results of our study demonstrate that fentanyl-midazolam-flumazenil anesthesia is suitable for anesthesia in patients undergoing abortion. References
3
4
5 6
I
8
Crawford ME, Carl P, Andersen RS, Mikkelsen BO.: Comparison between midazolam and thiopentone based balanced anesthesia for day-case surgery. Br J Anaesth 56: 165, 1984. Dundee JW, Samuel JC, Toner W, Howard PJ: Midazolam: a water soluble benzodiazepine. Studies in volunteers. Anaesthesia 54: 507,198O. Dundee JW, Wilson DB: Amnesic action of midazolam. Anaesthesia 35: 459,198O. Hunkeler W, Mohler H, Pieri L, Pole P, Bonetti EP, Cumin R, Schaffer R, Haefely W: Selective antagonist of benzodiazepines. Nature 290: 514,198l. Manner T, Kanto J, Salonen M: Use of simple test to determine the residual effects of the analgesic component of balanced anesthesia. Br J Anaesth 59: 978,1987. Miihler H, Burhard WP, Keller HH, Richards JG, Haefely W: Benzodiazepine antagonist RO 15-1788: binding characteristics and interaction with drug induced changes in dopamine-turnover and cerebellar CGHP levels. J Neurochem37: 714,198l. Reves JG, Vinik R, Hirschfield RM, Holcomb C. Strong S: Midazolam compared with thiopentone as a hypnotic component in balanced anesthesia: a randomized double blind study. Can Anaesth Sot J 26: 42, 1979. Schulte-Sasse V, Hess W, Tamow J: Haemodynamic responses to induction of anesthesia using midazolam in cardiac surgical patients. Br J Anaesth 54: 1053, 1982. Verma R, Ramasubramanian R, Sachar RM: Anesthesia for termination of pregnancy: midazolam compared with methohexital. Anesth Analg 64: 792, 1985. Wolff J, Carl P, Clausen TG, Mikkelsen BO: RO 15-1788 for postoperative recovery. Anaesthesia 41: 1001,1986.
Address for reprints: 1 2
Aldrete JA, Kroulik D: A postanesthetic recovery score. Anesth Analg 49: 924, 1970. Avram MJ, Fragen RJ, Caldwell NJ: Midazolam kinetics in women of two age groups. Clin Pharmacol Ther 34: 5051983.
Int JGynecol Obstet 30
Ott6 Hnmar Second Obstetrics and Gynecological Clinic Semmelweis University Medical School 1082 Budapest, hi 6178/a Hungary