Acta Anaesthesiol Scand 1990: 34: 632-635
Recovery from total intravenous anaesthesia. Propofol versus midazolam-flumazenil A. STEIB,G. FREYS,D. JOCHUM, J. RAVANELLO, J. C. SCHAAL and J. C. OTTENI Departments of Anaesthesiology and Surgery, University Hospital Hautepierre, Strasbourg, France
The aim of this study was to compare recovery assessed with the Newman, deletion af a's and postbox tests after total intravenous anaesthesia for procedures lasting more than 90 min, with either propofol (PPF) or midazolam (MDZ), reversed or not by flumazenil (FMZ). Thirty patients scheduled for peripheral surgery were randomly allocated to 3 groups of 10, receiving by continuous infusion until the end of surgery either PPF ( n = 10) or MDZ (n=20) combined with alfentanil. F M Z was administered thereafter to 10 patients receiving MDZ until they opened their eyes on command or to a maximum dose of 1 mg. Recovery tests were performed 45, 90 and 180 min after the end of anaesthesia. Results were analysed with non-parametric tests. Recovery scores were significantly better in the PPF group at all times, reaching control values at 180 min for the three tests. FMZ reversal did not improve the scores compared to those resulting from MDZ alone. This study provides further data in favour of PPF as far as rapid and complete recovery is concerned. The efficiency of FMZ is incomplete and only transient when administered in a single dose.
Received 27 januaiy, accepted for publication 10 M a y 1990 Key words: Alfentanil; flumazenil; intravenous anesthesia; midazolam; propofol; recovery.
Total intravenous anaesthesia (TIVA) techniques are of great value when inhalational agents are for some reason precluded (1). However, most of the hypnotic agents such as barbiturates, ketamine and benzodiazepines given by continuous infusion have cumulative properties. They result in delayed recovery, which remains the greatest limitation to the development of TIVA, especially for day-case surgery (2). Etomidate is non-cumulative but has a depressant effect on adrenocortical function (1). Propofol, with a fast rate of metabolic clearance and no major deleterious side effects, seems to be the best choice among available hypnotic agents for TIVA. Good results have been reported in combination with alfentanil for short procedures (3). However, experience of its use in longterm infusions and its influence on recovery is still limited. Midazolam, with a half-life of about 3 h, is inappropriate for the maintenance of anaesthesia when rapid recovery is necessary. However, the ability of the new specific antagonist flumazenil to reverse the sedative and hypnotic effects of benzodiazepines seems to allow a greater flexibility in the use of midazolam in total intravenous techniques. The aim of this study was to compare different aspects of recovery following TIVA with either propoTo1 or midazolam, followed or not by flumazenil reversal for procedures of at least 90 min.
PATIENTS AND METHODS Thirty ASA grade I patients scheduled for peripheral surgery (extirpation of varicose veins or hernia repair) were included in the study, after the approval of the local Ethics Committee had been given. All the subjects gave written consent. They were randomly allocated to receive either propofol or midazolam with or without flumazenil reversal. O n the morning of surgery all patients received 100 mg of hydroxyzine orally. An 18-gauge intravenous teflon catheter was inserted into the back of the non-dominant hand, and a saline solution was administered at a rate of 5 m1.kg-l.h-l. Anaesthesia was induced with 1.5 mg'kg-' ofpropofol ( n = l O ) or 0.3 mg.kg-' of midazolam ( n = 20) in combination with pancuronium (0.08 mg. kg-') and alfentanil (0.05 mg. kg-'). After tracheal intubation, the patients were ventilated with an air-oxygen mixture (F10,=0.4). Anaesthesia was maintained with either propofol (9 mg. kg-'. h-', reduced by 50% after 30 min) or midazolam (0.6 m g . k g - ' . h - ' , reduced by 25% after 15 min). Alfentanil was continuously infused at a r a t e o f 0 . 0 6 m g . k g - ' . h - ' . Incrementsof20 mgofeitherpropofol or 5 mg of midazolam were administered in case of a somatic response, such as coughing or movements during surgery. At the end of the operation, drug infusions were stopped and the patients were transferred to the recovery room. I n ten patients, midazolam was reversed with a 0.2 mg initial bolus of flumazenil followed by 0.1 mg boluses, repeated every minute until the patients opened their eyes on command or until a total dose of 1 mg was reached. Neuromuscular blockade was reversed with atropine 1.25 mg and neostigmine 2.5 mg whenever the patients had a negative head lift test. Awakening times including recovery of eyelash reflex, opening eyes on command, onset of spontaneous ventilation and recall of birthdate were recorded for all patients. Recovery tests were performed 45, 90 and 180 min after the end of TIVA. Fine motor
633
RECOVERY FROM TIVA Table 1 Demographic data (mean f s.d.). ( ): number of patients. PPF: propofol; MDZ: midazolam. FMZ: midazolam with flumazenil reversal.
Age (years) Weight (kg) Height (cm) Duration of TIVA (min)
43.9 f 9.1 70.3f 13.1 169.8t8.5
45 t 10.3 69.4f 12.9 16523.2
114.5 f 26.4
125 f 36.3
I BAP
39.8 f 7.7 68.3f 11 171.3i 10.5 101 2 10.75
.....
.:.;:;::.:::. :..:.;:, ,:.>;.;.?.;‘:...........,-
’.‘;;w;;;::.*.’.’ .:-. .:.
coordination and perception were measured with the Newman test (4). Patients were asked to draw a geometric figure by connecting dots. The number of missed dots was considered as the test score. Vigilance was assessed by a deletion of a’s test. The latter required the patient to delete as many “a” letters as possible in less than 1 min from a sheet of paper containing sentences. This test is an adaptation ofDixon and Thornton’s deletion ofp’s test (5).One point was assigned for each omitted letter. Perception ofspace, decision and coordination were evaluated by the postbox test (6). The patient was asked to post three different types of shapes through corresponding holes in the lid of a child’s toy, three times consecutively in 20-s periods. The mean number of posted shapes was recorded as the test score. The results were compared to preoperative scores assessed the day before surgery. Anterograde amnesia was estimated by asking the patients whether they could recall any events between the period of their arrival in the recovery room and the next morning after operation. Statistical analysis was performed with a Kruskal-Wallis nonparametric analysis of variance. Intragroup comparison was carried out with a Wilcoxon test and the comparison between two different groups with a Mann Whitney test. The significance level was set at 0.05.
RESULTS The three groups of patients receiving either propofol (PPF) or midazolam alone (MDZ) or midazolam with flumazenil reversal (FMZ) were comparable with regard to age, weight and height. The length of TIVA was not significantly different between groups, despite the slightly longer mean duration of anaesthesia in the MDZ subjects (Table 1). The mean total doses of similar drugs were also comparable (Table 2). The extreme doses of flumazenil were, respectively, 0.2 and 0.9 mg. The administration of the antagonist was uneventful in all patients. Blood arterial pressure was lower during anaesthesia Table 2 Mean total doses of intravenous agents f s.d.
Propofol (mg) Midazolam (mg) Pancuronium (mg) Alfentanil (mg) Flumazenil (mg)
PFF
MDZ
FMZ
732 f 254
-
-
5 f 0.9 10.5 5.8
53.5 k 13.6 5.05 f 1.2 13k5.4
-
-
45.5 2 8 5.2 & 0.8 9.7f 1.9 0.5 f 0.2
‘1
.
...
0
‘
* T
I
V
MDZ FMZ
I
A
Fig. 1. Mean systolic and diastolic arterial blood pressure (mmHg) during total intravenous anaesthesia (TIVA) and recovery. Blood arterial pressure (BAP) is lower in the PPF group. The difference from the other patients became significant at 70 rnin following induction of anaesthesia (P
Recovery from total intravenous anaesthesia. Propofol versus midazolam-flumazenil A. STEIB,G. FREYS,D. JOCHUM, J. RAVANELLO, J. C. SCHAAL and J. C. OTTENI Departments of Anaesthesiology and Surgery, University Hospital Hautepierre, Strasbourg, France
The aim of this study was to compare recovery assessed with the Newman, deletion af a's and postbox tests after total intravenous anaesthesia for procedures lasting more than 90 min, with either propofol (PPF) or midazolam (MDZ), reversed or not by flumazenil (FMZ). Thirty patients scheduled for peripheral surgery were randomly allocated to 3 groups of 10, receiving by continuous infusion until the end of surgery either PPF ( n = 10) or MDZ (n=20) combined with alfentanil. F M Z was administered thereafter to 10 patients receiving MDZ until they opened their eyes on command or to a maximum dose of 1 mg. Recovery tests were performed 45, 90 and 180 min after the end of anaesthesia. Results were analysed with non-parametric tests. Recovery scores were significantly better in the PPF group at all times, reaching control values at 180 min for the three tests. FMZ reversal did not improve the scores compared to those resulting from MDZ alone. This study provides further data in favour of PPF as far as rapid and complete recovery is concerned. The efficiency of FMZ is incomplete and only transient when administered in a single dose.
Received 27 januaiy, accepted for publication 10 M a y 1990 Key words: Alfentanil; flumazenil; intravenous anesthesia; midazolam; propofol; recovery.
Total intravenous anaesthesia (TIVA) techniques are of great value when inhalational agents are for some reason precluded (1). However, most of the hypnotic agents such as barbiturates, ketamine and benzodiazepines given by continuous infusion have cumulative properties. They result in delayed recovery, which remains the greatest limitation to the development of TIVA, especially for day-case surgery (2). Etomidate is non-cumulative but has a depressant effect on adrenocortical function (1). Propofol, with a fast rate of metabolic clearance and no major deleterious side effects, seems to be the best choice among available hypnotic agents for TIVA. Good results have been reported in combination with alfentanil for short procedures (3). However, experience of its use in longterm infusions and its influence on recovery is still limited. Midazolam, with a half-life of about 3 h, is inappropriate for the maintenance of anaesthesia when rapid recovery is necessary. However, the ability of the new specific antagonist flumazenil to reverse the sedative and hypnotic effects of benzodiazepines seems to allow a greater flexibility in the use of midazolam in total intravenous techniques. The aim of this study was to compare different aspects of recovery following TIVA with either propoTo1 or midazolam, followed or not by flumazenil reversal for procedures of at least 90 min.
PATIENTS AND METHODS Thirty ASA grade I patients scheduled for peripheral surgery (extirpation of varicose veins or hernia repair) were included in the study, after the approval of the local Ethics Committee had been given. All the subjects gave written consent. They were randomly allocated to receive either propofol or midazolam with or without flumazenil reversal. O n the morning of surgery all patients received 100 mg of hydroxyzine orally. An 18-gauge intravenous teflon catheter was inserted into the back of the non-dominant hand, and a saline solution was administered at a rate of 5 m1.kg-l.h-l. Anaesthesia was induced with 1.5 mg'kg-' ofpropofol ( n = l O ) or 0.3 mg.kg-' of midazolam ( n = 20) in combination with pancuronium (0.08 mg. kg-') and alfentanil (0.05 mg. kg-'). After tracheal intubation, the patients were ventilated with an air-oxygen mixture (F10,=0.4). Anaesthesia was maintained with either propofol (9 mg. kg-'. h-', reduced by 50% after 30 min) or midazolam (0.6 m g . k g - ' . h - ' , reduced by 25% after 15 min). Alfentanil was continuously infused at a r a t e o f 0 . 0 6 m g . k g - ' . h - ' . Incrementsof20 mgofeitherpropofol or 5 mg of midazolam were administered in case of a somatic response, such as coughing or movements during surgery. At the end of the operation, drug infusions were stopped and the patients were transferred to the recovery room. I n ten patients, midazolam was reversed with a 0.2 mg initial bolus of flumazenil followed by 0.1 mg boluses, repeated every minute until the patients opened their eyes on command or until a total dose of 1 mg was reached. Neuromuscular blockade was reversed with atropine 1.25 mg and neostigmine 2.5 mg whenever the patients had a negative head lift test. Awakening times including recovery of eyelash reflex, opening eyes on command, onset of spontaneous ventilation and recall of birthdate were recorded for all patients. Recovery tests were performed 45, 90 and 180 min after the end of TIVA. Fine motor
633
RECOVERY FROM TIVA Table 1 Demographic data (mean f s.d.). ( ): number of patients. PPF: propofol; MDZ: midazolam. FMZ: midazolam with flumazenil reversal.
Age (years) Weight (kg) Height (cm) Duration of TIVA (min)
43.9 f 9.1 70.3f 13.1 169.8t8.5
45 t 10.3 69.4f 12.9 16523.2
114.5 f 26.4
125 f 36.3
I BAP
39.8 f 7.7 68.3f 11 171.3i 10.5 101 2 10.75
.....
.:.;:;::.:::. :..:.;:, ,:.>;.;.?.;‘:...........,-
’.‘;;w;;;::.*.’.’ .:-. .:.
coordination and perception were measured with the Newman test (4). Patients were asked to draw a geometric figure by connecting dots. The number of missed dots was considered as the test score. Vigilance was assessed by a deletion of a’s test. The latter required the patient to delete as many “a” letters as possible in less than 1 min from a sheet of paper containing sentences. This test is an adaptation ofDixon and Thornton’s deletion ofp’s test (5).One point was assigned for each omitted letter. Perception ofspace, decision and coordination were evaluated by the postbox test (6). The patient was asked to post three different types of shapes through corresponding holes in the lid of a child’s toy, three times consecutively in 20-s periods. The mean number of posted shapes was recorded as the test score. The results were compared to preoperative scores assessed the day before surgery. Anterograde amnesia was estimated by asking the patients whether they could recall any events between the period of their arrival in the recovery room and the next morning after operation. Statistical analysis was performed with a Kruskal-Wallis nonparametric analysis of variance. Intragroup comparison was carried out with a Wilcoxon test and the comparison between two different groups with a Mann Whitney test. The significance level was set at 0.05.
RESULTS The three groups of patients receiving either propofol (PPF) or midazolam alone (MDZ) or midazolam with flumazenil reversal (FMZ) were comparable with regard to age, weight and height. The length of TIVA was not significantly different between groups, despite the slightly longer mean duration of anaesthesia in the MDZ subjects (Table 1). The mean total doses of similar drugs were also comparable (Table 2). The extreme doses of flumazenil were, respectively, 0.2 and 0.9 mg. The administration of the antagonist was uneventful in all patients. Blood arterial pressure was lower during anaesthesia Table 2 Mean total doses of intravenous agents f s.d.
Propofol (mg) Midazolam (mg) Pancuronium (mg) Alfentanil (mg) Flumazenil (mg)
PFF
MDZ
FMZ
732 f 254
-
-
5 f 0.9 10.5 5.8
53.5 k 13.6 5.05 f 1.2 13k5.4
-
-
45.5 2 8 5.2 & 0.8 9.7f 1.9 0.5 f 0.2
‘1
.
...
0
‘
* T
I
V
MDZ FMZ
I
A
Fig. 1. Mean systolic and diastolic arterial blood pressure (mmHg) during total intravenous anaesthesia (TIVA) and recovery. Blood arterial pressure (BAP) is lower in the PPF group. The difference from the other patients became significant at 70 rnin following induction of anaesthesia (P
