Lack of Interaction Between Propofol and Vecuronium Gerard J. McCarthy,
FFARCSI,
Rajinder K. Mirakhur,
MD,
and Sujit K. Pandit,
MD
Department of Anaesthetics, The Queen's University of Belfast, Belfast, Northern Ireland and Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan
We estimated the potency of vecuronium and measured the onset and duration of its action during total intravenous anesthesia with propofol to examine the possibility of any interaction between these two drugs. Propofol infusion was administered according to a three-step dosage scheme, and neuromuscular block was monitored by measuring the force of contraction of the adductor pollicis muscle after singletwitch stimulation of the ulnar nerve at 0.1 Hz. A control group of patients were similarly studied during anesthesia with thiopental, nitrous oxide, oxygen, and fentanyl. The ED,, and ED,, (dose required to produce a 50% and 95% depression of twitch tension, respectively) of vecuronium in patients given total intravenous anesthesia (n = 24) were 24 (22-27, 95% confidence limits) and 41 (3748, 95%
P
ropofol was originally formulated in Cremophor but now is formulated as an emulsion in soybean oil and egg phosphatide. The original formulation of propofol in Cremophor may potentiate a vecuronium neuromuscular blockade in both experimental and clinical settings (1,2). Lack of significant interaction has been reported between the emulsion formulation of propofol and vecuronium (3,4). However, a cumulative instead of a single dose-response method for estimating the potency of vecuronium was used in one study (3), whereas only a single induction dose of propofol and a single relatively small dose of vecuronium were used in the other (4). Our study was designed to assess any interaction between the currently used emulsion formulation, of propofol and vecuronium in humans by first estimating the potency of vecuronium using a single-dose method and then measuring the onset
confidence limits) &kg, respectively, and in the control group ( n = 24), 20 (17-24) and 39 (34-37) pg/kg, respectively. The onset of action of an 80-pglkg dose (2 x ED,,) of vecuronium was 3.6 & 1.2 and 4.1 5 1.7 min (mean -C SD), in the propofol (n = 10) and control ( n = 10) groups, respectively. The respective times to recovery of the twitch height to 25% of control and the recovery indices (25%-75% recovery of twitch height) in the propofol versus control groups were 28.3 5 6.6 and 28.0 +- 1.7 min and 13.3 +- 6.8 and 15.4 2 11.9 min, respectively. There were no significant differencesin any of the measured variables between the propofol and control groups, indicating the lack of any interaction between propofol and vecuronium. (Anesth Analg 1992;75:53&8)
and duration of its action during total intravenous anesthesia with propofol.
Methods Sixty-eight adult patients, aged 18-65 yr, undergoing body surface operations were included in the study after they gave their informed consent and after the approval of the Research Ethical Committee. All patients conformed to ASA physical status class I or 11, and those with a weight >120% of ideal or on medication known to interact with neuromuscular blocking agents were excluded. Premedication consisted of oral diazepam (10 mg) administered 90 min preoperatively. All patients were monitored in the usual manner. Ventilation was adjusted to end-tidal carbon dioxide concentration of 4.5%-5.5%. Patients were randomly allocated to be anesthetized with either a continuous urouofol infusion (propofol group) and ventilation with air and oxygen Or thiopental with nitrous Oxide and Oxygen group). Both groups received fentanyl (2-3 pg/kg) at induction, followed by further increments if required. In the propofol group, anesthesia was induced with a dose of 2-5 mg/kg and maintained with an infusion of propofol at a starting rate of 1
The results of this study were presented at the Annual Meeting of the American Society of Anesthesiologists, October 1990, Las Vegas, Nevada, and an abstract was published in Anesthesiology 1990;73:A899.
Accepted for publication June 1, 1992. Address correspondence to Dr. Pandit, University of Michigan Medical Center, Department of Anesthesiology, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0048.
536
1
01992 by the International Anesthesia Research Society Anesth Analg 1992;75:53&8
0003-2999/92/$5.00
ANESTH ANALG 1992;75:53H3
10 mg.kg-’.h-l, which was reduced at intervals of 10 min each to 8 and 6 mg.kg-’.h-l and then maintained at that rate, as previously reported by Roberts et al. (5). In the control group, anesthesia was induced with thiopental ( 4 5 mg/kg) and maintained with 70% nitrous oxide in oxygen and fentanyl as required. The study was conducted in two phases. In phase I, 48 patients, in two groups of 24 each, were studied for estimation of potency of vecuronium during the two anesthetic techniques by constructing doseresponse curves. After induction of anesthesia, the ulnar nerve was stimulated at the wrist with supramaximal stimuli at a frequency of 0.1 Hz and the resultant force of contraction of the adductor pollicis muscle was recorded with a force transducer and a neuromuscular function analyzer (Myograph 2000, Biometer Ltd.). After a 10-min stabilization period, eight patients within each anesthetic technique were randomly allocated to receive a bolus dose of 20, 30, or 40 &kg of vecuronium, and maximal block was allowed to supervene, regardless of the time taken to achieve it. An arc-sine transformation of the data relating to twitch height was carried out, as used previously to allow analysis of the response between 0% and 100% block (6). Dose-response curves were constructed to allow linear regression analysis to be performed and ED50 and ED,, (dose required to produce a 50% and 95% depression of twitch tension, respectively) determined. In the second phase of the study, 80 pgkg of vecuronium was administered as a single bolus dose to 10 patients, each anesthetized with the two techniques after baseline neuromuscular monitoring was established along the same lines as in phase I. The times to onset of maximal block and to recovery of the twitch height to 25% and 75% of control (for estimating the recovery index) were determined. Analysis of variance, analysis of covariance, and t-tests were used to assess the statistical significance of the results, which was accepted at the 5% level.
Results The groups were comparable as to age and weight in both phases of the study. The dose-response curves as shown in Figure 1are close to each other. The lines did not differ significantly in their slopes. The derived values of ED50 and ED,, are given in Table 1. The ED50 values of 24 and 20 p g k g and the ED,, values of 41 and 39 pg/kg, in the propofol and control groups respectively were not significantly different. The time to maximal block (100% in all cases) was similar between the groups (3.6 and 4.1 min in the propofol and control groups, respectively) without
McCARTHY ET AL. PROPOFOL-VECURONIUM INTERACTION
537
X
0
1 d!
20
30 40 5 0
Dose (gg/kg)
Figure 1. Dose-response curves for vecuronium during anesthesia with propofol (A---A)and with thiopental-nitrous oxide-oxygenThe points are the average degree of block fentanyl (0----0). obtained with each dose and the bars represent standard deviation.
Table 1. Patient Characteristics and Estimated ED,, and ED,, (95% confidence limits) in the Propofol and Control Groups
Age (yr) Weight (kg) ED50
(PgW
ED,, ( P g W
Propofol group (n = 24)
Control group (n = 24)
49 (15.9) 69 (13.9) 24 (22-27) 41 (3748)
42 (14.3) 74 (8.4) 20 (17-24) 39 (34-37)
ED,,, ED,,, dose required to produce a 50% and 95% depression of twitch tension, respectively. Mean (?sD).
Table 2. Patient Characteristics and Results From the Onset and Duration Phase of the Study
Age (yr) Weight (kg) Time to maximal block (min) Time to return of T-1 to 25% (min) Recovery index (min)
Propofol group (n = 10)
Control group ( n = 10)
46 (15.2) 71 (10.5) 3.6 (1.2) 28.3 (6.6)
46 (15.9) 67 (11.1) 4.1 (1.7) 28 (1.7)
13.3 (6.8)”
15.4 (11.9)b
Mean ( ~ s D ) . “Nine patients. bseven patients.
any significant difference. The time to 25% recovery of twitch height (-28 min) and the recovery indices (13-15 min) also showed no significant difference between the groups (Table 2).
538
ANESTH ANALG
McCARTHY ET AL.
PROPOFOL-VECURONIUM INTERACTION
Discussion Our results showed no differences in the estimates of potency or the onset and duration of action of vecuronium when used in single doses during propofolfentanyl anesthesia and thiopental-fentanyl-N,O anesthesia. This is contrary to the results of an in vitro study in which the effects of vecuronium were potentiated (l),but in that study the Cremophor formulation was used. The difference may thus have been due to Cremophor, although it has been proposed that Cremophor may actually have anticholinesterase properties (1). In the first phase of our study, we assessed the dose-response relationship for vecuronium in humans. There was no significant difference in our final estimates of the ED,, for vecuronium with or without propofol, and the values obtained were indeed similar to those previously reported using a similar technique of estimation (6). In the second phase of the study, we found no difference between the groups in terms of the onset time. Onset of neuromuscular blockade is largely dependent on cardiac output and muscle blood flow to deliver the drug to its receptor site, and the potency, affinity, or diffusion characteristics of the drug are of secondary importance (7). Hence, the lack of any difference in onset time is not surprising. We might have expected a difference only if there was a marked alteration in cardiac output between the two anesthetic techniques used. The subsequent recovery of neuromuscular function occurs as the plasma concentration of vecuronium declines with redistribution and metabolism. Because there was no significant difference between the groups in the time to recovery to 25% of control twitch height, or in the time for spontaneous recovery from 25% to 75% of control, we must conclude that there is no evidence for any significant interaction. We are able to confirm the findings of previous workers with respect to a lack of interaction between the emulsion formulation of propofol and vecuronium (3), although these authors used a cumulative dose-response technique. In addition, they used a relatively small dose of 43 pg/kg of vecuronium to study the onset and duration in contrast to a clinically applicable dose of 80 pglkg used in the present study. The study of Nightingale et al. (4) is not directly comparable to ours, even though the results were similar. Whereas we used propofol for both induction and maintenance of anesthesia, they assessed the effects of only an induction dose of propofol. Moreover, they examined the effects of
1992;75:53@
only a small single dose of vecuronium that produced approximately 50% block; in addition, they used electromyography for measurement of neuromuscular block. The original animal studies using the Cremophor preparation led to the suggestion that any interaction was a direct intracellular effect of propofol on the muscle (1)rather than due to the effect of Cremophor, because Cremophor was suggested by these authors to have an anticholinesterase effect. They further speculated that a non-Cremophor preparation may prolong the effect of muscle relaxants even more markedly. However, these explanations are not relevant in the context of the present study, where the emulsion formulation showed no potentiation of the effects of vecuronium. Moreover, the Cremophor preparation is no longer in use. As no interaction has been observed between clinically useful doses of thiopental and vecuronium (8), the possibility that we have masked the action of propofol by the use of thiopental in our control groups seems unlikely. In conclusion, the emulsion formulation of propofol does not have any significant effect on the neuromuscular blocking properties of vecuronium in humans.
References 1. Fragen RJ, Booij LHDJ, Van der Pol F, Robertson EN, Crul JF. lnteractions of di-isopropyl phenol (ICI 35 868) with suxamethonium, vecuronium and pancuronium in vitro. Br J Anaesth 1983;55:433-5. 2. Robertson EN, Fragen RJ, Booij LHDJ, Van Egmond J, Crul JF. Some effects of di-isopropyl phenol (ICI 35 868) on the pharmacodynamics of atracurium and vecuronium in anaesthetized man. Br J Anaesth 1983;55:72?-7. 3. De Grood PMRM, Van Egmond J, Van de Wetering M, Van Beem HB, Booij LHDJ, Crul JF. Lack of effects of emulsified propofol (Diprivan) on vecuronium pharmacodynamicspreliminary results in man. Postgrad Med J 1985;61:2&30. 4. Nightingale P, Petts NV, Healy TEJ, Kay B, McGuinness K. Induction of anaesthesia with propofol ('Diprivan') or thiopentone and interactions with suxamethonium, atracurium and vecuronium. Postgrad Med J 1985;61:31-4. 5. Roberts FL, Dixon J, Lewit GTR, Tackley RM, Prys-Roberts C. Induction and maintenance of propofol anaesthesia. A manual infusion scheme. Anaesthesia 1988;43:14-7. 6. Gibson FM, Mirakhur RK, Clarke RSJ, Lavery GG. Comparison of cumulative and single bolus dose techniques for determining the potency of vecuronium. Br J Anaesth 1985;57 1060-2. 7 . Donati F. Onset of action of relaxants. Can J Anaesth 1988;35: S52-8. 8 . McIndewar IC, Marshall RJ. Interactions between the neuromuscular blocking drug Org NC45 and some anaesthetic, analgesic and antimicrobial agents. Br J Anaesth 1981;53:78.592.
FFARCSI,
Rajinder K. Mirakhur,
MD,
and Sujit K. Pandit,
MD
Department of Anaesthetics, The Queen's University of Belfast, Belfast, Northern Ireland and Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan
We estimated the potency of vecuronium and measured the onset and duration of its action during total intravenous anesthesia with propofol to examine the possibility of any interaction between these two drugs. Propofol infusion was administered according to a three-step dosage scheme, and neuromuscular block was monitored by measuring the force of contraction of the adductor pollicis muscle after singletwitch stimulation of the ulnar nerve at 0.1 Hz. A control group of patients were similarly studied during anesthesia with thiopental, nitrous oxide, oxygen, and fentanyl. The ED,, and ED,, (dose required to produce a 50% and 95% depression of twitch tension, respectively) of vecuronium in patients given total intravenous anesthesia (n = 24) were 24 (22-27, 95% confidence limits) and 41 (3748, 95%
P
ropofol was originally formulated in Cremophor but now is formulated as an emulsion in soybean oil and egg phosphatide. The original formulation of propofol in Cremophor may potentiate a vecuronium neuromuscular blockade in both experimental and clinical settings (1,2). Lack of significant interaction has been reported between the emulsion formulation of propofol and vecuronium (3,4). However, a cumulative instead of a single dose-response method for estimating the potency of vecuronium was used in one study (3), whereas only a single induction dose of propofol and a single relatively small dose of vecuronium were used in the other (4). Our study was designed to assess any interaction between the currently used emulsion formulation, of propofol and vecuronium in humans by first estimating the potency of vecuronium using a single-dose method and then measuring the onset
confidence limits) &kg, respectively, and in the control group ( n = 24), 20 (17-24) and 39 (34-37) pg/kg, respectively. The onset of action of an 80-pglkg dose (2 x ED,,) of vecuronium was 3.6 & 1.2 and 4.1 5 1.7 min (mean -C SD), in the propofol (n = 10) and control ( n = 10) groups, respectively. The respective times to recovery of the twitch height to 25% of control and the recovery indices (25%-75% recovery of twitch height) in the propofol versus control groups were 28.3 5 6.6 and 28.0 +- 1.7 min and 13.3 +- 6.8 and 15.4 2 11.9 min, respectively. There were no significant differencesin any of the measured variables between the propofol and control groups, indicating the lack of any interaction between propofol and vecuronium. (Anesth Analg 1992;75:53&8)
and duration of its action during total intravenous anesthesia with propofol.
Methods Sixty-eight adult patients, aged 18-65 yr, undergoing body surface operations were included in the study after they gave their informed consent and after the approval of the Research Ethical Committee. All patients conformed to ASA physical status class I or 11, and those with a weight >120% of ideal or on medication known to interact with neuromuscular blocking agents were excluded. Premedication consisted of oral diazepam (10 mg) administered 90 min preoperatively. All patients were monitored in the usual manner. Ventilation was adjusted to end-tidal carbon dioxide concentration of 4.5%-5.5%. Patients were randomly allocated to be anesthetized with either a continuous urouofol infusion (propofol group) and ventilation with air and oxygen Or thiopental with nitrous Oxide and Oxygen group). Both groups received fentanyl (2-3 pg/kg) at induction, followed by further increments if required. In the propofol group, anesthesia was induced with a dose of 2-5 mg/kg and maintained with an infusion of propofol at a starting rate of 1
The results of this study were presented at the Annual Meeting of the American Society of Anesthesiologists, October 1990, Las Vegas, Nevada, and an abstract was published in Anesthesiology 1990;73:A899.
Accepted for publication June 1, 1992. Address correspondence to Dr. Pandit, University of Michigan Medical Center, Department of Anesthesiology, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0048.
536
1
01992 by the International Anesthesia Research Society Anesth Analg 1992;75:53&8
0003-2999/92/$5.00
ANESTH ANALG 1992;75:53H3
10 mg.kg-’.h-l, which was reduced at intervals of 10 min each to 8 and 6 mg.kg-’.h-l and then maintained at that rate, as previously reported by Roberts et al. (5). In the control group, anesthesia was induced with thiopental ( 4 5 mg/kg) and maintained with 70% nitrous oxide in oxygen and fentanyl as required. The study was conducted in two phases. In phase I, 48 patients, in two groups of 24 each, were studied for estimation of potency of vecuronium during the two anesthetic techniques by constructing doseresponse curves. After induction of anesthesia, the ulnar nerve was stimulated at the wrist with supramaximal stimuli at a frequency of 0.1 Hz and the resultant force of contraction of the adductor pollicis muscle was recorded with a force transducer and a neuromuscular function analyzer (Myograph 2000, Biometer Ltd.). After a 10-min stabilization period, eight patients within each anesthetic technique were randomly allocated to receive a bolus dose of 20, 30, or 40 &kg of vecuronium, and maximal block was allowed to supervene, regardless of the time taken to achieve it. An arc-sine transformation of the data relating to twitch height was carried out, as used previously to allow analysis of the response between 0% and 100% block (6). Dose-response curves were constructed to allow linear regression analysis to be performed and ED50 and ED,, (dose required to produce a 50% and 95% depression of twitch tension, respectively) determined. In the second phase of the study, 80 pgkg of vecuronium was administered as a single bolus dose to 10 patients, each anesthetized with the two techniques after baseline neuromuscular monitoring was established along the same lines as in phase I. The times to onset of maximal block and to recovery of the twitch height to 25% and 75% of control (for estimating the recovery index) were determined. Analysis of variance, analysis of covariance, and t-tests were used to assess the statistical significance of the results, which was accepted at the 5% level.
Results The groups were comparable as to age and weight in both phases of the study. The dose-response curves as shown in Figure 1are close to each other. The lines did not differ significantly in their slopes. The derived values of ED50 and ED,, are given in Table 1. The ED50 values of 24 and 20 p g k g and the ED,, values of 41 and 39 pg/kg, in the propofol and control groups respectively were not significantly different. The time to maximal block (100% in all cases) was similar between the groups (3.6 and 4.1 min in the propofol and control groups, respectively) without
McCARTHY ET AL. PROPOFOL-VECURONIUM INTERACTION
537
X
0
1 d!
20
30 40 5 0
Dose (gg/kg)
Figure 1. Dose-response curves for vecuronium during anesthesia with propofol (A---A)and with thiopental-nitrous oxide-oxygenThe points are the average degree of block fentanyl (0----0). obtained with each dose and the bars represent standard deviation.
Table 1. Patient Characteristics and Estimated ED,, and ED,, (95% confidence limits) in the Propofol and Control Groups
Age (yr) Weight (kg) ED50
(PgW
ED,, ( P g W
Propofol group (n = 24)
Control group (n = 24)
49 (15.9) 69 (13.9) 24 (22-27) 41 (3748)
42 (14.3) 74 (8.4) 20 (17-24) 39 (34-37)
ED,,, ED,,, dose required to produce a 50% and 95% depression of twitch tension, respectively. Mean (?sD).
Table 2. Patient Characteristics and Results From the Onset and Duration Phase of the Study
Age (yr) Weight (kg) Time to maximal block (min) Time to return of T-1 to 25% (min) Recovery index (min)
Propofol group (n = 10)
Control group ( n = 10)
46 (15.2) 71 (10.5) 3.6 (1.2) 28.3 (6.6)
46 (15.9) 67 (11.1) 4.1 (1.7) 28 (1.7)
13.3 (6.8)”
15.4 (11.9)b
Mean ( ~ s D ) . “Nine patients. bseven patients.
any significant difference. The time to 25% recovery of twitch height (-28 min) and the recovery indices (13-15 min) also showed no significant difference between the groups (Table 2).
538
ANESTH ANALG
McCARTHY ET AL.
PROPOFOL-VECURONIUM INTERACTION
Discussion Our results showed no differences in the estimates of potency or the onset and duration of action of vecuronium when used in single doses during propofolfentanyl anesthesia and thiopental-fentanyl-N,O anesthesia. This is contrary to the results of an in vitro study in which the effects of vecuronium were potentiated (l),but in that study the Cremophor formulation was used. The difference may thus have been due to Cremophor, although it has been proposed that Cremophor may actually have anticholinesterase properties (1). In the first phase of our study, we assessed the dose-response relationship for vecuronium in humans. There was no significant difference in our final estimates of the ED,, for vecuronium with or without propofol, and the values obtained were indeed similar to those previously reported using a similar technique of estimation (6). In the second phase of the study, we found no difference between the groups in terms of the onset time. Onset of neuromuscular blockade is largely dependent on cardiac output and muscle blood flow to deliver the drug to its receptor site, and the potency, affinity, or diffusion characteristics of the drug are of secondary importance (7). Hence, the lack of any difference in onset time is not surprising. We might have expected a difference only if there was a marked alteration in cardiac output between the two anesthetic techniques used. The subsequent recovery of neuromuscular function occurs as the plasma concentration of vecuronium declines with redistribution and metabolism. Because there was no significant difference between the groups in the time to recovery to 25% of control twitch height, or in the time for spontaneous recovery from 25% to 75% of control, we must conclude that there is no evidence for any significant interaction. We are able to confirm the findings of previous workers with respect to a lack of interaction between the emulsion formulation of propofol and vecuronium (3), although these authors used a cumulative dose-response technique. In addition, they used a relatively small dose of 43 pg/kg of vecuronium to study the onset and duration in contrast to a clinically applicable dose of 80 pglkg used in the present study. The study of Nightingale et al. (4) is not directly comparable to ours, even though the results were similar. Whereas we used propofol for both induction and maintenance of anesthesia, they assessed the effects of only an induction dose of propofol. Moreover, they examined the effects of
1992;75:53@
only a small single dose of vecuronium that produced approximately 50% block; in addition, they used electromyography for measurement of neuromuscular block. The original animal studies using the Cremophor preparation led to the suggestion that any interaction was a direct intracellular effect of propofol on the muscle (1)rather than due to the effect of Cremophor, because Cremophor was suggested by these authors to have an anticholinesterase effect. They further speculated that a non-Cremophor preparation may prolong the effect of muscle relaxants even more markedly. However, these explanations are not relevant in the context of the present study, where the emulsion formulation showed no potentiation of the effects of vecuronium. Moreover, the Cremophor preparation is no longer in use. As no interaction has been observed between clinically useful doses of thiopental and vecuronium (8), the possibility that we have masked the action of propofol by the use of thiopental in our control groups seems unlikely. In conclusion, the emulsion formulation of propofol does not have any significant effect on the neuromuscular blocking properties of vecuronium in humans.
References 1. Fragen RJ, Booij LHDJ, Van der Pol F, Robertson EN, Crul JF. lnteractions of di-isopropyl phenol (ICI 35 868) with suxamethonium, vecuronium and pancuronium in vitro. Br J Anaesth 1983;55:433-5. 2. Robertson EN, Fragen RJ, Booij LHDJ, Van Egmond J, Crul JF. Some effects of di-isopropyl phenol (ICI 35 868) on the pharmacodynamics of atracurium and vecuronium in anaesthetized man. Br J Anaesth 1983;55:72?-7. 3. De Grood PMRM, Van Egmond J, Van de Wetering M, Van Beem HB, Booij LHDJ, Crul JF. Lack of effects of emulsified propofol (Diprivan) on vecuronium pharmacodynamicspreliminary results in man. Postgrad Med J 1985;61:2&30. 4. Nightingale P, Petts NV, Healy TEJ, Kay B, McGuinness K. Induction of anaesthesia with propofol ('Diprivan') or thiopentone and interactions with suxamethonium, atracurium and vecuronium. Postgrad Med J 1985;61:31-4. 5. Roberts FL, Dixon J, Lewit GTR, Tackley RM, Prys-Roberts C. Induction and maintenance of propofol anaesthesia. A manual infusion scheme. Anaesthesia 1988;43:14-7. 6. Gibson FM, Mirakhur RK, Clarke RSJ, Lavery GG. Comparison of cumulative and single bolus dose techniques for determining the potency of vecuronium. Br J Anaesth 1985;57 1060-2. 7 . Donati F. Onset of action of relaxants. Can J Anaesth 1988;35: S52-8. 8 . McIndewar IC, Marshall RJ. Interactions between the neuromuscular blocking drug Org NC45 and some anaesthetic, analgesic and antimicrobial agents. Br J Anaesth 1981;53:78.592.
