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Duration of the pharmacodynamic interaction between pancuronium and mivacurium
British Journal of Anaesthesia 1998; 81: 251–252
Duration of the pharmacodynamic interaction between pancuronium and mivacurium M. BEAUSSIER, H. DERIAZ, A. DETRAVERSE, Z. ABDELHALIM AND A. LIENHART Summary The aim of this study was to determine for how long the duration of action of increments of mivacurium can be influenced by previous pancuronium administration. Fifteen patients, ASA I or II, undergoing general anaesthesia for major abdominal surgery were investigated. The post-tetanic count (PTC) was measured at the adductor pollicis muscle. Pancuronium 0.1 mg kg91 was injected first. At recovery of the 10th response of the PTC (PTC10), a second dose of pancuronium was injected (0.02 mg kg91). On recovery to PTC10, a bolus of mivacurium (0.04 mg kg91) was given and regularly repeated at recovery of PTC10 until the end of surgery. The mean duration of the second dose of pancuronium was 53 min (SD 13 min) and of the first dose of mivacurium, 66 min (SD 14 min) (P:0.01). The duration of action of further mivacurium boluses decreased significantly until the fifth dose. It took 222 minutes (95% confidence interval 190, 253 min) after the second pancuronium dose before the duration of action of mivacurium returned to normal values and became constant and predictable. (Br. J. Anaesth. 1998; 81: 251–252) Keywords: antagonists; neuromuscular block, pancuronium; neuromuscular block, mivacurium; recovery
Long-acting neuromuscular blocking drugs are often used during major abdominal surgery to provide adequate surgical conditions throughout the procedure. Such practice leads to a high incidence of residual neuromuscular block in the recovery room.1 To avoid this adverse effect, some anaesthetists use short-acting agents for closure of the abdominal wall after previous administration of long-acting neuromuscular blocking drugs, and expect a faster recovery from neuromuscular block at the end of surgery. However, when using more than one non-depolarizing neuromuscular blocking drug, unpredictable pharmacodynamic interactions may occur. Indeed, a significant prolongation of action of mivacurium has already been shown after previous administration of pancuronium.2 3 The purpose of the previous studies was to demonstrate supra-additive effects during concomitant administration of two neuromuscular blocking agents. A single dose of mivacurium and pancuronium was given. However, the duration of the interaction between the two neuromuscular blocking drugs remains unknown. Pharmacokinetic data and concentration-response relations suggests that such interaction could possibly last many hours: pancuronium remains in the biophase for a long time.4 The aim of the study was to determine for how long the duration of action of mivacurium can be influenced by previous pancuronium administration.
Methods and results Fifteen patients, ASA I or II, scheduled for prolonged major abdominal procedures were studied. This investigation was approved by the local ethics committee. Exclusion criteria were the presence of neuromuscular, hepatic or renal disease, and concurrent administration of any drugs known or suspected to interfere with neuromuscular transmission. Anaesthesia was induced with propofol (2–3 mg kg91) and fentanyl (2–3 g kg91). After induction, supramaximal transcutaneous train-of-four stimulation (TOF) at the ulnar nerve was applied. Responses were measured on the adductor of the thumb with an accelerometer (Tof-Guard, Organon, Teknika NV, Belgium). After calibration, pancuronium (0.1 mg kg91) was administered and tracheal intubation was performed. Anaesthesia was maintained with a continuous infusion of propofol and incremental bolus doses of fentanyl at the discretion of the anaesthetist. End-tidal concentrations of carbon dioxide were kept constant within 4–4.5% (Capnomac, Datex, Helsinski, Finland). Intraoperative hypothermia was prevented with forced air-warming blankets (Bair Hugger, Augustine Medicale, Minneapolis, USA) covering the upper part of the body and forearms of the patient, without interfering with thumb mobility. When the response to TOF stimulation disappeared after pancuronium administration, the post-tetanic count (PTC) was measured every 5 min (50 Hz tetanus for 5 s followed 3 s later by single twitch stimulation at 1 Hz). At the time of reappearance of the tenth response of the PTC (PTC10), a bolus of pancuronium 0.02 mg kg91 was given. Recovery of the PTC10 was again awaited before an approximately equipotent dose of mivacurium (0.04 mg kg91) was given. Further boluses of mivacurium (0.04 mg kg91) were again given at the same depth of neuromuscular block (PTC10) until the end of the procedure. The time to recovery of the PTC10 after each injection of neuromuscular blocking drug, and the interval between the second pancuronium dose and the time when the duration of action of two consecutive mivacurium doses did not differ significantly, were recorded for each patient. The Wilcoxon paired-sample test (StatView 4–5, Abacus Concepts Inc, Berkeley, USA) was used for statistical analysis. A P value of 0.05 or less was considered statistically significant. Results are expressed M. BEAUSSIER*, H. DERIAZ, A. De TRAVERSE, Z. ABDELHALIM, A. LIENHART, Department of Anaesthesiology and Intensive Care, St Antoine Hospital, Paris, France. Accepted for publication: March 19, 1998. *Address for correspondence: Département d’AnesthésieRéanimation, Hôpital St-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cédex 12, France.
252 as mean (SD) unless otherwise stated. The physical characteristics of the population (9 females and 6 males) were 55 years (range 40–63) and 63 (14) kg. The mean duration of anaesthesia was 323 min (range : 160 to 494 min). Every injection of pancuronium and mivacurium abolished the PTC response. The mean time from first injection of pancuronium until reappearance of the PTC10 was 55 (15) min. The duration of action of the first injection of mivacurium was 66 (14) min, exceeding significantly the duration of action of the second dose of pancuronium (53 (13) min, P:0.01). The duration of action of the incremental doses of mivacurium decreased progressively with time (fig. 1). The time between two consecutive mivacurium doses did not differ significantly after the fifth increment, corresponding to a mean of 222 minutes after the last pancuronium injection (95% confidence interval 190, 253 min). Core intraoperative hypothermia did not occur in any patient.
Comment The duration of the pharmacodynamic interaction between pancuronium and mivacurium has never been investigated. We found that the duration of action of repeated mivacurium bolus doses returned to a constant and predictable level approximately 4 h after the last pancuronium administration. The first part of our findings corroborates previous studies showing prolongation of the duration of action of mivacurium when administrated after pancuronium.2 3 We found that after pancuronium administration, the duration of action of mivacurium was significantly longer than the duration of action of approximately equipotent doses of pancuronium. The ED95 for pancuronium is wide ranging (0.05–0.07 mg kg91) and we probably used a slightly underestimated value. However, Erkola and colleagues showed that large differences in the size of the administrated doses of mivacurium after pancuronium administration did not have a great effect on the magnitude of the pharmacodynamic interaction between the two drugs.2 Moreover, the ED95 refers especially to the post-synaptic activity of non-depolarizing neuromus-
British Journal of Anaesthesia cular blocking drugs but the potentiating effect of different agents may be related at least in part to differences in presynaptic activity.5 Furthermore, presynaptic mechanisms are also involved in the response to tetanic stimulation. The longer depression of the PTC stimulation we observed after mivacurium could reflect a greater degree of presynaptic inhibition than with pancuronium alone. It took nearly 4 h for the duration of action of mivacurium to become stable. It is a minimum value, as the probability of failing to find a difference in duration between two consecutive mivacurium boluses when there really is one (type II error) is high because of the small sample size. Pancuronium is a long-acting neuromuscular blocking drug which remains at the neuromuscular junction for an extended period. The clinical effect of pancuronium in healthy subjects is known to last over 90–120 min.4 When recovery from neuromuscular block occurs, pancuronium is still present in the synaptic cleft.6 The rate of elimination of residual pancuronium from the biophase is affected by the plasma concentration of pancuronium. In healthy subjects, the elimination half-life of pancuronium have been found to be around 110 min.7 Thus it can be expected that the post-synaptic receptors remain occupied by pancuronium for many hours after a bolus of the drug. In the circumstances of this study, the prolongation of action of repeated doses of mivacurium suggests residual occupation of acetylcholine receptors by pancuronium. The magnitude of the prolongation of the duration of action of mivacurium decreases concomitantly with time from the last pancuronium injection, probably in a similar manner to the fall in the residual concentration of pancuronium in the biophase. In conclusion, clinicians must be aware that the duration of action of mivacurium is altered for a mean of approximately 4 h after a dose of pancuronium. Thus, substitution of pancuronium with mivacurium for abdominal wall closure at the end of prolonged surgery is inadvisable. It seems preferable to administer mivacurium by continuous infusion throughout the operation, thus providing a more easily controlled neuromuscular block with a predictable rate of recovery when the infusion is terminated.
References
Figure 1 Duration of action of mivacurium increments (M1–M8) after the second pancuronium dose (P). Vertical lines represents SD of the duration of action of the bolus dose of mivacurium. Horizontal lines represent the SD of the time to injection of the mivacurium dose. Number of patients are given in parentheses under the bolus number. *Duration of action significantly different from the previous injection (P:0.05).
1. Bevan DR, Smith CE, Donati F. Postoperative neuromuscular blockade: A comparison between atracurium, vecuronium, and pancuronium. Anesthesiology 1988; 69: 272–276. 2. Erkola O, Rautoma P, Meretoja OA. Mivacurium when preceded by pancuronium becomes a long-acting muscle relaxant. Anesthesiology 1996; 84: 562–565. 3. Kim KS, Shim JC, Kim DW. Interactions between mivacurium and pancuronium. British Journal of Anaesthesia 1997; 79: 19–23. 4. Hull CJ. Pharmacodynamics of non-depolarizing neuromuscular blocking agents. British Journal of Anaesthesia 1982; 54: 169–182. 5. Bowman WC, Gibb AJ, Harvey AL, Marshall IG. Prejunctional actions of cholinoceptors agonists and antagonists and of anticholinesterase drugs. In: Kharkevich DA, ed. New neuromuscular blocking agents. Handbook of experimental pharmacology. Vol 79. Berlin: Springer Verlag, 1986; 141–170. 6. Waud BE, Waud DR. The relation between tetanic fade and receptor occlusion in the presence of competitive neuromuscular blockade. Anesthesiology 1971; 35: 456–459. 7. Duvaldestin P, Saada J, Berger JL, D’Hollander A, Desmonts JM. Pharmacokinetics, pharmacodynamics, and doseresponse relationships of pancuronium in control and elderly subjects. Anesthesiology 1982; 56: 36–40.
Duration of the pharmacodynamic interaction between pancuronium and mivacurium M. BEAUSSIER, H. DERIAZ, A. DETRAVERSE, Z. ABDELHALIM AND A. LIENHART Summary The aim of this study was to determine for how long the duration of action of increments of mivacurium can be influenced by previous pancuronium administration. Fifteen patients, ASA I or II, undergoing general anaesthesia for major abdominal surgery were investigated. The post-tetanic count (PTC) was measured at the adductor pollicis muscle. Pancuronium 0.1 mg kg91 was injected first. At recovery of the 10th response of the PTC (PTC10), a second dose of pancuronium was injected (0.02 mg kg91). On recovery to PTC10, a bolus of mivacurium (0.04 mg kg91) was given and regularly repeated at recovery of PTC10 until the end of surgery. The mean duration of the second dose of pancuronium was 53 min (SD 13 min) and of the first dose of mivacurium, 66 min (SD 14 min) (P:0.01). The duration of action of further mivacurium boluses decreased significantly until the fifth dose. It took 222 minutes (95% confidence interval 190, 253 min) after the second pancuronium dose before the duration of action of mivacurium returned to normal values and became constant and predictable. (Br. J. Anaesth. 1998; 81: 251–252) Keywords: antagonists; neuromuscular block, pancuronium; neuromuscular block, mivacurium; recovery
Long-acting neuromuscular blocking drugs are often used during major abdominal surgery to provide adequate surgical conditions throughout the procedure. Such practice leads to a high incidence of residual neuromuscular block in the recovery room.1 To avoid this adverse effect, some anaesthetists use short-acting agents for closure of the abdominal wall after previous administration of long-acting neuromuscular blocking drugs, and expect a faster recovery from neuromuscular block at the end of surgery. However, when using more than one non-depolarizing neuromuscular blocking drug, unpredictable pharmacodynamic interactions may occur. Indeed, a significant prolongation of action of mivacurium has already been shown after previous administration of pancuronium.2 3 The purpose of the previous studies was to demonstrate supra-additive effects during concomitant administration of two neuromuscular blocking agents. A single dose of mivacurium and pancuronium was given. However, the duration of the interaction between the two neuromuscular blocking drugs remains unknown. Pharmacokinetic data and concentration-response relations suggests that such interaction could possibly last many hours: pancuronium remains in the biophase for a long time.4 The aim of the study was to determine for how long the duration of action of mivacurium can be influenced by previous pancuronium administration.
Methods and results Fifteen patients, ASA I or II, scheduled for prolonged major abdominal procedures were studied. This investigation was approved by the local ethics committee. Exclusion criteria were the presence of neuromuscular, hepatic or renal disease, and concurrent administration of any drugs known or suspected to interfere with neuromuscular transmission. Anaesthesia was induced with propofol (2–3 mg kg91) and fentanyl (2–3 g kg91). After induction, supramaximal transcutaneous train-of-four stimulation (TOF) at the ulnar nerve was applied. Responses were measured on the adductor of the thumb with an accelerometer (Tof-Guard, Organon, Teknika NV, Belgium). After calibration, pancuronium (0.1 mg kg91) was administered and tracheal intubation was performed. Anaesthesia was maintained with a continuous infusion of propofol and incremental bolus doses of fentanyl at the discretion of the anaesthetist. End-tidal concentrations of carbon dioxide were kept constant within 4–4.5% (Capnomac, Datex, Helsinski, Finland). Intraoperative hypothermia was prevented with forced air-warming blankets (Bair Hugger, Augustine Medicale, Minneapolis, USA) covering the upper part of the body and forearms of the patient, without interfering with thumb mobility. When the response to TOF stimulation disappeared after pancuronium administration, the post-tetanic count (PTC) was measured every 5 min (50 Hz tetanus for 5 s followed 3 s later by single twitch stimulation at 1 Hz). At the time of reappearance of the tenth response of the PTC (PTC10), a bolus of pancuronium 0.02 mg kg91 was given. Recovery of the PTC10 was again awaited before an approximately equipotent dose of mivacurium (0.04 mg kg91) was given. Further boluses of mivacurium (0.04 mg kg91) were again given at the same depth of neuromuscular block (PTC10) until the end of the procedure. The time to recovery of the PTC10 after each injection of neuromuscular blocking drug, and the interval between the second pancuronium dose and the time when the duration of action of two consecutive mivacurium doses did not differ significantly, were recorded for each patient. The Wilcoxon paired-sample test (StatView 4–5, Abacus Concepts Inc, Berkeley, USA) was used for statistical analysis. A P value of 0.05 or less was considered statistically significant. Results are expressed M. BEAUSSIER*, H. DERIAZ, A. De TRAVERSE, Z. ABDELHALIM, A. LIENHART, Department of Anaesthesiology and Intensive Care, St Antoine Hospital, Paris, France. Accepted for publication: March 19, 1998. *Address for correspondence: Département d’AnesthésieRéanimation, Hôpital St-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cédex 12, France.
252 as mean (SD) unless otherwise stated. The physical characteristics of the population (9 females and 6 males) were 55 years (range 40–63) and 63 (14) kg. The mean duration of anaesthesia was 323 min (range : 160 to 494 min). Every injection of pancuronium and mivacurium abolished the PTC response. The mean time from first injection of pancuronium until reappearance of the PTC10 was 55 (15) min. The duration of action of the first injection of mivacurium was 66 (14) min, exceeding significantly the duration of action of the second dose of pancuronium (53 (13) min, P:0.01). The duration of action of the incremental doses of mivacurium decreased progressively with time (fig. 1). The time between two consecutive mivacurium doses did not differ significantly after the fifth increment, corresponding to a mean of 222 minutes after the last pancuronium injection (95% confidence interval 190, 253 min). Core intraoperative hypothermia did not occur in any patient.
Comment The duration of the pharmacodynamic interaction between pancuronium and mivacurium has never been investigated. We found that the duration of action of repeated mivacurium bolus doses returned to a constant and predictable level approximately 4 h after the last pancuronium administration. The first part of our findings corroborates previous studies showing prolongation of the duration of action of mivacurium when administrated after pancuronium.2 3 We found that after pancuronium administration, the duration of action of mivacurium was significantly longer than the duration of action of approximately equipotent doses of pancuronium. The ED95 for pancuronium is wide ranging (0.05–0.07 mg kg91) and we probably used a slightly underestimated value. However, Erkola and colleagues showed that large differences in the size of the administrated doses of mivacurium after pancuronium administration did not have a great effect on the magnitude of the pharmacodynamic interaction between the two drugs.2 Moreover, the ED95 refers especially to the post-synaptic activity of non-depolarizing neuromus-
British Journal of Anaesthesia cular blocking drugs but the potentiating effect of different agents may be related at least in part to differences in presynaptic activity.5 Furthermore, presynaptic mechanisms are also involved in the response to tetanic stimulation. The longer depression of the PTC stimulation we observed after mivacurium could reflect a greater degree of presynaptic inhibition than with pancuronium alone. It took nearly 4 h for the duration of action of mivacurium to become stable. It is a minimum value, as the probability of failing to find a difference in duration between two consecutive mivacurium boluses when there really is one (type II error) is high because of the small sample size. Pancuronium is a long-acting neuromuscular blocking drug which remains at the neuromuscular junction for an extended period. The clinical effect of pancuronium in healthy subjects is known to last over 90–120 min.4 When recovery from neuromuscular block occurs, pancuronium is still present in the synaptic cleft.6 The rate of elimination of residual pancuronium from the biophase is affected by the plasma concentration of pancuronium. In healthy subjects, the elimination half-life of pancuronium have been found to be around 110 min.7 Thus it can be expected that the post-synaptic receptors remain occupied by pancuronium for many hours after a bolus of the drug. In the circumstances of this study, the prolongation of action of repeated doses of mivacurium suggests residual occupation of acetylcholine receptors by pancuronium. The magnitude of the prolongation of the duration of action of mivacurium decreases concomitantly with time from the last pancuronium injection, probably in a similar manner to the fall in the residual concentration of pancuronium in the biophase. In conclusion, clinicians must be aware that the duration of action of mivacurium is altered for a mean of approximately 4 h after a dose of pancuronium. Thus, substitution of pancuronium with mivacurium for abdominal wall closure at the end of prolonged surgery is inadvisable. It seems preferable to administer mivacurium by continuous infusion throughout the operation, thus providing a more easily controlled neuromuscular block with a predictable rate of recovery when the infusion is terminated.
References
Figure 1 Duration of action of mivacurium increments (M1–M8) after the second pancuronium dose (P). Vertical lines represents SD of the duration of action of the bolus dose of mivacurium. Horizontal lines represent the SD of the time to injection of the mivacurium dose. Number of patients are given in parentheses under the bolus number. *Duration of action significantly different from the previous injection (P:0.05).
1. Bevan DR, Smith CE, Donati F. Postoperative neuromuscular blockade: A comparison between atracurium, vecuronium, and pancuronium. Anesthesiology 1988; 69: 272–276. 2. Erkola O, Rautoma P, Meretoja OA. Mivacurium when preceded by pancuronium becomes a long-acting muscle relaxant. Anesthesiology 1996; 84: 562–565. 3. Kim KS, Shim JC, Kim DW. Interactions between mivacurium and pancuronium. British Journal of Anaesthesia 1997; 79: 19–23. 4. Hull CJ. Pharmacodynamics of non-depolarizing neuromuscular blocking agents. British Journal of Anaesthesia 1982; 54: 169–182. 5. Bowman WC, Gibb AJ, Harvey AL, Marshall IG. Prejunctional actions of cholinoceptors agonists and antagonists and of anticholinesterase drugs. In: Kharkevich DA, ed. New neuromuscular blocking agents. Handbook of experimental pharmacology. Vol 79. Berlin: Springer Verlag, 1986; 141–170. 6. Waud BE, Waud DR. The relation between tetanic fade and receptor occlusion in the presence of competitive neuromuscular blockade. Anesthesiology 1971; 35: 456–459. 7. Duvaldestin P, Saada J, Berger JL, D’Hollander A, Desmonts JM. Pharmacokinetics, pharmacodynamics, and doseresponse relationships of pancuronium in control and elderly subjects. Anesthesiology 1982; 56: 36–40.