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BACKGROUND: Pipecuronium is a steroidal neuromuscular blocking agent. Sugammadex, a relaxant binding [gamma]-cyclodextrin derivative, reverses the effect of rocuronium, vecuronium, and pancuronium. We investigated whether sugammadex reverses moderate pipecuronium-induced neuromuscular blockade (NMB) and the doses required to achieve reversal. METHODS: This single-center, randomized, double-blind, 5-group parallel-arm study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX(R)) according to international standards. When the NMB recovered spontaneously to train-of-four count 2, patients randomly received 1.0, 2.0, 3.0, or 4.0 mg/kg of sugammadex or placebo. Recovery time from sugammadex injection to normalized train-of-four (TOF) ratio 0.9 was the primary outcome variable. The recovery time from the sugammadex injection to final T1 was the secondary end point. Postoperative neuromuscular functions were also assessed. RESULTS: Each patient who received sugammadex recovered to a normalized TOF ratio of 0.9 within 5.0 minutes (95% lower confidence interval for the lowest dose 70.1%; for all doses 90.8%) and 79% of these patients reached a normalized TOF ratio 0.9 within 2.0 minutes (95% lower confidence interval for the lowest dose 26.7%; for all doses 63.7%). T1 recovered several minutes after the TOF ratio. No residual postoperative NMB was observed. CONCLUSIONS: Sugammadex adequately and rapidly reverses pipecuronium-induced moderate NMB during sevoflurane anesthesia. Once the train-of-four count has spontaneously returned to 2 responses following pipecuronium administration, a dose of 2.0 mg/kg of sugammadex is sufficient to reverse the NMB.

Neuromuscular blocking drugs can induce intraoperative bronchospasm. We characterized the magnitude and the temporal profile of the constriction in normal or in hyperresponsive airways after injections of neuromuscular blocking drugs. Respiratory system impedance (Zrs) was measured continuously over a 90-s apneic period in naïve and rabbits sensitized to allergens by ovalbumin. Fifteen s after the start of Zrs recordings, succinylcholine, mivacurium, or pipecuronium was administered in random order. Zrs was then also recorded during the administration of increasing doses of exogenous histamine. To monitor the changes in the airway mechanics during these maneuvers, Zrs was averaged for 2-s time windows, and the airway resistance (Raw) was determined by model fitting. The increases in Raw were significantly larger in the sensitized rabbits than in the naïve animals. The largest increases in Raw and the maximum rate of change in Raw were obtained for succinylcholine (146% +/- 29% and 0.80 +/- 0.12 cm H2O/L, respectively) and mivacurium (80% +/- 25% and 0.71 +/- 0.13 cm H2O/L) and the smallest were obtained for pipecuronium (40% +/- 12% and 0.41 +/- 0.04 cm H2O/L). Allergic sensitization leads to severe and rapidly developing bronchospasm after administrations of mivacurium or succinylcholine. These deleterious side effects should be considered when succinylcholine or mivacurium is administered in the presence of bronchial hyperreactivity.

We have studied the dose-response relationships for neostigmine and edrophonium during antagonism of neuromuscular block induced by pipecuronium bromide. Fifty-six ASA physical status I or II adults were given pipecuronium 70 micrograms/kg during fentanylthiopental-nitrous oxide-halothane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 20% of its initial control value, edrophonium (0.125, 0.25, 0.75, or 1 mg/kg) or neostigmine (0.015, 0.03, 0.045, or 0.06 mg/kg) was administered by random allocation. Neuromuscular function in another seven subjects was allowed to recover spontaneously. This study demonstrated that the dose-response curves for these two drugs for reversal of first twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% (ED50) and 80% (ED80) recovery of the first twitch after 10 min were 8.5 (7.3-9.7) and 17.4 (16.2-18.7) microgram/kg [mean (95% confidence intervals)], respectively. Corresponding ED50 and ED80 values for endrophonium were 84.1 (72.9-96.9) and 233 (215.7-253.3) microgram/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.89 (7.4-12.3) and 13.4 (11.8-14.9) for first twitch ED50 and ED80 height, respectively. The calculated doses producing 50% (ED50) recovery of the TOF ratio at 10 min were 18.8 (17.5-20.2) and 271.3 (246.5-298.6) microgram/kg for neostigmine and edrophonium, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the influence of CO2-induced acid-base changes on the potencies of the monoquaternary relaxants (rocuronium, vecuronium, and d-tubocurarine) and bisquaternary relaxants (pancuronium, pipecuronium, and metocurine), and on the antagonism of their neuromuscular block by neostigmine. Phrenic nerve-hemidiaphragm preparations of rats were used. The pH changes were induced by changing the CO2 concentration aerating the modified Krebs solution. The potencies of the monoquaternary relaxants increased at 9% CO2 (pH 7.2) and decreased at 2.5% CO2 (pH 7.6) from those of 5% CO2 (pH 7.4) both with and without neostigmine (P < 0.05), whereas the potencies of the bisquaternary drugs did not change significantly at different pH levels from control (pH 7.4) both with and without neostigmine. The slopes of the log concentration-percent response curves of each drug were not significantly different at each pH level. The ratios of inhibitory concentrations, 50% (IC50) values with and without neostigmine at each pH value for each drug were not significantly different indicating that the neostigmine-induced antagonism for each drug was not affected by the CO2-induced acid-base changes. But the ratios of the IC50 values of the steroidal relaxants (rocuronium, vecuronium, pancuronium, and pipecuronium) were significantly lower (P < 0.05) than those of the isoquinolinium drugs (d-tubocurarine and metocurine) at each pH level, suggesting that the antagonism is enhanced at each pH level for the isoquinolinium relaxants. The difference was independent of their monoquaternary or bisquaternary nature. These results suggest that CO2 increases the potency of the monoquaternary relaxants but does not affect the bisquaternary relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the effect of liver cirrhosis on the pharmacokinetics and pharmacodynamics of pipecuronium, the authors administered 100 micrograms/kg of pipecuronium intravenously to eight patients with liver cirrhosis and eight patients with normal liver and renal function undergoing elective abdominal surgery. All patients were anesthetized with thiopental (5-7 mg/kg), nitrous oxide (50-70% in oxygen), and fentanyl in repeated doses (2 micrograms/kg). Plasma concentrations of pipecuronium were determined by high-pressure liquid chromatography. A two-compartment open model was used for pharmacokinetic analysis. Thumb-elicited mechanical response to single-twitch ulnar nerve stimulation was also measured. Total plasma clearance did not differ between controls (2.96 +/- 1.05 mL.min-1.kg-1, mean +/- SD) and cirrhotics (2.61 +/- 1.16 mL.min-1.kg-1). Terminal elimination half-life was 111 +/- 46 min in controls and 143 +/- 25 min in cirrhotics. The total apparent volume of distribution at steady state did not differ between controls (350 +/- 81 mL/kg) and cirrhotics (452 +/- 222 mL/kg). The volume of the central compartment was not different between the two groups. The onset of neuromuscular blocking effect was longer in cirrhotics (233 +/- 112 s) (P0.05) than in controls (170 +/- 33 s). The clinical duration (injection until single twitch returned to 25%) was similar between the two groups: 167 +/- 41 min in controls and 165 +/- 48 min in cirrhotics. The authors conclude that hepatic insufficiency due to cirrhosis does not alter the pharmacokinetics and pharmacodynamics of pipecuronium (100 micrograms/kg).

We compared the pharmacodynamic effects and hospital costs of three long-acting neuromuscular blocking drugs in a prospective, randomized, double-blind manner. Each neuromuscular blocking drug was administered with fentanyl (50 μg/kg) for intravenous induction of anesthesia for coronary artery bypass surgery. Each patient received twice the 95% effective dose (ED95) of either pancuronium (0.14 mg/kg, n = 10), pipecuronium (0.10 mg/kg, n = 10), or doxacurium (0.05 mg/kg, n = 10). Hemodynamic measurements were recorded at baseline, 5 min after completion of anesthetic induction, immediately after endotracheal intubation, and 5 min after intubation. Only small hemodynamic differences between neuromuscular blocking drugs were observed. Doxacurium (but not pancuronium or pipecuronium) significantly decreased mean arterial blood pressure (from 94 ± 4 mm Hg before induction to 83 ± 3 mm Hg 5 min after intubation); nevertheless, there were no significant between-group differences at any time. Pancuronium increased heart rate (from 68 ± 4 beats/min before induction to 76 ± 5 beats/min 5 min after intubation); however, pancuronium differed significantly from doxacurium and pipecuronium only 5 min after induction and 5 min after intubation. Central venous pressure, pulmonary artery occlusion pressure, cardiac index, and systemic and pulmonary vascular resistance indices did not change. Electrocardiographic abnormalities were observed in two pipecuronium patients: ST segment depression in one and premature ventricular contractions in another. No other electrocardiographic changes were observed. There were no significant between-group differences in the need for hemodynamic interventions. The time from muscle relaxant administration to 95% twitch depression was significantly longer for doxacurium (530 ± 49 s) than for either pancuronium (264 ± 31 s) or pipecuronium (234 ± 23 s). The cost to a 70-kg patient of twice the ED95 dose was: pancuronium, $1.69; pipecuronium, $22.88; and doxacurium, $19.60. We conclude that whereas doxacurium and pipecuronium may be less likely than pancuronium to increase heart rate during induction of anesthesia, these two neuromuscular blocking drugs are no less likely to produce hemodynamic aberrations requiring drug interventions and are considerably more expensive.

This study was designed to determine the capacity of several anesthetics to augment pipecuronium neuromuscular blockade. The potency of pipecuronium was determined with single-bolus administration of 20-50 micrograms/kg in 160 patients. Patients were anesthetized with N2O/O2 (60:40) supplemented with fentanyl (4-5 micrograms/kg), halothane (0.8%), isoflurane (1.2%), or enflurane (1.7%). Neuromuscular blockade was measured by an acceleration-responsive transducer (the Accelograph, Biometer International, Odense, Denmark). Responses were defined in terms of percent depression in first-twitch height and train-of-four response, and the dose-response curves were constructed after probit transformation of the responses. The dose-response curves were found to be parallel for both first twitch height and train-of-four responses. The dose-response lines for the enflurane and isoflurane groups were displaced significantly (P less than 0.01) to the left of the line for the fentanyl-N2O group. The calculated doses producing 50% depression of first twitch height were 21.9, 21.2, 18.9, and 17.8 micrograms/kg for the N2O-fentanyl, halothane, isoflurane, and enflurane groups, respectively. Corresponding calculated doses for 50% depression of train-of-four response were significantly smaller (15.5, 14.4, 13.7, 11.9 micrograms/kg, respectively). The enhancing effects of the volatile anesthetics were reflected by significant prolongation of the clinical duration of neuromuscular blockade by pipecuronium. It is concluded that the potency of pipecuronium is enhanced more by enflurane and isoflurane than halothane or fentanyl-N2O anesthesia.

The dose-response of pipecuronium bromide, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine and edrophonium have been investigated in patients undergoing various types of anesthesia. The estimated doses of pipecuronium required for 95% depression of the twitch height were 44.6, 46.9, and 48.7 micrograms.kg-1 during anesthesia with nitrous oxide (65%) and isoflurane (group 1), halothane (group 2), or droperidol/fentanyl (group 3), respectively. The potentiating effects of the volatile anesthetics were reflected by the significant prolongation of the duration of both initial (50.0 +/- 4.3, 36.0 +/- 3.3, and 29.0 +/- 2.0 minutes) and maintenance doses (56.0 +/- 2.5, 49.5 +/- 3.3, and 41.2 +/- 1.6 minutes) of pipecuronium during anesthesia with nitrous oxide and isoflurane, halothane, or droperidol/fentanyl, respectively. Both edrophonium chloride (0.5 mg.kg-1) and neostigmine methylsulphate (40 micrograms.kg-1) promptly reversed the residual block induced by pipecuronium. No side effects attributable to pipecuronium were seen in this study.

Although many studies have presented data based on administration of nondepolarizing neuromuscular blocking agents to patients given inhalation anesthesia for 30-45 min, no data exist on the interaction in a clinical situation where the relaxant is administered immediately after the start of anesthesia. We therefore studied the effect of the commonly used inhalation anesthetics, halothane and enflurane, on the clinical pharmacology of atracurium, vecuronium, pipecuronium, and pancuronium. No significant influence of the anesthetic technique on the onset time of the various neuromuscular blocking agents was observed. The duration of action of atracurium, pipecuronium, and pancuronium was significantly prolonged during enflurane anesthesia as compared with the other two anesthetic techniques. The duration of vecuronium blockade was not significantly influenced by enflurane. Halothane, in contrast to enflurane, did not significantly prolong the blockade induced by these agents. The prolongation of atracurium blockade was clinically irrelevant. A fact that is statistically significant but clinically irrelevant is that a cumulative effect with atracurium and vecuronium was only seen during enflurane anesthesia and after the fourth maintenance dose. We conclude that there is no clinical indication that the dosage of atracurium and vecuronium during inhalation anesthesia should be reduced, but the doses of pipecuronium and pancuronium should be reduced when prolonged paralysis is not desired.