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Background Perioperative medicines can affect the body's immune response, according to data reported a variety of anesthetic drugs can directly or indirectly affect the immune response, this study aims to preliminarily common muscle relaxant presence of anti-inflammatory effects. Methods To collect peripheral blood of healthy adults, and designed the following treatment groups: [A] blank group; [B] static and unstimulated drug groups: the group contained two concentrations of both pipecuronium and vecuronium respectively (0.5/0.1g•ml-1); [L] simple lipopolysaccharide (LPS) group; [C] under stimulated drug groups: two concentrations (0.5/0.1g•ml-1) muscle relaxants were added with lipopolysaccharide in each group. Detection of average fluorescence emphasized expression of CD11b on neutrophils by flow cytometry. Results Compared with the blank control group [A], the expression of CD11b in each group was significantly increased in the LPS group [L] and the stimulus drug groups [C](p 0.05). Conclusions The concentration of vecuronium and pipecuronium that approximates clinical maintenance dose has effect of inhibiting the CD11b expression of human neutrophil in venous blood in vitro. The results of this study can provide the reference for muscle relaxant immunological research and clinical rational use .

Background Certain surgical interventions may require a deep neuromuscular block (NMB). Reversal of such a block before tracheal extubation is challenging. Because anticholinesterases are ineffective in deep block, sugammadex 4 mg/kg has been recommended for the reversal of rocuronium- or vecuronium-induced deep NMB. However, this recommendation requires opening 2 vials of 200 mg sugammadex, which results in an increase in drug costs. Therefore, we sought a less expensive solution for the induction and reversal of deep NMB. Although the optimal dose of sugammadex for antagonism of deep block from pipecuronium has not been established, data pertaining to moderate block are available. Accordingly, we hypothesized that sugammadex 2 mg/kg would be a proper dose to reverse deep pipecuronium block, enabling us to avoid cost increases. In the present study, we compared sugammadex 2 mg/kg with the standard dose of 4 mg/kg for reversal of deep block from pipecuronium. Methods This single-center, randomized, double-blind, 2 parallel-arms, noninferiority study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX). Noninferiority margin was specified beforehand as an increase in reversal time of no >10% (corresponding to 1 minute for the primary outcome). When the block spontaneously recovered to posttetanic count 1, the patients randomly received sugammadex 2 or 4 mg/kg, and the time from the injection to the train-of-four (TOF) ratio of 1.0 was measured. Primary outcome was the time to achieve the normalized TOF ratio of 0.9 in a particular patient. Residual or recurrent postoperative NMB was additional end point. Results Each patient recovered to the normalized TOF ratio of 0.9. In the 2 mg/kg group, reversal time was 1.73 ± 1.03 minutes (95% confidence interval [CI], 1.33-2.13; n = 25), and in the 4 mg/kg group, reversal time was 1.42 ± 0.63 minutes (mean ± standard deviation) (95% CI, 1.17-1.67; n = 25). The mean difference in reversal times between the 2 groups was 0.31 minutes (95% CI, -0.18 to 0.8), and the upper limit of CI was below the noninferiority margin of 1 minute. Postoperative block did not occur. Conclusions The effect of sugammadex 2 mg/kg was noninferior to that of 4 mg/kg in reversing posttetanic count-1 degree pipecuronium block. Sugammadex reversal of deep pipecuronium block appears to be effective.

Background and objectives For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic–pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect. Methods Pigs (20–28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED 90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response. Results For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account. Conclusions The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.

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.

Conventional risk assessment process utilizes a 10-fold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and elderly. The purpose of this investigation was to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharmacody-namic data are incorporated to characterize human sensitivity. An extensive literature search was conducted on seven neuromuscular blocking agents (mivacurium, atracurium, rocuronium, vecuronium, doxacurium, pancuronium, pipecuronium). Composite factors (kinetics × dynamics) were calculated using the highest data-derived kinetic and dynamic values. For the drugs examined, all of the composite factors for the sensitivity of children were lower than 5. In the elderly, all of the composite factors were lower than 10, and five of seven composite factors were less than 5. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce the uncertainties associ...

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.

Purpose. The kinetics of the inhibition of human plasma cholinesterase (ChE) and erythrocyte acetylcholinesterase (AChE) by alcuronium, atracurium, d-tubocurarine, pancuronium, pipecuronium, and vecuronium were studied in blood drawn from 35 surgical patients. Methods. The activities of plasma ChE and erythrocyte AChE were determined by the calorimetric method of Ellman et al., using acetylthiocholine as the substrate. Lineweaver-Burk plots and Dixon plots were used for the analysis of the kinetics of both enzymes. Results. The dissociation constants (K m) of plasma ChE and erythrocyte AChE were 5.00 × 10−5 M and 5.28 × 10−5 M, respectively, indicating that both enzymes have similar affinity to acetylthiocholine. Both Lineweaver-Burk plots and Dixon plots indicated that the six nondepolarizing neuromuscular blocking agents (NMBAs) at different concentrations induce linear mixed-type inhibition. The apparent inhibition constants (K i) of pancuronium (8.72 × 10−8 M) and vecuronium (3.53 × 10−7 M) for plasma ChE inhibition were lower than that of neostigmine (7.36 × 10−7 M), whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly higher than that of neostigmine. Conclusions. Both plasma ChE and erythrocyte AChE were inhibited by six nondepolarizing NMBAs, and the pattern of inhibition of both enzymes was of mixed type. The inhibitory potencies of pancuronium and vecuronium for plasma ChE were larger than that of neostigmine, whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly lower than that of neostigmine. The rank order of relative potency for plasma ChE was pancuronium > vecuronium > pipecuronium > alcuronium > d-tubocurarine > atracurium.

We have studied the effect of non-depolarizing neuromuscular blocking agents, at concentrations present in serum during anaesthesia, on release of [3H]-norepinephrine ([3H]NE) from superfused atrial appendage obtained during cardiac surgery from 48 patients. Three of the neuromuscular blocking agents (pancuronium, gallamine and rocuronium), which are known to cause an increase in heart rate during anaesthesia, increased stimulation-evoked release of [3H]NE. In contrast, (+)tubocurarine and pipecuronium, neuromuscular blocking agents that do not cause tachycardia, did not affect release of NE. Org 9487 significantly enhanced release while SZ1677 was ineffective, even at concentrations higher than those expected after administration of a 2 x ED95 dose. Atropine enhanced release. These data suggest that the axon terminals of sympathetic nerves in human heart have muscarinic heteroreceptors whose activation by acetylcholine (ACh) released from the vagal nerve reduces release of NE. This action contributes to lowering of heart rate. Therefore, any neuromuscular blocking agent with antimuscarinic actions and capable of increasing the release of NE may produce tachycardia.

There is a large difference in sensitivity between respiratory muscles and other limb muscles. This phenomenon, known as the respiratory sparing effect (RSE), is well established withd-tubocurarine, pancuronium, and succinylcholine. The purpose of this study is to evaluate the RSE of these new relaxants, vecuronium, pipecuronium, and ORG9426. The study was done in vivo using rats. Mechanical twitch responses of tibialis anterior muscle and diaphragm stimulated with the sciatic nerve and phrenic nerve, respectively, were recorded simultaneously to monitor neuromuscular transmission. Changes of mechanical twitch responses from both muscles were compared following the injection of four kinds of muscle relaxants (pancuronium, picuronium, recuronium, and ORG9426). T, D (%) represents the maximum depression in tibialis anterior and diaphragm, respectively. T−D (%), which means the sensitivity difference between the two kinds of muscle, was calculated by subtracting D from T. The T−Ds of pancuronium, pipecuronium, vecuronium, and ORG9426 were 86.0±2.6%, 81.4±1.9%, 77.7±2.1%, and 74.6±2.7%, respectively. The results indicated that the blockade produced by each muscle relaxant was lower in the diaphragm than in the anterior tibialis muscle. T−D was significantly smaller with vecuronium or ORG9426 than with pancuronium.

OBJECTIVE Cardiovascular effects of four commonly used non-depolarising muscle relaxants and their ability to increase histamine plasma concentrations were studied in patients scheduled for coronary artery bypass grafting. METHODS 40 patients were included in the study after informed consent. After premedication with Flunitrazepam (2 mg p.o.) on the evening before and 1 hour prior to surgery anaesthesia was induced with Flunitrazepam (4-6 micrograms kg-1). Fentanyl (3 micrograms kg-1) und Etomidate (150 micrograms kg-1) and the patients were ventilated via face mask with 50% N2O in oxygen. Patients were randomly allocated to one of four groups, and, 15 min after induction of anaesthesia, received equipotent doses of either Pancuronium (0.09 mg kg-1, n = 10). Pipecuronium (0.08 mg kg-1, n = 10), Atracurium (0.6 mg kg-1, n = 10), or Vecuronium (0.1 mg kg-1, n = 10) injected over 20 seconds via a central venous catheter. Cardiovascular variables were determined in the awake patient, 15 min after induction of anaesthesia and following administration of the respective muscle relaxant. In addition, plasma histamine concentrations were assessed before and after relaxation. Evoked muscular response to TOF simulation of the ulnar nerve (plethysmo-mechanogram) was continuously recorded to determine the onset of neuromuscular blockade. RESULTS Heart rate, mean arterial pressure and cardiac index significantly decreased in all patients following induction of anaesthesia while systemic vascular resistance remained unchanged. Only Pancuronium caused a significant increase in heart rate (53 +/- 11 to 61 +/- 15 min-1) whereas cardiac index and mean arterial pressure did not change significantly. No other neuromuscular blocking agent caused any changes in the cardiovascular variables measured and histamine plasma concentrations remained within the reference range in all of the four groups with no differences detectable between groups. CONCLUSIONS All investigated neuromuscular blocking agents exhibited marked cardiovascular stability which permits their use, being based exclusively on pharmacodynamic and pharmakokinetic considerations even in patients with coronary heart disease. If an increase in heart rate appears beneficial Pancuronium may be advantageous.

Background Neuromuscular relaxants such as pancuronium bind to M2 and M3 muscarinic receptors as antagonists. Blockade of muscarinic receptors in atria of the M2 subtype mediates tachycardia. In the lung, blockade of M2 receptors on parasympathetic nerves potentiates vagally induced bronchospasm, whereas blockade of M3 receptors on bronchial smooth muscle inhibits bronchospasm. The current study was designed to quantify the affinity of a series of neuromuscular relaxants for the M2 and M3 muscarinic receptors, which were individually stably transfected in Chinese hamster ovary cell lines. Methods Competitive radioligand binding assays determined the relative binding affinities of the neuromuscular relaxants pancuronium, succinylcholine, mivacurium, doxacurium, atracurium, rocuronium, gallamine, and pipecuronium for the muscarinic receptor in the presence of a muscarinic receptor antagonist (3H-QNB) in membranes prepared from cells individually expressing either the M2 or M3 muscarinic receptor. Results All muscle relaxants evaluated displaced 3H-QNB from muscarinic receptors. The relative order of potency for the M2 muscarinic receptor (highest to lowest) was pancuronium, gallamine, rocuronium, atracurium, pipecuronium, doxacurium, mivacurium, and succinylcholine. The relative order of potency for the M3 muscarinic receptor (highest to lowest) was pancuronium, atracurium, pipecuronium, rocuronium, mivacurium, gallamine, succinylcholine, and doxacurium. Conclusions All neuromuscular relaxants studied had affinities for the M2 and M3 muscarinic receptor, but only pancuronium and gallamine had affinities within the range of concentrations achieved with clinical use. The high affinities of gallamine and pancuronium for the M2 muscarinic receptor are consistent with a mechanism of M2 receptor blockade in relaxant-induced tachycardia.

Dyke, Christopher K., Niki M. Dietz, Robert L. Lennon, David O. Warner, and Michael J. Joyner. Forearm blood flow responses to handgripping after local neuromuscular blockade. J. Appl. Physiol. 84(2): 754–758, 1998.—To test the hypothesis that acetylcholine “spillover” from motor nerves contributes significantly to skeletal muscle vasodilation during exercise, we measured the forearm blood flow responses during attempted handgripping after local paralysis of the forearm with the neuromuscular-blocking drug pipecuronium. This compound blocks postsynaptic nicotinic receptors but has no impact on acetylcholine release from motor nerves. The drug was administered selectively to one forearm by using regional intravenous drug administration techniques in five subjects. Pipecuronium reduced maximum forearm grip strength from 40.0 ± 3.2 kg before treatment to 0.0 kg after treatment. By contrast, drug administration had no effect on maximum voluntary contraction in the untreated forearm (41.3 ± 3.3 vs. 41.4 ± 2.7 kg). During 2 min of attempted maximal contraction of the paralyzed forearm, the forearm blood flow increased from only 3.4 ± 0.8 to 4.8 ± 1.2 ml ⋅ 100 ml−1 ⋅ min−1( P < 0.05). Heart rate increased from 63 ± 3 to 73 ± 8 beats/min ( P > 0.05) during attempted contraction, and only three of five subjects showed obvious increases in heart rate. Mean arterial pressure increased significantly ( P < 0.05) from 102 ± 6 to 109 ± 9 mmHg during attempted contractions. When these increases in flow are considered in the context of the marked (10-fold or greater) increases in flow seen in contracting forearm skeletal muscle, it appears that acetylcholine spillover from motor nerves has, at most, a minimal impact on the hyperemic responses to contraction in humans.

Grundlagen: Vecuronium und Atracurium als nicht depolarisierende Muskelrelaxantien mit mittellanger Wirkdauer und Erholungszeit haben seit nunmehr uber 10 Jahren wesentlich zur optimalen Steuerung der bedarfsgerechten neuromuskularen Blockade in Anasthesie und Intensivmedizin beigetragen. Neue Substanzen sollen nun entweder durch kurzere Anschlagzeit und Wirkdauer oder durch hamodynamische Stabilitat Eingang in die klinische Praxis finden.

Study Objective To compare dose-response relationship and maintenance requirement of pipecuronium in anesthetized infants, children, and adults. Design Prospective, consecutive sample trial. Setting Operating room at a university hospital. Patients: 15 infants (1–11 months), 15 children (3–10 years), and 15 adults (35–50 years) of ASA physical status I and II. Interventions Anesthesia was induced and maintained with N 2 O:O 2 2:1 and 1 minimum alveolar concentration end-tidal halothane. The neuromuscular function was recorded by adductor pollicis electromyogram evoked by a train-of-four ulnar nerve stimulation at 20 second intervals. An individual cumulative log-probit dose-response curve was established and maintenance requirement of pipecuronium determined. Between-group comparisons were made by analysis of variance and Scheffe F-test. Measurements and Main Results Dose-response curves were parallel with a doserequirement of pipecuronium similar in infants and adults (ED 95 of 40–42 μg/kg) and greater in children (ED 95 of 52 μg/kg). After 30 minutes of surgical neuromuscular block, pipecuronium was required in each age group at a rate oj 0.6 to 0. 7 individual ED 95 doses per hour to maintain an 85 % to 95% neuromuscular block. Conclusions Bolus dose requirement of pipecuronium is greatest in children. Maintenance requirement is related to potency in each age group studied.

Pipecuronium bromide, a long acting non-depolarizing neuromuscular blocking agent was administered to four groups of 10 patients using the priming technique. The effects of the combination of two different priming doses (0.01 or 0.015 mg kg-1) given at two different time intervals (3 or 4 min) before the 'main' intubating dose (0.07 or 0.065 mg kg-1) were investigated. Onset times were recorded and the intubation conditions were scored and compared with a group of patients receiving the same total amount of pipecuronium (0.08 mg kg-1) in a single bolus injection. Intubating conditions at 90 s after administration of the intubating dose were found to be significantly improved in all primed groups but the onset times, evaluated using the response of the adductor pollicis muscle to a single twitch stimulation, were similar to that observed after the single bolus injection. The optimal priming combination is considered to be 0.01 mg kg-1 of pipecuronium followed 3 to 4 min later by 0.07 mg kg-1.

Large-dose opioid induction of anesthesia can lead to difficult ventilation via a mask. Poor ventilatory compliance (VC) may be secondary to "rigid" chest and abdominal wall musculature, glottic closure, or upper airway obstruction. This double-blind study assessed the contribution of the upper airway to poor VC by inducing sufentanil anesthesia in patients undergoing cardiac surgery who are ventilated via a mask (Group M) or endotracheal tube fiberoptically inserted (Group E). After induction of anesthesia with sufentanil 3 microgram/kg from time (T) = 0 min to T = 2 in Group M (n = 17) or Group E(n = 23), VC and adductor pollicis (AP) twitch tension was measured continuously. Immediately prior to muscle relaxant (pipecuronium or doxacurium) administration at T = 3, Group E demonstrated significantly better VC (46 mL/cm H2O [39-55 interquartile range (IQR)]) than Group M (19 mL/cm H2O [7-24 IQR]). The effect of muscle relaxant administration on VC preceded its effect at the AP. After complete relaxation of the AP at T = 9, both groups had similar VC. Difficult ventilation during sufentanil induction of anesthesia lies at the level of the glottis or above. Bypassing these structures with an endotracheal tube overcomes the usual decreased VC.

Muscle relaxants are used to support mechanical ventilation in the ICU. Large doses of muscle relaxant are given to ICU patients in particular who are sometimes much sicker than general surgical patients.Many problems are related to use muscle relaxants in the ICU. We presented and discussed problems which occured in our ICU patients who received large doses of two different kinds of muscle relaxants-vecuronium and pipecuronium for more than 24 hours. We found that it took much longer to recover from the blockade with vecuronium than pipecuronium.Based on these clinical experience, we would like to suggest that data obtained from surgical anesthesia may not apply to ICU patients with many pathophysiological risks. We do not recommend to use muscle relaxants more than 24 hour sand recommend to give sedatives instead of muscle relaxants for supporting mechanical ventilation. We also recommend to monitor neuromuscular function to prevent profound block.

Patients receiving anticonvulsants are resistant to nondepolarizing muscle relaxants (NDMR). This study examines the effect of plasma anticonvulsant levels on pipecuronium-induced neuromuscular blockade. Twenty adult patients scheduled for neurosurgery were assigned to one of two groups. Group 0 (G0) consisted of 10 patients not on anticonvulsant therapy; group 1 (G1) included 10 patients treated either with phenytoin or carbamazepine. G1 patients were further divided into G1u (n = 4) and G1w (n = 6) subgroups, according to the plasma anticonvulsant level measured the day before surgery--under (G1u) or within (G1w) the therapeutic range. Neuromuscular transmission was monitored with a Biometer International A/S Accelograph. Anesthesia was induced and maintained using propofol and sufentanil. After calibration of the accelograph, a bolus of pipecuronium 0.08 mg/kg was given IV. The time from pipecuronium injection to the peak reduction of T1 was taken as the onset time. The time in min from pipecuronium injection to recovery of T1% (first accelograph response/baseline response) x 100 and TR% (fourth accelograph response/first accelograph response) x 100 were recorded at 25, 50, and 75% of baseline. The recovery index (RI) was taken as the time from 25 to 75% of baseline. The recovery index (RI) was taken as the time from 25 to 75% recovery of the baseline response. The onset time was not different in G0 (203 +/- 60.4 s), G1 (230.5 +/- 79.3 s), and G1u (181.8 +/- 60.4 s) but prolonged in G1w (279.2 +/- 67.7 s).(ABSTRACT TRUNCATED AT 250 WORDS)

The objective of this study was to compare the haemodynamic and myocardial effects of pipecuronium and pancuronium in patients undergoing coronary artery bypass grafting (CABG) during benzodiazepine/sufentanil anaesthesia. Twenty-seven ASA III-IV patients received lorazepam (1-3 mg) po and midazolam ( < 0.1 mg.kg-1) i.v. before induction of anaesthesia with sufentanil (3-8 micrograms.kg-1) was administered to facilitate tracheal intubation. According to random allocation, each patient received either pipecuronium (150 micrograms.kg-1) or pancuronium (120 micrograms.kg-1) after sternotomy but before heparinization. Mean arterial pressure, central venous pressure (CVP), pulmonary artery pressure (PAP), ST segment position and ECG (leads III, V5, AVF) were monitored continuously throughout the procedure. Thermodilution determinations of CO in triplicate were made immediately before, and at two and five minutes after muscle relaxant administration. Multiplane transoesophageal echocardiography (TEE, midpapillary short axis views of the left ventricle) images were continuously recorded from ten minutes before until ten minutes after muscle relaxant administration and graded by two experienced echocardiographic readers. Heart rate, MAP and CO increased after administration of pancuronium (by 13.6 beats.min-1, 10.8 mmHg and 1.0 L.min-1 respectively) but not after pipecuronium (P < 0.05). Evidence of myocardial ischaemia was not detected in any patients using ECG ST segment analysis or TEE assessment of left ventricular wall motion. We conclude that pancuronium caused increases in HR, MAP and CO but that neither pancuronium nor pipecuronium caused myocardial ischaemia.

We have determined the relative potency of rocuronium, pancuronium, pipecuronium and vecuronium, and examined the nature of the interaction of rocuronium with the other three steroidal neuromuscular blocking drugs. We studied the dose-response relationships of each drug and their combination with rocuronium in 200 ASA I or II patients during propofol-fentanyl-nitrous oxide-oxygen anaesthesia. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to single twitch stimulation of the ulnar nerve at 10-s intervals. The dose-response curves were determined by probit analysis. Isobolographic and algebraic (fractional) analyses were used to assess the combined effect of equipotent doses of rocuronium and vecuronium, pipecuronium or pancuronium and to define the type of interaction between these drugs. The isobolograms were constructed by plotting single-drug ED50 points on the dose co-ordinates, and a combined ED50 point in the dose field. The calculated doses producing 50% depression (ED50) of the twitch height for rocuronium, pancuronium, pipecuronium and vecuronium were 144.8 (95% confidence intervals 140.4-149.3), 32.4 (31.7-32.9), 27.1 (26.5-27.6) and 23.7 (22.7-24.8) micrograms kg-1, respectively. Corresponding doses producing 95% depression (ED95) of twitch height were, respectively, 322.1 (307.5-337.3), 58.1 (56.2-60.1), 48.7 (46.9-50.5) and 39.9 (38.4-41.4) micrograms kg-1. Based on the estimate of ED50, the relative potency was 1:4.5:5.4:6, respectively. The interaction between rocuronium and vecuronium, pipecuronium or pancuronium was found to be additive.

We have compared the antagonism of neuromuscular block produced by pipecuronium with pancuronium in 80 anaesthetized surgical patients using mechanomyography and electromyography. Pancuronium 0.1 mg kg-1 or pipecuronium 0.07 mg kg-1 was given after induction of anaesthesia and neuromuscular block was adjusted to 75% twitch depression at the time of antagonism. The following regimens were used: edrophonium 0.5 and 1.0 mg kg-1, neostigmine 0.04 mg kg-1, pyridostigmine 0.3 mg kg-1 and edrophonium 0.25 mg kg-1 with pyridostigmine 0.15 mg kg-1. Antagonism was evaluated also by the head lift test. There was no difference between the reversibility of neuromuscular block produced by pancuronium or pipecuronium. Edrophonium produced a significantly faster antagonism than neostigmine or pyridostigmine but onset of action was not significantly faster than that of edrophonium with pyridostigmine. All regimens produced 100% (or near 100%) antagonism of twitch response within 15 min. However, TOF fade antagonism was more complete with pyridostigmine, neostigmine and edrophonium 1.0 mg kg-1 than with edrophonium 0.5 mg kg-1. The head lift test indicated somewhat less antagonism with edrophonium 0.5 and 1.0 mg kg-1. Using five monitoring methods, the rank order of reversal potency was: pyridostigmine approximately neostigmineedrophonium 1.0 mg kg-1edrophonium+pyridostigmineedrophonium 0.5 mg kg-1.

Summary In a little over 10 years, six new muscle relaxants have been introduced into clinical practice. The first two, the intermediate-duration vecuronium and atracurium were outstanding drugs and clearly an advance over the long-acting drugs which had been available previously. The next two, the long-acting doxacurium and pipecuronium were relics of an earlier era, and have made little clinical impact. Mivacurium created a new class, the short-acting nondepolarizer, and caused succinylcholine to be reclassified as an ultrashort-acting drug. However, mivacurium has neither the rapid onset nor the ultrashort duration of succinylcholine and is to some extent still trying to establish a significant clinical role. Rocuronium is the first non-depolarizer to have an onset approaching that of succinylcholine, and has spurred the development of drugs of low potency. It is likely that we will see the introduction of at least two more drugs, ORG 9487 and 51W89 by the end of this decade, but the goal of a nondepolarizing relaxant which is a complete replacement for succinylcholine still seems some distance in the future.

T HIS ARTICLE reviews the complications of muscle relaxants in clinical practice. Their introduction more than 50 years ago revolutionized the practice of anesthesia but was also associated with a new set of anesthetic-induced complications. Much of the development of new compounds has been with the aim of avoiding or reducing these effects, some of which contributed to postoperative morbidity and mortality. This review emphasizes the complications that have attracted recent attention, and is restricted to those agents in current use and to the recently introduced compounds, doxacurium, mivacurium, pipecuronium, and rocuronium. It should be considered an update of the article published in this journal 10 years ago. ~ Complications of muscle relaxants can be unwanted effects of the normal action of the drugs at the neuromuscular junction, actions at other sites, abnormal or idiosyncratic responses, or result from their use in unusual situations. Some of the complications are common to all relaxants (general complications), eg, slow recovery from block or residual blockade, anaphylaxis, etc, others are restricted to a few or single drugs (specific complications), eg, prolonged block after succinylcholine or mivacurium from a decrease in plasma cholinesterase activity. This review has less emphasis on succinylcholine, in part because most of its specific complications are well recognized but also because it is now used much less frequently than the estimate 10 years ago of its use in 75% of all anesthetics.

Two groups of 15 patients each, with American Society of Anesthetists’ (ASA) physical status I or II, were administered two single bolus doses of propofol 2 mg/kg or thiopental 4 mg/kg, followed by pipecuronium 0.08 mg/kg. Neuromuscular block was studied using both single twitch and train-of-four (TOF) nerve stimulation. The onset time, duration of clinical action and TOF recovery of pipecuronium were measured. The onset time of pipecuronium was significantly more rapid in patients receiving propofol compared with those administered thiopental (2.75 ± 0.54 vs 3.85 ± 1.08 minutes; p

We have studied in seven healthy conscious volunteers the correlation between the electro-myographic (EMG) and clinical criteria used to identify adequate recovery from sub-paralysing doses of pipecuronium. Pipecuronium (mean dose 1.88 (range 0.92–3.16) mg) was administered to reach a T4/T1 ratio of 0.5; full recovery to 1.0 was produced in a mean time of 25.3 (14–39) min. During recovery from neuromuscular block, we measured tidal volume, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) negative inspiratory pressure (NIP), peak expiratory flow rate (PEFR), mid-expiratory flow rate (MEFR) and 5-s head lift. The assessments were started when the train-of-four (TOF) ratio reached 0.5 ± 0.001 and repeated at each 0.1 ± 0.001 increase up to a ratio of 1.0. All volunteers showed ptosis and diplopia after the first dose and difficulty in swallowing with subsequent doses. They also experienced a pleasant, relaxing sedative sensation. All could sustain head lift for 5 s at a TOF ratio of 0.5 and higher, except for one subject who could not lift his head only at a ratio of 0.5. There was a statistically significant decrease in FVC, FEV, and PEFR with a nonsignificant decrease in other pulmonary measurements, except for NIP which only decreased significantly at a ratio of 0.5. These changes are probably of no clinical importance. All the measured respiratory variables returned to control values at a TOF ratio of 0.9. (Br.J. Anaesth. 1995; 74: 16–19)

The effect of different antiepileptic drugs on the pharmacokinetics of various neuromuscular blocking agents including atracurium, cisatracurium, doxacurium, mivacurium, pancuronium, pipecuronium, rapacuronium, rocuronium and vecuronium are described. Also, potential pharmacodynamic interactions are highlighted.

The use of neuromuscular blocking drugs during anaesthesia for patients with chronic renal failure is discussed. The disadvantages of the older non-depolarizing agents, such as tubocurarine, alcuronium, and pancuronium are outlined, as are the significant benefits of the use of atracurium or vecuronium in these patients. Preliminary reports on the new non-depolarizing drugs, pipecuronium, mivacurium, doxacurium, and rocuronium are also noted.

The acceptance of new and increasingly expensive technologies is a major component of the rising costs of health care. While the practice of anesthesia has been relatively immune from the effects of cost containment, it is inevitable that practitioners will have to justify costly practices. Available pharmacoeconomic methods can be applied to the use of all anesthetic drugs, particularly neuromuscular blocking drugs. Cost-effectiveness analysis allows the practicing anesthesiologist to prioritize the use of neuromuscular blocking drugs to maximize their benefit while reducing unnecessary costs.

In recent years work has progressed on four new compounds, pipecuronium bromide, doxacurium chloride, mivacurium chloride, and rocuronium bromide. ORG 9487 is a more recent compound which is starting to be investigated. Pipecuronium and doxacurium are long-acting agents with a slow onset of effect

Summary Four new non-depolarizing drugs offer advantages in different clinical situations. Pipecuronium and doxacurium are long-acting compounds with a relatively slow onset and a variable duration of action. Their main advantage is a lack of cardiovascular side-effects. Their use is likely to be confined to prolonged surgical procedures. Mivacurium has an onset of action similar to atracurium and vecuronium and a duration of action midway between these drugs and suxamethonium. It is metabolized by plasma cholinesterase and may not require to be routinely antagonized by anticholinesterases. Rocuronium (Org 9426) has a duration of action similar to atracurium and vecuronium but a more rapid onset of action. Whether it can replace suxamethonium in the rapid sequence induction requires further clinical assessment, but it would appear to be the drug of choice for rapid intubation where suxamethonium is contraindicated.

Hemodynamic responses to pipecuronium bromide or doxacurium chloride were compared in patients undergoing valvular heart surgery. Thirty ASA class III-IV patients of either sex, mean age 62 +/- 3 years (+/- SD), weight 70 +/- 3 kg, were randomly selected to receive either doxacurium (0.08 mg/kg) or pipecuronium (0.15 mg/kg). Hemodynamic parameters were determined at preinduction, induction, 2 minutes and 6 minutes following administration of the muscle relaxant. Anesthetic induction consisted of midazolam, 0.10 mg/kg, followed by fentanyl, 5 micrograms/kg. Measured or calculated parameters were as follows: mean arterial pressure, heart rate, cardiac index, mean pulmonary artery pressure, systemic vascular resistance index, central venous pressure, pulmonary capillary wedge pressure, stroke volume index, left and right stroke work indices, and pulmonary vascular resistance index. Awake patients who had been randomly assigned to the pipecuronium group had significantly higher pulmonary capillary wedge pressures (22 +/- 2 v 15 +/- 2 mmHg; P < 0.05) and heart rates (86 +/- 3 v 64 +/- 5 beats/min; P < 0.05) than awake patients in the doxacurium group. Following induction, both wedge pressure and heart rate were not significantly different between the two groups. Compared to hemodynamics at induction, there were no clinically significant changes following administration of pipecuronium or doxacurium.

Various new muscle relaxants are available: atracurium, rocuronium and vecuronium all have an intermediate duration of action, whereas doxacurium and pipecuronium are long-acting and mivacurium is a short-acting nondepolarizing muscle relaxant. The duration of action of atracurium and mivacurium is determined by their degradation, which makes them unique among the nondepolarizing muscle relaxants in this respect. The time of onset is shortest with rocuronium, while vecuronium is probably the muscle relaxant with the fewest undesirable side-effects. In clinical practice, muscle relaxants of short and intermediate duration of action should be preferred, since such agents carry the least risk of residual neuromuscular block postoperatively. Because recovery from them is slow, long-acting agents should preferentially be used only when postoperative mechanical ventilation is intended. The use of a peripheral nerve stimulator is the only reliable guide to appropriate administration of muscle relaxants.

In the early 1980s the clinical use of nondepolarizing neuromuscular blocking drugs (muscle relaxants) made a significant leap forward with the introduction of vecuronium and atracurium. These two drugs have an intermediate duration of action, vecuronium is free of cardiovascular effects, and atracurium has a unique non-organ-dependent mode of elimination [1]. Vecuronium and atracurium were a significant improvement over the previously available muscle relaxants, and the usefulness of intermediate-acting drugs became firmly established. Any muscle relaxant introduced since vecuronium and atracurium must have some aspect of its pharmacology that gives it a clinical advantage over these two drugs. In recent years, four new muscle relaxants, pipecuronium (Arduan), doxacurium (Neuromax), mivacurium (Mivacron), and rocuronium (Zemuron) have been introduced into clinical practice in the United States. Other muscle relaxants are at the stage of clinical trials. I will discuss the pharmacology of the drugs recently released into clinical practice, and provide an outline of the drugs undergoing clinical trials.

We have studied the neuromuscular effects of pipecuronium, vecuronium and their combination in 130 ASA group I or II patients. Patients were anaesthetized with 0.8% halothane and 60% nitrous oxide in oxygen. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to train-of-four stimulation of the ulnar nerve (2Hz at 10-s intervals). The dose-response curves were determined by probit analysis. The calculated doses producing 50% depression of the first twitch height were 15.6, 16.9 and 15.0 μg kg−1 for the pipecuronium, vecuronium and pipecuronium-vecuronium combination groups, respectively. Isobolo graphic and algebraic (fractional) analyses were used to assess quantitatively the combined neuromuscular effect of pipecuronium and vecuronium and to define the type of interaction between these drugs. The interaction between pipecuronium and vecuronium was found to be additive. (Br. J. Anaesth. 1993; 71: 556–560)

Study Objective : To measure the interaction of two antibiotics (clindamycin and colistin) on neuromuscular blockade induced by Pipecuronium bromide (a new long-acting, steroidal, nondepolarizing neuromuscular blocking drug). Design : Prospective, randomized, placebo-controlled study. Setting : Inpatient gynecologic and gastroenterologic service at a university Medical center. Patients : Three groups of 20 ASA physical status 1 and II patients with normal kidney and liver function, taking no medication, and undergoing elective surgery under general anesthesia. Interventions : Anesthesia was induced with propofol and alfentanil intravenously (IV) and maintained with a propofol infusion and 60% nitrous oxide in oxygen. Pipecuronium bromide 50 μg/kg was administered after reaching a stable baseline of single-twitch response. At 25% recovery of Pipecuronium-induced neuromuscular blockade, patients received one of two antibiotics, clindamycin 300 mg or colistin 1 million I U, or a placebo. Measurements and Main Results : The recovery index (RI, defined as time from 25% to 75% recovery of neuromuscular blockade) was measured using the single-witch response of the adductor pollicis muscle with supramaximal stimulation of the ulnar nerve at the wrist. RI after administration of an antibiotic (given at 25% recovery) was measured and compared with RI of the control group using Student's unpaired t -test. Statistical analyses of the results showed a significant prolongation of the recovery time (from 25% to 75% recovery) of 40 minutes for colistin. Conclusions : When this type of antibiotic is used during anesthesia with pipecuronium as a muscle relaxant, one must be aware of a significant prolongation of an already long-acting neuromuscular blockade and (although not observed in this study) possible problems in antagonism.

The dose-response relation of pipecuronium, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine have been investigated in patients under sevofluraney N2O Anesthesia using a neuromuscular transmission analyzer (Accelograph®, Biometer, Denmark). After an initial dose of pipecuronium (0.04 mg·kg−1, i.v., the maximum block rate, onset time, the time from administration until 25% recovery and 50% recovery of control twitch height of the first response to train-of-four nerve stimulation and the interval time of administration of maintenance dose (0.005 mg·kg−1, i.v.) were 93.7±7.68%, 5.0±1.84, 55.4 ±23.92,73.0±29.44 and 38.7±15.50 minutes, respectively. The average intubation score (excellent; 0, good; 1 fair; 2, poor; 3) was 0.63±0.56 at the level of 95.88±5.06% block. Neostigmine (1.5 mg) promptly reversed the residual neuromuscular blockade induced by pipecuronium (reversal time: 10.1±2.98 minutes). No side effects attributable to pipecuronium was seen in this study.

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives to the established agents atracurium besilate and vecuronium bromide. Pipecuronium and Org 9426 are steroidal compounds, the latter being a monoquaternary agent, whereas doxacurium and mivacurium are bisquaternary benzylisoquinolinium compounds. Pipecuronium and doxacurium have a relatively slow onset and a long duration of action. Pipecuronium produces maximum block in 3 to 6 min when given in a dose of 45 to 80 micrograms/kg, and a duration of clinical relaxation of between 40 and 110 min. Doxacurium is more potent, but is the least rapid and the longest acting relaxant currently available. When administered in doses of 37 to 80 micrograms/kg, it produces maximum block within 3.5 to 10 min, with a duration of clinical relaxation of 77 to 164 min. The advantage of both pipecuronium and doxacurium is their cardiovascular stability. Both agents are primarily eliminated via the kidneys and both have now been licensed for use in the US. Mivacurium is a muscle relaxant with a short duration of action. When administered in doses of 0.1 to 0.25 mg/kg it produces maximum block in 2 to 4 min, but the duration of clinical relaxation is less than 20 min. Higher doses which could induce a faster neuromuscular block are unfortunately associated with some histamine liberation. The drug is metabolised by plasma cholinesterase. Mivacurium has also been licensed for use in the US. Org 9426 is an agent with a rapid onset but an intermediate duration of action. A dose of 0.5 to 0.6 mg/kg induces maximum block in about 1.5 min and has a duration of clinical relaxation of about 30 min. The rapid onset of effect could be useful for early intubation as an alternative to suxamethonium chloride. However, much more clinical experience is needed with this agent, particularly with regard to duration of action of larger doses and occurrence of side effects. The drug is mainly eliminated via the liver.

In this study, combined neuromuscular blocking effects of ORG9426 with other non-depolarizing neuromuscular blocking agents were investigated. About 20% steady state neuromuscular block was established by a continuous infusion of one of 6 neuromuscular blocking agents (ORG9426, vecuronium, pancuronium, pipecuronium, d-tubocurarine and metocurine). Then 1/7 of the ED50 of ORG9426 or one of other neuromuscular blocking agents was administered in a single injection, and the increase in the neuromuscular block was observed. The combined neuromuscular blocking effect of ORG9426 and d-tubocurarine or ORG9426 and metocurine was significantly (P < 0.05) greater than that of each corresponding control (the combination of same neuromuscular blocking agent). The effect of d-tubocurarine was also potentiated by vecuronium, pancuronium and pipecuronium. These potentiations were not observed between ORG9426 and pancuronium, pipecuronium or vecuronium. Possible mechanisms of these synergistic interactions were discussed.

We have investigated the effects of adenosine i.v. on neuromuscular block induced by rocuronium, vecuronium and pipecuronium in an in vivo guinea-pig sciatic nerve-tibialis anterior preparation. The ED50 of each neuromuscular blocker was determined from cumulative log dose-response regression lines (n = 14). In separate experiments, adenosine 0.1 mg kg-1 min-1 or the same volume of 0.9% NaCl was given i.v. via a constant infusion and the ED50 of each neuromuscular blocking agent was then administered (n = 24). Adenosine 0.1 mg kg-1 min-1 increased significantly maximal block induced by the ED50 of these neuromuscular blockers (55-72%, 49-73% and 60-96%, respectively, for rocuronium, vecuronium and pipecuronium; P0.05). Time to maximal block after rocuronium was significantly prolonged by adenosine (1.4-2.1 min; P0.05) and time to maximal block after vecuronium and pipecuronium was unchanged by adenosine. Time to maximal recovery of twitch tension after administration of the ED50 of all neuromuscular blocking agents was prolonged significantly by adenosine (4.5-10.7 min, 8.2-15.8 min and 47.0-128.7 min, respectively, for rocuronium, vecuronium and pipecuronium; P0.05). We conclude that continuous infusion of adenosine 0.1 mg kg-1 min-1 potentiated the effects of neuromuscular blocking agents in this in vivo guinea-pig preparation.

Background and objective Porcine anaesthesia remains a great problem for cardiac surgery research and especially with cardiopulmonary bypass procedures. This study was designed to develop a suitable anaesthesia model in which miniature pigs could be induced smoothly and be maintained stably during and after a cardiopulmonary bypass procedure. Methods Thirty-one miniature pigs were randomly divided into two groups and induced using ketamine and pentobarbital (K-P group, n = 15) or pentobarbital (P group, n = 16) alone, respectively. Animals in group K-P were induced with intramuscular injections of ketamine 5 mg kg -1 and pentobarbital 20 mg kg -1 body weight, and those in group P were induced with pentobarbital 30 mg kg -1 alone. After intubation and intravenous catheterization, group K-P was maintained by continuous infusion of ketamine and pentobarbital, and pentobarbital was withdrawn after cardiopulmonary bypass started. Group P received a continuous infusion of pentobarbital throughout the operation. In addition, both groups were injected hourly with midazolam and pipecuronium bolus to achieve optimal surgical conditions. Results All of the group K-P animals survived for 24 h postoperatively. Five of the group P animals died from anaesthesia-related respiratory and cardiac arrest: three after induction and two after extubation. The animals in group K-P had more stable haemodynamics and arterial blood gas indices than animals in group P. Furthermore, the percentage of animals achieving satisfactory anaesthetic effects was significantly higher in group K-P than in group P. Conclusion Combination anaesthesia with low-dose ketamine and pentobarbital demonstrated superior haemodynamic and respiratory indices in comparison with pentobarbital. The combination regimen can achieve both hypnosis and analgesia effects with stable circulatory parameters.

This study was designed to investigate the effect of divided administration of edrophonium on the course of neuromuscular recovery from a pipecuronium neuromuscular blockade. During thiopentone-nitrous oxide-halothane anaesthesia 48 patients were given pipecuronium 70 micrograms.kg-1. Patients were randomly assigned to one of four groups (n = 12 in each) to receive either edrophonium 1 mg.kg-1 (Groups I and II) or edrophonium 0.75 mg.kg-1 (Groups III and IV). In Groups I and III (single-dose groups), edrophonium was administered as a single bolus dose. In Groups II and IV (divided-dose groups) edrophonium was administered as an initial dose of 0.25 mg.kg-1 followed three minutes later by either 0.75 or 0.50 mg.kg-1 respectively. Reversal was attempted at 20% spontaneous recovery of twitch height. Administration of edrophonium in divided doses (Groups II and IV) accelerated the reversal of the pipecuronium neuromuscular blockade. At ten minutes post-reversal, train-of-four (TOF) ratio recovery reached 0.75 or more in 12 (100%) and in ten (83%) patients in Groups II and IV respectively. Similarly, times to attain a TOF of 0.75 (SEM) were shorter in the divided-dose groups than in the single-dose groups (P less than 0.05), being 354.5 (38.7) and 398.3 (49.1) sec in Groups II and IV vs 705.4 (66.6) and 651.2 (54.3) sec in Groups I and III respectively. Time was counted from the first administration of edrophonium. It is concluded that administration of edrophonium in divided doses produced a faster reversal of residual pipecuronium-induced neuromuscular blockade than single bolus administration. Also, administration in divided doses reduced the requirements of edrophonium needed for reversal of pipecuronium neuromuscular blockade.

Study Objective : To determine the incubating conditions following the administration of pipecuronium bromide in doses of two (0.07 mg/kg) or three (0.1 mg/kg) times ED 95 (average dose that gives 95% block of the first twitch). Design : To compare intubating conditions at 1 tl2 and 21/2 minutes in 41 patients receiving balanced anesthesia. Setting : Surgical patients at Thomas Jefferson University Hospital. Patients : Forty-one patients undergoing surgical procedure who received general anesthesia. Interventions : After obtaining a stable baseline of train-of f our (TOF), 41 patients r randomly received either 0.07 mg/kg or 0.1 mg/kg of pipecuronium as a single intravenous (IV) bolus dose, and the trachea was intubated either at 112 or 212 minutes. minutes. Measurements and Main Results : Intubating conditions at 212 minutes appeared significantly better than those at 12 minutes, regardless of the pipecuronium dose. The mean time for TI (first twitch of TOF) to reach 50% and 90% suppression was 1.36 ± 0.51 minutes and 2.29 ± 0.8 minutes, respectively, for the 0.07 mg/kg dose and 1.07 ± 0.27 minutes and 1.72 ± 0.45 minutes, respectively, for the 0.1 mglkg dose. This did not make a significant difference in intubating conditions at either time. The time to 25% recovery of TI was 68.2 ± 22 minutes for the 0.07 mg/kg dose and 121.5 ± 49 minutes for the 0.1 mg/kg dose. In patients who had spontaneous recovery of T1 to between 10% and 25% of control, administration of neostigmine or edrophonium resulted in identical recovery in 10 minutes. However, in patients with less than 10% spontaneous recovery of T1, neostigmine appeared to be superior to edrophonium. Conclusion : Pipecuronium has a relatively rapid onset. The trachea could be intubated successfully in 112 minutes with a dose of either 0.07 mg/kg or 0.1 mg/kg. If the clinical situation requires perfect relaxation with no movement or bucking, we recommend waiting at least 212 minutes.

Neostigmine 0.06 mg · kg−1 or edrophonium 1 mg · kg−1 were administered to two groups of 15 patients each for antagonism of pipecuronium-induced neuromuscular block at 20% spontaneous recovery of the first twitch (T1) of the train-of-four (TOF) stimulation. The mean onset of action (± SEM) of edrophonium (18.1 ± 2.4 sec) was significantly more rapid (P < 0.01) than that of neostigmine (47.6 ± 4 sec), as were the times taken to attain a TOF ratio of 0.25 and 0.5. Nevertheless, the reversal time (time taken from the end of injection of the antagonist until TOF ratio value had reached 0.75) was significantly shorter (P < 0.01) in the neostigmine than in the edrophonium group (499.3 ± 62 vs 767 ± 52 sec respectively). The TOF ratio ten minutes after reversal was greater in the neostigmine group than in the edrophonium group (P < 0.01), 0.78 ± 0.02 vs 0.68 ± 0.02 min respectively. At that time, 33% (5 out of 15) and 80% (12 out of 15) patients failed to be reversed adequately (TOF ratio of 0.75) after neostigmine 0.06 mg · kg−1 and edrophonium 1 mg · kg−1, respectively. Administration of one additional dose (one-third of the initial dose) of the same antagonist resulted in adequate antagonism in the remaining five patients in the neostigmine group and in nine patients in the edrophonium group. Two such doses were required in the remaining three patients in the latter group. The mean total dose of neostigmine and edrophonium employed in this study was 0.067 ± 0.002 and 1.3 ± 0.05 mg · kg−1, respectively. Under the conditions of this study, edrophonium in a dose of 1 mg · kg−1 did not consistently antagonize residual neuromuscular blockade induced by pipecuronium at 20% recovery of T1.

Pipecuronium bromide (Arduan) is a bisquaternary, steroid-type neuromuscular blocking agent in clinical use in Eastern Europe. Before its introduction into clinical practice in the USA, in the first phase of this study the neuromuscular potency of pipecuronium was determined under "balanced" and enflurance anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset times, clinical duration of the first and repeated doses, spontaneous recovery index, reversibility of its residual neuromuscular effect by an anticholinesterase and its effect on heart rate and blood pressure was compared with the same variables observed in patients, anaesthetized with identical techniques but who had received vecuronium or pancuronium. The neuromuscular potency of pipecuronium was greater under enflurane (ED95 = 23.6 +/- 1.1 micrograms.kg-1 (mean +/- SEM)] than under balanced (ED95 = 35.1 +/- 17 micrograms.kg-1) anaesthesia. Pipecuronium was more potent than vecuronium under both balanced (ED95 = 45.8 micrograms.kg-1) and enflurane anaesthesia (ED95 = 27.4 micrograms.kg-1). Following the administration of 2 x ED95 doses there were no clinically significant differences in the intubation or onset times of pipecuronium, vecuronium and pancuronium. Under balanced anaesthesia the clinical duration of 2 x ED95 dose of pipecuronium (110.5 +/- 0.3 min) or pancuronium (115.8 +/- 8.1 min) were similar and about three times longer than that of vecuronium (36.3 +/- 2.1 min). The recovery indices of pipecuronium (44.5 +/- 8.2 min) and pancuronium (41.3 +/- 4.2 min) were also similar and about three times longer than that of vecuronium (14.3 +/- 1.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)

The haemodynamic effects of 200 micrograms.kg-1 pipecuronium and pancuronium were compared under etomidate/piritramide anaesthesia in 20 patients scheduled for elective coronary artery surgery. Following the completion of the haemodynamic measurements (ten minutes), anaesthesia was maintained by etomidate/sufentanil infusion. The mean changes in cardiac output were approximately -19 and -2 per cent and in heart rate -1 and +26 per cent for pipecuronium and pancuronium respectively. Plasma and urine concentrations of pipecuronium were also measured and the pharmacokinetic variables obtained indicated rapid initial decrease in plasma concentration (t1/2 = 7.6 minutes) followed by a longer terminal phase (t1/2 = 161 minutes). The central compartment volume was 102 +/- 24 ml.kg-1 and plasma clearance was 1.8 +/- 0.4 ml.kg-1 min-1. Approximately 56 per cent of the dose was recovered from the urine within 24 hours of administration and about 25 per cent of this was the metabolite, 3-desacetyl pipecuronium. High-dose pipecuronium administration under the anaesthetic regimen employed did not produce deleterious haemodynamic effects. The pharmacokinetic variables after bolus injection of pipecuronium did not deviate from those reported under normothermic conditions.

To determine in infants and children the neuromuscular effect of pipecuronium during alfentanil-N2O/O2 anesthesia, the authors studied 32 ASA Physical Status 1 and 2 pediatric patients undergoing minor elective surgery, divided into three groups according to their age: group 1 included 12 infants, 1.9 +/- 0.2 months old (mean +/- SE; range, 20 days to 3 months), weighing 5.2 +/- 0.3 kg; group 2, 10 infants, 6.1 +/- 0.9 months old (range, 3-11 months), 6.9 +/- 0.4 kg; and group 3, 10 children 5.6 +/- 0.9 yr old (range, 2-9 yr), 19.6 +/- 2.2 kg. Neuromuscular blockade at the ulnar nerve-adductor pollicis muscle was measured by electromyography. Incremental iv doses of pipecuronium were given (one 20 micrograms/kg first dose, followed by 10 micrograms/kg increments) to reach a 95 +/- 2% twitch depression (ED95). In children ED50 and ED95 of pipecuronium were 45.0 +/- 5.8 micrograms/kg (mean +/- SE) and 70.5 +/- 9.3 micrograms/kg, respectively. In 3- to 12-month-old infants ED50 and ED95 were 25.8 +/- 1.5 micrograms/kg and 48.7 +/- 3.5 micrograms/kg, respectively, and both significantly (P less than 0.05) less than those in children. In 0- to 3-month-old infants ED50 and ED95 were 23.7 +/- 1.7 micrograms/kg and 46.5 +/- 2.9 micrograms/kg, respectively, and also significantly (P less than 0.05) less than those measured in children. Time from maximal initial neuromuscular blockade to 75% recovery was 64.5 +/- 8.8 min in children and significantly shorter (P less than 0.05) in the two infant groups (0- to 3-month-old: 38.7 +/- 5.7 min, 3- to 12-month-old: 43.8 +/- 5.3 min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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.