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Мета статті полягає в комплексному аналізі теоретичних і практичних аспектів ідентифікації піпекуронію відповідно до схеми застосування аналітичних методів дослідження, зумовленої їхньою селективністю, та розробленні методики дослідження стандартного зразка піпекуронію фізико-хімічними методами для підтвердження аргументованості, достовірності, відтворюваності результатів його ідентифікації та достатності для підготовки науково обґрунтованого висновку судового експерта. Методологія. Достовірність отриманих результатів і висновків забезпечено використанням комплексу загальнонаукових і спеціальних методів дослідження. Методи аналізу, синтезу, порівняння, узагальнення дозволили проаналізувати інформаційні джерела за напрямом дослідження, а також аналітичну схему комплексу фізико-хімічних методів дослідження, рекомендовану SWGDRUG. Апробаційне аналітичне дослідження стандартного зразка піпекуронію із застосуванням методів експерименту, аналізу, порівняння, а також спеціальних фізичних, хімічних, статистичних методів дослідження дозволило апробувати комплекс фізико-хімічних методів дослідження цієї речовини й дійти висновків щодо достатності для цілей дослідження певних їх видів та окреслити напрями подальших науково-дослідних розвідок. Наукова новизна. В умовах лабораторії Державного науково-дослідного експертно-криміналістичного центру МВС України апробовано аналітичну схему фізико-хімічних методів дослідження для ідентифікації сильнодійних та отруйних лікарських засобів, рекомендовану SWGDRUG, і запропоновано методику дослідження стандартного зразка піпекуронію фізико-хімічними методами відповідно до схеми застосування аналітичних методів дослідження, зумовленої їхньою селективністю. Висновки. Проаналізовано рекомендації SWGDRUG стосовно комбінації аналітичних методів і cхарактеризувано мінімальні вимоги для їх застосування. При цьому наголошено, що в контексті достатності для ідентифікації сильнодійних і отруйних лікарських засобів, зокрема важколетких речовин, експертні лабораторії, зважаючи на фізико-хімічні властивості таких речовин і наявне в експертних установах країни аналітичне обладнання, мають самостійно визначати комбінацію методів, щоб забезпечити достовірність результатів аналітичних досліджень. Засвідчено комплексним аналітичним дослідженням стандартного зразка піпекуронію можливість його ідентифікації за допомогою методів: якісних хімічних реакцій (із найбільш доступними реактивами, такими як: Маркі, родонід кобальту, Драгендорфа, Вагнера, йодоплатинат калію, Несслера), ІЧ-спектрометрії, мас-спектрометрії, високоефективної рідинної хроматографії з мас-спектрометричним та коронорозрядним детектуванням. Аргументовано доцільність комбінування методів, що дозволяє реалізовувати застосування аналітичної схеми методів дослідження, рекомендованої SWGDRUG. Констатовано необхідність, з огляду на те, що використання методів категорії B не є загальнодоступним, розроблення процесу дериватизації для дослідження похідних піпекуронію загальнодоступними методами: газовою хроматографією з мас-селективним детектуванням і тонкошаровою хроматографією з використанням різних видів сорбентів. Узагальнено результати, отримані під час апробації комплексного аналітичного дослідження піпекуронію за рекомендованою міжнародною схемою, і започатковано певні пропозиції, які можуть стати підґрунтям методики дослідження стандартного зразка піпекуронію фізико-хімічними методами для підтвердження аргументованості, достовірності, відтворюваності результатів його ідентифікації та достатності для підготовки науково обґрунтованого висновку судового експерта.

Bitter taste receptors (TAS2R) are expressed in many non-sensor tissues including skeletal muscles but their function remains unexplored. The aim of this study is to investigate the role of TAS2R in rat abdominal skeletal muscles contractions using denatonium, a TAS2R agonist. Low concentration of denatonium (0.01 mmol/l) caused a significant decrease of amplitudes of the electrical field stimulation (EFS)-induced contractions in abdominal skeletal muscles preparations in vitro. This inhibitory effect was significantly reduced when the preparations were pre-incubated with gentamicin (0.02 mmol/l) used as a non-specific inhibitor of IP3 formation or with BaCl(2) (0.03 mmol/l) applied to block the inward-rectifier potassium current. All experiments were performed in the presence of pipecuronium in order to block the nerve stimulation of the contractions. The data obtained suggest that denatonium decreases the force of rat abdominal muscles contractions mainly via activation of TAS2R, phosphatidylinositol 4,5-biphosphate and its downstream signal metabolites.

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.

Impact of a durable action of myorelaxant pipecuronium bromide on intraabdominal pressure (IAP) in rats in experimentally simulated acute peritonitis was studied. In the rats in purulent pancreatitis, іnduced by L-аrginin, IAP was in 4,5 times high (p0.001), than in intact laboratory animals. Pipecuronium bromide have lowered IAP by 33.4%, witnessing efficacy of application of myorelaxants in treatment of intraabdominal hypertension in purulent pancreatitis.

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.

A system is proposed for the classification of related organic impurities in drugs and drug products including among others (separated and non-separated) intermediates, various kinds of by-products, among them products of different side reactions, epimeric/diastereomeric, enantiomeric impurities, impurities in natural products, and finally degradation products. Examples are taken mainly from the author's own experience and from among the named impurities in the European Pharmacopoeia with focus on impurities in hydrocortisone, prednisolone, enalapril maleate, lisinopril, ethynodiol diacetate, pipecuronium bromide, cimetidine, and ethynylsteroids. The methodological aspects of impurity profiling from the detection to the identification/structure elucidation and quantitative determination of impurities are briefly summarized.

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.

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.

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.

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.

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)

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)

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.

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.

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 is a non-depolarizing neuromuscular blocker with similar properties to pancuronium, but without cardiovascular effects. Neuromuscular effects, conditions of tracheal intubation, and hemodynamic repercussions of two different doses of pipecuronium were evaluated.Patients were divided into two groups according to the dose of pipecuronium: Group I (0.04 mg x kg(-1)) and Group II (0.05 mg x kg(-1)). Intramuscular midazolam (0.1 mg x kg(-1)) was administered 30 minutes before the surgery. Propofol (2.5 mg x kg(-1)), preceded by fentanyl (5 microg x kg(-1)) and pipecuronium (0.04 and 0.05 mg x kg(-1) for Groups I and II, respectively), was administered for anesthetic induction. Patients were ventilated with 100% oxygen via a face mask until a 75% reduction in the amplitude of the response to an isolated stimulus (1 Hz) is achieved, at which time laryngoscopy and intubation were carried out. Anesthetic maintenance was achieved with isoflurane (0.5 to 1%) with a mixture of 50% O2 and N2O. Mechanical ventilation was used to maintain P(ET)CO2 between 32 and 36 mmHg. The pharmacodynamics of pipecuronium was evaluated by acceleromyography.Mean times and standard deviation for the onset of action, clinical duration (T1(25%)), and recovery index (T1(25-75%)) were: Group I (122.10 +/- 4.18 sec, 49.63 +/- 9.54 min, and 48.21 +/- 6.72 min), and Group II (95.78 +/- 8.91 sec, 64.84 +/- 13.13 min, and 48.52 +/- 4.95 min). Onset of action, clinical duration, and conditions of tracheal intubation were significantly different for both groups.Pipecuronium at a dose of 0.05 mg x kg(-1) can be used in prolonged procedures in which cardiovascular changes should be avoided.

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.

JUSTIFICATIVA E OBJETIVOS: Uma das mais importantes propriedades dos bloqueadores neuromusculares é o rápido início de ação, possibilitando intubação traqueal precoce. A administração de pequena dose de bloqueador não-despolarizante antes da dose plena é sabidamente redutora da latência da maioria dos bloqueadores neuromusculares utilizados. O brometo de pipecurônio é um agente aminoesteróide de longa duração com grande estabilidade cardiovascular, porém, com início de ação tardio. O objetivo desse estudo foi avaliar o efeito do priming do pipecurônio em pacientes adultos submetidos a cirurgias eletivas sob anestesia geral. MÉTODO: Foram estudados 33 pacientes adultos de ambos os sexos, com idade entre 20 e 65 anos, estado físico ASA I ou II, submetidos a cirurgias eletivas sob anestesia geral. Foram excluídos do estudo pacientes com insuficiência renal ou hepática, neuromiopatia, uso concomitante de drogas que influenciem a sua farmacocinética ou pacientes com histórico familiar de hipertermia maligna. Foram divididos em dois grupos: Grupo 1 onde foi utilizado o priming com 0,01 mg.kg-1 e três minutos depois completada a dose de 0,08 mg.kg-1 e o Grupo 2, sem dose priming (Grupo Controle). O relaxamento neuromuscular foi controlado pela aceleromiografia (Aparelho TOF-Guard) e no momento em que T1 < 10% era realizada a laringoscopia. A análise estatística foi feita pelos testes T para amostras independentes e a normalidade pelo Shapiro Wilks. RESULTADOS: Os grupos foram homogêneos e observou-se que o tempo para T1 < 10% no Grupo 1 foi de 161,4 ± 13,7 segundos e no Grupo 2 foi 217,8 ± 23,4 segundos, com p < 0,001, havendo diferença estatística significativa entre os grupos. CONCLUSÕES: Os resultados do estudo mostraram diferença estatística significativa entre os grupos com e sem priming, indicando que o pipecurônio também tem latência reduzida, assim como os demais bloqueadores neuromusculares conhecidos. BACKGROUND AND OBJECTIVES: One of the most important neuromuscular blockers property is short onset, allowing early tracheal intubation. Low nondepolarizing blocker dose before the full dose is known to decrease the onset of most neuromuscular blockers. Pipecuronium bromide is a long-lasting aminosteroid with major cardiovascular stability, however, with late onset. This study aimed at evaluating pipecuronium priming effect in adult patients submitted to elective surgeries under general anesthesia. METHODS: Participated in this study 33 adult patients of both genders, aged 20 to 65 years, physical status ASA I or II, to be submitted to elective surgeries under general anesthesia. Exclusion criteria were patients with kidney or liver failure, neuromuscular diseases, in concurrent use of drugs influencing pipecuronium pharmacokinetics, and patients with family history of malignant hyperthermia. Patients were divided in 2 groups: Group 1 = priming with 0.01 mg.kg-1 and 3 minutes later the remaining 0.07 mg.kg-1 (total 0.08 mg.kg-1); Group 2 = no priming dose (group control). Neuromuscular relaxation was controlled by acceleromyography (TOF-Guard device) and laryngoscopy was accomplished when T1 < 10%. T test for independent samples was used for statistical analysis and Shapiro Wilks was used to test normality. RESULTS: Groups were homogeneous. Time for T1 < 10% was 161.4 ± 13.7 seconds for Group 1 and 217.8 ± 23.4 seconds for Group 2, with p < 0.001 and statistically significant differences between groups. CONCLUSIONS: Our results have shown statistically significant differences between groups with and without priming, indicating that pipecuronium also has its onset decreased, similarly to other known neuromuscular blockers. JUSTIFICATIVA Y OBJETIVOS: Una de las más importantes propiedades de los bloqueadores neuromusculares es el rápido inicio de acción, posibilitando intubación orotraqueal precoz. La administración de pequeña dosis del bloqueador no despolarizante antes de la dosis completa es consabidamente reductora de la latencia de la mayoría de los bloqueadores neuromusculares utilizados. El bromuro de pipecuronio es un agente aminoesteroide de larga duración con grande estabilidad cardiovascular, sin embargo, con inicio de acción tardía. El objetivo de ese estudio es evaluar el efecto del priming del pipecuronio en pacientes adultos sometidos a cirugías electivas bajo anestesia general. MÉTODO: Fueron estudiados 32 pacientes adultos de ambos sexos, con edad entre 20 y 65 años, estado físico ASA I ó II, a ser sometidos a cirugías electivas bajo anestesia general. Fueron excluidos del estudio pacientes con insuficiencia renal o hepática, neuromiopatia, uso concomitante de drogas que influencien la farmacocinética de la droga o pacientes con histórico familiar de hipertermia maligna. Fueron divididos en dos grupos: Grupo 1 donde fue utilizada el priming con 0,01 mg.kg-1 3 minutos después de completada la dosis de 0,08 mg.kg-1 y el Grupo 2, sin dosis priming (Grupo Control). El relajamiento neuromuscular fue controlado por la aceleromiografía (Aparato TOF-Guard) y en el momento en que T1 < 10% era realizada la laringoscopia. El análisis estadístico fue hecha por la prueba T para muestras independientes y la normalidad testada por el Shapiro Wilks. RESULTADOS: Los grupos fueron homogéneos y se observó que el tiempo para T1 < 10% en el Grupo 1 fue de 161,4 ± 13,7 segundos y en el Grupo 2 fue 217,8 ± 23,4 segundos, con p < 0,001, habiendo diferencia estadísticamente significativa entre los grupos. CONCLUSIONES: Los resultados del estudio mostraron diferencia estadísticamente significativa entre los grupos con y sin priming, indicando que el pipecuronio también tiene latencia reducida, así como también los demás bloqueadores neuromusculares conocidos.

Summary Fetal movement during intra-uterine fetal therapy makes these procedures technically more dificult and increases the likelihood of trauma to the fetus. Pancuronium or pipecuronium were used in a randomised study to temporarily arrest movement in 16 fetuses undergoing intra-uterine procedures. Under ultrasound guidance, pancuronium or pipecuronium 0.2 mg.kg−1 was injected into the fetal gluteal region. Fetal movements ceased within 4.6 ± 2.3 min in the pancuronium group and 4.5 ± 2.8 min in the pipecuronium group and returned by 115±26 min in the pancuronium group and 121 ± 3 2 min in the pipecuronium group. No adverse effects of the relaxant were observed in the mothers. There bvas no evidence of soft tissue, nerve or muscle damage at the fetal injection site after delivery. Both muscle relaxants provided a safer method for diagnostic and therapeutic procedures. However, four cases in the pancuronium group (50%) developed a fetal tachycardia, and two cases in the same group showed loss of beat-to-beat variability. Pipecuronium appeared to be more suitable for intra-uterine procedures.

Interaction of the steroidal neuromuscular blocking drugs pancuronium, pipecuronium, rocuronium and vecuronium with cardiac muscarinic receptors in rat hearts was investigated in vitro by a tritiated N-methyl hyoscine binding assay. We showed an interaction with cardiac muscarinic receptors with a rank order of potency pancuronium > vecuronium > pipecuronium > rocuronium and demonstrated complex binding characteristics for pancuronium, vecuronium and rocuronium, with "Hill coefficient" of less than unity. We conclude that the haemodynamic differences seen during the use of these neuromuscular blocking drugs may be a result of their interactions with cardiac M2 muscarinic receptors.

We have examined the prolongation of a maintenance dose of vecuronium after an intubating dose of pipecuronium in 45 patients who received either pipecuronium 70 μg kg-1 or vecuronium 200 μg kg-1 i.v. for tracheal intubation, followed by either pipecuronium 10 μg kg-1 or vecuronium 15 μg kg-1 for maintenance of neuromuscular block. The duration of the vecuronium maintenance dose was greater after pipecuronium (40 (so 12) min) than after vecuronium (29 (9) min) (P = 0.02). The duration of pipecuronium after pipecuronium (49 (15) min) was similar to that of vecuronium after pipecuronium. We conclude that the duration of action of vecuronium is prolonged by prior administration of pipecuronium. (Br. J. Anaesth. 1993; 70: 446–448)

A prospective, randomised, single blind study was conducted to evaluate and compare the intracranial pressure (ICP) and cardiovascular effects of pipecuronium (PPC) and pancuronium (PNC) in 20 patients undergoing supratentorial surgery. Patients were randomly divided into two groups. Patients in Group I (n = 10) received pancuronium (0.1 mg kg(-1)) and in Group II (n = 10) pipecuronium (0.07 mg kg(-1)) for intubation. Intracranial pressure (ICP), heart rate (HR), systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), central venous pressure (CVP), nasopharyngeal temperature and arterial blood gases (ABG) were monitored at the following time periods: before induction (0 minutes); 3 minutes after thiopentone and muscle relaxant; immediately after intubation; and 4, 6, 8, 10, 20 and 30 minutes following intubation. The rise in intracranial pressure at intubation was significantly greater in group I (21.10+/-3.97 torr, 122.59%) when compared to group II patients (1.80+/-0.70 torr, 10.04%) (p0.0 1). Cardiovascular parameters also showed a significantly greater degree of rise in group I when compared to group II patients. Heart rate increased by 29+/-6.32 beats min(-1) (33.52%) and systolic arterial pressure by 11.60+/-7.37 torr (9.47%) in group I. These parameters did not change significantly in group II. No significant alterations were observed in the other measured parameters in either of the two groups.

Summary The onset time and tendency to cumulation of pipecuronium and high-dose vecuronium were compared during nitrous oxide anaesthesia supplemented with a propofol infusion. Pipecuronium 0.06 mg·kg−1 had a similar duration of action to vecuronium 0.2 mg·kg−1 (49 vs 43). Patients who received vecuronium had a shorter onset time of neuromuscular blockade (p < 0.01). Neither pipecuronium nor vecuronium showed marked cumulation.

Background Patients on chronic anticonvulsant drugs are relatively resistant to certain nondepolarizing neuromuscular blockers such as pancuronium, vecuronium, pipecuronium, doxacurium, or metocurine, but not resistant to mivacurium and atracurium. This study investigated the influence of chronic carbamazepine therapy on the neuromuscular block induced by the new muscle relaxant rocuronium. Methods Twenty-two otherwise healthy individuals scheduled for neurosurgical operations were studied: 11 of them were on chronic treatment with carbamazepine; the others served as control subjects. The median duration of carbamazepine therapy was 9 weeks (range, 4-312 weeks). After premedication with oral diazepam, anesthesia was induced with fentanyl and thiopental and maintained with nitrous oxide/oxygen and 0.5% inspired isoflurane. Rocuronium, 0.6 mg/kg (2 x ED95), was given for intubation. The ulnar nerve was stimulated, and the evoked electromyogram recorded using a Datex NMT monitor. Results Based on the response to the first of four stimuli, neither the lag time nor the onset-time differed between the two groups. However, the intervals of recovery to 10%, 25%, 50%, and 75% of the baseline response and the recovery index (RI, 25%-75%) were significantly shorter in patients on chronic carbamazepine therapy. Conclusions The authors conclude that the duration of the rocuronium-induced neuromuscular block is significantly shortened by preceding chronic carbamazepine therapy.

The effect of various non-depolarizing neuromuscular blocking agents (gallamine, pancuronium, vecuronium, d-tubocurarine, metocurine, atracurium and pipecuronium) on [3H] acetylcholine release in the response to field electrical stimulation was investigated in vitro in preparations of the guinea pig right atrium. In this preparation, atropine enhanced and oxotremorine, a muscarinic agonist, reduced the release of [3H] acetylcholine. Atropine reversed the inhibitory effect of oxotremorine in a concentration dependent manner, indicating that there is negative feedback modulation of acetylcholine release from the vagal nerve. While pancuronium, gallamine and atracurium enhanced the release of [3H] acetylcholine, d-tubocurarine, metocurine, vecuronium and pipecuronium did not affect it. Pancuronium and gallamine also reduced the inhibitory effect of oxotremorine and the Kd value of pancuronium for muscarinic receptors located on cholinergic nerve terminals was 2.31 μM. These findings indicate that pancuronium and gallamine enhanced the release of acetylcholine from the atrial parasympathetic nerve, probably by inhibiting presynaptic muscarinic receptors.

Presence of endocrine disorders, malfunction of liver and kidneys requests special approach application concerning general anaesthetic use in patients with the hormone producing insulinomas. There were 44 patients examined, in whom tumor was removed. Sodium hydroxybutyrate application while introducing anaesthesia promoted the haemodynamics stabilization. Arduan dosage ought to be reduced because of it possible cumulation in blood due to hepatorenal disorders existing in this patients. The dominance of the blood glucagon at the end of operation and the glucagon-insulin coefficient shift causes the tachycardia and the shock index increase. The proposed direct binasal stimulation of respiration after the anaesthesia conduction promoted rapid muscle tone and respiratory movements restoration in patients.

The Council on Scientific Affairs of the California Medical Association presents the following epitomes of progress in anesthesiology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and clinical importance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of progress in medicine, whether in their own field of special interest or another. The epitomes included here were selected by the Advisory Panel to the Section on Anesthesiology of the California Medical Association, and the summaries were prepared under the direction of Dr Jackson and the panel.

The effect of temperature on the potencies of neuromuscular blocking agents remains unclear. This study was undertaken to examine the effects of different neuromuscular blocking agents at 37 and 27 degrees C at a constant carbon dioxide content (alpha stat principle). The effect of neostigmine 1 mumol litre-1 induced antagonism of these agents was also investigated. Phrenic nerve-hemidiaphragm preparations of rats were mounted in modified Krebs solution, maintained at 37 degrees C and aerated with a 5% carbon dioxide-95% oxygen gas mixture, and at 27 degrees C with 4% carbon dioxide to maintain the carbon dioxide content of the solution constant. Phrenic nerves were stimulated with 0.1-Hz supra-maximal impulses of 0.2-ms duration and the elicited tension of the diaphragm recorded. The potencies of the steroidal neuromuscular blocking agents (rocuronium, vecuronium, pancuronium and pipecuronium) increased significantly at 27 degrees C (P0.05), while the potencies of the benzylisoquinolinium agents (tubocurarine and dimethyltubocurarine) did not change. Neostigmine-induced antagonism of the steroidal agents did not differ significantly between each other but differed significantly from the benzylisoquinolinium agents (P0.05) at both temperatures. The ratios of IC50 (inhibitory concentration, 50%) with and without neostigmine at hypothermia were slightly higher for the steroidal agents, indicating slight enhancement of antagonism by neostigmine at 27 degrees C. In contrast, the ratios were significantly greater at 27 degrees C (P0.05) for isoquinolinium agents, implying significant enhancement of antagonism. Our results indicate that at 27 degrees C the potency of all steroidal agents increased and neostigmine-induced antagonism was slightly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaesthetists choose daily among wide varieties of neuromuscular blocking drugs and rapidly acting hypnotic agents. This study sought to determine whether definitive, immediate knowledge of drug cost might influence clinician choices, ultimately reducing the cost of anaesthesia care. Faculty anaesthetists, residents in training, and nurse anaesthetists served as subjects in this prospective, sequential, blinded study of prescribing habits. Weekly inventories of selected neuromuscular blocking and rapidly acting hypnotic agents were performed over 24 wk at a tertiary- care hospital. Supermarket style price stickers plainly indicating the hospital cost of each unit of drug appeared continually for 13 wk following an initial 11 wk control period. Both actual usage data in priced units as well as data normalized by total anaesthesia duration underwent comparison between control and priced periods. The usage of pancuronium, vecuronium, atracurium, mivacurium, succinylcholine, thiopentone, etomidate, and propofol did not differ in the control from the priced periods. Pipecuronium decreased after sticker placement (2 vs 1 viab · wk−1 median, P < 0.05), as did methohexitone (39 ± 9.0 [SD] vs 29 ± 11 syringes · wk−1, P < 0.05). Ketamine usage normalized by total anaesthesia duration increased (P < 0.05) following sticker placement. The weekly cost of all drugs inventoried normalized for caseload did not differ during the measurement periods. Immediate cost awareness, implemented simply as price stickers on drug units, had minimal impact on clinicians’ drug usage in a tertiary care setting.

Pipecuronium bromide, a new neuromuscular relaxant with steroidal structure, is devoid of effects on the autonomic nervous system and may be useful in patients where haemodynamic stability is mandatory. However, tracheal intubation may alter this haemodynamic profile. Therefore, we carried out a prospective double-blind study in 30 patients undergoing coronary artery bypass surgery with the purpose (1) of determining if intubation influenced the haemodynamic stability in patients paralyzed with pipecuronium and (2) of comparing plasma catecholamine concentrations after pipecuronium with those after pancuronium. Thirty patients were randomized into two groups receiving either pipecuronium 100 micrograms.kg-1 or pancuronium 150 micrograms.kg-1 after induction of anaesthesia with midazolam and fentanyl. Haemodynamic variables and plasma catecholamines were measured before and after induction, after the muscle relaxant three times and twice after intubation. After anaesthesia induction decreases in heart rate (HR), mean arterial pressure (MAP) and cardiac index (CI) were observed in both groups. These haemodynamic variables were unchanged after pipecuronium whereas after pancuronium HR increased from 53 +/- 11 b.min-1 to 64 +/- 9 b.min-1 after induction (P0.05) and CI from 2.5 +/- 0.5 L.min-1 to 3.0 +/- 0.8 L.min-1 (P0.05). Furthermore ECG signs of myocardial ischaemia appeared in four patients after pancuronium and the decay of plasma norepinephrine concentration was slower than with pipecuronium. We conclude that pipecuronium given after induction of anaesthesia is free of sympathomimetic or vagolytic activity and does not influence haemodynamic variables for up to ten minutes after tracheal intubation.

This study was performed to determine the optimum dose of pancuronium (n = 30) and pipecuronium (n = 30) under continuous sedation and analgesia in the intensive care unit (ICU). This was an open clinical investigation in 60 critically ill patients with head injury, multiple trauma (in some complicated with sepsis and multi-organ failure), requiring neuromuscular block for ventilation for at least 48 h. Emphasis was placed on the neuromuscular monitoring with a peripheral nerve stimulator and adequate sedation and analgesia. Satisfactory block was achieved in all cases with an average dose of 3 mg/h with either compound. None of the patients experienced prolonged paralysis, muscle weakness, or other neuromuscular dysfunctions in the postventilatory period. We suggest that adequate use of sedative hypnotics and opioids plus neuromuscular monitoring allowed us to optimize the dose of muscle relaxants according to the need of individual patients.

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)

Four neuromuscular blocking drugs, doxacurium, mivacurium, pipecuronium, and rocuronium have been or are about to be introduced into clinical practice. The purpose of this MiniReview is to describe their pharmacology, to consider their place in clinical anaesthetic practice, and to examine whether the needs of the clinician have been met. Two of the agents (doxacurium, mivacurium) are benzylisoquinolines resembling atracurium and two (pipecuronium, rocuronium) are aminosteroids related to pancuronium and vecuronium. Two (doxacurium, pipecuronium) are long-acting compounds, similar in duration of action to pancuronium, although the need for such a profile is questionable. Rocuronium has an intermediate duration of action and produces its maximum effect within two minutes which is much more rapid than any other non-depolarizing relaxant and this is probably a result of its poor potency. However, the onset of paralysis is not as quick as after succinylcholine. Mivacurium is unique because it is metabolized by plasma cholinesterase which produces a rapid recovery although slower than succinylcholine. All of the new drugs are devoid of serious cardiovascular or other side effects. The anaesthetist is now presented with an armamentarium of safe, nondepolarizing muscle relaxants with varying durations of action. However, the rapid onset and recovery associated with succinylcholine are unique and important in the urgent control of a patient's airway and respiration. The indications for succinylcholine will not disappear and the search for a non-polarizing replacement will continue.

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).

Ten patients received increasing doses of pipecuronium at induction of anaesthesia. A dose response relationship was then constructed from which ED90 and ED95 values were measured as 43.4 micrograms.kg-1 and 50.5 micrograms.kg-1 respectively. A further 30 patients received pipecuronium in a dose sufficient to produce greater than 90% neuromuscular block. When the first contraction of the train-of-four had returned to 10% of control, a small increment of atracurium (1.1 mg), vercuronium (0.25 mg) or pipecuronium (0.21 mg) was administered, and this was repeated subsequently using the same criterion of recovery on each occasion. The duration and intensity of the block with pipecuronium increments remained constant. The duration of the block following atracurium or vecuronium was progressively less with subsequent increments until steady state was reached. The final mean durations at steady state were pipecuronium 7.37 min, atracurium 6.99 min, and vecuronium 5.15 min.

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.