John J. Savarese

The Clinical Neuromuscular Pharmacology of Mivacurium Chloride (bw B1090u). A Short-acting Nondepolarizing Ester Neuromuscular Blocking Drug

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titralorat 88% of the rate of succinylcholine at pH 7.4,37°C and 5 μM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 ± 0.5 min, and recovery to 95% twitch height occurred 24.5 ± 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 ± 0.3 min; 95% recovery developed within 30.4 ± 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 ± 7.1/47.1 min, SE/SD) for maintenance of 95 ± 4% twitch inhibition, the mean 5–95% and 25–75% recovery indices after discontinuation of infusion were 14.4 ± 0.6 and 6.5 ± 0.3 min (P > 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 ± 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 ± 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 ± 1.9% within 3.4 ± 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test case of reverals, eight patients electively received ncostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 ± 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 ± 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.

Monitoring of neuromuscular function.

Monitoring neuromuscular transmission provides valuable information to the anesthesiologist. The acquisition of relevant data contributes to a more predictable and rational approach to the use of muscle relaxants and assures improved patient care during and in the immediate postoperative period. Clinical noninvasive criteria such as the presence or absence of diplopia and or ptosis, the ability to open the eyes widely, protrude the tongue or swallow, measurement of hand grip strength or head lift or assessment of the vital capacity are limited to awake and cooperative patients. Measurement of inspiratory force and tidal volume can be evaluated in anesthetized patients breathing spontaneously. Central depressant drugs tend to depress these respiratory parameters. Accordingly, the assumption that relaxants are responsible for respiratory depression at the end of an anesthetic can only be documented when impairment of neuromuscular transmission can be demonstrated. The most reliable method of measuring neuromuscular function is to stimulate an accessible peripheral motor nerve and measurement of the evoked response of the skeletal muscle or muscles innervated by the stimulated motor nerve. The evoked muscle response depends on the pattern of motor nerve stimulation: Single twitch stimuli at a defined frequency, tetanic stimulation, posttetanic single twitch stimulation or train-of-four stimulation. The response to these different modes of stimulation can be assessed either mechanically (evoked tension response) or electrically (evoked electromyography: EMG or integrated EMG). These response criteria can be employed either individually or combined to evaluate the response to muscle relaxants and to assess the adequacy of recovery from neuromuscular blockade.

Histamine Release during Morphine and Fentanyl Anesthesia

High doses of morphine produce peripheral vasodilation and frequently significant hypotension. These effects are thought to be due, in part, to the release of histamine. One putative advantage of high-dose fentanyl anesthesia is its relatively small effect on peripheral vascular resistance. In a randomized study, the authors examined the possibility that the hemodynamic differences between morphine and fentanyl might be attributable to histamine release. Fifteen patients were studied prior to coronary artery bypass surgery. Subjects received an infusion of morphine (1 mg·kg−1, iv at 100 Amg-·kg−1·min−1 [n – 8]) or fentanyl (50 μg·kg−1 at 5 μg·kg−1·min−1 [n = 7]). Patients in the morphine group had an average 750 per cent peak increase in plasma histamine accompanied by a significant decrease in mean arterial pressure (-27 mmHg) and systemic vascular resistance (-520 dyne·s·cm−1). The greatest decrease in systemic vascular resistance occurred in those patients with the highest levels of plasma histamine (r = −0.81). Patients in the fentanyl group had no change in plasma histamine and no decrease in arterial pressure or systemic vascular resistance. Cardiac output and heart rate were comparable between the two groups. Differences in the release of histamine account for most, if not all, of the different effects of morphine and fentanyl on the peripheral vasculature.

The Clinical Neuromuscular Pharmacology of 51W89 in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia

Background Atracurium is a mixture of ten stereoisomers. 51W89, one of these isomers, is a potent nondepolarizing intermediate‐duration neuromuscular blocking agent. Preclinical studies have shown 51W89 to be significantly more potent than atracurium but with a similar neuromuscular blocking profile. This study was undertaken to establish the neuromuscular blocking potency and pharmacodynamics of 51W89 in patients undergoing elective surgical procedures. Methods Ninety‐nine ASA physical status 1 or 2 patients undergoing elective surgical procedures under nitrous oxide/opioid/barbiturate anesthesia were studied. The neuromuscular blocking effect of 51W89 was assessed after administration of bolus doses from 0.015 to 0.4 mg/kg, as well as during and after continuous infusions from 11 to 249 min in length. Results The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.048 mg/kg. At 0.10 mg/kg, maximum block developed within 5.2 plus/minus 0.3 min, and recovery to 95% twitch height occurred 64.4 plus/minus 3.9 min after injection. At 0.4 mg/kg, onset was 1.9 plus/minus 0.1 min, and 95% recovery developed within 121.0 plus/minus 5.9 min. Comparative recovery indexes from 5% to 95% or from 25% to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.4 mg/kg (means ranged from 29.6 to 32.3 min and from 12.6 to 14.3 min, respectively). The average infusion rate necessary to maintain approximately 95% twitch suppression was 1.35 micro gram/kg/min. Recovery indexes from infusions were 5–95% 33.2 plus/minus 1.8 min and 25–75% 15.0 plus/minus 0.6 min, not differing significantly from recovery indexes from single bolus doses. Twenty‐ five patients received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at twitch height recovery of between 6% and 21%. Antagonism to 95% control twitch height developed within 6.8 plus/minus 0.3 min, and the neostigmine‐accelerated 25–75% recovery index was 2.8 plus/minus 0.2 min. Conclusions 51W89 is a potent nondepolarizing neuromuscular blocking agent that shows noncumulative intermediate‐duration neuromuscular blocking pharmacodynamics.

The use of H1 and H2 histamine antagonists with morphine anesthesia: a double-blind study.

High doses of morphine can produce significant cardiovascular effects generally attributed to histamine release. The authors examined the possibility that H1 and H2 histamine antagonists might prove beneficial in preventing these responses. In a randomized double-blind study, four groups of 10 patients each received 1 mg/kg morphine and either a placebo, diphenhydramine (H1), cimetidine (H2), or both of the histamine antagonists. The morphine-placebo group demonstrated a marked elevation in plasma histamine levels (880 ± 163 to 7437 ± 2684 pg/ml), a decrease in systemic vascular resistance (SVR) (15.5 to 9.0 l torr/(1 ± min−1) and diastolic BP (71 ± 3 to 45 ± 4 torr) and an increase in cardiac index (CI) (2.4 ± 0.2 to 3.0 ± 0.21·min−1·m−2). The administration of either cimetidine or diphenhydramine with morphine provided minimal protection. Those patients who received morphine and both antagonists demonstrated significant attenuation of these responses (CI 2.5 ± 0.2 to 2.5 ± 0.1 1·min−1·m−2; SVR 17.4 to 14.6 torr/(1·min−1) although plasma histamine levels showed a comparable increase (1059 ± 222 to 7653 ± 4242 pg/ml). These data demonstrate directly that many of the hemodynamic effects of morphine can be attributed to histamine release. They further demonstrate that significant hemodynamic protection can be obtained by the use of histamine antagonists and the combination of H1 and H2 antagonists is superior to either given alone.

The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia

The dose-effect relationship of mivacurium chloride on arterial blood pressure, heart rate, and plasma histamine was determined in 97 consenting ASA physical status I-II patients receiving nitrous oxide-oxygen-opiate-barbiturate anesthesia. In the absence of surgical stimulation during steady state anesthetic conditions with controlled ventilation, average maximum change in tachograph-counted heart rate was 7% or less after 10-15-s injection of mivacurium at all doses from 0.03 to 0.30 mg/kg. Average peak change in mean arterial pressure measured via radial arterial catheter was 7% or less after all doses from 0.03 to 0.15 mg/kg. Transient (0.2-4.5 min) decreases in arterial blood pressure were noted after 10-15-s injection in some patients at 0.20, 0.25, and 0.30 mg/kg. When they occurred, these changes were usually accompanied by facial erythema lasting 2-5 min and were correlated with increases in plasma histamine level (P less than 0.001). Facial erythema, decrease in blood pressure, and elevation of histamine level were all accentuated by increasing the dose of mivacurium and by more rapid injection of the drug. For example, mean blood pressure decreased an average of 13% after injection of mivacurium 0.25 mg/kg over 10-15 s. In contrast, during administration over 30 and 60 s of this dose, arterial pressure decreased 7.6 and 1.5%, respectively (P less than 0.001, 10-15 s vs. 60-s injection). Average peak histamine level, which increased to 132% of control after administration of 0.25 mg/kg over 10-15 s, did not change after injection over 60 s.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant.

Atracurium, a new non-depolarizing neuromuscular blocking agent, was studied in 70 patients anesthetized with fentanyl, thiopental, and nitrous oxide-oxygen. The dose found to produce 95% twitch inhibition (ED95) was 0.2 mg/ kg. The onset time from injection to maximum depression of twitch was 4.0 minutes at this dose; the duration to 95% recovery was 44.1 minutes. Twice the ED95 dose (0.4 mg/kg) had an onset time of 1.7 minutes and a duration of 63.5 minutes. No cardiovascular effects were observed in this dosage range. At higher doses (0.5 and 0.6 mg/kg) arterial pressure decreased 13% and 20% and heart rate increased 5% and 8%, respectively. Sixteen patients received at least four successive doses of atracurium. No clinically significant cumulative effect could be shown when recovery from 25% to 75% of control twitch height was compared for initial and final doses in the series. Atracurium spontaneously decomposes at physiologic pH via the Hofmann elimination reaction and may also undergo ester hydrolysis independent of plasma cholinesterase. These proposed pathways of inactivation may explain the lack of cumulative effect and the drugs intermediate duration of action. Based on the results of this study, atracurium offers several clinical advantages and should undergo more extensive clinical trials.

The Cardiovascular Effects and Histamine-releasing Properties of 51W89 in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia

Background Atracurium consists of a mixture of ten stereoisomers. One of these isomers, 51W89, is a potent intermediate‐acting nondepolarizing neuromuscular blocking agent. Its ED95 is 0.05 mg *symbol* kg1 in patients receiving nitrous oxide/opioid anesthesia. In preclinical trials, 51W89 did not show evidence of histamine release in cats at doses up to 80 times the human ED95. This study was undertaken to determine the cardiovascular effects and histamine‐ releasing properties of 51W89 in patients undergoing elective surgical procedures. Methods Sixty patients, ASA physical status 1 or 2, anesthetized with nitrous oxide/fentanyl/thiopental were studied. Patients received either 2 times the ED95 of atracurium or 51W89 or 4 or 8 times the ED95 of 51W89 as a rapid intravenous bolus under stable anesthesia, before surgical stimulation. Blood pressure and heart rate were measured by oscillometry and the electrocardiogram in patients receiving 2 times the ED95 of 51W89 or atracurium and by an intraarterial catheter and a tachograph triggered by the arterial pulse waveform in patients receiving 4 or 8 times the ED95 of 51W89. Maximal blood pressure and heart rate changes during the 5 min after administration of the muscle relaxant were recorded. Venous blood samples were obtained before the administration of relaxant and at 2 and 5 min after the administration of relaxant for determination of plasma histamine concentrations by radioenzymatic assay. Results Maximal blood pressure and heart rate changes in all groups of patients receiving 51W89 were small and similar to those observed in patients receiving 2 times the ED95 of atracurium. The mean maximum percent changes (plus/minus SE) in heart rate and mean arterial pressure were ‐0.6 plus/minus 1.5 and 0.4 plus/minus 2.5, respectively, in the group receiving 2 times the ED95 atracurium; ‐ 1.3 plus/minus 3.3 and 2.3 plus/minus 4.4, respectively, in the group receiving 2 times the ED95 51W89; ‐2.6 plus/minus 1.0 and 2.6 plus/minus 1.5, respectively, in the group receiving 4 times the ED95 51W89; and 2.4 plus/minus 1.5 and 1.0 plus/minus 1.3, respectively, in the group receiving 8 times the ED95 51W89. No patient developed a decrease in blood pressure greater or equal to 20% or an increase in heart rate greater or equal to 20% that was attributable to muscle relaxant administration. There was no dose‐related change in plasma histamine concentration associated with the administration of 51W89. One patient in the study developed transient facial flushing after the administration of atracurium. Conclusions 51W89 is a benzylisoquinolinium‐type, nondepolarizing muscle relaxant that does not affect plasma histamine concentrations. No cutaneous flushing or clinically important cardiovascular effects were noted after rapid injection of doses up to and including 8 times its ED sub 95 (0.4 mg *symbol* kg1) in healthy patients undergoing elective surgical procedures.

The Phamtacokinetics and Pharmacodynamics of the Stereoisomers of Mivacurium in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia

BackgroundMivacurium consists of a mixture of three stereoisomers: cis-trans (34–40%), trans-trans (52–60%), and cis-cis (4–8%). These isomers differ in potency (the trans-trans and the cis-trans isomers are equipotent and the cis-cis isomer is l/13th as potent a neuromuscular blocking agent) and in rates of in vitro hydrolysis (in vitro half-lives are less than 2 min for the cis-trans and trans-trans isomers and 276 min for the cis-cis Isomer). The current study was undertaken to determine the pharmacoklnetic profile of the individual stereoisomers of mivacurium, to evaluate the dose-proportionality of the more potent trans-trans and cis-trans isomers, and to evaluate the pharmacodynamics of mivacurium in healthy adult patients receiving a consecutive two-step infusion of mivacurium. MethodsEighteen ASA physical status 1 or 2 adult male patients undergoing elective surgery under nitrous oxide/oxygen/fentanyl anesthesia were studied. Neuromuscular function was monitored using a mechanomyograph at a frequency of 0.15 Hz. An infusion of mivacurium was begun at 5 μg. kg−1. min−1. Sixty minutes later, the infusion rate was doubled to 10 μg. kg−1. min−1, and, 60 min after that, the infusion was discontinued. All patients were allowed to recover spontaneously from mlvacurium-lnduced neuromuscular block. Venous blood samples were drawn for the determination of the plasma concentrations of each isomer of mivacurium by a stereospecific high performance liquid chromatographic method. Pharmacokinetic parameters were determined using noncompartmental analysis. ResultsDuring the 5-μg. kg−1. min−1 infusion, patients developed 83–2 ± 13.6% neuromuscular block. Increasing the infusion to 10 μg. kg−1. min−1 increased the depth of block to 99.0 ± 2.0%. After discontinuation of the infusion, patients returned to 25% of their baseline muscle strength in 9.3 ± 3.7 min and had 25–75% and 5–95% recovery indexes of 7.2 ± 1.8 and 16.8 ± 3.7 min, respectively. The volumes of distribution (Vβ) of the cis-trans, trans-trans, and cis-cis isomers were 0.29 ± 0.24, 0.15 ± 0.05, and 0.34 ± 0.08 1/kg, respectively. During the 5-μg. kg−1. min−1 infusion, the steady-state clearances of the potent cis-trans and trans-trans isomers were 106 ± 67 and 63 ± 34 ml. min−1. kg−1, respectively; the clearance of the less potent cis-cis isomer was 4.6 ± 1.1 ml.min−1.kg−1. The elimination half-lives of the cis-trans and trans-trans isomers were 1.8 ±1.1 and 1.9 ± 0.7 min, respectively, and that of the cis-cis isomer was 52.9 ± 19.8 min. Clearance of the cis-trans and trans-trans isomers did not vary with infusion rate. ConclusionsThe short elimination half-lives and high metabolic clearances of the potent cis-trans and trans-trans isomers are consistent with the short duration of action of mivacurium. The cis-cis isomer does not appear to produce significant neuromuscular block as evident by the return of twitch height to baseline despite persistent cis-cis isomer concentrations.

Clinical Pharmacology of Doxacurium Chloride A New Long-acting Nondepolarlzlng Muscle Relaxant

Doxacurium chloride (BW A938U) is a bis-quaternary benzyl-isoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 Mg/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygenfentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 μg/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 μg/kg. At 1.3 times the EDg5 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 ± 4.1 (n = 23 of 26) and 75.7 ± 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 ± 10.3 (n = 8 of 8) and 83.0 ± 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 μg/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED05. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.