Patricia B. Embree

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.

Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men

BACKGROUND Recovery from general anesthesia is governed by pharmacodynamic and pharmacokinetic factors. Gender has not previously been recognized as a factor influencing the time to emergence from general anesthesia. METHODS This multicenter study was originally designed to measure the effects of the bispectral index on intraoperative anesthetic management and patient recovery. We compared the wake-up and recovery times of 274 adults after propofol/alfentanil/nitrous oxide anesthesia. Patients were randomly assigned to have the titration of propofol performed with or without the use of bispectral index monitoring. Specific guidelines were given for the titration of drugs. The aim in all cases was to provide a safe anesthetic with the fastest possible recovery. RESULTS There was a significant reduction in propofol dose, time to eye opening, and response to verbal command when the anesthetic was titrated using the bispectral index. Unexpectedly, gender proved to be a highly significant independent predictor for recovery time. Women woke significantly faster than men: the time from end of anesthesia to eye opening was 7.05 versus 11.22 min, P < 0.05, and response to verbal command was 8.12 versus 11.67 min, P < 0.05. These differences were significant at all four study sites and in each treatment group. Men consistently had prolonged recovery times compared to women, P < 0.001. There was no difference in the dose of anesthetic used between gender. CONCLUSIONS Gender appears to be an important variable in recovery from general anesthesia. These findings may explain the increased reported incidence of awareness in women (three times more frequent) and support the need to include gender as a variable in pharmacokinetic and pharmacodynamic studies of anesthetic drugs.

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)

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.

Pharmacokinetics and Pharmacodynamics of Doxacurium in Young and Elderly Patients During Isoflurane Anesthesia

Preliminary disposition studies of the investigational, long-acting muscle relaxant doxacurium chloride (Nuromax) have demonstrated dual elimination by renal and hepatobiliary pathways, as well as slow hydrolysis by plasma cholinesterase. The present study compares the kinetics and dynamics of doxacurium in eight ASA physical status I or II elderly patients (67–72 yr of age) and eight ASA I or II young patients (22–49 yr of age). After institutionally approved written informed consent, kinetic and dynamic measurements were made after a 25-μg/kg bolus injection of doxacurium during 1.25 MAC nitrous oxide/oxygen/ isoflurane anesthesia. Maximum twitch depression was similar in older patients (96.4% ± 1.3%) to that in the young patients (96.6% ± 1.8%). The time to achieve this level of block was significantly longer in the elderly than in the young (11.2 ±1.1 min versus 7.7 ±1.0 min, respectively). Recovery times to twitch heights of 5% and 25% of control tended to be prolonged and were more variable in the elderly (82.6 ± 17.2 and 97.1 ± 20.1 min, respectively) than in the young (54.8 ± 9 and 67.5 ± 8.2 min, respectively). Elimination half-life (96 ± 20 min) and clearance (2.47 ± 0.69 mL-kg−1-min−1) in the elderly patients were not statistically different from values found in the younger group. Volume of distribution at steady state in the elderly (220 ± 80.2 mL/kg) was significantly larger than in the young (150 ± 40.0 ml/kg). Renal excretion of unchanged drug was an important route of elimination, accounting for 24% of the dose in the elderly and 31% in the young. The observed pharmacokinetic and dynamic profile suggests that doxacurium may be given in a similar dosage regimen to both young and elderly patients.

Inhaled induction and emergence from desflurane anesthesia in the ambulatory surgical patient: the effect of premedication.

We studied the effect of premedication (1 microgram/kg fentanyl and 0.04 mg/kg midazolam 5 min before induction of anesthesia) on airway reactivity and hemodynamic stability during inhaled induction using desflurane in 10 ambulatory surgical patients. Eight patients who were anesthetized without premedication served as the controls. Induction and emergence were rapid and unaffected by premedication. End-tidal and inspired concentrations of desflurane at loss of consciousness were significantly reduced by premedication (10.1% end-tidal/14.1% inspired, no premedication, vs. 5.3% end-tidal/8.9% inspired, premedication). Airway irritability was markedly attenuated by premedication (100% no premedication versus 30% premedicated), as was apnea (37.5% no premedication versus 0% premedicated). We observed an increase in mean arterial blood pressure and heart rate after loss of consciousness (mean arterial pressure 103 vs 121 mm Hg, heart rate 73 vs 100 bpm) in the unpremedicated patients, whereas both groups demonstrated a decrease in mean arterial blood pressure with no change in heart rate when baseline values were compared to those at incision (103 vs 74 mm Hg, no premedication, 99 vs 81 mm Hg premedicated). Patient acceptability was satisfactory and unchanged by premedication. We recommend the use of such premedication when desflurane is used during the induction of anesthesia.

The Effect of Ondansetron on Atracurium-Induced Neuromuscular Blockade

STUDY OBJECTIVE To determine whether treatment with ondansetron, a new antiemetic drug, affects nondepolarizing neuromuscular blockade. DESIGN Randomized, double-blind, prospective study. SETTING Operating room at a university medical center. PATIENTS 30 ASA physical status I and II patients scheduled for elective surgery. INTERVENTIONS After the induction of anesthesia with midazolam 2 to 4 mg/kg, sodium thiopental 6 to 8 mg/kg, and fentanyl 4 to 8 micrograms/kg, the ulnar nerve was stimulated at the wrist through subcutaneous needle electrodes at a frequency of 0.15 Hz. The response to stimulation was measured and recorded with a force-displacement transducer applied to the thumb. Patients were randomized to one of three treatment groups. A steady baseline to ulnar nerve stimulation with nitrous oxide-oxygen-opioid-thiopental anesthesia was established. The first study group (Group 1) received a placebo, the second group (Group 2) received 8 mg of ondansetron, and the third group (Group 3) received 16 mg of ondansetron as an intravenous infusion over 5 minutes. Patients were then given incremental doses of atracurium 0.05 mg/kg at 3-minute intervals to establish approximately 95% twitch inhibition so as to construct a dose-response curve. An atracurium infusion was then begun to maintain a constant degree of neuromuscular blockade. At the end of surgery, patients were allowed to recover spontaneously, or pharmacologic antagonism of residual neuromuscular blockade was achieved with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Mechanomyographic response to train-of-four stimuli (2 Hz for 2 seconds) every 20 seconds was monitored during the atracurium infusion and recovery from neuromuscular blockade. MEASUREMENTS AND MAIN RESULTS Log dose-response curves were determined for the study groups and compared using analysis of variance (ANOVA). The 50%, 75%, and 95% effective doses (ED50, ED75, and ED95) were calculated from the equation describing the log dose-response. Maintenance infusion rates were determined, and the neostigmine-accelerated recovery index of 25% to 75% was measured for each group. The results were compared using ANOVA. There were no significant differences among the treatment groups with respect to maintenance infusion rate (7.8 +/- 1.8 micrograms/kg/min for Group 1, 7.7 +/- 2.5 micrograms/kg/min for Group 2, and 7.3 +/- 2.3 micrograms/kg/min for Group 3) or neostigmine-accelerated recovery interval of 25% to 75% (4.5 +/- 2.3 minutes, 4.4 +/- 3.1 minutes, 6.6 +/- 3.9 minutes in Groups 1, 2, and 3, respectively). The log dose-response data for Groups 1, 2, and 3 did not differ significantly (p = 0.068), and the calculated ED95 in each treatment group demonstrated no dose-related change (0.254 +/- 0.022, 0.279 +/- 0.033, and 0.240 +/- 0.022 for Groups 1, 2, and 3, respectively). CONCLUSIONS Ondansetron is an antiemetic drug that can be used in the perioperative period without concern for potentiation of nondepolarizing neuromuscular blockade, change in atracurium maintenance dose, or change in rate of neostigmine-induced recovery from neuromuscular blockade with atracurium.