Cynthia A. Lien

A survey of current management of neuromuscular block in the United States and Europe.

BACKGROUND: Postoperative residual neuromuscular block is a frequent occurrence. Recent surveys of clinical practice in Europe suggest that neuromuscular blocking drugs are often administered without appropriate monitoring. No comparable survey has been undertaken in the United States (US). From this survey, we compared current clinical neuromuscular practice and attitudes between anesthesia practitioners in the US and Europe. METHODS: We conducted an Internet-based survey among anesthesia practitioners in the US and Europe. The Anesthesia Patient Safety Foundation and the European Society of Anaesthesiology e-mailed all of their active members, inviting them to anonymously answer a series of questions on a dedicated Internet Protocol address–sensitive website. The survey was available online for 60 days. The &khgr;2 test and Fishers exact test were used to compare clinical survey items between the 2 cohorts. RESULTS: A total of 2636 completed surveys were received. Most respondents from the US (64.1%) and Europe (52.2%) estimated the incidence of clinically significant postoperative residual neuromuscular weakness to be <1% (P < 0.0001). Routine pharmacologic reversal was less common in Europe than in the US (18% vs 34.2%, respectively; P < 0.0001), and quantitative monitors were available to fewer clinicians in the US (22.7%) than in Europe (70.2%) (P < 0.0001). However, 19.3% of Europeans and 9.4% of Americans never use neuromuscular monitors. Most respondents reported that neither conventional nerve stimulators nor quantitative train-of-four monitors should be part of minimum monitoring standards. CONCLUSIONS: Our results suggest a lack of agreement among anesthesia providers about the best way to monitor neuromuscular function. Efforts to improve awareness by developing formal training programs and/or publishing official guidelines on best practices to reduce the incidence of postoperative neuromuscular weakness and patient morbidity are warranted.

A Randomized, Dose-Finding, Phase II Study of the Selective Relaxant Binding Drug, Sugammadex, Capable of Safely Reversing Profound Rocuronium-Induced Neuromuscular Block

BACKGROUND:The reversal of a deep neuromuscular blockade remains a significant clinical problem. Sugammadex, a modified &ggr;-cyclodextrin, encapsulates steroidal neuromuscular blocking drugs, promoting their rapid dissociation from nicotinic receptors. Sugammadex is the first drug that acts as a selective relaxant binding agent. METHODS:We enrolled 50 patients into a Phase II dose-finding study of the efficacy and safety of sugammadex. Subjects, anesthetized with nitrous oxide and propofol, were randomized to one of two doses of rocuronium (0.6 or 1.2 mg/kg) and to one of five doses of sugammadex (0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg). Neuromuscular monitoring was performed using the TOF Watch SX® acceleromyograph. Recovery was defined as a train-of-four ratio ≥0.9. Sugammadex was administered during profound block when neuromuscular monitoring demonstrated a posttetanic count of one or two. RESULTS:Reversal of neuromuscular block was obtained after administration of sugammadex in all but the lowest dose groups (0.5–1.0 mg/kg) where several subjects could not be adequately reversed. At the 2 mg/kg dose all patients were reversed with sugammadex, but there was significant variability (1.8–15.2 min). Patient variability decreased and speed of recovery increased in a dose-dependent manner. At the highest dose (8 mg/kg), mean recovery time was 1.2 min (range 0.8–2.1 min). No serious adverse events were reported during this trial. CONCLUSIONS:Sugammadex was well tolerated and effective in rapidly reversing profound rocuronium-induced neuromuscular block. The mean time to recovery decreased with increasing doses. Profound rocuronium-induced neuromuscular block can be reversed successfully with sugammadex at doses ≥2 mg/kg.

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.

Dexmedetomidine and neurocognitive testing in awake craniotomy.

Patients are selected for awake craniotomy when the planned procedure involves eloquent areas of the brain, necessitating an awake, cooperative patient capable of undergoing neurocognitive testing. Different anesthetic combinations, including neurolept, propofol with or without opioid infusions, and asleep-awake-asleep techniques, have been reported for awake craniotomy. In all these techniques, respiratory depression has been reported as a complication. In this case series dexmedetomidine, the highly selective alpha-2 adrenoreceptor agonist, was selected for its lack of respiratory depression as well as its sedative and analgesic properties. The charts of 10 consecutive patients who underwent awake craniotomy with dexmedetomidine infusion were reviewed. Five of the patients underwent “asleep-awake” technique with a laryngeal mask airway and volatile agent. Five patients received moderate to conscious sedation. All patients received a dexmedetomidine load of 0.5 to 1.0 &mgr;g/kg over 20 minutes followed by an infusion at rates of 0.01 to 1.0 &mgr;g/kg per hour. Four patients had extensive sensory and motor testing, and six underwent neurocognitive testing, including naming, reading, counting, and verbal fluency. There were no permanent neurologic deficits, except one patient who had an exacerbation of preoperative language difficulties. Dexmedetomidine appears to be a useful sedative for awake craniotomy when sophisticated neurologic testing is required.

The comparative effects of sevoflurane versus propofol in the induction and maintenance of anesthesia in adult patients.

A randomized, prospective study was performed at four institutions to compare anesthetic induction, maintenance, and recovery characteristics between sevoflurane-and propofol-based anesthesia in 186 ASA physical status I and II patients undergoing elective surgical procedures of 1-3 h. Group 1 (n = 93) patients received sevoflurane-nitrous oxide for both induction and maintenance of anesthesia while Group 2 (n = 93) received propofol-nitrous oxide anesthesia. Induction of anesthesia and tracheal intubation times were significantly shorter with propofol (2.2 +/- 0.2 min, 5.1 +/- 0.3 min, respectively) than with sevoflurane (3.1 +/- 0.2 min, 7.2 +/- 0.3 min, respectively). Emergence times after sevoflurane (8.8 +/- 1.2 min) were significantly shorter than with propofol (13.2 +/- 1.2 min). Overall frequency of complication-free induction, maintenance, and emergence did not differ between the two anesthetic groups. However, side effects involving airway excitement were more prevalent during mask induction with sevoflurane as compared to propofol. Patients in the sevoflurane group were oriented and required postoperative analgesia much earlier than those who received propofol. Both groups were hemodynamically stable throughout the study period. The incidence of postoperative nausea, vomiting, and pain-discomfort scores were similar between the two groups. Urinary specific gravity decreased in the sevoflurane-treated group while serum creatinine and urinary pH were unchanged from preoperative values in both groups. Sevoflurane compared favorably with propofol when used for anesthesia for elective procedures of 1-3 h duration. (Anesth Analg 1996;82:479-85)

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.

Importance of the organ-independent elimination of cisatracurium.

Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL [centered dot] min-1 [centered dot] kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans. (Anesth Analg 1996;83:1065-71)

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 GW280430A in Humans

BackgroundAn ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans. MethodsThirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring. ResultsThe ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25–75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 × ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 × ED95 exhibited plasma histamine concentrations indicative of significant histamine release. ConclusionsGW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 × ED95 seem to be free of side effects and seem to be able to provide relaxation within 60–90 s.

Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia

Background Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED95. Methods Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus dose of 0.1 or 0.2 mg *symbol* kg sup -1 (2 or 4 times the ED95, respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio greater or equal to 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite. Results The clearances (5.28+/-1.23 vs. 4.66+/- 0.67 ml *symbol* min sup -1 *symbol* kg sup -1) and terminal elimination half-lives (22.4+/-2.7 vs. 25.5+/-4.1 min) were not statistically different between patients receiving 0.1 mg *symbol* kg sup -1 and 0.2 mg *symbol* kg sup -1, respectively. Maximum concentration values for laudanosine averaged 38+/-21 and 103+/-34 ng *symbol* ml sup -1 for patients receiving the 0.1 and 0.2 mg *symbol* kg sup -1 doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101+/-27 and 253+/-51 ng *symbol* ml sup -1, respectively. Monoquaternary acid was not quantified in any plasma sample. Conclusions Cisatracurium undergoes Hofmann elimination to form laudanosine. The pharmacokinetics of cisatracurium are independent of dose after single intravenous doses of 0.1 and 0.2 mg *symbol* kg sup -1.