Development and potential clinical impairment of ultra-short-acting neuromuscular blocking agents.

Developing a non-depolarizing neuromuscular blocking agent that, like succinylcholine, has a rapid onset and a short duration of effect remains a goal of ongoing research. While rocuronium fills a portion of this need, the large doses required for rapid intubation render it a much longer-acting neuromuscular blocking agent. Postoperative residual neuromuscular block (NMB) is an increasingly recognized complication of non-depolarizing neuromuscular blocking agents. This occurs because of dosing choices for neuromuscular blocking agents and anticholinesterases as well as insensitivity of typically used monitors of depth of NMB. While antagonism of NMB is necessary with partial recovery, it is unnecessary with more complete recovery. Even when monitoring with an accelerograph, reversal of NMB is complicated. In addition to the pharmacodynamics of the individual neuromuscular blocking agents, factors such as timing of anticholinesterase administration, dose of anticholinesterase, concomitant medications, electrolyte abnormalities, and hepatic or renal disease can influence the degree of reversal. Sugammadex works differently than anticholinesterases and, when administered in appropriate doses, can reverse even profound block induced with vecuronium or rocuronium. Two new fumarate neuromuscular blocking agents have a rapid onset of effect and can be reversed at any time by administration of cysteine, which could significantly reduce the risk of postoperative residual NMB.

Neuromuscular dose-response studies: determining sample size.

BACKGROUND: Investigators planning dose-response studies of neuromuscular blockers have rarely used a priori power analysis to determine the minimal sample size their protocols require. Institutional Review Boards and peer-reviewed journals now generally ask for this information. This study outlines a proposed method for meeting these requirements. METHODS: The slopes of the dose-response relationships of eight neuromuscular blocking agents were determined using regression analysis. These values were substituted for γ in the Hill equation. When this is done, the coefficient of variation (COV) around the mean value of the ED50 for each drug is easily calculated. Using these values, we performed an a priori one-sample two-tailed t-test of the means to determine the required sample size when the allowable error in the ED50 was varied from ±10-20%. RESULTS: The COV averaged 22% (range 15-27%). We used a COV value of 25% in determining the sample size. If the allowable error in finding the mean ED50 is ±15%, a sample size of 24 is needed to achieve a power of 80%. Increasing 'accuracy' beyond this point requires increasing greater sample sizes (e.g. an 'n' of 37 for a ±12% error). CONCLUSIONS: On the basis of the results of this retrospective analysis, a total sample size of not less than 24 subjects should be adequate for determining a neuromuscular blocking drug's clinical potency with a reasonable degree of assurance.

Determining the potency of neuromuscular blockers: are traditional methods flawed?

BACKGROUND: Traditionally, the clinical potency of neuromuscular blocking drugs has been measured using linear regression analysis (LRA) after log dose and probit or logit data transformation. However, probit and logit analyses are meant to handle only quantal responses with binomial error distributions, not continuous data such as per cent of maximal response. Some statisticians now consider this approach outmoded and assert that non-linear regression (NLR) is the preferred way to analyse sigmoidal dose-response relationships. We were interested in the degree to which the method of regression analysis alters calculated ED(50) and ED(95) values. METHODS: We analysed raw data for succinylcholine, rocuronium, rapacuronium, and cisatracurium from previously published studies using both LRA and NLR to determine the ED(50) and ED(95) values and the respective slopes of the dose-response relationships. We also estimated drug potency using the Hill equation (HE) using the slopes obtained from LRA and NLR. RESULTS: ED(50) values calculated by NLR, LRA, or the HE were interchangeable. LRA resulted in ED(95) values that were 13-18% lower than those determined by NLR. The 95% confidence limits (CL) for the ED(50) did not exceed +/-8% of the estimated value no matter how it was calculated vs +/-20-30% for the ED(95). CONCLUSIONS: The ED(50) is a very robust parameter. When comparing the potency of neuromuscular blockers, it is this value rather than the ED(95) that should be used. The CL for the ED(95), regardless of how it is calculated, are so wide that this parameter must be viewed, at best, as an approximation.

Postoperative narcotic requirement after microscopic lumbar discectomy is not affected by intraoperative ketorolac or bupivacaine.

STUDY DESIGN: Prospective, randomized, double-blind study. OBJECTIVE: To assess the efficacy of ketorolac and bupivacaine in reducing postoperative pain after microsurgical lumbar discectomy. SUMMARY OF BACKGROUND DATA: Microsurgical lumbar discectomy often is performed as an ambulatory procedure. Pain, nausea, and urinary retention may delay discharge. It was hypothesized that intraoperative ketorolac or bupivacaine would reduce postoperative pain as measured by morphine demand. METHODS: After Institutional Review Board (IRB) approval and informed consent, 30 patients undergoing single-level microsurgical lumbar discectomy under general anesthesia randomly received either intravenous ketorolac, intramuscular bupivacaine, or placebo before wound closure. After surgery, all patients received intravenous, MSO4, patient-controlled analgesia. MSO4 demand was compared between groups at 30 minutes and at 1, 4, 8, 16, 20, and 24 hours after surgery by one-way ANOVA. Pre- and postoperative pain was assessed by using a standard scale and was correlated to postoperative MSO4 demand by Pearson correlation. Significance was assumed at P < 0.05. RESULTS: There were no group differences in age, gender, weight, disc level, preoperative pain, or preoperative use of pain medication. Neither ketorolac nor bupivacaine decreased pain or nausea scores, MSO4 demand, or time to void and ambulation. Preoperative pain was significantly correlated to postoperative narcotic demand (r = 0.46, P < 0.01). Preoperative narcotic or NSAID use was not correlated to either preoperative pain scores or postoperative MSO4 requirement. CONCLUSIONS: Neither ketorolac nor bupivacaine decreased the postoperative narcotic requirement in patients undergoing microsurgical lumbar discectomy. Postoperative narcotic requirements are increased in patients who are in severe pain before surgery, regardless of preoperative narcotic use.

Effect of massive intraoperative thiopental loading on cardiovascular hemodynamics and myocardial performance.

Anesthetics that protect the brain may also depress the heart. We recently anesthetized a patient with a giant cerebral aneurysm of the basilar artery who had it clipped during circulatory arrest. Thiopental loading was carried out prior to and during cardiopulmonary bypass, and we monitored transesophageal echocardiographic function and the hemodynamic profile throughout. The patient demonstrated little change in cardiovascular parameters or myocardial performance, and we conclude that the massive dose of thiopental was well tolerated.

A comparison: the efficacy of sevoflurane-nitrous oxide or propofol-nitrous oxide for the induction and maintenance of general anesthesia.

STUDY OBJECTIVE: To compare sevoflurane-nitrous oxide with propofol-nitrous oxide for the induction and maintenance of anesthesia, and to determine the rates of recovery following each anesthetic. DESIGN: Randomized, controlled study. SETTING: Teaching hospital. PATIENTS: 50 ASA physical status I and II patients, ranging in age from 18 to 70 years. INTERVENTIONS: General anesthesia was induced with either sevoflurane or propofol and maintained with 60% to 70% nitrous oxide and either sevoflurane or a propofol infusion and supplemental fentanyl. At the conclusion of surgery, the oxygen flow was increased to 6 L/min and all anesthetics were discontinued simultaneously. Patients were monitored for the nature and speed of induction and emergency from anesthesia. MEASUREMENTS AND MAIN RESULTS: Induction of anesthesia was significantly slower in the sevoflurane group than in the propofol group (2.0 +/- 1.1 vs. 0.8 +/- 0.5 min, respectively). The ease of induction and the time required for emergence from anesthesia were the same in both study groups (eye opening: 9.0 +/- 4.4 min vs. 8.0 +/- 5.0 min; following commands: 11.2 +/- 5.0 min vs. 9.8 +/- 6.9 min; extubation: 9.1 +/- 4.5 min vs. 8.6 vs. 5.1 min in the sevoflurane and propofol groups, respectively). Patients in the sevoflurane group experienced nausea and vomiting more frequently than patients in the propofol group (13 and 5 patients vs. 3 and 0 patients in the sevoflurane and propofol groups, respectively), which were not related to the administration of neostigmine or intraoperative opioids. CONCLUSION: Sevoflurane allows for rapid inhalation induction of, and emergence from, general 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.

Efficacy and safety of divided dose administration of mivacurium for a 90-second tracheal intubation.

STUDY OBJECTIVE: To compare the safety and effectiveness of 0.25 mg divided doses of mivacurium chloride to succinylcholine for a 90-second tracheal intubation. DESIGN: Randomized, double-blind, multicenter study in two groups. SETTING: Operating rooms at four university medical centers. PATIENTS: 200 healthy ASA status I and II adult patients scheduled for elective surgery with general anesthesia and endotracheal intubation. INTERVENTIONS: Patients were premedicated with 1 to 2 mg midazolam and 2 micrograms/kg fentanyl. Anesthesia was induced with 2 mg/kg propofol. Group A received 0.25 mg/kg mivacurium given as a divided dose (0.15 mg/kg followed in 30 seconds with 0.1 mg/kg). Group B (control) received 1.5 mg/kg succinylcholine (SCh) preceded two minutes earlier by 50 micrograms/kg d-tubocurarine (dtc). MEASUREMENTS AND MAIN RESULTS: Tracheal intubation grading, train-of-four response of the adductor pollicis, heart rate (HR), and mean arterial blood pressure (MAP) were measured and evaluated. Chi-square analysis was performed for comparison between Group A and Group B with respect to the frequency distribution of intubation using the scores excellent, good, and poor and not possible (combined). Group B had a significantly higher excellent score of intubation than Group A, 84% versus 56% (p < 0.0001). No significant difference was found between the two groups when the scores excellent and good were combined (Fisher's Exact test, p = 0.28). The changes in MAP and HR were similar for the two groups. CONCLUSIONS: When Sch is not desirable, mivacurium 0.25 mg/kg given as a divided dose provides good to excellent intubation conditions 90 seconds after the initial dose without significant changes in MAP or HR. It can be an appropriate alternative for short surgical procedures. It must be emphasized that this conclusion does not apply to rapid-sequence induction-intubation.

Combining non-depolarizing neuromuscular blocking agents: synergism, addition or antagonism?

As the quality of currently available relaxants has improved, the need to combine relaxants to minimize the incidence and severity of their side-effects has decreased. Little work has been done in the past year characterizing the effects of combining different non-depolarizing neuromuscular blocking agents. That which has been done sheds some light on the nature of their interactions.

Distribution, elimination, and action of vecuronium in the elderly.

The effects of age on the pharmacokinetics and pharmacodynamics of vecuronium in eight elderly patients aged 72-86 yr and eight younger adults aged 26-48 yr undergoing elective surgical procedures under nitrous oxide-fentanyl anesthesia were studied. Vecuronium (0.1 mg/kg) was given as an intravenous bolus, and the ulnar nerve was stimulated with a square-wave impulse of 0.2-ms duration. The response to stimulation at a frequency of 0.1 Hz was measured and recorded with a force displacement transducer applied to the thumb. Spontaneous recovery was significantly longer in elderly patients than in younger patients (50% recovery time, 97.1 +/- 29 vs 39.8 +/- 14 min, mean +/- SD; recovery index [25%-75%], 49.4 +/- 11 vs 15.0 +/- 8 min). In addition, in elderly patients elimination half-life of vecuronium was significantly prolonged (125 +/- 55 vs 78 +/- 21 min, P = 0.04) and plasma clearance reduced (2.6 +/- 0.6 vs 5.6 +/- 3.2 mL.kg-1.min-1, P = 0.049). The prolonged duration of action of vecuronium in the elderly surgical patients thus appears to be secondary to altered pharmacokinetics consistent with an age-related decrease in renal and hepatic functions.

The clinical and basic pharmacology of mivacurium: a short-acting nondepolarizing benzylisoquinolinium diester neuromuscular blocking drug.

Mivacurium is a benzylisoquinolinium diester. The drug is a nondepolarizing relaxant which is hydrolysed by plasma cholinesterase at 70-88% of the rate of suxamethonium. Enzymatic hydrolysis gives the drug its short duration of action. The length of paralysis is about 2-2.5 times that of suxamethonium and one-half to one-third that of the intermediate-acting nondepolarizers. The development of mivacurium represents a collaboration between industrial pharmacologists and chemists at Burroughs Wellcome Co. (USA) and investigators at the Massachusetts General Hospital, Boston, MA, USA.

[The clinical pharmacology of new benzylisoquinoline-diester compounds, with special consideration of cisatracurium and mivacurium]. / Die klinische Pharmakologie neuer Benzylisochinolin-Diester-Verbindungen. Unter besonderer Berücksichtigung von Cisatracurium und Mivacurium.

The benzylisochinoline muscle relaxants have a highly selective affinity to the motor endplate which is associated with an absence of autonomic side effects such as ganglionic and vagus block. The requirement of only low clinical doses also reduces histamine liberation. Muscle relaxants with high neuromuscular blocking potency have a slow onset. Both atracurium and cisatracurium undergo Hofmann-Elimination in the plasma whereas mivacurium is hydrolyzed by pseudocholinesterase. The difference in kinetics between these pathways render atracurium and cisatracurium muscle relaxants of intermediate duration of action while mivacurium is short acting. Cisatracurium, one of the ten stereoisomeres of atracurium, is 3 to 4 times as potent as atracurium, does not release histamine, has no cardiovascular side effects and, due to the small clinical doses resulting from its high neuromuscular blocking potency, produces only negligible quantities of laudanosine. Its ED95 is 0.05 mg/kg. Good intubation conditions can be expected within 1.5 to 2 min following 3- to 4-times the ED95. Thereafter is takes about 65 min for T1 to recover to 25% of control. Maintenance doses of 0.02 to 0.04 mg/kg have a duration of action of 15 to 20 min. An infusion of cisatracurium of 1.0 to 2.0 mcg/kg/min, is adequate to maintain a 90 to 95% neuromuscular block. The time of recovery is largely independent on the total dose of cisatracurium administered by either repeated injection or infusion. Mivacurium is a racemate of 3 stereoisomeres of which the trans-trans- and the cis-trans-compound account for 95% of the neuromuscular blocking effect. In adults the ED95 is 0.08 mg/kg. The ensuing recovery of T1 to 25% of control is about 15 min. Rapid injection of 3xED95 may transiently lower the arterial blood pressure and may produce skin flushing in an incidence of 30 to 40%. Larger doses should be injected slowly with 30 to 60 s. The onset of mivacurium neuromuscular block following 3xED95 is relatively slow (2 min). Maintenance doses of 0.05 to 0.1 mg/kg have a duration of action of 5 to 10 min. A 95% neuromuscular block may be maintained by an infusion of 3 to 12 micrograms/kg/min. The time of recovery does not depend on the total cumulative dose given by either repeated injection or by infusion. The duration of mivacurium neuromuscular block may be drastically prolonged in the presence of low or atypical plasmacholinesterase. Both neostigmine and edrophonium are suitable reversal agents. None of the presently available benzylisochinoline muscle relaxants has the potential to completely replace succinylcholine.

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 11 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 (2.21 +/- 0.2 min, 5.11 +/- 0.3 min, respectively) than with sevoflurane (3.11 +/- 0.2 min, 7.21 +/- 0.3 min, respectively). Emergence times after sevoflurane (8.81 +/- 1.2 min) were significantly shorter than with propofol (13.21 +/- 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.

The nature of spontaneous recovery from mivacurium-induced neuromuscular block.

UNLABELLED: The hypothesis of this study was that, in a given patient, recovery from a tracheal intubating dose of mivacurium would indicate the time course of spontaneous recovery after discontinuation of an infusion of mivacurium. Thirty-eight male patients consented to participate in the study. After induction of anesthesia and endotracheal intubation, the ulnar nerve was stimulated with train-of-four (TOF) stimuli at 12-s intervals. Patients received 0.3 mg/kg mivacurium in two evenly divided doses of 0.15 mg/kg each, separated by 30 s. Complete ablation of TOF responses occurred in most patients. Once the first twitch in the TOF (T ) had recovered to 25% of its baseline height, a mivacurium infusion was begun to maintain 95% suppression of T1. As surgery was nearing completion, the infusion was discontinued, and neuromuscular function was allowed to recover spontaneously. Data were analyzed for recovery intervals after the administration of the initial doses of mivacurium and after discontinuation of the infusion. Analysis of variance was used to determine the strength of correlation between the time from administration of the initial 0.3 mg/kg dose to 5% recovery of T1 and the times to recovery of TOF ratios of 70% and 90%. The 25%-75% recovery interval after discontinuation of the infusion ranged from 2.8 to 11.3 min. The time interval after administration of mivacurium 0.3 mg/kg to 5% recovery of T1 correlated with both the time to recovery of a TOF ratio of 70% and 90%. Recovery to a TOF of 90% after discontinuation of the infusion required approximately the same amount of time as recovery to 5% T1 after the administration of 0.3 mg/kg mivacurium. Each patient's recovery of neuromuscular function after discontinuation of a mivacurium infusion was related to his recovery after the administration of 0.3 mg/kg mivacurium. Therefore, the need for pharmacologic antagonism of block can be anticipated well before the end of an anesthetic. IMPLICATIONS: Mivacurium (0.3 mg/kg) was administered to 38 patients. As they began to recover muscle strength, a mivacurium infusion was begun and later discontinued as surgery was nearing completion. Each patient's early recovery (administration to 5% recovery of T1) after the initial dose of mivacurium correlated well with more complete recovery of muscle strength after discontinuation of an infusion. This relationship enables early prediction of recovery speed after a mivacurium infusion.

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.min-1.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.

The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.

BACKGROUND: Mivacurium 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 1/13th 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 pharmacokinetic 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. METHODS: Eighteen 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 micrograms.kg-1.min-1. Sixty minutes later, the infusion rate was doubled to 10 micrograms.kg-1.min-1, and, 60 min after that, the infusion was discontinued. All patients were allowed to recover spontaneously from mivacurium-induced 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. RESULTS: During the 5-micrograms.kg-1.min-1 infusion, patients developed 83.2 +/- 13.6% neuromuscular block. Increasing the infusion to 10 micrograms.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 (V beta) of the cis-trans, trans-trans, and cis-cis isomers were 0.29 +/- 0.24, 0.15 +/- 0.05, and 0.34 +/- 0.08 l/kg, respectively. During the 5-micrograms.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. CONCLUSIONS: The 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.

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 ED(95). 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 does of 0.1 or 0.2 mg x kg-1 (2 or 4 times the ED(95), respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio > or = 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 x min(-1) x kg(-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 x kg(-1) and 0.2 mg x kg(-1), respectively. Maximum concentration values for laudanosine averaged 38 +/- 21 and 103 +/- 34 ng x ml(-1) for patients receiving the 0.1 and 0.2 mg x kg(-1) doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101 +/- 27 and 253 +/- 51 ng x ml(-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 x kg(-1).

Pharmacodynamics and pharmacokinetics of cisatracurium in geriatric surgical patients.

BACKGROUND: Cisatracurium, one of ten stereoisomers that comprise atracurium, is more potent than atracurium and has less propensity to release histamine. This study compares the pharmacokinetics and pharmacodynamics of cisatracurium in elderly and young patients. METHODS: Twelve elderly (aged 65-82 yr) and 12 younger patients (aged 30-49 yr) were anesthetized with nitrous oxide, fentanyl, and isoflurane (0.7%, end-tidal). The mechanomyographic response to train-of-four stimulation was assessed every 15 s after the administration of cisatracurium (0.1 mg/kg). Arterial samples were obtained over 6 h. Plasma cisatracurium concentration versus time data were fit to compartmental models. Pharmacokinetic parameters were determined assuming that elimination occurred from the central compartment only. This provides accurate clearance and half-life estimates but underestimates V(ss) (reported herein as V(ss). The pharmacodynamic response was described by the neuromuscular blocking profile. RESULTS: Onset to 90% paralysis (mean +/- SD) was delayed in the elderly (3.4 +/- 1.0 vs. 2.5 +/- 0.6 min). Recovery profiles were the same for both groups. Elimination half-life was minimally prolonged in the elderly (25.5 +/- 3.7 vs. 21.5 +/- 2.4 min). The Vss was larger in the elderly (126 +/- 16 vs. 108 +/- 13 ml/kg), although the clearances were the same for the two groups (5.0 +/- 0.9 vs. 4.6 +/- 0.8 ml.kg(-1).min(-1). CONCLUSIONS: There are minor differences in the pharmacokinetics of cisatracurium between elderly and young patients. These differences are not associated with changes in recovery profile after a single bolus dose, although the mean time to onset was approximately 1 min longer in elderly patients.

Pharmacodynamics and the plasma concentration of mivacurium during spontaneous recovery and neostigmine-facilitated recovery.

BACKGROUND: The authors examined the plasma concentrations of the isomers of mivacurium and its pharmacodynamics during spontaeous and neostigmine-facilitated recovery after a mivacurium infusion. METHODS: Sixteen patients receiving nitrous oxide-opioid anesthesia received 0.25 mg/kg mivacurium. Patient response to neuromuscular stimulation was determined using a mechanomyograph Once T1 had recovered to 25% of its baseline height, a mivacurium infusion was begun and adjusted to maintain 95-99% neuromuscular block. The infusion was discontinued after 90 min and muscle strength allowed to recover either spontaneously or after neostigmine/glycopyrrolate (0.05/0.01 mg/kg). Plasma concentrations of the isomers of mivacurium after discontinuation of the infusion were determined using an HPLC assay. Differences between the groups were determined using a one-way analysis of variance with a Bonferroni-corrected t test or Student t test as appropriate. P < or = 0.05 was considered significant. RESULTS: Differences in the times for recovery to a train-of-four ratio of 70% did not achieve statistical significance (mean+/-SD, 13.3+/-6.0 vs. 16.3+/-2.5 min for the neostigmine and spontaneous groups, respectively). Plasma cholinesterase activity decreased significantly from baseline values after administration of neostigmine (5.88+/-0.21 vs. 0.43+/-0.04 U/ml plasma). Plasma concentrations of the trans-trans isomer were significantly greater in the neostigmine group than in the spontaneous recovery group 5, 6, 8, and 10 min after discontinuation of the infusion. Differences in the plasma concentration of the cis-trans isomer did not achieve statistical significance. CONCLUSIONS: Although administration of neostigmine decreased plasma cholinesterase activity and caused the trans-trans isomer to remain in the plasma at higher concentration, it did not delay recovery from mivacurium-induced block.

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 +/- 0.3 min, and recovery to 95% twitch height occurred 64.4 +/- 3.9 min after injection. At 0.4 mg/kg, onset was 1.9 +/- 0.1 min, and 95% recovery developed within 121.0 +/- 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 micrograms/kg/min. Recovery indexes from infusions were 5-95% 33.2 +/- 1.8 min and 25-75% 15.0 +/- 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 +/- 0.3 min, and the neostigmine-accelerated 25-75% recovery index was 2.8 +/- 0.2 min. CONCLUSIONS: 51W89 is a potent nondepolarizing neuromuscular blocking agent that shows noncumulative intermediate-duration neuromuscular blocking pharmacodynamics.