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PubMed2000

Train-of-four fade and neuromuscular block in rats: a comparison between pancuronium, vecuronium, and rocuronium.

PURPOSE: To clarify the relationship between neuromuscular block and train-of-four fade and to investigate the causes of these drug-dependent differences, we compared the neuromuscular block and TOF fade after pancuronium, vecuronium and rocuronium. METHODS: In 24 anesthetized rats, the sciatic nerve was stimulated, and the twitch of left tibialis anterior muscle was recorded. After T1 (first twitch response) was kept constant at 95% block by administration of pancuronium, vecuronium, or rocuronium (n=8, in each), the TOF fade was measured when T1 block was decreased to 40% and 20%. In addition, using 24 phrenic nerve-diaphragm preparations, the fade was measured when the T1 block increased to 20% and 40% by titrating of either one of the three drugs (n=8, in each). RESULTS: In in vivo experiments, the fade produced by pancuronium was greater than that by vecuronium or rocuronium when T1 block was at 40% (81 +/- 9 vs 63 +/- 15 and 63 +/- 6%, respectively) and at 20% (66 +/- 13 vs 34 +/- 17 and 40 +/- 6%, respectively). In contrast, in in vitro experiments, the differences did not reach significant levels among the three drugs either at 20% (32 +/- 19 vs 33 +/- 10 and 32 +/- 17%) or 40% of block (62 +/- 29 vs 65 +/- 14 and 55 +/- 14%). CONCLUSIONS: For vecuronium and rocuronium, the results were similar in vivo and in vitro. For pancuronium, fade was greater in vivo. These results suggest that different neuromuscular blocking agent have different relationships between the fade and the block. In vitro results might not be the same as in vivo, possibly due to pharmacokinetic differences.

Acetylcholine↗
PubMed2000

[Time course of neuromuscular blockade after rocuronium. A comparison between women and men].

BACKGROUND: We studied 40 patients (20 female and 20 male) undergoing elective surgery under general anaesthesia to evaluate the effect of gender on the pharmacodynamics of rocuronium. METHODS: Using electromyography (EMG) we determined the maximal neuromuscular block and time course of action of 0.45 mg/kg rocuronium (1.5 x ED95). RESULTS: Age and body mass index were comparable between females and males (38 (+/- 8) vs. 37 (+/- 10) years and 24.2 (+/- 2.9) vs. 25.2 (+/- 1.7) kg/m2. However, significant differences in weight and height were found between females and males (65.7 +/- 9.3 kg vs. 77.5 +/- 5.5 kg; p < 0.01 and 178 +/- 6.8 cm vs. 164 +/- 6.7 cm; p < 0.01). Onset time was shorter in females (168 +/- 65 s vs. 211 +/- 56 s; p < 0.05). Maximal neuromuscular blockade after 0.45 mg/kg rocuronium was 94 (+/- 3) % in females and 89 (+/- 6) % in males; p < 0.01. Clinical duration was increased in females (23 +/- 5 min vs. 17 +/- 5 min; p < 0.05), while the recovery index was comparable between both groups (9 +/- 4 min in females and 9 +/- 3 min in males; n.s.). CONCLUSION: Compared to men neuromuscular blockade after 0.45 mg/kg rocuronium was more pronounced in women. The onset time was shortened and the clinical duration increased in female patients.

Adult↗
PubMedDate not supplied

Determination of interstitial rocuronium concentrations in the muscle tissue of anesthetized dogs by microdialysis.

INTRODUCTION: The objective was to establish and validate a microdialysis technique for the quantification of interstitial concentrations of the neuromuscular blocker, rocuronium, in the muscle tissue of dogs under steady-state conditions. METHODS: The standard and combined retrodialysis approaches were used for in vivo microdialysis probe calibration. After induction of anesthesia with pentobarbital (30 mg/kg), the left femoral vein was cannulated and blood drawn for protein binding determination. Microdialysis probes were inserted in the muscle and calibrated in vivo, using vecuronium as the calibrator. Each dog received a short 2-min infusion followed by a 120-min infusion of rocuronium via the right jugular vein and three microdialysis samples were collected at steady-state during a 2-h period. Samples were stored at -70 degrees C until HPLC analysis. RESULTS: Using combined retrodialysis, rocuronium unbound interstitial (C(ISFu)) and venous plasma (C(pssuv)) concentrations are in good agreement; with a ratio C(ISFu)/C(pssuv) of 100+/-11%. Using standard retrodialysis, this ratio was 47+/-7%. CONCLUSIONS: Combined retrodialysis is a more reliable and accurate technique for quantitative assessment of rocuronium interstitial concentrations especially for lengthy anesthetic procedures. These findings have potential implications, as drug concentrations in the site of action would be more relevant for concentration-effect relation of muscle relaxants.

Androstanols↗
PubMed2003

Predicting recovery from deep neuromuscular block by rocuronium in the elderly.

STUDY OBJECTIVE: To determine the influence of aging on the relationship between posttetanic count (PTC) and train-of-four (TOF) response during intense neuromuscular blockade caused by rocuronium. DESIGN: Prospective, observational, clinical comparison study. SETTING: Operating room of a university hospital. PATIENTS: 42 ASA physical status I and II patients, 20 of whom were elderly (ages 65 to 80 yrs) and 22 younger control patients (ages 18 to 40 yrs), who were scheduled for elective orthopedic surgery and ear, nose, and throat surgery with a planned duration of 2 hours. INTERVENTIONS: Neuromuscular blockade was evaluated with accelerometry of the thumb, using posttetanic twitch (PTT) and TOF stimulation of the ulnar nerve, in patients who received rocuronium 1 mg x kg(-1). MEASUREMENTS AND MAIN RESULTS: The first responses to posttetanic nerve stimulation were seen at mean times of 38.5 and 35.2 minutes after the injection of rocuronium in the elderly and in the young, respectively (NS). The average interval between the appearance of a posttetanic response and the first response to TOF stimulation (T1) was longer in the elderly than the young (22.3 +/- 8.1 (SD) vs.14.8 +/- 4.2 min, p < 0.05). There was a significant correlation between PTC and the time to first response to TOF nerve stimulation both in the elderly and in the young (r = -0.73, p < 0.0001 and r = -0.87, p < 0.0001, respectively). CONCLUSIONS: Posttetanic twitch stimulation is a useful method of monitoring intense neuromuscular blockade caused by rocuronium in both age groups. The interval between the earliest appearance of a posttetanic response and the first response to TOF stimulation (T1) is greater in the elderly than in the young.

Adolescent↗
PubMed2002

2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker rocuronium bromide.

A series of secondary face modified cyclodextrins (CDs) were synthesised with the aim of constructing host molecules capable of forming host-guest complexes with neuromuscular blockers, especially with rocuronium bromide. Perfacial 2-O-substitution of gamma-CD with 4-carboxybenzyl resulted in a CD host molecule 1 that forms a 1:1 binary complex with rocuronium bromide (K(a) 6.2 x 10(5) M(-1)). The biological activities of this compound and other derivatives as reversal agents of rocuronium bromide were examined in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized guinea pigs). The host molecule 1 was found to exert potent reversal activity (ED(50) 0.21 micromol/kg, iv) against rocuronium-induced neuromuscular block, and thus proved the viability of using host molecules as antidotes of a biologically active compound.

Androstanols↗
PubMed1995

Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium.

OBJECTIVE: To study the influence of hypothermic cardiopulmonary bypass (CPB) on the pharmacodynamics and pharmacokinetics of rocuronium. DESIGN: Prospective, descriptive study. SETTING: Operating room at a university hospital. PARTICIPANTS: Ten ASA class III and IV patients, ranging in age from 35 to 75 years, scheduled for elective coronary artery bypass grafting. INTERVENTIONS: Neuromuscular transmission was monitored mechanomyographically. The time course of action of maintenance doses and plasma concentration-response relationships were determined before, during, and after CPB. The plasma concentration decay and renal elimination were studied simultaneously. Plasma and urine concentration of rocuronium were determined by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Hypothermic CPB prolonged the duration of action of maintenance doses and coincided with a lower plasma concentration at a twitch response of 5% of control. The duration of action of maintenance doses returned to prehypothermic CPB level after rewarming to a nasopharyngeal temperature of 37 degrees C. The plasma concentration-response relationship did not return to precooling control value, probably owing to persisting peripheral hypothermia. Both the renal elimination of rocuronium and the plasma concentration decay after the last maintenance dose under normothermic conditions resembled values obtained in patients not undergoing hypothermic CPB. CONCLUSIONS: Hypothermic CPB prolongs the duration of action of maintenance doses and alters the plasma concentration-response relationship of rocuronium. These changes may be the result of, on the one hand, an increased sensitivity of the neuromuscular transmission and/or decreased muscle contractility and, on the other hand, the result of a reduced plasma clearance during hypothermia.

Adult↗
PubMed2002

Modified gamma-cyclodextrins and their rocuronium complexes.

A series of per-6-substituted cyclodextrin derivatives was synthesized as synthetic host molecules for rocuronium, a steroidal muscle relaxant. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo. The isothermal microcalorimetry data are consistent with the biological data supporting the encapsulation mechanism of action. Binary and biphasic complexes are reported with NMR experiments clearly showing free and bound rocuronium. [structure: see text]

Androstanols↗
PubMed1996

Performance assessment of an adaptive model-based feedback controller: comparison between atracurium, mivacurium, rocuronium and vecuronium.

The performance of an adaptive model-based controller for the administration of atracurium, mivacurium, rocuronium and vecuronium was compared in 159 adult surgical patients. The degree of neuromuscular block was set to 90% for atracurium, rocuronium and vecuronium and to 95% for mivacurium. Performance was assessed by calculating the median prediction error (bias), median absolute performance error (inaccuracy), divergence, wobble, the mean offset and the mean standard deviation from the setpoint. All indices of controller performance showed minimal deviation of the actual neuromuscular block from the setpoint. Although the controller appeared to be able to control rocuronium induced block at 90% and mivacurium induced block at 95% better than atracurium and vecuronium block at 90%, the differences in the controller performance between the four studied relaxants were small and have hardly any clinical significance. We conclude that a model-based adaptive controller is useful in the administration of atracurium, mivacurium, rocuronium or vecuronium.

Adult↗
PubMed2001

Rocuronium and anaphylaxis--a statistical challenge.

Drug induced anaphylaxis is frequently attributed to the use of muscle relaxants during anaesthesia. Recently The Norwegian Medicines Agency recommended that rocuronium bromide (Esmeron) be withdrawn from routine practice due to frequent reports of anaphylaxis. Over a period of two and a half years approximately 150,000 patients received rocuronium as part of their anaesthesia. In this period the Norwegian drug authorities received 29 reports of anaphylaxis or anaphylactoid reactions in patients treated with rocuronium. This is in stark contrast to the situation in other Nordic countries where a total of only seven cases of anaphylaxis in approximately 800,000 patients treated with rocuronium had been recorded by December 2000. This situation highlights the many potential problems of the surveillance of adverse drug reactions: reporting bias may lead to an over-estimate of the risk of one drug compared to another, and the possibility of under-reporting of adverse events (due to a weak reporting culture) further limit the validity of such comparisons. The surveillance of adverse drug reactions also represents a statistical challenge. While adverse event reports may help us to estimate the anaphylaxis rate we need to appreciate the uncertainty of such estimates. Adverse reactions are rare, random, and mostly independent events, resulting from the successive exposure of patients to a low risk intervention. The frequency distribution of adverse events will therefore conform to that of a Poisson process. The resulting Poisson distribution may inform us about the variability of adverse event data. An understanding of these methodological problems and statistical challenges will allow anaesthesiologists to make informed decisions concerning the use of muscle relaxants and other drugs associated with severe adverse reactions.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

Rocuronium and cisatracurium-positive skin tests in non-allergic volunteers: determination of drug concentration thresholds using a dilution titration technique.

BACKGROUND: Muscle relaxants are believed to be responsible for 2/3 of the cases of anaphylactic reactions during anesthesia. This assumption is based mainly on positive skin tests obtained in individuals that have experienced anesthesia-related anaphylaxis. A positive skin test is supposed to be associated with mast cell degranulation of vasoactive amines. In the present study we tested the frequency of positive skin tests with two commonly used muscle relaxants, rocuronium and cisatracurium, in a selected group of volunteers with low potential for allergic reactions. METHODS: Thirty healthy volunteers without known allergy or previous exposure to muscle relaxants were studied. Low potential for allergic reactions was determined prior to inclusion in the study, using various allergy tests. Each individual was tested with intradermal and skin prick tests, and molar drug concentration thresholds for positive skin reactions were determined using a dilution titration technique. The presence or absence of mast cell degranulation was tested by electron microscopic investigation of skin biopsies obtained from positive and negative skin reactions. RESULTS: None of the volunteers had a positive skin prick test. More than 90% of the volunteers had a positive intradermal test with both rocuronium and cisatracurium. The highest molar drug concentration that was not associated with a positive intradermal test was 10(-6) M (rocuronium) and 10(-7) M (cisatracurium), equivalent to vial dilution 1 : 1000 for both drugs. In none of the volunteers was mast cell degranulation detected. CONCLUSION: Non-mast-cell-mediated positive intradermal skin reactions are frequently occurring with rocuronium and cisatracurium, even at vial dilution 1 : 1000. A clinically applicable test technique is needed that is able to separate positive skin tests associated with mast cell degranulation from non-mast-cell-mediated reactions.

Adolescent↗
PubMed2005

Mutual induced fit in cyclodextrin-rocuronium complexes.

The binding of rocuronium bromide to 6-perdeoxy-6-per(4-carboxyphenyl)thio-gamma-cyclodextrin sodium salt, displays biphasic behaviour characteristic of the formation of a binary and 2 : 1 ternary guest-host complex in aqueous solution. Thermodynamic and structural data on this sequential complexation process can be rationalised within a single model involving switching of the conformational equilibria of both the rocuronium bromide and cyclodextrin molecules. Isothermal titration calorimetry (ITC), NMR and fluorescence experiments in solution, together with X-ray crystallography and molecular modelling, suggest that in order to induce encapsulation both rocuronium bromide and the modified cyclodextrin undergo conformational changes. Ring A of rocuronium bromide 'switches' from the more sterically encumbered chair to the sterically less demanding twist-boat, whilst the modified cyclodextrin "opens" its cavity to allow the steroid to enter. The recognition and mutual induced fit between cyclodextrin and steroid represents a classic example of dynamic host-guest chemistry.

Androstanols↗
PubMed1998

Evaluation of intubating conditions with rocuronium and either propofol or etomidate for rapid sequence induction.

We have assessed the effect of two induction agents on tracheal intubating conditions after rocuronium 0.6 mg.kg-1 in unpremedicated patients undergoing simulated rapid sequence induction. Following pre-oxygenation, anaesthesia was induced with propofol up to 2.5 mg.kg-1 (n = 35) or etomidate 0.3 mg.kg-1 (n = 36), and further increments as required. After loss of verbal contact, cricoid pressure was applied and rocuronium was injected. Laryngoscopy was performed at 45 s and intubation attempted at 60 s after rocuronium had been given. Ninety-four per cent of patients in the propofol group had clinically acceptable (good or excellent) intubating conditions compared to only 75% in the etomidate group (p = 0.025). Owing to coughing, one patient in the etomidate group could not be intubated on the first attempt. A greater pressor response also followed intubation after induction with etomidate. We conclude that etomidate and rocuronium alone cannot be recommended for intubation at 60 s under rapid sequence induction conditions.

Adolescent↗
PubMed1999

Influence of induction of anaesthesia on intubating conditions one minute after rocuronium administration: comparison of ketamine and thiopentone.

We compared the effect of thiopentone and ketamine on intubating conditions after rocuronium 0.6 mg.kg-1 in two groups of patients (n = 16 each), aged 21-44 years, undergoing elective surgery. Premedication consisted of alprazolam 1 mg by mouth 1 h before surgery. All patients received midazolam 2 mg intravenously 2 min before intravenous administration of thiopentone 5 mg.kg-1 or ketamine 2.5 mg.kg-1. Muscle relaxation was provided by rocuronium 0.6 mg.kg-1. One minute after rocuronium administration, tracheal intubation was performed within 15 s by a skilled anaesthetist blinded to the treatment group assignment. Intubating conditions were graded as excellent, good, fair or poor on the basis of jaw relaxation, position of vocal cords and diaphragmatic response. Neuromuscular transmission was assessed at the adductor pollicis muscle using a TOF-GUARD monitor. Excellent and good intubating conditions were obtained in 100% of patients in the ketamine group and in 50% of patients in the thiopentone group (p = 0.002). Jaw relaxation was similar in both groups but vocal cord conditions were better and the diaphragmatic response less marked in the ketamine group compared with the thiopentone group (p = 0.002). The degree of neuromuscular block [% decrease of T1, mean (SD)] at the time of intubation was similar: 51.8 (25)% (ketamine group) and 54.3 (23.1)% (thiopentone group). We conclude that ketamine 2.5 mg.kg-1 provides better intubating conditions than thiopentone 5 mg.kg-1 1 min after administration of rocuronium 0.6 mg.kg-1.

Adult↗
PubMed1999

A comparison of the effect of rocuronium and vecuronium on heart rate during gynaecological laparoscopy.

The effect on intra-operative heart rate of two nondepolarising muscle relaxants, rocuronium and vecuronium, was compared in 116 fit out-patients undergoing gynaecological laparoscopic procedures. Both groups received an anaesthetic technique which differed only in the choice of muscle relaxant. Intra-operatively it was noted that patients given rocuronium (20 mg) had significantly fewer episodes of bradycardia (heart rate < 50 beat.min-1) than patients given vecuronium 4 mg (p < 0.05). Profound bradycardias (heart rate < 30 beat.min-1) did not occur in any of the patients in the rocuronium study group, whereas 5% of patients receiving vecuronium had a period of transient asystole. We conclude that, at the doses stated, rocuronium results in significantly fewer episodes of bradycardia than vecuronium when used as a muscle relaxant for laparoscopic gynaecological procedures.

Adult↗
PubMed2000

A comparison of antagonism of rocuronium-induced neuromuscular blockade during sevoflurane and isoflurane anaesthesia.

Volatile anaesthetic agents potentiate neuromuscular blocking agents and retard their rate of reversal. We hypothesised that there was a difference in the rate of reversal of rocuronium-induced neuromuscular blockade based on the selection of inhalation agent. Thirty-eight patients undergoing elective surgical procedures received either sevoflurane or isoflurane, by random allocation. Neuromuscular blockade was induced using rocuronium 0.6 mg.kg-1 followed by continuous intravenous infusion to maintain 90% suppression of the single twitch response. Upon completion of surgery, the rocuronium infusion was discontinued, neostigmine 50 microg.kg-1 and glycopyrrolate 10 microg.kg-1 were administered. Times from reversal to T1 = 25, 50 and 60% and train-of-four ratio = 0.6 were recorded. The mean (SD) times to train-of-four ratio = 0.6 in the isoflurane and sevoflurane groups were 327 (132) and 351 (127) s, respectively. The mean (SD) times to single twitch response T1 = 25, 50 and 60% in the isoflurane group were 81 (33), 161 (59) and 245 (84) s, respectively, and in the sevoflurane group were 95 (35), 203 (88) and 252 (127) s, respectively. It is concluded that reversal of rocuronium-induced neuromuscular blockade is similar during isoflurane and sevoflurane anaesthesia.

Adult↗
PubMed2003

Prospective randomised double-blind comparative study of rocuronium and pancuronium in adult patients scheduled for elective 'fast-track' cardiac surgery involving hypothermic cardiopulmonary bypass.

The majority of cardiac anaesthetists in the UK use pancuronium for fast-track cardiac surgery. We compared the duration of action of pancuronium and rocuronium in patients undergoing fast-track hypothermic cardiopulmonary bypass and cardiac surgery. We determined whether patients would have had residual neuromuscular blockade at extubation. Twenty patients were randomly allocated to receive either pancuronium 0.1 mg x kg(-1) or rocuronium 1 mg x kg(-1). Neuromuscular function was assessed by acceleromyography; spontaneous recovery was evaluated by the train-of-four ratio measured at the adductor pollicis longus muscle. Median times to recover train-of-four ratio of 0.9 were 3 h 38 min for rocuronium and 7 h 52 min for pancuronium. The median difference in recovery times was 4 h 15 min (95% CI 2 h 30 min to 6 h 20 min; p = 0.0003 by Mann-Whitney test). None of the patients in the rocuronium group and seven of 10 patients in the pancuronium group had their extubations delayed because of residual neuromuscular blockade. Unless fast-track patients have neuromuscular function assessed before extubation, pancuronium should not be used.

Aged↗
PubMed1997

The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis.

AIMS: To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide. METHODS: We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child-Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg(-1) was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c. RESULTS: The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T1:T0, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T1:T0, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T1:T0, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T4:T1 to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg(-1) min (-1); P<0.005). The central (V1) and steady state volumes of distribution (V(ss)) did not differ significantly between the groups. The slow redistribution (t1/2,lambda1) and elimination (t1/2,z) half-lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P < 0.005; and 143 (80) vs 92 (40) min, P < 0.05 respectively). The exit rate constant for the effect compartment k(eo) was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min(-1); P < 0.05), but cirrhosis had no significant effect on the parameters of the concentration-effect relationship Cp(ss)(50) and gamma. CONCLUSIONS: Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.

Adult↗
PubMed1999

The onset of neuromuscular block at the masseter muscle as a predictor of optimal intubating conditions with rocuronium.

After an intubating dose of rocuronium satisfactory intubating conditions are achieved before the onset time at the adductor pollicis. We examined the possibility that measurement of the relaxation of the masseter muscle is a more appropriate guide when determining the intubating time. Simultaneous accelerometry with a 0.1-Hz single twitch stimulation of the chin and thumb was performed in 20 patients after 0.6 mg kg-1 rocuronium. We observed a significantly more brief mean lag time and onset time at the masseter muscle (22.5 and 61 vs. 32.5 and 160 s). The corresponding mean relaxation at the onset time was also significantly more pronounced at the masseter muscle (99.6 vs. 97.6%). A mean onset time at the masseter muscle of 61 s as produced by rocuronium corresponds clinically with excellent or good intubating conditions. From these results, we suggest that measurement of the onset time of muscle relaxation at the masseter muscle appears to be a better predictor of good intubating conditions than measurements made using the adductor pollicis muscle after administration of rocuronium.

Adolescent↗