Sugammadex in clinical practice.

The availability of sugammadex allows greater flexibility in the use of rocuronium and vecuronium during anaesthesia and surgery. The neuromuscular block induced by both drugs can be reversed from both superficial and deep levels of block by adjusting the dose of sugammadex. The dose of sugammadex for reversal of shallow block produced by these neuromuscular blocking drugs is approximately 2 mg.kg(-1) and for deep block the dose is 4 mg.kg(-1). A larger dose of sugammadex (16 mg.kg(-1)) administered 3 min after the neuromuscular blocking drug allows rapid reversal of a neuromuscular block induced by 1-1.2 mg.kg(-1) of rocuronium, thereby raising the possibility of using rocuronium as a replacement for suxamethonium. The use of sugammadex has not been reported to be associated with recurrence of block provided a dose that is adequate for reversal has been used. Sugammadex appears to have an acceptable safety profile. There are no requirements for dose adjustment for age or the use of potent volatile anaesthetic agents.

Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine.

BACKGROUND: Reversal of the residual effect of rocuronium or cisatracurium by neostigmine may be slow and associated with side-effects. This randomized, safety-assessor-blinded study compared the efficacy of sugammadex, a selective relaxant binding agent for reversal of rocuronium-induced neuromuscular block, with that of neostigmine for reversal of cisatracurium-induced neuromuscular block. The safety of sugammadex and neostigmine was also evaluated. METHODS: Adult surgical patients (ASA class I-III) were randomized to sugammadex 2.0 mg kg(-1) for reversal of block induced by rocuronium 0.6 mg kg(-1), or neostigmine 50 microg kg(-1) for reversal of block induced by cisatracurium 0.15 mg kg(-1). Anaesthesia was induced and maintained using i.v. propofol and remifentanil, fentanyl, or sufentanil. Neuromuscular function was monitored using acceleromyography (TOF-Watch SX). Sugammadex or neostigmine was administered at reappearance of T(2). The primary efficacy variable was time for recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Eighty-four patients were randomized, 73 of whom received sugammadex (n=34) or neostigmine (n=39). Time from start of administration of reversal agent to recovery of the TOF ratio to 0.9 was 4.7 times faster with sugammadex than with neostigmine (geometric mean=1.9 vs 9.0 min, P<0.0001). Reversal of block was sustained in all patients. There were no serious adverse effects from either reversal agent and no significant changes in any measure of safety, except for similar elevations in urinary N-acetyl glucosaminidase in both groups. CONCLUSIONS: Sugammadex 2.0 mg kg(-1) administered at reappearance of T(2) was significantly faster in reversing rocuronium-induced blockade than neostigmine was in reversing cisatracurium-induced block.

Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision.

The set of guidelines for good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents, which was developed following an international consensus conference in Copenhagen, has been revised and updated following the second consensus conference in Stockholm in 2005. It is hoped that these guidelines will continue to help researchers in the field and assist the pharmaceutical industry and equipment manufacturers in enhancing the standards of the studies they sponsor.

Org 25969 (sugammadex), a selective relaxant binding agent for antagonism of prolonged rocuronium-induced neuromuscular block.

BACKGROUND: Org 25969 is a cyclodextrin compound designed to reverse a rocuronium-induced neuromuscular block. The aim of this study was to explore the efficacy, dose-response relation and safety of Org 25969 for reversal of a prolonged rocuronium-induced neuromuscular block. METHODS: Thirty anaesthetized adult patients received rocuronium 0.6 mg kg(-1) as an initial dose followed by increments to maintain a deep block at a level of <10 PTCs (post-tetanic counts) recorded every 6 min. Neuromuscular monitoring was carried out using accelerometry, in a train-of-four (TOF) mode using TOF-WatchSX. At recovery of T2, following at least 2 h of neuromuscular block, patients received their randomly assigned dose of 0.5, 1.0, 2.0, 4.0 or 6.0 mg kg(-1) of Org 25969. Anaesthesia and neuromuscular monitoring were continued for a minimum period of 30 min after Org 25969 administration. The main end-point of the study was the time to achieve a sustained recovery of TOF ratio to 0.9. Patients were followed up for 7 days after anaesthesia. RESULTS: The results showed a dose-related decrease in the average time taken to attain a TOF ratio of 0.9 from 6:49 (min:s) with the 0.5 mg kg(-1) dose to 1:22 with the 4.0 mg kg(-1) dose. Weighted non-linear regression analysis showed the fastest achievable time to TOF ratio of 0.9 to be 1:35. Org 25969 produced no major adverse effects. CONCLUSION: Org 25969 effectively reversed a deep and prolonged neuromuscular block induced by rocuronium. The effective reversal dose appears to be 2-4 mg kg(-1).

Manual versus target-controlled infusions of propofol.

Target-controlled infusion systems have been shown to result in the administration of larger doses of propofol, which may result in delayed emergence and recovery from anaesthesia. The aim of this study was to investigate if this was due to a difference in the depth of hypnosis (using the bispectral index monitoring) between the manual and target controlled systems of administration. Fifty unpremedicated patients undergoing elective surgery were randomly allocated to have their anaesthesia maintained with manual or target-controlled propofol infusion schemes. In both groups, the rate of propofol administration was adjusted according to standard clinical criteria while bispectral index scores were recorded by an observer not involved in the delivery of anaesthesia. The total dose of propofol used was higher in the target controlled group (mean 9.9 [standard deviation 1.6] compared with 8.1 [1.0] mg.kg(-1).h(-1) in the manual group [p < 0.0001]). The times to emergence and recovery end-points were comparable between the two groups. The difference in the total dosage of propofol was mainly due to higher rate of propofol administration in the first 30 min in the target controlled infusion group. The bispectral index scores were lower in the target controlled group during this time, being significantly so over the first 15 min of anaesthesia. We conclude that propofol administration by a target controlled infusion system results in the administration of higher doses of propofol and lower bispectral index values mainly in the initial period of anaesthesia.

A new mirrored laryngoscope.

A new laryngoscope has been designed, incorporating an adjustable mirror and a levered tip similar to the McCoy blade, in an attempt to bridge the gulf between simple direct laryngoscopy and fiberoptic laryngoscopy. Manual in-line neck stabilisation was used to simulate difficult laryngoscopy in 14 anaesthetised patients after full neuromuscular blockade. The best view at laryngoscopy was assessed using a standard Macintosh laryngsocope, a size 3 McCoy laryngoscope and the mirrored laryngoscope. The best laryngeal view obtained in all cases with the Macintosh blade was a grade 3. The mirrored laryngoscope improved this view in 10 cases (71%) compared with five cases (36%) with the McCoy laryngoscope (p = 0.005); in seven cases (50%), the view improved to a grade 1 compared with no cases when the McCoy was used (p = 0.02). We conclude that the mirrored laryngoscope offers considerable advantages over the Macintosh and the McCoy laryngoscopes in simulated difficult laryngoscopy, is simple to use and requires no special training.

The use of remifentanil in the anaesthetic management of patients undergoing adrenalectomy: a report of three cases.

The use of remifentanil has been recommended because of its ability to minimise the hypertensive response to tracheal intubation and surgical stimulation in various types of surgery. We describe the use of remifentanil in the anaesthetic management of three cases of open adrenalectomy, two for removal of a phaeochromocytoma and one for removal of an adrenal cortical tumour. Although the use of remifentanil was associated with no adverse events in the patient undergoing resection of the adrenal cortical tumour, its administration was associated with significant hypotension and bradycardia in the two phaeochromocytoma patients, who had both been given alpha- and beta-adrenergic receptor blocking drugs before surgery. It did not prevent the increases in blood pressure or plasma catecholamine levels associated with tumour manipulation in these patients. Remifentanil should therefore be used with caution in patients receiving alpha- and beta-adrenergic receptor blocking drugs. The use of potent vasodilators may still be necessary during tumour manipulation even if remifentanil is being infused.

Recovery from propofol anaesthesia supplemented with remifentanil.

We have examined the effects on recovery end-points of supplementation of a propofol-based anaesthetic with remifentanil. After induction of anaesthesia with propofol and remifentanil 1.0 microg kg(-1), 15 patients each were randomly allocated to target plasma propofol concentrations of 2, 3, 4 or 5 microg ml(-1) for maintenance of anaesthesia. Remifentanil was administered by infusion for supplementation in doses required for maintenance of adequate anaesthesia. All patients received 50% nitrous oxide in oxygen and ventilation was controlled. The total amount of drugs used and times to different recovery end-points were recorded. Cognitive function was also assessed using a Mini-Mental State questionnaire. The median dose of remifentanil for maintenance of adequate anaesthesia (excluding the initial bolus dose) in the four groups was 0.21, 0.15, 0.11 and 0.13 microg kg(-1) min(-1) respectively (P=0.0026). The median times to eye opening and orientation were shortest in the 2 microg ml(-1) group [6.0 and 6.5 min, 8.5 and 10.8 min, 13.4 and 15.8 min, and 14.2 and 19.5 min respectively in the propofol 2, 3, 4, and 5 microg ml(-1) groups respectively (P<0.001)]. The times to discharge from the recovery ward and the Mini-Mental State scores were not significantly different.

Frequency of haemoglobin desaturation with the use of succinylcholine during rapid sequence induction of anaesthesia.

BACKGROUND: The perceived safety of the use of succinylcholine is based on the fact that recovery from its effects will occur before oxygen desaturation occurs in case of failure to intubate or ventilate. The purpose of this study was to examine the incidence of oxygen desaturation after the use of succinylcholine prior to resumption of spontaneous ventilation following four different preoxygenation techniques. METHODS: Twenty-five patients each were randomly allocated to preoxygenation with 4 deep breaths of 100% oxygen or by breathing oxygen for 1, 3 or 5 min following which they received a rapid sequence induction of anaesthesia with fentanyl 1 microg kg(-1), a sleep dose of thiopentone and succinylcholine 1 mg kg(-1). Oxygen saturation was monitored continuously using a finger probe. Ventilation was not assisted unless the saturation decreased to

Neostigmine antagonism of rocuronium block during anesthesia with sevoflurane, isoflurane or propofol.

PURPOSE: To examine the influence of continuing administration of sevoflurane or isoflurane during reversal of rocuronium induced neuromuscular block with neostigmine. METHODS: One hundred and twenty patients, divided into three equal groups, were randomly allocated to maintenance of anesthesia with sevoflurane, isoflurane or propofol. Neuromuscular block was induced with rocuronium and monitored using train-of-four (TOF) stimulation of the ulnar nerve and recording the force of contraction of the adductor pollicis muscle. Neostigmine was administered when the first response in TOF had recovered to 25%. At this time the volatile agent administration was stopped or propofol dosage reduced in half the patients in each group (n = 20 in each group). The times to attain TOF ratio of 0.8, and the number of patients attaining this end point within 15 min were recorded. RESULTS: The times (mean +/- SD) to recovery of the TOF ratio to 0.8 were 12.0 +/- 5.5 and 6.8 +/- 2.3 min in the sevoflurane continued and sevoflurane stopped groups, 9.0 +/- 8.3 and 5.5 +/- 3.0 min in the isoflurane continued and isoflurane stopped groups, and 5.2 +/- 2.8 and 4.7 +/- 1.5 min in the propofol continued and propofol stopped groups (P < 0.5-01). Only 9 and 15 patients in the sevoflurane and isoflurane continued groups respectively had attained a TOF ratio of 0.8 within 15 min (P < 0.001 for sevoflurane). CONCLUSIONS: The continued administration of sevoflurane, and to a smaller extent isoflurane, results in delay in attaining adequate antagonism of rocuronium induced neuromuscular block.

Postoperative residual block after intermediate-acting neuromuscular blocking drugs.

The frequency and duration of postoperative residual neuromuscular block on arrival of 150 patients in the recovery ward following the use of vecuronium (n = 50), atracurium (n = 50) and rocuronium (n = 50) were recorded. Residual block was defined as a train-of-four ratio of <0.8. An additional group of 10 patients received no neuromuscular blocking drugs during anaesthesia. The incidence of postoperative residual neuromuscular block was 64%, 52% and 39% after the use of vecuronium, atracurium and rocuronium, respectively. Similar numbers of patients were not able to maintain a sustained head or leg lift for 5 s on arrival in the recovery ward. The mean [range] times to attaining a train-of-four ratio of > or =0.8 after arrival in the recovery ward were 9.2 [1-61], 6.9 [1-24] and 14.7 [1.5-83] min for vecuronium, atracurium and rocuronium, respectively. None of the 10 patients who did not receive neuromuscular blocking drugs had train-of-four ratios <0.8 on arrival in the recovery ward. It is concluded that a large proportion of patients arrive in the recovery ward with a train-of-four ratio <0.8, even with the use of intermediate-acting neuromuscular blocking drugs. Although the residual block is relatively short lasting, it may occasionally be prolonged, requiring close observation and monitoring of such patients in the recovery ward.

Sevoflurane--nitrous oxide anaesthesia supplemented with remifentanil: effect on recovery and cognitive function.

The aim of this study was to compare recovery and psychomotor performance after maintenance of anaesthesia with sevoflurane or sevoflurane supplemented with remifentanil. Sixty-six per cent nitrous oxide was used in all patients. Twenty patients each were randomly allocated to maintenance of anaesthesia with sevoflurane only in concentrations necessary to maintain adequate anaesthesia or with 1.5, 1.0 or 0.5 MAC (end-tidal) of sevoflurane supplemented with remifentanil. The median dosage of remifentanil required in the last three groups was 0.21, 0.25 and 0.34 microg x kg(-1) x min(-1), respectively (p < 0.05). The median times to eye opening were 10.3, 12.7, 11.0 and 6.5 min in the four groups (p < 0.05 between the 0.5 MAC and the other groups) and for orientation 12.1, 14.9, 12.3 and 8.3 min, respectively (p < 0.05 between 0.5 and 1.5 MAC groups). There was no significant difference in the mini-mental state assessment scores or the actual discharge times from the recovery ward among the groups. Significantly greater numbers of patients could perform the critical flicker fusion test at 15 min in the group receiving the lowest concentration of sevoflurane and the highest dosage of remifentanil (p < 0.05). Patients in this group also showed the highest incidence of chest wall rigidity (p < 0.003). We conclude that, while the use of remifentanil with lower concentrations of sevoflurane facilitates early recovery, it does not influence discharge time from recovery ward and may be associated with side-effects such as chest wall rigidity.

Rapacuronium: clinical pharmacology.

The need for a rapid-acting non-depolarizing neuromuscular blocking agent with a short duration of action resulted in the synthesis of rapacuronium. The onset of maximum block with rapacuronium occurs in 60-90 s with doses of 1.5-2.5 mg kg-1 with a duration of clinical relaxation of 15-30 min. Rapacuronium provides clinically acceptable intubating conditions in 60 s in a majority of patients with these doses, although the conditions are somewhat inferior to those obtained with succinylcholine in lightly anaesthetized patients, such as those undergoing a rapid-sequence induction. The main drawbacks of rapacuronium are the occurrence of dose-related pulmonary side-effects (increased airway pressure and/or overt bronchospasm) and hypotension and tachycardia. The cause of pulmonary side-effects is not certain but these have been serious enough to make its worldwide introduction doubtful.

Urinary, biliary and faecal excretion of rocuronium in humans.

The excretion of rocuronium and its potential metabolites was studied in 38 anaesthetized patients, ASA I-III and 21-69 yr old. Rocuronium bromide was administered as an i.v. bolus dose of 0.3 or 0.9 mg kg-1. In Part A of the study, the excretion into urine and bile, and the liver content were studied. Plasma kinetics (n = 19) were similar to those reported previously. Urinary recovery within 48 h after administration was 26 (8)% (mean (SD)) (n = 8) of the dose. In bile obtained from T-drains, the recovery within 48 h was 7 (6)% (n = 11). The rocuronium concentration in bile declined bi-exponentially, with half-lives of 2.3 (0.7) and 16 (11) h respectively (n = 6). In three patients from whom stoma fluid was collected, the amount of rocuronium recovered ranged from 0.04 to 12.0% of the dose. In liver tissue obtained from four patients undergoing hemihepatectomy, the estimated amount of rocuronium at 2-5 h after administration ranged between 6.3 and 13.2% (n = 4). In the second part of the study (Part B), urine and faeces were collected over 4-8 days and the recovery was 27 (13)% and 31 (23)% of the dose respectively (n = 10). In most samples, irrespective of the type of biological material, only small amounts of the metabolite 17-desacetyl-rocuronium was found. The results demonstrate that rocuronium is taken up by the liver and excreted into bile in high concentrations. The faecal and urinary excretion of unchanged rocuronium are the major routes of rocuronium elimination.

Rapacuronium 2.0 or 2.5 mg kg-1 for rapid-sequence induction: comparison with succinylcholine 1.0 mg kg-1.

The purpose of this nine-centre study in 602 patients was to show that the frequency of acceptable intubating conditions after rapacuronium 2.0 or 2.5 mg kg-1 is not more than 10% lower than the frequency after succinylcholine 1.0 mg kg-1 during rapid-sequence induction of anaesthesia with fentanyl 1-2 micrograms kg-1 and thiopental 2-7 mg kg-1. Laryngoscopy and intubation were carried out 60 s after administration of muscle relaxant by an anaesthetist blinded to its identity. Intubating conditions were clinically acceptable (excellent or good) in 91.8% of patients given succinylcholine and in 84.1 and 87.6% of patients given rapacuronium 2.0 and 2.5 mg kg-1 respectively. With respect to the percentage of clinically acceptable intubating conditions, the estimated difference (and the upper limit of the one-sided 97.5% confidence interval) between succinylcholine and rapacuronium 2.0 mg kg-1 was 7.8 (14.4)% and between succinylcholine and rapacuronium 2.5 mg kg-1 it was 4.0 (10.2)%. For both comparisons, the upper limit of the one-sided confidence interval exceeded the predefined 10% difference. Hence, it could not be demonstrated that the intubating conditions with either of the two doses of rapacuronium were not inferior to those with succinylcholine 1.0 mg kg-1. The increase in heart rate was significantly greater during the first 5 min in the rapacuronium groups, but the arterial pressure increased significantly only in the succinylcholine group (P < 0.001). Respiratory side-effects were observed in 4.0, 13.5 and 18.5% of patients after succinylcholine and rapacuronium 2.0 and 2.5 mg kg-1 respectively (P < 0.05). As the non-inferiority of intubating conditions after rapacuronium 2.0 and 2.5 mg kg-1 could not be proven, succinylcholine should be considered the neuromuscular blocking agent that provides better intubating conditions for rapid-sequence induction.