Jørgen Viby-Mogensen

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.

Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study.

Background: Sugammadex (Org 25969) forms a complex with steroidal neuromuscular blocking agents, thereby reversing neuromuscular block. This study investigated the dose–response relation, safety, and pharmacokinetics of sugammadex to reverse rocuronium-induced block. Methods: Twenty-seven male surgical patients aged 18–64 yr were randomly assigned to receive placebo or sugammadex (0.5, 1.0, 2.0, 3.0, or 4.0 mg/kg) for reversal of 0.6 mg/kg rocuronium–induced neuromuscular block. Anesthesia was induced and maintained using intravenous fentanyl and propofol. Neuromuscular function was assessed using acceleromyography. Sugammadex or placebo was administered at reappearance of T2 of the train-of-four. The primary efficacy variable was the time required for recovery to a train-of-four ratio of 0.9. Results: Sugammadex decreased median recovery time in a dose-dependent manner from 21.0 min in the placebo group to 1.1 min in the group receiving 4.0 mg/kg sugammadex. Doses of sugammadex of 2.0 mg/kg or greater reversed rocuronium-induced neuromuscular block within 3 min. A median of 59–77% of sugammadex was excreted unchanged in the urine within 16 h, mostly in the first 8 h. Sugammadex increased the proportion of the rocuronium dose excreted unchanged in the urine (from a median of 19% in the placebo group to 53% in the 4.0-mg/kg group within 16 h). Sugammadex was safe and well tolerated. No evidence of recurarization was observed in any patient. Conclusion: At doses of 2.0 mg/kg or greater, sugammadex safely reversed 0.6 mg/kg rocuronium–induced neuromuscular block in a dose-dependent manner. Sugammadex enhanced renal excretion of rocuronium and was excreted unchanged by the kidneys.

Tactile and Visual Evaluation of the Response to Train-of-four Nerve Stimulation

168 adultes subissent une chirurgie gynecologique ou gastroenterologique. Levaluation manuelle de la reponse a la stimulation nerveuse «train de quatre» permet lajustement des posologies individuelles pour les curarisants au cours de lanesthesie pour eviter un surdosage et assurer la reversibilite

Manual evaluation of residual curarization using double burst stimulation: a comparison with train-of-four

Double burst stimulation (DBS) is a new mode of stimulation developed to reveal residual neuromuscular blockade under clinical conditions. The stimulus consists of two short bursts of 50 Hz tetanic stimulation, separated by 750 ms, and the response to the stimulation is two short muscle contractions. Fade in the response results from neuromuscular blockade as with train-of-four stimulation (TOF). The authors compared the sensitivity of DBS and TOF in the detection of residual neuromuscular blockade during clinical anaesthesia. Fifty-two healthy patients undergoing surgery were studied. For both stimulation patterns the frequencies of manually detectable fade in the response to stimulation were determined and compared at various electromechanically measured TOF ratios. A total of 369 fade evaluations for DBS and TOF were performed. Fade frequencies were statistically significantly higher with DBS than with TOF, regardless of the TOF ratio level. Absence of fade with TOF implied a 48% chance of considerable residual relaxation as compared with 9% when fade was absent with DBS. The results demonstrate that DBS is more sensitive than TOF in the manual detection of residual neuromuscular blockade.

Acceleromyography for use in scientific and clinical practice: a systematic review of the evidence.

This systematic review describes the evidence on the use of acceleromyography for perioperative neuromuscular monitoring in clinical practice and research. The review documents that although acceleromyography is widely used in research, it cannot be used interchangeably with mechanomyography and electromyography for construction of dose–response curves or for recording different pharmacodynamic variables after injection of a neuromuscular blocking agent. Some studies indicate that it may be beneficial to use a preload to increase the precision of acceleromyography, and to “normalize” the train-of-four ratio to decrease the bias in relation to mechanomyography and electromyography. However, currently the evidence is insufficient to support the routine clinical use of preload and “normalization.” In contrast, there is good evidence that acceleromyography improves detection of postoperative residual paralysis. A train-of-four ratio of 1.0 predicts with a high predictive value recovery of pulmonary and upper airway function from neuromuscular blockade.

Does perioperative tactile evaluation of the train-of-four response influence the frequency of postoperative residual neuromuscular blockade?

The authors conducted a randomized controlled clinical trial to evaluate the usefulness of perioperative manual evaluation of the response to train-of-four (TOF) nerve stimulation. A total of 80 patients were divided into four groups of 20 each. For two groups (one given vecuronium and one pancuronium), the anesthetists assessed the degree of neuromuscular blockade during operation and during recovery from neuromuscular blockade by manual evaluation of the response to TOF nerve stimulation. In the other two groups, one of which received vecuronium and the other pancuronium, the anesthetists evaluated the degree of neuromuscular blockade solely by clinical criteria. The use of a nerve stimulator was found to have no effect on the dose of relaxant given during anesthesia, on the need for supplementary doses of anticholinesterase in the recovery room, on the time from end of surgery to end of anesthesia, or on the incidence of postoperative residual neuromuscular blockade evaluated clinically. The median (and range of) TOF ratios recorded in the recovery room were 0.75 (0.33-0.96) and 0.79 (0.10-0.97) in the vecuronium groups monitored with and without a nerve stimulator, respectively. These ratios were significantly higher than those found in the pancuronium groups, which wre 0.66 (0.06-0.90) and 0.63 (0.29-0.95), respectively. However, no difference was found between the vecuronium and pancuronium groups in the number of patients showing clinical signs of residual neuromuscular blockade, as evaluated by the 5-s head-lift test.(ABSTRACT TRUNCATED AT 250 WORDS)

Succinylcholine neuromuscular blockade in subjects heterozygous for abnormal plasma cholinesterase.

The relationship between plasma cholinesterase genotype and duration and type of succinylcholine neuromuscular blockade was studied in 43 anesthetized patients heterozygous for abnormal plasma cholinesterase using train-of-four nerve stimulation. Twenty-eight patients were heterozygous for the usual and the atypical gene (EluEla), eight were heterozygous for the usual and the silent gene (EluEls), three were heterozygous for the usual and the fluoride-resistant gene (EluElf), three were heterozygous for the fluoride-resistant and the atypical gene (EluEla), and one was heterozygous for the fluoride-resistant and the silent gene (ElfEls).Mean time to 90 per cent recovery of twitch height in patients with genotypes EluEla, EluEls and EluElf (14.6, 12.4, and 12.0 min, respectively) was significantly prolonged compared to patients with normal cholinesterase genotype (9.3 min). No significant difference was found between the three groups of patients with one abnormal gene (EluEla, EluEls, and EluElf). In 13 (46 per cent) of the 28 patients with genotype EluEla the twitch height did not return to control for more than 15 min after the administration of succinylcholine and in three patients (10.7 per cent) for more than 20 min after succinylcholine.The four patients with abnormal genes on both chromosomes (ElfEla and ElfEls) all showed significantly prolonged paralysis following the administration of succinylcholine (mean time to 90 per cent twitch recovery was 30 min).Patients heterozygous for the usual and one of the abnormal genes (EluElu, EluEls, and EluElf) had typically depolarizing blocks following the administration of succinylcholine, 1 mg/kg. Patients with abnormal genes on both chromosomes (ElfEla and ElfEls), however, all showed desensitization type of neuromuscular blockade (phase II block).

Clinical Recovery and Train-of-Four Ratio Measured Mechanically and Electromyographically Following Atracurium

Indices of clinical recovery were compared with mechanically (adductor pollicis muscle) and electromyographically (first dorsal interosseal muscle) recorded train-of-four (TOF) ratios during antagonism of atracurium blockade in 23 healthy neurolept anesthetized patients. Clinical recovery was evaluated from the ability to lift the head, sustain headlift for 5 or 10 s, protrude the tongue, open the eyes, and the presence of ptosis of the eyelids. In all patients the mechanical TOF ratio was recorded. In 17 patients TOF ratios based on measurements of the potential area and the amplitude of the major negative deflection of the compound EMG response were recorded as well. At each TOF ratio interval of 0.05 from a TOF ratio of 0.5-0.85, the number of patients being able to perform the individual tests was recorded. Further, the mechanical TOF ratio during recovery was compared with the EMG TOF ratios. Headlift could not be sustained for 5 s in any patient at a TOF ratio of 0.5, whether recorded mechanically or by EMG, and TOF ratio had to recover to 0.8 before all patients could sustain headlift for 5 s. All patients could open the eyes and protrude the tongue at a TOF ratio of 0.65, and ptosis remained present during the entire testing period. There was no statistically significant difference between the mechanical and the EMG methods with regard to the TOF ratios at which the tests could be performed. During recovery a linear relationship was found between mechanical TOF ratios and the square root of the EMG TOF ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged Neuromuscular Block from Mivacurium in Two Patients with Cholinesterase Deficiency

M ivacurium’s short duration of action, like the ultra-short action of succinylcholine, is due to its rapid hydrolysis by plasma cholinesterase (ChE); an inverse relationship has been found between ChE activity and the duration of action of mivacurium in phenotypically normal patients (1). Reports of prolonged paralysis from succinylcholine in the presence of ChE deficiency have been reported (2), and there has been a case report of prolonged mivacurium block in a patient with dermatomyositis and muscle weakness (3). The following two incidents of prolonged paralysis occurred during the evaluation phases of mivacurium; they were seen in separate institutions and managed with different approaches.

Is the performance of acceleromyography improved with preload and normalization? A comparison with mechanomyography.

Background:Many studies have indicated that acceleromyography and mechanomyography cannot be used interchangeably. To improve the agreement between the two methods, it has been suggested to use a preload and to refer all train-of-four (TOF) ratios to the control TOF (normalization) when using acceleromyography. The first purpose of this study was to test whether a preload applied to acceleromyography would increase the precision and the agreement with mechanomyography. The second purpose was to evaluate whether normalization would improve the agreement with mechanomyography. Methods:Sixty patients were randomized to acceleromyography with or without a preload (Hand Adapter; Organon, Oss, the Netherlands). On the contralateral arm, mechanomyography was used. Anesthesia was induced with propofol and an opioid, and neuromuscular block with 0.6 mg/kg rocuronium. The precision and the bias and limits of agreement (with or without normalization) between the methods were evaluated using TOF stimulation. Results:Preload improved the precision of acceleromyography by 21%, but it also increased the mean control TOF ratio from 1.07 to 1.13. Normalization of the acceleromyographic TOF ratios diminished the bias to mechanomyography during recovery (e.g., from 0.15 to 0.05 at TOF 0.90); when the mechanomyographic TOF values were normalized as well, the bias was eliminated. However, normalization did not exclude wide individual differences between acceleromyography and mechanomyography (± 0.10–0.20 at TOF 0.90). Conclusion:Preload increases the precision of acceleromyography, and normalization of the TOF ratios decreases bias in relation to mechanomyography. When both acceleromyography and mechanomyography are normalized, there is no significant bias between the two methods.