Arm-to-arm variation when evaluating neuromuscular block: an analysis of the precision and the bias and agreement between arms when using mechanomyography or acceleromyography.

BACKGROUND: Studies comparing acceleromyography and mechanomyography indicate that the two methods cannot be used interchangeably. However, it is uncertain to what extent differences in precision between the methods and the naturally occurring arm-to-arm variation have influenced the results of these studies. Accordingly, the purpose of this study was to examine the precision and the arm-to-arm variation, when the same method is used on both of the arms. METHODS: In the first part (n=20), mechanomyography was applied bilaterally and in the second part acceleromyography (n=20). Anaesthesia was induced with propofol and opioid, and neuromuscular block with rocuronium 0.6 mg kg(-1). The precision of the two methods and the bias and limits of agreement between the arms were evaluated using train-of-four (TOF) stimulation, without and with referral to the initial baseline value, that is, normalization. RESULTS: Both methods were found to be precise (<5% variation) without any difference between the dominant and non-dominant arms. There were no significant biases between the arms, except for the onset time obtained with acceleromyography, which was 10% longer for the dominant arm. However, the individual differences (limits of agreement) were wide (0.20-0.25 at TOF 0.90). Normalization during recovery did not change bias or limits of agreement between the arms. CONCLUSIONS: In the research setting, acceleromyography and mechanomyography are both precise methods without difference between the arms. Although there is no mean bias between the arms, both methods show wide individual differences (limits of agreement), which might to a large extend explain the differences often found when two different methods are compared on the contralateral arms. ClinicalTrial.gov identifier: NCT00472121; URL: http://clinicaltrials.gov/ct2/show/study/NCT00472121.

Acceleromyography and mechanomyography for establishing potency of neuromuscular blocking agents: a randomized-controlled trial.

BACKGROUND: Acceleromyography (AMG) is increasingly being used in neuromuscular research, including in studies establishing the potency of neuromuscular blocking and reversal agents. However, AMG is insufficiently validated for use interchangeably with the gold standard, mechanomyography (MMG) for this purpose. The aim of this study was to compare AMG and MMG for establishing dose-response relationship and potency, using rocuronium as an example. METHODS: We included 40 adult patients in this randomized-controlled single-dose response study. Anaesthesia was induced and maintained with propofol and opioid. Neuromuscular blockade was induced with rocuronium 100, 150, 200 or 250 microg/kg. Neuromuscular monitoring was performed with AMG (TOF-Watch SX) with pre-load (Hand Adapter) at one arm and MMG (modified TOF-Watch SX) on the other, using 0.1 Hz single twitch stimulation. Dose-response relationships were determined for both recording methods using log (dose) against probit (maximum block). The obtained slopes of the regression lines, ED(50), ED(95) and the maximum block were compared. RESULTS: The ED(50) and ED(95) [95% confidence interval (CI)] for AMG were 185 microg/kg(167-205 microg/kg) and 368 microg/kg(288-470 microg/kg), compared with 174 microg/kg(159-191 microg/kg) and 338 microg/kg(273-418 microg/kg) for MMG. There were no statistically significant biases in maximum block, ED(50), ED(95) or slopes obtained with the two methods. CONCLUSION: Our results indicate that any possible difference between AMG and MMG is so small that it justifies AMG to be used for establishing the potency of neuromuscular blocking agents. However, the wide CIs show that we cannot rule out a 13% higher ED(50) and a 26% higher ED(95) for AMG.

The undesirable effects of neuromuscular blocking drugs.

Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking drugs including the definitions, diagnosis and causes of hypersensitivity reactions and postoperative residual curarisation.

Prolonged residual paralysis after a single intubating dose of rocuronium.

It is often argued that neuromuscular monitoring is unnecessary when only one dose of an intermediate-acting neuromuscular blocking agent is given. This case report documents that it may take more than 3.5 h before it is possible to antagonize a block caused by a normal dose of rocuronium (0.6 mg kg(-1)). Possible causes of the extremely prolonged duration of action are discussed, as is the importance of quantitative neuromuscular monitoring.

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.

Scandinavian research in anaesthesiology 1981-2000: visibility and impact in EU and world context.

BACKGROUND: We wished to assess the development in number and impact of publications in anaesthesiology and intensive care medicine from 1981 to 2000 in the four Scandinavian countries: Sweden, Norway, Finland, and Denmark. For comparison, we also analyzed data from the UK and the Netherlands. METHODS: Publication and citation data from 1981 to 2000 were gathered from National Science Indicators (2001), covering 33 journals indexed in Current Contents. Data were analyzed in running 5-year periods. The following informetric indicators were used: absolute number of publications; absolute number of citations; absolute citation impact (average number of citations per publication per 5-year period); citation impact relative to the European Union and the world; and the percentage of cited papers from each country. RESULTS: The annual number of publications from Denmark was stable over the 20-year period. Sweden increased its production by 35%, while the remaining four countries showed increases from 100% to 146%. Thus, Sweden and Denmark lost visibility within the European Union (EU) and in world context. The EU and world citation shares of Finland and Norway increased slightly, whereas those of Sweden, Denmark, the UK, and the Netherlands all declined significantly. The absolute citation impact (ACI) increased for all the four Scandinavian countries. The ACI of the Netherlands did not change and was surpassed by all the Scandinavian countries by 1994-98, while the UK finished below the other five countries. CONCLUSIONS: (1) The annual number of publications from Sweden, Norway, Finland, the UK, and the Netherlands increased after the late eighties, whereas the net publication output from Denmark was stagnant over the 20-year period investigated; (2) the international publication and citation visibility of Finland and Norway increased slightly, as opposed to the significant decrease seen by the other four countries; (3) judging from the increase in absolute and relative citation impact and in the percentage of cited papers, the recognition of publications from the four Scandinavian countries increased over the past 20 years.

Remifentanil vs. alfentanil infusion in non-paralysed patients: a randomized, double-blind study.

BACKGROUND AND OBJECTIVE: Remifentanil has a short duration of action and constant elimination, which allow administration of high doses, without prolonging recovery. Remifentanil has been compared to alfentanil, as part of a total intravenous anaesthetic technique, where remifentanil provided better anaesthetic conditions than alfentanil, without adverse effect on recovery. However, these results were obtained during anaesthesia involving neuromuscular blockade, which may mask both signs of insufficient anaesthesia and side-effects such as muscle rigidity. The aim of this study was to compare remifentanil with alfentanil for anaesthesia without neuromuscular blockade. METHODS: We performed a prospective, randomized, double-blind, four-centre study to compare remifentanil infusion 15 microg kg(-1) h(-1) and alfentanil infusion 60 microg kg(-1) h(-1), using a total intravenous technique for non-paralysed patients, and the laryngeal mask airway for airway management. We enrolled 192 patients, 18-65 yr of age with ASA I-II, undergoing minor surgery. The primary endpoint was the number of patients having pre-defined responses to surgical stimulation. A number of secondary criteria was evaluated to assess undesirable properties of the procedures. RESULTS: In the alfentanil group, 85% of patients responded to surgical stimulation, vs. 35% in the remifentanil group (P < 0.0001). No difference was found in recovery data, or in any other parameter than those related to insufficient anaesthesia. CONCLUSIONS: The remifentanil-based technique provided significantly better anaesthetic conditions than the alfentanil-based technique in the setting of this study, without causing any significant adverse effects.

Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically heterozygous for the usual and atypical plasma cholinesterase variants (UA).

BACKGROUND: Mivacurium is hydrolyzed by plasma cholinesterase (pChe). The purpose of this study was to evaluate the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium in patients phenotypically heterozygous for the usual and the atypical pChe variant (UA). METHODS: Thirty-two patients were included in a dose-response study, in which the patients received one of four doses of mivacurium. An additional bolus dose of mivacurium, to a total of 0.1 mg kg-1, was given followed by a continuous infusion adjusted to maintain 91-99% neuromuscular block. The times to different levels of recovery following the infusion were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Twelve of the patients with an estimated duration of anaesthesia of more than 90 min were (randomly) selected for the pharmacokinetic part of the study. Venous samples were taken for determination of the three isomers of mivacurium. These results were compared with results from a previous study in phenotypically normal patients (UU). RESULTS: The estimated ED50 and ED95 were 24 and 69 microg kg-1, respectively. The median (range) infusion rate was 3.7 microg kg-1 min-1 (1.2-2.9) and the time to a TOF ratio of 0.7 was 29.8 min (16.1-44.8). The median clearances of the cis-cis, cis-trans and trans-trans isomers were 3.7, 29 and 28 ml kg-1 min-1, respectively. The elimination half-lives of the isomers were 45, 6.7 and 6.3 min, respectively. CONCLUSION: In patients heterozygous for the usual and the atypical variant (UA), the potency of mivacurium is higher, the infusion requirements lower and the rate of spontaneous recovery prolonged, compared with phenotypically normal patients. The clearances of the active isomers are significantly lower and the elimination half-lives longer in heterozygous patients than in phenotypically normal patients (UU). The pharmacokinetics of the inactive cis-cis isomer was not affected.

Remifentanil vs. alfentanil for direct laryngoscopy: a randomized study comparing two total intravenous anaesthesia techniques. TIVA for direct laryngoscopy.

The ideal anaesthesia for direct laryngoscopy is profound and yet brief. The present study sought to determine whether a new anaesthetic technique based on infusion of the ultra short-acting opioid remifentanil was superior to our routine alfentanil multiple-dose technique in terms of haemodynamic stability, stress responses and recovery. A total of 58 patients were randomized to receive propofol and either remifentanil or alfentanil as part of a total intravenous anaesthesia. In the remifentanil group, systolic blood pressure during anaesthesia remained significantly lower than baseline values, while it increased significantly in the alfentanil group. None of the patients receiving remifentanil showed stress responses (hypertension, tachycardia, somatic or autonomic responses), compared to 22 patients (79%) in the alfentanil group (P < 0.0001). In the remifentanil group, hypotension or bradycardia requiring intervention arose in 5 (18%) and 3 patients (11%); neither response was seen in the alfentanil group. The period from the end of propofol infusion until extubation was 5 min longer in the remifentanil group (P < 0.0001), whereas the time from extubation until discharge was similar in the two groups. Thus, neither technique showed sufficient haemodynamic stability, and further studies are needed to determine optimal dosages of propofol and opioid.

Mortality among anesthesiologists in Denmark, 1973-95.

BACKGROUND: Preliminary data from Sweden indicating that anesthesiologists have a high mortality risk has caused a lot of concern in Denmark. The aim of this study therefore was to compare mortality between consultant anesthesiologists and other consultants in Denmark. METHODS: A historical prospective cohort study based on the membership register of the Danish Medical Association from 1973 to 1992. The study population consisted of 6854 consultants who were members of the Association of Medical Specialists, 406 of whom were anesthesiologists. The all-cause mortality between the two groups was compared during the period 1972-95 using Cox's proportional hazard regression model. RESULTS: The study covered approximately 86000 person-years. A total of 1205 deaths occurred within the period studied, 41 of whom were anesthesiologists. The relative risk for all-cause mortality among the anesthesiologists compared with all the other consultants was 1.0 (95% confidence limit: 0.7-1.4). CONCLUSION: In Denmark there is no evidence of a high mortality risk in consultant anesthesiologists compared with other consultants.

Acceleromyography of the orbicularis oculi muscle I: significance of the electrode position.

BACKGROUND: This study aimed to establish the best position of the stimulating electrodes for facial nerve stimulation during acceleromyographic monitoring from the orbital part of the orbicularis oculi muscle. METHODS: In 59 anaesthetised patients, an acceleration transducer was positioned over the middle of the eyebrow. In 47 patients, supramaximal train-of-four (TOF) stimulation was established for four electrode pairs with different positions along the facial nerve and behind the ear. The electrode pair with the lowest, the intermediate, and the highest supramaximal stimulating current based on first response (T1) in TOF was found in each patient. A possible response from direct muscle stimulation was evaluated during complete vecuronium block. In 12 patients, supramaximal stimulation was established using a stimulation sequence different from the one used in the first part of the study. RESULTS: The best positions for the stimulating electrodes were either with both electrodes just lateral to the eye, or with one electrode lateral to the eye and one in front of the ear. In most patients, supramaximal stimulation was obtained at these positions at 20-60 mA. However, in 10-21% of the patients, supramaximal stimulation could not be obtained. During complete block, 1-4 responses with a twitch height of 3-11% were recorded in 80% of the patients. CONCLUSION: The best placements of the stimulation electrodes are either just lateral to the eye or along the zygomatic arch. However, supramaximal stimulation may often not be obtainable, and activation of other facial muscles may be a confounding factor that may impede correct evaluation of the degree of neuromuscular block.

Acceleromyography of the orbicularis oculi muscle II: comparing the orbicularis oculi and adductor pollicis muscles.

BACKGROUND: The orbicularis oculi (OO) muscle has been recommended for neuromuscular monitoring when the adductor pollicis (AP) muscle is not available. We investigated whether neuromuscular block could be measured reliably from the orbital part of the OO muscle by the use of acceleromyography. METHODS: During propofol, fentanyl, and alfentanil anaesthesia two TOF-Guards (Organon Teknika NV, Boxtel, the Netherlands) with acceleration transducers placed on the distal phalanx of the thumb and over the middle of the eyebrow, respectively, were used to measure neuromuscular block simultaneously in 23 patients during vecuronium-induced and neostigmine-antagonized neuromuscular block. For both muscles, the simultaneously recorded first response (T1) in the train-of-four (TOF) and TOF-ratio were measured both during onset and recovery of the block. Furthermore, both the AP muscle T1 and TOF-ratio responses were plotted against 10% intervals of the OO muscle responses during onset and recovery, respectively. RESULTS: The orbicularis oculi muscle had a shorter latency and a faster recovery to TOF-ratio 0.80 compared with the AP muscle. During onset and recovery, pronounced variations of the AP muscle T1 and TOF-ratio responses were observed when compared with the OO muscle. CONCLUSION: A significant clinical disagreement exists between the degree of paralysis measured at the OO and the AP muscles. It is impossible to obtain a reasonable estimate of the degree of block at the AP muscle when the block is measured from the OO muscle with acceleromyography. If used, there is substantial risk of overlooking a residual block, and adequate recovery of the block should be confirmed by a final AP muscle measurement.

Rapid simultaneous genotyping of the frequent butyrylcholinesterase variants Asp70Gly and Ala539Thr with fluorescent hybridization probes.

BACKGROUND: The clinically important variants of butyrylcholinesterase (BChE) are the A- (Asp70Gly) and K-variants (Ala539Thr), which are common among Caucasians. These variants are associated with abnormal drug metabolism during anaesthesia, which leads to a prolonged neuromuscular block following administration of the neuromuscular blocking agents, mivacurium and succinylcholine. In addition, the K-variant has been proposed to be associated with Alzheimer's disease together with apolipoprotein E epsilon4. To facilitate diagnostics, we set out to establish a rapid and simple method for simultaneous genotyping of the A- and K-variants. METHODS: Using the LightCycler, a rapid-cycle duplex PCR is combined with generation of allele-specific fluorescent probe melting profiles. This allows simultaneous detection of both of the mutations in the BChE gene. The results were compared with direct sequencing and phenotyping results. RESULTS: Samples from 80 subjects were genotyped. The genotypes determined using the LightCycler were identical to those obtained by direct sequencing of conventional polymerase chain reaction products and was more accurate than phenotyping based on biochemical assays. CONCLUSIONS: A high-speed and easy to perform mutation detection assay has been established for the two most common mutations, Asp70Gly and Ala539Thr, in BChE, using the LightCycler technology and melting curves.

Plasma cholinesterase activity and duration of action of mivacurium in phenotypically normal patients.

BACKGROUND: The short duration of action of mivacurium is due to its rapid hydrolysis by plasma cholinesterase (pChe). In patients with normal phenotype, low pChe activity because of, for instance, disease or intake of drugs may prolong the duration of action of mivacurium. The purpose of this study was to evaluate the relationship between pChe activity and the duration of action of mivacurium 0.2 mg/kg in phenotypically normal patients. MATERIAL: Forty-three adult patients with normal pChe phenotype and low or normal pChe activity, undergoing a variety of surgical procedures were included in the study with their informed consent and Ethics Committee approval. The neuromuscular block was monitored using TOF stimulation every 12 s and mechanomyography. The time to reappearance of the first response to TOF stimulation was measured. RESULTS: The patients pChe activities ranged from 45 to 1272 U/l (normal range 660-1620 U/l) and the time to first response to TOF from 8.1 to 62.7 min. An inverse relationship between enzyme activity and duration of action of mivacurium was found. The relationship was described by the equation: log10 (time) =alpha- beta log10 (pChe), where alpha (SD) is 2.547 (0.186) and beta (SD) 0.454 (0.069). CONCLUSION: In patients with phenotypically normal pChe, prediction of the duration of action of mivacurium is possible from the patients actual pChe activity. In patients with pChe activities below the normal range, the time to reappearance of the first response to TOF stimulation may vary from 10 to 180 min Only patients with pChe activities <220 U/l had a significantly prolonged duration of action of mivacurium.