Aaron F. Kopman

Relationship of the Train-of-four Fade Ratio to Clinical Signs and Symptoms of Residual Paralysis in Awake Volunteers

Background:Recovery of the train-of-four (TOF) ratio to a value > 0.70 is synonymous with adequate return of neuromuscular function, but there is little information available concerning the subjective experience that accompanies residual neuromuscular block wherein the TOF ratio is in the range of 0

Pancuronium, Gallamine, and d-Tubocurarine Compared: Is Speed of Onset Inversely Related to Drug Potency?

The relative potency and speed of onset of action of pancuronium, gallamine, and d-tubocurarine was studied in 55 adult female patients receiving nitrous oxide/oxygen-narcotic anesthesia. The integrated electromyogram of the adductor pollicis muscle was monitored using a cumulative dose-response technique; train-of-four stimuli were administered at 0.05 Hz. The measured ED95 values for pancuronium and gallamine were 0.069 and 2.38 mg/kg, respectively. In three separate groups, pancuronium 0.07 mg/kg, gallamine 2.4 mg/kg, or d-tubocurarine 0.45 mg/kg were given as a single bolus and the speed of onset and time to maximum effect determined. Peak twitch depression was essentially identical in all groups (92.7 +/- 1.4 [SE] vs. 93.3 +/- 1.1 vs. 93.7 +/- 1.1%, respectively). The rate of onset of neuromuscular blockade in these three groups was, however, quite different. After administration of pancuronium (n = 10) the times to 5%, 20%, 50%, and 80% twitch depression were 68 +/- 5, 97 +/- 6, 141 +/- 8, and 222 +/- 18 s. The comparable times following gallamine (n = 10) were 29 +/- 2, 42 +/- 3, 66 +/- 5, and 136 +/- 14 s; d-tubocurarine (n = 10) was intermediate in speed with onset times of 40 +/- 4, 63 +/- 6, 99 +/- 11, and 178 +/- 25 s. It appears that the onset times of different nondepolarizing blocking agents (even when given in equipotent doses) may vary by clinically appreciable amounts. The results of this study support the hypothesis that nondepolarizing neuromuscular blocking agents of low potency may have a more rapid onset of action than that seen with agents of high potency.

Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP).

In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.

Residual postoperative paralysis. Pancuronium versus mivacurium, does it matter?

Background Based on a train-of-four (TOF) ratio greater than 0.70 as the standard of acceptable clinical recovery, undetected postoperative residual paralysis occurs frequently in postanesthesia care units. In most published studies, detailed information regarding anesthetic management is not provided. The authors reexamined the incidence of postoperative weakness after the administration of long- and short-acting neuromuscular blockers because few, if any, such comparative studies are available. Methods Ninety-one adult patients were studied. In group 1 (mivacurium, n = 35), anesthesia was induced with propofol/fentanyl and maintained with nitrous oxide, desflurane, and opioid supplementation. The response of the adductor pollicis to ulnar nerve stimulation was estimated by palpating the thumb. Mivacurium (0.20 mg/kg) was administered for tracheal intubation, and an infusion was adjusted to maintain the TOF count at 1. When surgery was completed, the infusion was discontinued. When a second twitch could be detected, 7.0 micro gram/kg atropine and then 0.5 mg/kg edrophonium were administered. At 5 and 10 min, the mechanical TOF response was measured. Additional measurements were recorded if possible. Patients were tracheally extubated and discharged from the operating room when they could respond to verbal commands and no TOF fade was palpable. In group 2 (pancuronium-desflurane anesthesia, n = 29), the protocol was identical to that of group 1, except that 0.07 mg/kg pancuronium was administered for tracheal intubation. Additional increments (0.5 to 1 mg) were given as needed. Antagonism was accomplished with 0.05 mg/kg neostigmine and 0.01 mg/kg glycopyrrolate. In group 3 (pancuronium propofol-opioid, n = 27), the protocol was identical to that of group 2, except that anesthesia was maintained with nitrous oxide and a propofol-alfentanil infusion. In all groups, patients were assessed until a TOF ratio of 0.90 or more was achieved Results All of the patients in group 1 had TOF ratios greater than 0.80 on arrival in the postanesthesia care unit. Twenty of 35 patients had TOF ratios 0.90 or more while they were still in the operating room. Thirty-three of 35 patients had TOF ratios 0.90 or more within 30 min of reversal, and this value was reached in all patients by 45 min. Recovery parameters in groups 2 and 3 did not differ from each other. Hence data from these groups were pooled. Fifty-four of 56 patients who received pancuronium had TOF values of 0.70 or more, the remaining two patients had values of 0.6 to 0.7. In contrast to the mivacurium group, however, only four patients achieved a TOF ratio of 0.90 or greater while still in the operating room. Finally, eight of these patients did not achieve this degree of recovery within 90 min of reversal. Conclusions These results suggest that if nondepolarizing neuromuscular blockers are administered using tactile evaluation of the TOF count as a guide, critical episodes of postoperative weakness in the postanesthesia care unit should occur infrequently even with long-acting relaxants. Nevertheless, if full recovery is defined as return to a TOF ratio of 0.90 or more, then short-acting agents would appear to offer a wider margin of safety.

Recovery times following edrophonium and neostigmine reversal of pancuronium, atracurium, and vecuronium steady-state infusions.

The ability of edrophonium and neostigmine to antagonize nondepolarizing neuromuscular blockade produced by steady-state infusions of atracurium, pancuronium, and vecuronium was studied in 71 adult patients anesthetized with nitrous oxide and halothane. Infusion rates of blocking drugs were adjusted so that single twitch depression as measured by the evoked integrated EMG of the hypothenar muscles was kept at 10% of control. Two minutes after the termination of the infusion either edrophonium (0.75 mg/kg) or neostigmine (0.05 mg/kg) was administered. Single twitch depression and train-of-four (T4/T1) fade was recorded during the recovery period. T4/T1 fade ratios observed at 20 min postreversal were 0.80 (atracurium-edrophonium); 0.76 (vecuronium-edrophonium); 0.44 (pancuronium-edrophonium); 0.95 (atracuriumneostigmine); 0.89 (vecuronium-neostigmine); and 0.68 (pancuronium- neostigmine). Under conditions of this study neostigmine produced more rapid and complete recovery than did edrophonium. Although edrophonium produced adequate antagonism of atracurium if 20–30 min were allowed to elapse, edrophonium reversal of pancuronium was rarely acceptable even at 30 min. Increasing the dose of edrophonium to 1.0 mg/kg produced single twitch values of 0.90 at 5 min postreversal but did not increase the rate of recovery of the train-of-four fade ratio. Neostigmine reversal of pancuronium, on the other hand, generally produced T4/T1 ratios of >0.70 in 20–30 min. Although the pattern of recovery seen after reversal of vecuronium was in general quite similar to that seen after atracurium, two patients in the vecuronium-edrophonium group showed delayed recovery and also failed to respond significantly to subsequent doses of neostigmine. Following steady-state infusions of vecuronium, it appears that marked patient variability in the speed of recovery can occur. Our results do not confirm other published reports that suggest that edrophonium and neostigmine may be used interchangeably.

Edrophonium antagonism of pancuronium-induced neuromuscular blockade in man: a reappraisal.

The ability of edrophonium to reverse the nondepolarizing neuromuscular blockade produced by pancuronium was studied in 40 adult patients during light nitrous oxide–enflurane anesthesia. Antagonism of paralysis was attempted when the train-of-four fade ratio had spontaneously recovered to various extents. Edrophonium was administered in incremental doses intravenously either until the fade ratio increased to 0.70 or more or until the total dose of drug amounted to 0.5 mg/kg. All patients who had spontaneous recovery of train-of-four fade ratios to at least 0.10 had adequate reversal with edrophonium. When the train-of-four count was three or fewer visible twitches, the response to edrophonium was unpredictable. No evidence of recurarization was seen.

Tactile evaluation of train-of-four count as an indicator of reliability of antagonism of vecuronium- or atracurium-induced neuromuscular blockade

Recent evidence suggests that edrophonium is not the agent of choice to reverse profound neuromuscular blockade but remains an efficacious drug when the level of neuromuscular blockade to be antagonized is modest. We studied 90 healthy adults in an attempt to address the questions: 1) How much variability in such neuromuscular parameters as single twitch height and the train-of-four (TOF) fade ratio (T4/T1) exist when the TOF count first returns to four palpable responses? 2) Is edrophonium a reliable antagonist at this measured point of recovery? 3) What is the optimal dose of edrophonium needed to produce prompt (less than 10 min) and satisfactory (T4/T1 greater than 0.7) reversal when the fourth response of the thumb to indirect TOF stimulation just becomes palpable? Patients were given a bolus atracurium or vecuronium (n = 45 in each group) followed by an iv infusion sufficient to maintain single twitch as measured by electromyography at 10-15% of control values. At the end of surgery, the infusion was terminated and spontaneous recovery was allowed to begin. Once the tactile TOF count was four, edrophonium 0.3, 0.5, or 0.75 mg/kg was administered. At a count-of-four the first twitch averaged 37% of control (+/- 8.5% standard deviation; pooled data from all groups) and the mean T4/T1 ratio was 0.14 +/- 0.049. After atracurium neuromuscular blockade, edrophonium 0.3 mg/kg produced adequate antagonism in 10 min. At this time the mean T4/T1 ratio was 0.79 +/- 0.07 and the lowest observed value was 0.67. Increasing the edrophonium dose to 0.75 mg/kg accelerated recovery by 4-5 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of Mivacurium-induced Neuromuscular Blockade in Humans: Edrophonium Dose Requirements at Threshold Train-of-four Count of 4

Background:Mivacuriums rapid rate of recovery has led to the suggestion that routine reversal of its residual effects may be unnecessary once signs of spontaneous recovery are evident. When antagonism is attempted at 90% twitch depression, the time saved to return to traln-of-four (TOF) ratios >0.70 compared to control has been reported to average ≤8 min. This study was an attempt to determine whether similar savings in time could be achieved once spontaneous recovery was well underway. Also investigated was the ability of a TOF count of 4 to serve as a marker that might predict the dose of edrophonium necessary for satisfactory antagonism of mivacurium. Methods:Fifty-eight adult patients were studied under nitrous oxide/propofol/opioid anesthesia. Neuromuscular block was monitored electromyographically and maintained by infusion of mivacurium at a level sufficient to abolish any palpable response of the thumb. TOF stimuli were delivered to the ulnar nerve at the wrist every 20 s throughout the period of observation. When the infusion was terminated, an observer was asked to note the time when the 1st through the 4th twitches first became detectable. In group 1, recovery to a TOF ratio >0.90 was allowed to proceed spontaneously. In groups 2, 3, and 4, 0.3, 0.5, and 0.75 mg/kg edrophonium, respectively, was administered when the 4th response to TOF stimulation first became palpable. Times to TOF ratios of 0.70 and 0.90 were recorded in all groups. Results.TOF counts of 1, 2, 3, and 4 first became palpable at 8 ± 4% (SD), 20 ± 6%, 33 ± 9%, and 44 ± 10% of control twitch height. Fade on TOF stimulation could no longer be detected once the TOF ratio exceeded a value of 0.41 ± 0.07 (range 0.25-0.51). Once the 1st evoked response was palpable, the 2nd, 3rd, and 4th responses could be detected 2.5 ± 1.1 (SD), 4.6 ± 1.6, and 6.1 ± 1.6 min later. Spontaneous recovery to TOF fade ratios of 0.7 and 0.9 occurred on average 10.7 ± 2.3 and 16.9 ± 4.7 min, respectively, after a threshold count of 4. Administration of 0.3 mg/kg edrophonium shortened the recovery process by about 7.5 min. Increasing the dose of edrophonium beyond 0.3 mg/kg did not further accelerate recovery. Conclusions:After recovery from profound mivacurlum-induced neuromuscular block, TOF counts of 1, 2, 3, and 4 approximate 10%, 20%, 30%, and 40% return to control twitch height, respectively. Finally, ≥0.3 mg/kg edrophonium will accelerate recovery from mivacurium by approximately 7-8 min.

The influence of changes in hand temperature on the indirectly evoked electromyogram of the first dorsal interosseous muscle

The evoked EMG response commonly decreases in amplitude during the first few minutes of anaesthesia. The purpose of this study was to determine if a relationship exists between changes in hand temperature, which are known to occur with induction of anaesthesia, and drift in the EMG signal. The indirectly evoked response of the 1st dorsal interosseous muscle was measured using a Datex™ Relaxograph® in 15 patients undergoing elective surgery. The test arm was wrapped in towels in order to minimize heat loss. Core body temperature, hand temperature, and T1 were recorded at two minute intervals for the next 30 min. Patients then received a bolus of mivacurium 0.08 mg · kg−1 and additional doses were given as needed. Complete recovery was defined as a TOF ratio > 0.90. Regression analysis plotting Atemperature against Δ T1 was performed for each individual. The slope of the regression line for the relationship between Δ°C and δ T1 was then used to calculate a correction factor (CF) which might be used to “fine tune” the last measured T1. The initial hand temperature averaged 30.8 ± 1.4° C and this increased by 4.1 ± 1.2° C over the next 30 min. During this period T1 decreased by 24.8 ± 5.9% or-6.05%/° C. The final mean T1 value at the end of anaesthesia (uncorrected) was 70.6 ± 7% of control. The average corrected T1 value was 94.7 ± 8.5% (range, 83–111%). It is concluded that there was a correlation between Δ°C and ΔT1 during the first 30 min of anaesthesia (r2 = 0.77, P < 0.0001). However, in 5 of 15 individuals it was not possible to “temperature correct” the final T1 value to within ± 10% of control. Hence, while changes in muscle temperature probably play a major role in the T1 drift seen with the Datex monitor, other factors remain to be identified.RésuméLa réponse évoquée à l’EMG diminue ordinairement pendant les premières minutes de l’anesthésie. Le but de cette étude était de déterminer la relation possible entre les changements de température de la main qui surviennent à l’induction, et la dérive du signal de l’EMG. La réponse indirecte évoquée au 1er muscle interosseux dorsal a été mesurée avec un Relaxograph® Datex® chez 15 patients en chirurgie réglée. Le bras servant à l’expérience a été enveloppé dans des serviettes pour en atténuer la perte de chaleur. La température centrale, la température de la main et T1 ont été enregistrés aux deux minutes pendant 30 min. Les patients ont alors reçu un bolus de mivacurium 0,08 mg · kg−1 et des doses additionnelles administrées au besoin. La récupération complète a été définie comme un rapport de TOF > 90%. L’analyse de régression établissant la relation entre Δ température et ΔT1 a été effectuée pour chacun des sujets. La pente de régression pour la relation entre Δ°C et ΔT1 a été utilisée pour calculer un facteur de correction (FC) utilisable pour une mise au point finale du dernier T1 mesuré. La température initiale de la main était en moyenne de 30,8 ± 1,4° C. Elle augmentait de 4,1 ± 1,2° C pendant les 30 min suivantes. Pendant cette période, T1 diminuait de 28,4 ± 5,9% ou −6,05%/° C. La valeur finale moyenne de T1 à la fin de l’anesthésie (sans correction) était de 70,6 ± 7% du contrôle. La valeur moyenne corrigée de T1 était de 94,7 ± 8,5% (écart, 83–111%). En conclusion, il existe une corrélation entre Δ° C et AT1 au cours des 30 premières min d’anesthésie (r2 = 0,77, P < 0,0001). Toutefois, chez cinq des 15 sujets, il a été impossible d’appliquer la correction de température à la valeur finale de T1 à ±10% du contrôle. En conclusion, bien que les changements de température musculaire puissent jouer un rôle majeur dans la dérive de T1 observée avec le moniteur Datex, les autres facteurs en cause sont encore inconnus.

Acceleromyography as a guide to anesthetic management: a case report

We present a case of prolonged recovery from mivacurium. Neuromuscular monitoring using acceleromyography was extremely helpful following attempted reversal of residual block in determining when tracheal extubation could be safely performed. If a method of objective estimation of the TOF ratio had not been available, tracheal extubation would have taken place at a time when the train-of-four fade ratio was below 0.40.