Edrophonium requirements for reversal of deep neuromuscular block following infusion of mivacurium

Mivacurium is a new non-depolarizing muscle relaxant consisting of three stereoisomers. The two active isomers (cis-trans andtrans-trans) undergo rapid metabolism by plasma cholinesterase (t_1/2 β<2 min). Due to its rapid elimination, the need for reversal of mivacurium-induced neuromuscular block is controversial, and to date there have been no studies evaluating reversal of deep blocks. The object of the current investigation was to establish the lowest effective dose of edrophonium required to reverse deep mivacurium-induced neuromuscular block. One hundred ASA Class I and II patients undergoing outpatient surgery in two teaching institutions were studied in this randomized, placebo-controlled double-blind trial. Under balanced propofol/nitrous oxide/alfentanil anaesthesia, a continuous infusion of mivacurium was adjusted to maintain between 5– 10% of control T₁ amplitude. Upon completion of surgery, neuromuscular block was reversed by injecting normal saline (Group PLAC), edrophonium 0.125 mg · kg^{? 1} (Group EDR- 1), 0.25 mg · kg^{? 1} (Group EDR- 2), or 0.50 mg · kg^{? 1} (Group EDR- 3), in addition to a corresponding dose of atropine. 4Spontaneous recovery, from a T₁ response of<10% to a TOF ratio ≥0.7, required 13.5 ± 2.6 min (PLAC Group). In comparison, patients in the EDR- 1 group required 9.2 ± 2.6 min (P < 0.01). Higher doses of edrophonium conferred no advantage. Four patients (4%) had not achieved a TOF ratio of ≥ 70%, 20 min after reversal, and required additional edrophonium. Two patients (PLAC group), had dibucaine numbers and cholinesterase levels consistent with an E^UE^A genotype, whereas the two patients with delayed recovery in the EDR- 1 group had characteristics of a normal genotype. We conclude that a very low dose of edrophonium (0.125 mg · kg^{? 1}) hastens reversal of deep mivacurium-induced neuromuscular block by approximately four minutes, and that edrophonium doses exceeding 0.125 mg · kg^{? 1} provide no additional benefit. Heterozygous patients with atypical plasma cholinesterase levels, as well as certain individuals with normal dibucaine numbers and plasma cholinesterase activity, are at risk for prolonged neuromuscular block, but the block is easily reversed with edrophonium.     

Edrophonium antagonism of vecuronium at varying degrees of fourth twitch recovery

The purpose of this study was to determine the optimal dose of edrophonium needed for successful antagonism (train-of-four ratio, or T₄/T₁ > 0.7) of vecuronium-induced blockade when all four twitches were visible in response to indirect train-offour (TOF) stimulation. Forty patients, scheduled for elective surgical procedures not exceeding 120 min, received vecuronium, 0.08 mg · kg^?1, during thiopentone-N₂O-isoflurane anaesthesia. Train-of-four stimulation was applied every 20 sec and the force of contraction of the adductor pollicis muscle was recorded. Increments of vecuronium, 0.015 mg · kg^?1, were given as required. At the end of surgery, and provided that neuro-muscular activity had recovered to four visible twitches, edrophonium, 0.1 mg · kg^?1, was given. Two minutes later, edrophonium, 0.1 mg · kg^?1, was given if T₄/T₁ did not reach 0.7. After another two minutes, edrophonium, 0.2 mg · kg^?1, was given if T₄/T₁ did not reach 0.7 or more. Finally, if T₄/ T₁ was still < 0.7, a dose of 0.4 mg · kg^?1 was given. Seventeen patients (42.5%) required 0.1 mg · kg^?1 of edrophonium for successful reversal, sixteen patients (40%) needed a cumulative dose of 0.2 mg · kg^?1 and six patients (15%) required 0.4 mg · kg^?1. Only one patient received 0.8 mg · kg^?1. There was a good correlation between T₄/ T₁ two minutes after the first dose of edrophonium and pre-reversal T₄/T₁ (r = 0.6; P = 0.00014). All patients with pre-reversal T₄/ T₁ > 0.23 required at most 0.2 mg · kg^?1 of edrophonium for successful reversal. We conclude that when all four twitches are clearly visible following train-of-four stimulation, small doses of edrophonium (0.1-0.2 mg · kg^?1) might be sufficient to antagonize vecuronium neuromuscular blockade.     

Different properties of the bradycardia produced by neostigmine and edrophonium in the cat

Purpose

The bradycardia produced by neostigmine and edrophonium was examined according to its relation to cholinesterase inhibition and to its sensitivity to block by muscarinic receptor antagonists. For comparison, the ability of muscdrinic antagonists to block the bradycardia produced by electrical stimulation of the vagus nerve was determined.

Methods

Cats were anaesthetized, vagotomized and propranolol-treated. Heart rate was continuously recorded. Erythrocyte cholinesterase activity of arterial blood was measured using a radiometric technique. The right vagus nerve was isolated for electrical stimulation. The muscarinic antagonists used were atropine, glycopyrrolate, pancuronium, gallamine, and AFDX-116.

Results

Neostigmine produced a dose-dependent decrease in cholinesterase activity which, reached a plateau at a cumulative dose of 0.16 mg · kg^?1 (ED₅₀ 0.009 ± 0.003 mg · kg^?1). Neostigmine produced a dose-dependent decrease in heart rate with the. dose-response relationship (ED₅₀ 0.1 ± 0.01 mg · kg^?1; P = 0.0006) shifted to the right of that for the inhibition of cholinesterase activity. In contrast to the anticholinesterase effect, the bradycardic effect did not reach a plateau and continued to increase even at doses at which the cholinesterase inhibition was maximal. The maximal decrease in heart rate when the heart was still in sinus rhythm was by 81 ± 13 bpm (49 ± 7% of baseline), which was produced by a dose of 0.32 mg · kg^?1. Edrophonium produced dose-dependent decreases in cholinesterase activity and heart rate, which were highly correlated (correlation coefficient r = 0.99, P < 0.0001).The ED₅₀ of the reduction in heart rate (0.9 ± 0.75 mg · kg^?1) and cholinesterase activity (0.89 ± 0.12 mg · kg^?1) produced by edrophonium were similar. Moreover, the reduction in heart rate and cholinesterase activity produced by edrophonium reached a plateau at the same dose (6.4 mg · kg^?1). At this dose, heart rate decreased by 22 ± 2 bpm (14.6 ± 0.9% of baseline). Compared to the bradycardia produced by stimulation of the vagus nerve, that produced by neostigmine was blocked by muscarinic antagonists at significantly lower doses while that produced by edrophonium was blocked at similar doses.

Conclusions

The neostigmine-induced bradycardia is poorly correlated with cholinesterase inhibition compared to that produced by edrophonium, and has a higher sensitivity to muscarinic receptor antagonists compared to that produced by edrophonium or vagus nerve stimulation. These results are consistent with the hypothesis that the neostigmine-induced bradycardia is, in pari, the result of neostigmine directly activating cholinergic receptors within the cardiac parasympathetic pathway. The bradycardia produced by edrophonium may be accounted for solely by an anticholinesterase action.     

Effets de différentes doses d’édrophonium sur la neutralisation du bloc neuromusculaire induit par le mivacurium en présence de N2O,de propofol et d’alfentanil

Objectif

Cette étude a pour but de déterminer la dose optimale d’édrophonium nécessaire à l’antagonisme d’un bloc neuromusculaire induit par le mivacurium.

Méthode

Une dose initiale de mivacurium (0,15 mg · kg^?1) suivie d’une perfusion (7 μg · kg^?1 · min^?1) ont été administrées à 75 malades (ASA I, II) lors d’une anesthésie associant alfentanil-propofol-N₂O. Une stimulation «train-de-quatre» (TOF) du nerf cubital était appliquée aux 20 secondes et la réponse de l’adducteur du cinquième doigt était enregistrée (Relaxograph NMT-100, DATEX, Helsinki, Finlande). La vitesse d’administration du mivacurium était revue aux 5 minutes afin de maintenir la hauteur de la première stimulation du TOF (T₁) à 5% de sa valeur initiale. Les malades étaient divisés de façon aléatoire en cinq groupes afin de recevoir édrophonium 0,0, 0,05, 0,1, 0,5 ou 1,0 mg · kg^?1 + glycopyrrolate 0,0, 0,0005, 0,001, 0,005 ou 0,01 mg · kg^?1 à l’arrêt de la perfusion de mivacurium.

Résultats

Toutes les doses d’édrophonium étudiées ont permis l’obtention d’un ratio TOF (quatrième stimulation du TOF/T₁) = 0,7 plus rapidement que le placebo (0,05:780 ± 179, 0,1:727 ± 216, 0,5:547 ± 287 et 1,0:640 ± 236 vs 0,0 mg · kg^?1:1089 ± 323 sec P < 0.05). Les doses de 0,1, 0,5 et 1,0 mg · kg^?1 ont toutes trois permis une récupération plus rapide du T₁ de 10 à 95% (T_10–95) (567 ± 236, 419 ± 166, 555 ± 288 vs 861 ± 224 sec P < 0.05) et de 25 à 75% (T_25–75) (253 ± 121, 147 ± 92, 217 ± 175 vs 429 ± 154 sec P < 0.05) lorsque comparées au placebo. Cependant, il faut noter la grande dispersion des résultats obtenus, et ce avec toutes les doses d’édrophonium étudiées.

Conclusion

Lorsque comparées au placebo, des doses d’édrophonium égales ou supérieures à 0,1 mg · kg^?1 ont accéléré la vitesse de récupération de tous les indices associés au bloc produit par le mivacurium pendant une anesthésie associant l’alfentanil, le propofol et le N₂O.     

Recovery of neuromuscular function after atracurium and pancuronium maintenance of pancuronium block

The study was undertaken to determine whether a neuromuscular blockade induced with pancuronium but maintained with atracurium was associated with a shorter time to complete recovery after administration of neostigmine than if the blockade was maintained with pancuronium alone. Anaesthesia consisted of thiopentone, N₂O/O₂/enflurane and fentanyl, and the neuromuscular blockade, induced by pancuronium 0.1 mg · kg^?1 was monitored by the force of contraction of adductor pollicis during major abdominal surgery lasting 2–5 hr. In 24 patients — Group 1 — atracurium 0.07 mg · kg^?1 was repeated when the first twitch of the train-of-four (TOF) returned to 25% of control (T₁/ TC 25). In 28 patients — Group 2 — pancuronium 0.015 mg · kg^?1 was given at similar recovery of T₁/ TC. At the end of surgery, neostigmine 0.07 mg · kg^?1 and glycopyrrolate 0.015 mg · kg^?1 were given to reverse the residual neuromuscular blockade which was indicated by a T₁/TC of less than 25% in all patients. The time from injection of the reversal drugs to a TOF ratio of 70% was similar in both groups (Group 1, 11.6 ± 7.6 min; Group 2, 10.1 ± 6 min; P = NS), but the recovery index was smaller in Group 2 (Group 1, 4 ± 2.6 min; Group 2, 2.61 ± 1.2 min; P < 0.05). Furthermore, there was no difference between groups in the duration of action of each redose. The study showed that when compared with pancuronium, equipotent doses of atracurium were not associated with (a) a shorter time to complete recovery from a neuromuscular blockade induced with pancuronium or (b) a shorter duration of action.     

Sevoflurane and isoflurane impair edrophonium reversal of vecuronium-induced neuromuscular block

Purpose

A dose-response relationship study for edrophonium to examine the modification of volatile anaesthetics on reversal of vecuronium block.

Methods

One hundred and twenty ASA (I–II) patients were anaesthetized with sevoflurane, isoflurane (I minimum alveolar anaesthetic concentration [MAC] end-tidal concentration), or fentanyl-diazepam anaesthesia, in combination with 66% nitrous oxide (n = 40 for each group). The evoked electromyogram (EMG) response of the abductor digiti minimi was monitored at 20 sec intervals following train-of-four (TOF) stimulation of the ulnar nerve. The initial neuromuscular block was produced by vecuronium 100 μg · kg^?1. When the amplitude of the first response (T₁) had spontaneously recovered to 10% of the control, edrophonium (0, 125, 400, 700 or 1000 μg · kg^?1; eight patients each) was randomly administered, and the ratio of the fourth TOF to the first response (TOFR ) was monitored at one minute intervals for 10 min.

Results

Sevoflurane and isoflurane impaired the edrophonium-assisted TOFR recovery in an edrophonium dose and time dependent manner. The dose-response curves at 10 min exhibited a greater shift to the right in the sevoflurane and isoflurane groups than in the fentanyl-diazepam-nitrous oxide group (P < 0.05). Higher ED₅₀ values (the edrophonium dose required to obtain TOFR value of 50%) in the sevoflurane (> 1000 μg · kg^?1) and isoflurane groups (851 · μg · kg^?1) were observed than in the fentanyl-diazepam-nitrous oxide group (339 μg · kg^?1) (P < 0.05).

Conclusion

One MAC sevoflurane and isoflurane anaesthesia impair edrophonium reversal of vecuronium block to a similar degree.     

Heart rate changes in cardiac transplant patients and in the denervated cat heart after edrophonium

Purpose

The effect of edrophonium on heart rate in cardiac transplant patients and in an animal model of acute cardiac denervation were studied, to evaluate the functional state of the peripheral parasympathetic pathway fol lowing cardiac denervation.

Methods

Edrophonium was studied in patients with normally innervated hearts (controls) and m cardiac trans plants. Edrophonium was also studied in vagotomized. beta-blocked cats. In Group I animals, the vagus nerve was not stimulated. In Groups 2 & 3 the right vagus nerve was electrically stimulated to produce approximately 20% and 40% reductions in baseline heart rate, respectively.

Results

Maximum heart rate reduction in transplants (7.3 ± 0.8 beats·min^?1 with 0.6 ± 0.08 mg·kg^?1) was less than in controls (13.3 ± 1.6 beatsmm with 0.4 + 0.05 mg·kg^?1, P < 0.01). In Group I animals heart rate decreased maximally by 20.9 ± 2.5 beats·min^?1 with 9.0 ± 1.9 mg·kg^?1. In Groups 2 and 3, with doses < 15 mg·kg^?1, reduc tions m heart rate were greater than in Group I and maximual reductions were obtained with lower doses (Group 2: maximum reduction by 20.3 ± 2.8 beats·min^?1 with 1.3 ± 0.1 mg·kg^?1: Group 3: 22.6 ± 4.0 beats·min^?1 with 0.8±0.2 mg·kg^?1, P < 0.001) Doses > 1.5 mg·kg^?1 in Groups 2 and 3 produced increases in heart rate.

Conclusion

Edrophonium produced bradycardia in cardiac transplants suggesting spontaneous release of acetylcholinee from parasympathetic postganglionic neurons m the transplanted heart. The magnitude of the brady cardia was less in transplant than in control patients. Findings from animal studies suggest that the reduction in transplants can be attributed to diminution or absence of tonic cardiac parasympathetic drive. At high doses, edrophonium may interfere with parasympathetic neuron activation.     

Surgeon-controlled mivacurium administration during elective Caesarean section

We have compared the dose requirements and recovery characteristics of a continuous mivacurium infusion given by the anaesthetist to maintain 95–100% block at the hand muscles with that of a surgeon-controlled, on-demand dosing technique based on the direct assessment of abdominal muscle tone during elective Caesarean section. Twenty-four full term pregnant patients were included. A rapid-sequence induction using thiopentone 3–5 mg· kg^?1 and succinylcholine 1 mg· kg^?1 was used. Anaesthesia was maintained with fentanyl, N₂O and iso-flurane 0.5%. The mechanomyographic response of the adductor pollicis muscle to supramaximal train-of-four (TOF) ulnar nerve stimulation was recorded. Muscle relaxation was achieved initially with mivacurium 0.1 mg· kg^?1 followed either by a continuous infusion of mivacurium to maintain 95–100% block at the adductor pollicis muscle (n = 12) or by surgeon-controlled relaxation (SCR) technique using a syringe pump for patient-controlled analgesia to administer on-demand doses of mivacurium 0.05 mg · kg^?1 (n = 12). The lockout interval was three minutes and the maximum hourly dose of mivacurium allowed was 0.6 mg · kg^?1. The total doses of mivacurium (mean ±SD) were 23.2 ± 10.4 and 12.4 ± 3.5 mg in the infusion and SCR groups, P < 0.01. On-demand, surgeon-controlled doses of mivacurium were injected at a mean of T₁ 42.3 ± 36%. At the end of surgery, T₁ and TOF ratio were respectively 16.7 ± 13%, 5 ± 10% and 48 ± 37%, 30 ± 24% in the infusion and SCR groups. Five patients in the SCR group and one patient in the infusion group did not receive antagonist at the end of surgery. The time to adequate recovery, TOF 75%, after skin closure was 8.2 ± 2.3 and 5.3 ± 4 min in the infusion and SCR groups, P = 0.05. It is concluded that, compared with a continuous mivacurium infusion, the SCR technique is associated with reduced mivacurium requirements, a substantial degree of neuromuscular recovery at the end of surgery and a reduced need for neostigmine reversal in full term pregnant patients undergoing elective Caesarean section.     

Nondepolarizing neuromuscular blocking drugs and train-of-four fade

The aim of this study was to examine differences in prejunctional effects of different relaxants by measuring the train-offour (TOF) fade during the onset and recovery of neuromuscular block. The relaxants studied were atracurium (225 μg · kg^?1), mivacurium (65 μg · kg^?1) rocuronium (300 μg · kg^?1)) and vecuronium (40 μg · kg^?1)). The TOF ratios were measured at approximate heights of T₁) (first response in the TOF) of 90, 75, 50, and 25%. The TOF fade (as shown by lower TOF ratios) increased with a decrease in the T₁) during onset of neuromuscular block. Although there was a slightly greater fade with atracurium and rocuronium during the onset of block, the differences among the relaxants were insignificant. It is concluded that the relative prejunctional effects of these relaxants are similar.     

Neuromuscular blocking effects of rocuronium during desflurane, isoflurane, and sevoflurane anaesthesia

Purpose

To determine the magnitude of the potentiation of rocuronium by desflurane, isoflurane and sevoflurane 1.5 MAC anaesthesia.

Methods

In a prospective, randomised, study in 80 patients, the cumulative dose-effect curves for rocuronium were determined during anaesthesia with desflurane, sevoflurane and isoflurane (with N₂O 70%, 15 min steady state) or total intravenous anaesthesia (TIVA) using propofol/fentanyl. Neuromuscular block was assessed by acceleromyography (TOF-Guard®) after train-of-four (TOF) stimulation of the ulnar nerve (2Hz every 12sec, 200 μsec duration), Rocuronium was administered in increments of 100 μg·kg^?1 until first twitch (T₁) depression > 95%.

Results

Rocuronium led to more pronounced T₁ depression with desflurane or sevoflurane anaesthesia than with TIVA. The ED₅₀ and ED₉₅ were lower during desflurane (95 ± 25 and 190 ± 80 μg·kg^?1) and sevoflurane (120 ±30 and 210 ± 40 μg·kg^?1) than with TIVA (150 ± 40 and 310 ± 90 μg·kg^?1) (P < .01), while the difference was not significant for isoflurane (130 ± 40 and 250 ± 90 μg·kg^?1). Following equi-effective dosing (T₁ > 95%) the duration to 25% T₁ recovery, recovery index (25/75), and TOF_0.70 was: 13.2 ± 1.8, 12.7 ± 3.4, and 26.9 ± 5.7 min during anaesthesia with desflurane; 15.5 ± 5.0, 11.4 ± 3.8, and 31.0 ± 6.0 min with sevoflurane; 13.9 ± 4.7, 10.7 ± 3.3, and 26.3 ± 8.9 min with isoflurane; and 13.9 ± 3.9, 11.3 ± 5.7, and 27.5 ± 8,2 min with TIVA anaesthesia (P: NS).

Conclusion

Interaction of rocuronium and volatile anaesthetics resulted in augmentation of the intensity of neuromuscular block but did not result in significant effects on duration of or recovery from the block.     

Recovery of train-of-four after mivacurium

The present study was designed to determine the time-course of recovery of the train-of-four (TOF) ratio during spontaneous recovery from mivacurium-induced block. Fifteen patients, free of neuromuscular disease, undergoing general endotracheal anaesthesia with isoflurane were studied. After anaesthetic induction, patients received a bolus dose of mivacurium 0.15 mg · kg^?1. The TOF was then recorded continuously every 12 sec with a mechanogram (adductor pollicis monitor). When the TOF ratio recovered spontaneously to 0.9, an additional 0.05 mg · kg^?1 of mivacurium was given. The durations required for recovery from a TOF ratio of 0.3 to 0.7 (DUR_0.3–0.7) and from a TOF ratio of 0.3 to 0.9 (DUR_0.3–0.9) were determined. The DUR_0.3–0.7 averaged 7.0 ± 2.5 min (range 3.4–12.2 min). The DUR_0.3–0.9 averaged 11.8 ± 3.9 min (range 6.0–20.2 min). There was no evidence of prolongation of recovery times (cumulation) following repeated dosing. The present data indicate that, in patients with normal cholinesterase activity (clinical duration 7–25 min), waiting 20 min beyond the time when fade is no longer apparent by visual or tactile evaluation is sufficient to attain a TOF ratio greater than 0.7–0.9 during spontaneous recovery from mivacurium, and may enable anaesthetists to avoid antagonism of mivacurium-induced block.     

The reversal of profound mivacurium-induced neuromuscular blockade

Purpose

Mivacurium is metabolized by plasma cholinesterase catalyzed ester hydrolysis. Acetylcholinesterase antagonists used in the reversal of muscle relaxation may also inhibit plasma cholinesterase and, therefore, delay the hydrolysis of mivacurium. The clinical interaction between acetylcholinesterase antagonists and mivacurium induced neuromuscular blockade was studied.

Method

Intraoperative muscle relaxation was maintained with a mivacurium infusion to achieve a constant intense block (first twitch, T¹, 2–3% of control). Patients were randomly divided into three groups. Patients in Group 1 received no anticholinesterase, in Group 2 neostigmine 0.07 mg · kg^?1, and in Group 3 edrophonium 1 mg · kg^?1. The times between termination of the mivacurium infusion (Group 1) or the administration of the anticholinesterase (Groups 2 and 3) to 25%, 50%, 75% and 95% T₁ recovery, and to 50%, 70% and 90% recovery in the ratio, T₄/T₁ (TR) were recorded.

Result

In the neostigmine Group, T₁ recovery to 25%, 50% and 75% ( 2.32 ± 1.41, 3.90 ± 1.85 and 6.88 ± 2.66 min) was accelerated compared with control (3.36 ± 1.34, 5.78 ± 2.22, and 8.58 ± 3.60, and), but recovery to 95% (18.53 ± 9.09 vs 13.29 ± 5.24 min) was delayed. Also, TR recovery to 50%, 70%, and 90% was slower (14.47 ± 8.73, 21.25 ± 11.06 and 31.37 ± 12.11 min vs 11.75 ± 3.74, 13.78 ± 4.39 and 17.86 ± 6.44 min). However, all T₁ and TR recovery times were decreased in the edrophonium group (0.88 ± 0.51, 2.00 ± 1.50, 4.97 ± 2.96, and 9.35 ± 5.24 min for T₁ and 6.86 ± 3.93, 9.05 ± 4.51 and 12.24 ± 6.66 min for TR).

Conclusion

Neostigmine reversal of intense mivacurium neuromuscular block should be avoided, as this may result in prolongation of the block.     

Pharmacodynamics of doxacurium during cardiac surgery with hypothermic cardio-pulmonary bypass

Purpose

To determine the characteristics of neuromuscular block produced by two and three times the 95% effective dose (ED₉₅) of doxacurium in patients undergoing coronary artery surgery with hypothermic cardiopulmonary bypass.

Methods

In a prospective non randomized study, ten patients received doxacurium 0.05 mg·kg^?1 (Group 1) and ten others received 0.075 mg · kg^?1 (Group 2) with midazolam and sufentanil. The mechanomyographic response of the adductor pollicis muscle after supramaximal train-of-four (TOF) stimulation of the ulnar nerve was recorded intraoperatively and postoperatively. Additional doxacurium (10% of the initial dose) was administered until sternal closure whenever the first twitch (T₁) had recovered to 25% of control.

Results

The onset time (time to maximal T₁ depression) of doxacurium was 390 ± 148 sec in Group 1 and 370 ± 74 sec in Group 2 (P = 0.71). The clinical duration of neuromuscular block (time to 25% T₁ recovery) was 165 ± 90 min in Group 1 and 258 ± 86 min in Group 2 (P = 0.03). On arrival to recovery room the mean T₁ was 57 ± 23% in Group 1 and 24 ± 21% in Group 2(P = 0.003); the mean T₄/T₁ ratio was 0.25 ± 0.15 for five patients of Group 1 with four responses to TOF stimulation and 0.10 for the only patient of Group 2 with four twitches.

Conclusion

In contrast with findings in patients without cardiac disease, this study shows comparable onset times of doxacurium with doses of two and three times ED₉₅. The clinical duration of doxacurium is 60 to 100% longer than previously reported in noncardiac surgery.     

Neuromuscular effects of 600 μg·kg−1 of rocuronium in infants during nitrous oxide-halothane anaesthesia

Rocuronium bromide (Zemuron) is a new steroidal nondepolarizing neuromuscular blocking drug. We were interested in determining the effect of a bolus of rocuronium in infants during halothane anaesthesia as we did previously in older children. Eighteen infants (2-11 months) received a bolus of 600 μg·kg^?1, which is equal to twice the dose of rocuronium estimated to produce 95% depression of neuromuscular function (ED₉₅) in children (2-12 yr). Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Time (mean ± SEM, range) from administration of 600 μg·kg^?1 rocuronium to 90% (B₉₀) and 100% (B₁₀₀) neuromuscular block was 37 ± 2 (20-60) s and 64 ± 10 (20-180) s, respectively. The time to recovery of neuromuscular transmission to 10% (T₁₀) was 35.3 ± 3.0 (20.7-57.8) min and to 25% of baseline (T₂₅) was 41.9 ± 3.2 (24.3-67.7) min. The recovery index (T₂₅-T₇₅) was 26.6 ± 2.7 (11.7-44.5) min, and the time to recovery of the train-of-four ratio (T₄/T₁) ± 0.75 was 82.1 ± 6.9 (53.2-138.3) min. The plasma concentration of rocuronium when T₁ had recovered to about 30% was 654 ± 34 (417-852) ng·ml^?1 which is similar to that observed in children. Six-hundred μg·kg^?1 of rocuronium has a rapid onset of effect in infants and prolonged duration of action in infants compared to children.     

Détermination de la courbe dose-effet du vécuronium chez l'homme anesthésié

Dose-response curves have been determined in 37 healthy subjects, after injection of a single bolus of Organon NC 45 (vecuronium or Norcuron®). The doses used were 0.0125, 0.025, 0.037 and 0.05 mg · kg^?1. The ulnar nerve was stimulated at the wrist and the force of thumb adduction measured. No premedication was used. Anesthesia was induced with thiopentone and fentanyl, and maintained by a nitrous oxide/oxygen mixture under controlled ventilation. Paco₂ was 37 ± 0.5 mmHg and temperature 36.8 ± 0.1 °C. The effective doses (ED) were : ED₅₀ at 0.024 mg · kg^?1, ED₉₀ at 0.034 mg · kg^?1 and ED₉₅ at 0.037 mg · kg^?1. At 0.05 mg · kg^?1, the degree of twitch inhibition was 99.2 ± 0.6 %, the delay of maximum effect was 7.7 ± 1.4 min, and the length of action (up to 90 % recovery) was 27.2 ± 2.3 min. Vecuronium is therefore a potent neuromuscular blocking agent with a relatively short duration of action.     

Clindamycin-induced neuromuscular blockade

The purpose of this article is to report the case of a patient who developed prolonged neuromuscular block after a large dose of clindamycin (2400 mg). A 58-yr-old, 65 kg woman with severe rheumatoid arthritis was admitted for wrist arthrodesis. After d-tubocurarine (3 mg) and fentanyl (1.5 μg · kg^?1), anaesthesia was indúced with thiopentone (4 mg · kg^?1) followed by succinycholine (1.5 mg · kg^?1) and was maintained with N₂O in O₂ and isoflurane (0.75-1.0% end tidal) and ventilation was controlled. No further neuromuscular relaxants were given although full return of neuromuscular activity in response to train-of-four and 100 Hz tetanic stimulation was observed after succinylcholine. An overdose of clindamycin (2400 mg, instead of the intended 600 mg) was given iv soon after the start of surgery. At the end of surgery, 75 min later, the patient made no attempt at spontaneous ventilation, was unresponsive to painful stimuli and naloxone (0.2 mg iv) was ineffective. Controlled ventilation was continued in the Recovery Room where neuromuscular testing showed a train-of-four ratio of 0.27 which improved to only 0.47 five minutes after calcium chloride (1.5 mg · kg^?1 iv), and to 0.62 after edrophonium (20 mg) and neostigmine (2 mg). Nine hours later the patient began to cough, the TOF had returned to 1.0 and two hours later the trachea was extubated and spontaneous ventilation was resumed. Large doses of clindamycin can induce profound, long-lasting neuromuscular blockade in the absence of non-depolarizing relaxants and after full recovery from succinylcholine has been demonstrated.     

Pharmacodynamic behaviour of rocuronium in the elderly

This study compared the potency and time course of action of rocuronium (ORG 9426) in elderly and young patients during nitrous oxide-opioid anaesthesia. One hundred ASA physical status I– II patients (60, âgéd 65–80 yr, and 40, âgéd 20–45 yr) were studied by measuring the force of contraction of the adductor pollicis in response to train-of-four stimulation of the ulnar nerve. After induction of anaesthesia with thiopentone and maintenance with N₂O/O₂ and fentanyl, rocuronium 120,160, 200, or 240 μg · kg ^?1 was administered to determine dose-response curves. When maximum block had been obtained,further rocuronium to a total of 300 μg · kg ^?1 was given. Additional doses of 100 μg · kg^?1 were administered when the first twitch height (T₁) had recovered to 25% control. At the end of surgery neuromuscular blockade was allowed, whenever possible, to recover spontaneously until T₁ was 90% of control before administration of neostigmine. There was no difference in the potency of rocuronium in the elderly and the younger patients. The ED₅₀ was 196 ±8 (SEE for the mean) in elderly,vs 215 ±17 iμg · kg ^{? 1} in young patients (NS). When individual cumulative dose-response curves were constructed, the ED₅₀ was 203 ± 7(SEM) and 201 ± 10 μg · kg ^{? 1} in the elderly and the young respectively (NS). However, the onset of maximum neuromuscular block was slower in the elderly 3.7 ±1.1 (SD) vs 3.1 ± 0.9 min, P < 0.05). The time to 25% T ₁ recovery was longer in the elderly (11.8 ± 8.1 vs 8.0 ± 6.5 min,P <0.05) as was the recovery index, time from 25 to 75% T₁ recovery (15.5 ± 6.2 vs 11.2 ± 4.9 min, P< 0.05). The duration of neuromuscular block after each maintenance dose was longer in the elderly (P <0.01) and increased gradually with time. It is concluded that rocuronium is an intermediate-acting neuromuscular blocking drug with a similar potency in elderly and young patients, but the onset and recovery of neuromuscular blockade are slower in the elderly.     

Reversal of doxacurium and pancuronium neuromuscular blockade with neostigmine in children

Recovery after doxacurium and pancuronium neuromuscular blockade and their acceleration by neostigmine have not been compared in children. Therefore, 60 paediatric surgical patients aged 2–10 yr (ASA 1–2) were studied. They were randomized to receive doxacurium 30 μg · kg^?1 or pancuronium 70 μg · kg^?1 iv during propofol, fentanyl, isoflurane and nitrous oxide anaesthesia. Electromyographic (EMG) responses of the adductor pollicis to train-of-four (TOF) stimulation of the ulnar nerve were recorded every ten seconds using a Datex NMT monitor. Six patients in each relaxant group received neostigmine (0, 5, 10, 20 or 40 μg · kg^?1) with atropine by random allocation when first twitch height (T_I) had recovered to 25% of control. Spontaneous recovery after ten minutes was similar following doxacurium (mean ± SEM values of 45.0 ± 3.9 vs 49.5 ± 10.0 % for T_I and 25.2 ± 3.8 vs 14.8 ± 3.6% for TOF ratios). Dose-responses to neostigmine were calculated from the log dose vs logit of T_I or TOF ratio after ten minutes. Neostigmine-assisted recovery was not different in the two groups, with ED₇₀ and ED₉₀ doses for T_I of 14.3 ± 1.8 and 25.7 ± 2.7 μg·kg^?1 for doxacurium and 12.5 ± 1.7 and 25.3 ± 2.3 μg· kg^?1 for pancuronium. Time to recovery of TOF ratio to 70% after neostigmine 40 ng · kg^?1 was 2.3 ± 1.0 and 4.2 ± 1.7 min (P = NS) following pancuronium and doxacurium, respectively. Adjusted recovery due to neostigmine alone (spontaneous recovery subtracted from the total) required two to three times higher doses of neostigmine. Thus, in children, the spontaneous recovery and reversal of neuromuscular blockade is similar with doxacurium and pancuronium. However, compared with previous adult studies, they recover twice as quickly from doxacurium neuromuscular blockade and neostigmine antagonism is achieved at 25–50% of the adult doses.     

Optimum time for neostigmine reversal of atracurium-induced neuromuscular blockade

Purpose

The aim of the study was to determine the optimum time for administration of neostigmine during recovery from atracurium-induced neuromuscular blockade.

Methods

The study comprised 103 patients anaesthetised with midazolam, fentanyl, thiopentone, halothane, and nitrous oxide. Relaxation was induced with atracurium 0.5 mg·kg^?1 and maintained with supplements of 0.15 mg·kg^?1. The ulnar nerve was stimulated with train-of-four (TOF) and double burst stimulation (DBS). Evoked MMG responses were recorded. Patients were randomized to spontaneous recovery (n = 20) or to assisted recovery by neostigmine (0.07 mg ·kg^?1) at varying intervals (6–50 min) from the last atracurium dose (n = 83).

Results

The reversal time (time from administration of neostigmine to TOF ratio 0.7) was always < 13 min, when T₁ (first twitch in TOF) was detectable or when D₁ (first twitch in DBS) was > 5%. Total assisted recovery time (time from last supplemental atracurium dose to TOF ratio 0.7) increased with increasing T₁ and D₁ twitch heights (P < 0.05). The curve fitted to the scattergram with total assisted recovery time vs time from last atracurium supplement to neostigmine administration decreased to reach a minimum after which it increased to approach the line of identity. The minimum of the curve (total assisted recovery time 30.7 min) was reached when neostigmine was given 18.6 min after last atracurium supplement. At this time the T₁ and D₁ twitch height averaged 4 and 8% respectively. If prolongation of the minimum total recovery time of 2.5% is accepted, neostigmine can be given at T₁ and D₁ twitch height values of 0 to 8% and 4 to 15%, respectively.

Conclusion

The optimum time for neostigmine administration, taking both the reversal time and total recovery time into consideration, is when 0 < T₁ < 8% or when 5 < D₁ < 15%. Giving neostigmine at more profound degrees of blockade prolongs reversal time, while giving neostigmine later in the recovery phase prolongs total recovery time.     

Neostigmine requirements for reversal of neuromuscular blockade following an infusion of mivacurium

Purpose

To study the efficacy of neostigmine compared with placebo for the antagonism of neuromuscular blockade at the end of a mivacunum infusion, and to determine its optimal dose.

Methods

One hundred adult patients undergoing an elective surgical procedure received a standardized anaesthetic with 20–30 mg·kg^?1 alfentanil, a propofol infusion and nitrous oxide. Muscle relaxation was maintained at 90–95% T1 depression with 0.2 mg·kg^?1 mivacunum followed by an infusion. Neuromuscular blockade was measured with an integrated evoked electromyogram in response to train-of-four (TOF) stimuli at the ulnar nerve every 20 sec. Patients were randomized into four groups. At the end of surgery, the mivacunum infusion was stopped and patients received. immediately, in a double-blind manner, neostigmine (10, 20. or 40 mg·kg^?1) or placebo according to a random number table. The Tl and TOF ratio were recorded until adequate recovery of neuromuscular function (TOF ratio > 0.70). During the reversal penod, non-invasive blood pressure and heart rate were recorded every minute. The incidence of postoperative nausea and vomiting (PONV) was recorded in the recovery room.

Results

Data from 94 patients who completed the protocol were analysed. Compared with placebo, neostigmine 10 gmg·kg did not reduce the time to TOF > 0.70 (17.0 ± 5.1 vs 14.6 ± 4.2 mm respectively). However the time was decreased with neostigmine 20μg·kg and 40 μ·?^?1 (P < 0.001), but with no difference between these last two groups (11.4 ± 3.0 and 11.4 ± 3.5 min respectively). Changes in systolic blood pressure and heart rate were not different between the four groups. Very few PONV events were observed in all groups (global incidence 7.4%).

Conclusion

Recovery of neuromuscular blockade following a mivacunum infusion is accelerated by neostigmine. A dose of neostigmine 20μ·kg^?1 appears optimal with no further reduction in recovery time obtained from a larger dose.