In vitro alteration on erythrocytes mechanical properties by propofol, remifentanil and vecuronium.

Several studies report flow disturbance and microcirculation disorders upon anesthesia treatment. These alterations are often related to blood rheology changes. In this work, it was attempted to make a detailed description of the alterations in erythrocyte mechanical properties by the action of propofol, remifentanil, and vecuronium. For this, an in vitro study was performed on red blood cell samples from healthy donors incubated with solutions of propofol (4 µg/mL whole blood), remifentanil (10 ng/mL plasma), and vecuronium (0.15 µg/mL plasma). Erythrocyte viscoelastic parameters were determined by octuplicate using a Reómetro Eritrocitario. Also, a Wilcoxon signed rank-test with Yates correction for continuity was performed to analyze the overall alteration in the mechanical properties of erythrocytes. Statistical analysis showed that the three studied anesthetics changed the erythrocyte mechanical properties at different parts of the membrane. These results would imply an interaction of these anesthetics with the erythrocyte membrane. Finally, this could conduce to alterations in microcirculation.

Actual versus ideal body weight dosing of sugammadex in morbidly obese patients offers faster reversal of rocuronium- or vecuronium-induced deep or moderate neuromuscular block: a randomized clinical trial.

BACKGROUND: This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep (D-) neuromuscular block in morbidly obese adults dosed by actual (ABW) or ideal body weight (IBW). METHODS: Adults with BMI ≥40 kg/m2 were randomized to 1 of 5 groups: M-neuromuscular block, sugammadex 2 mg/kg ABW; M-neuromuscular block, sugammadex 2 mg/kg IBW; M-neuromuscular block, neostigmine 5 mg, and glycopyrrolate 1 mg; D-neuromuscular block, sugammadex 4 mg/kg ABW; or D-neuromuscular block, sugammadex 4 mg/kg IBW. Supramaximal train of four (TOF) stimulation of the ulnar nerve (TOF-watch SX®) monitored recovery. Primary endpoint was time to TOF ratio ≥ 0.9 for ABW and IBW groups pooled across neuromuscular blocking agent (NMBA)/blocking depth, analyzed by log-rank test stratified for agent and depth. Prespecified safety outcomes included treatment-emergent bradycardia, tachycardia, and other arrhythmias, and adjudicated hypersensitivity and anaphylaxis. RESULTS: Of 207 patients randomized, 188 received treatment (28% male, BMI 47 ± 5.1 kg/m2, age 48 ± 13 years). Recovery was 1.5 min faster with ABW vs IBW dosing. The sugammadex 2 mg/kg groups recovered 9-fold faster [time 0.11-fold, 95% CI 0.08 to 0.14] than the neostigmine group. ABW (5.3%) and IBW (2.7%) groups had similar incidences of recovery time > 10 min (95% CI of difference: - 4.8 to 11.0%); 84% for neostigmine group. Re-curarization occurred in one patient each in the 2 mg/kg IBW and neostigmine groups. Prespecified safety outcomes occurred with similar incidences. CONCLUSIONS: ABW-based sugammadex dosing yields faster reversal without re-curarization, supporting ABW-based sugammadex dosing in the morbidly obese, irrespective of the depth of neuromuscular block or NMBA used. TRIAL REGISTRATION: Registered on November 17, 2017, at ClinicalTrials.gov under number NCT03346070 .

The effects of intravenous anesthetics on QT interval during anesthetic induction with sevoflurane.

PURPOSE: Sevoflurane is known to prolong the QT interval. This study aimed to determine the effect of the interaction between intravenous anesthetics and sevoflurane on the QT interval. METHODS: The study included 48 patients who underwent lumbar spine surgery. Patients received 3 µg/kg fentanyl and were then randomly allocated to either Group T, in which they received 5 mg/kg thiamylal, or Group P, in which they received 1.5 mg/kg propofol, at 2 min after administration of fentanyl injection for anesthetic induction. Vecuronium (1.5 mg/kg) and sevoflurane (3 % inhaled concentration) were administered immediately after loss of consciousness and tracheal intubation was performed 3 min after vecuronium injection. Heart rate (HR), mean arterial pressure (MAP), bispectral index score (BIS), and the heart rate-corrected QT (QTc) interval on a 12-lead electrocardiogram were recorded immediately before fentanyl administration (T1), 2 min after fentanyl injection (T2), immediately before intubation (T3), and 2 min after intubation (T4). RESULTS: There were no significant differences between the two groups in baseline patient characteristics. BIS and MAP significantly decreased after anesthesia induction in both groups. At T3, MAP in Group T was higher than in Group P, while HR had reduced in both groups. The QTc interval was prolonged after anesthesia induction in Group T, but did not change at any time point in Group P. The QTc interval after anesthesia induction in Group T was longer than in Group P. CONCLUSION: We concluded that an injection of propofol could counteract QTc interval prolongation associated with sevoflurane anesthesia induction.

Sonographic optic nerve sheath diameter as a surrogate measure for intracranial pressure in anesthetized patients in the Trendelenburg position.

BACKGROUND: It remains to be elucidated whether the Trendelenburg position increases intracranial pressure (ICP). ICP can be evaluated by measuring the sonographic optic nerve sheath diameter (ONSD). We investigated the effect of the isolated Trendelenburg position on ONSD in patients undergoing robot-assisted laparoscopic radical prostatectomy. Additionally, we evaluated the effect of the Trendelenburg position combined with pneumoperitoneum on ONSD. METHODS: Twenty-one patients scheduled for robot-assisted laparoscopic radical prostatectomy were enrolled. Sonographic ONSDs and hemodynamic parameters were measured at specific time points: in the supine position after induction of anesthesia, 3 min after the steep Trendelenburg position (35° incline), 3 min after the steep Trendelenburg position combined with pneumoperitoneum, and in the supine position after desufflation of the pneumoperitoneum. RESULTS: The ONSD 3 min after the steep Trendelenburg position was significantly higher than that of the supine position after induction of anesthesia (5.1 ± 0.3 mm vs. 4.5 ± 0.4 mm). In addition, the ONSD 3 min after the steep Trendelenburg position combined with pneumoperitoneum was higher than that of the supine position after induction of anesthesia (4.9 ± 0.4 mm vs. 4.5 ± 0.4 mm). The ONSD in the supine position after desufflation of the pneumoperitoneum was similar to that in the supine position after induction of anesthesia. CONCLUSIONS: Use of the isolated steep Trendelenburg position, for even a short duration, increased the sonographic ONSD, providing a better understanding of the effect of only a transient steep Trendelenburg position on ONSD as a surrogate measure for ICP.

Haemodynamic differences between pancuronium and vecuronium in an experimental pig model.

OBJECTIVE: To compare baseline cardiovascular function in anesthetised pigs using either pancuronium or vecuronium as a neuromuscular blocker. STUDY DESIGN: Retrospective, non-randomized comparison. ANIMALS: Norwegian Land Race pigs (Sus scrofa domesticus) weighing mean 42 ± SD 3 kg. METHODS: One hundred and sixteen animals from four different research protocols premedicated with identical doses of ketamine, diazepam, atropine and isoflurane, and anaesthetised with pentobarbital, fentanyl, midazolam and N(2)O were arranged into three uniform groups with respect to neuromuscular blocking agent: pancuronium bolus of 0.063 mg kg(-1) followed by 0.14 mg kg(-1) hour(-1) (n = 54), low-dose vecuronium 0.4 mg kg(-1) /0.2 mg kg(-1) hour(-1) (n = 29) and high-dose vecuronium 0.6 mg kg(-1) /0.3 mg kg(-1) hour(-1) (n = 33). RESULTS: The majority of cardiovascular parameters demonstrated no significant differences between groups. For heart rate, there was an overall group difference, p = 0.036. Dromotropy was low in the pancuronium group, with an increased normalised PR-interval compared to the high-dose vecuronium group, median 0.200 interquartile range (0.190, 0.215) versus 0.182 (0.166, 0.199), p < 0.05. Left ventricular compliance was increased in pancuronium-treated animals, demonstrated as a reduction in the nonlinear end-diastolic pressure volume relationship ß compared to both vecuronium groups, 0.021 (0.016, 0.025) versus 0.031 (0.025, 0.046) and 0.031 (0.022, 0.048), p < 0.05. The linear end-diastolic pressure volume relationship EDPVR(lin) was reduced as well in the pancuronium group, compared to the low-dose vecuronium group, 0.131 (0.116, 0.169) versus 0.181 (0.148, 0.247), p < 0.05. CONCLUSIONS: There are only minor haemodynamic differences when using pancuronium compared to vecuronium in the fentanyl-pentobarbital-midazolam-N(2)O anesthetised domestic pigs. Furthermore, increasing doses of vecuronium have minimal haemodynamic effects. CLINICAL RELEVANCE: Experimental studies in pigs using either pancuronium or vecuronium as a neuromuscular blocking agent are comparable with regard to cardiac and haemodynamic performance.

Pharmacodynamic changes with vecuronium in sepsis are associated with expression of α7- and γ-nicotinic acetylcholine receptor in an experimental rat model of neuromyopathy.

BACKGROUND: Resistance to non-depolarizing neuromuscular blocking agents induced by sepsis is associated with the qualitative change in the nicotinic acetylcholine receptor (nAChR). This study aims to investigate the effects of sepsis on the neuromuscular block properties of vecuronium in relation to the expression of fetal and neuronal α7 type nAChR. METHODS: Male Sprague-Dawley rats were randomly divided into sham and sepsis groups. Sepsis was induced by caecal ligation and puncture (CLP). The rats were injected i.v. with ulinastatin or normal saline on Day 10. Neuromuscular block properties of vecuronium were evaluated and neuromuscular function was assessed by electromyography on Days 1, 3, 7, and 14 after CLP. Expression of fetal and neuronal type α7-nAChR on the tibialis anterior muscle was assessed using immunohistochemistry and western blot. The mRNA encoding for γ- and α7 subunits was evaluated by real-time polymerase chain reaction. RESULTS: The half maximal inhibitory response of vecuronium in the sepsis group significantly increased, peaked on Day 7, and then declined on Day 14 (P<0.05). The neuromuscular function decreased with increasing postoperation time in the sepsis group (P<0.05). Sepsis significantly increased the expression of γ- and α7-nAchR along with expression of γ- and α7 subunits mRNA, peaked on Day 7, and declined on Day 14 (P<0.05). Ulinastatin suppressed the expression of receptor protein and mRNA encoding for γ- and α7 subunits (P<0.05). CONCLUSIONS: Pharmacodynamic changes with vecuronium seem to be associated with the expression of γ- and α7-nAChR in the skeletal muscle. Ulinastatin can improve this effect by inhibiting the expression of these receptors.

Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade.

OBJECTIVE: To evaluate if return of spontaneous ventilation to pre-relaxation values indicates complete recovery from neuromuscular blockade. STUDY DESIGN: Prospective, with each individual acting as its own control. ANIMALS: Ten healthy adult female Beagle dogs weighing 6.2-9.4 kg. METHODS: Dogs were anesthetized with propofol, dexemedetomidine and isoflurane. Spontaneous ventilation was assessed by measuring end-tidal CO2 , expired tidal volume, peak inspiratory flow, respiratory rate and minute ventilation. Vecuronium 25 µg kg(-1) IV was administered and neuromuscular block was evaluated by measuring the train-of-four (TOF) ratio with acceleromyography in the hind limb. During spontaneous recovery from neuromuscular block, the TOF ratio when each ventilatory variable returned to baseline was recorded. RESULTS: This dose of vecuronium produced moderate neuromuscular block in all dogs, with TOF ratio values of 0-18% at maximal block. Expired tidal volume, peak inspiratory flow and minute ventilation returned to pre-relaxation values when the median TOF ratio was ≤ 20%. The median TOF ratio was 42% when the end-tidal CO2 returned to pre-relaxation values. CONCLUSIONS AND CLINICAL RELEVANCE: Significant residual neuromuscular block could be measured at the hind limb with acceleromyography when ventilation had spontaneously returned to pre-vecuronium values. Monitoring spontaneous ventilation, including end-tidal CO2 , expired tidal volume, peak inspiratory flow or minute ventilation cannot be used as a surrogate for objective neuromuscular monitoring, and this practice may increase the risk of postoperative residual paralysis.

Evaluation of neostigmine antagonism at different levels of vecuronium-induced neuromuscular blockade in isoflurane anesthetized dogs.

Residual neuromuscular block (NMB) during recovery from general anesthesia may be minimized by antagonizing NMB with neostigmine. We examined neostigmine for restoring neuromuscular function when administered at 2 levels of vecuronium-induced NMB in dogs. Eight healthy adult dogs received vecuronium 0.1 mg/kg body weight (BW), IV, during isoflurane anesthesia. Recovery from vecuronium occurred spontaneously (control group; C), or was enhanced with neostigmine, 0.04 mg/kg BW, IV, administered when 2 (N2) or 4 (N4) responses to train-of-four (TOF) stimulation were first observed. Duration of NMB was significantly shorter for N2 and N4 than for C. The period of complete NMB was equal for all groups; differences were observed during the recovery phase of NMB. Time of neostigmine-enhanced recovery was significantly shorter for N4 than N2, but overall duration of NMB was not reduced. Recovery from NMB was faster with neostigmine. There is no clinical advantage in delaying neostigmine administration once 2 responses to TOF are present.

Évaluation de l'antagonisme de la néostigmine à différents niveaux de blocage neuromusculaire induits par vécuronium chez les chiens anesthésiés à l'isoflurane. Le bloc neuromusculaire résiduel (BNR) durant le réveil de l'anesthésie générale peut être minimisé en antagonisant le BNR avec de la néostigmine. Nous avons examiné la néostigmine pour le rétablissement de la fonction neuromusculaire lors de l'administration à 2 niveaux de BNR induit par le vécuronium chez les chiens. Huit chiens adultes en santé ont reçu du vécuronium 0,1 mg/kg poids corporel (PC), IV, durant l'anesthésie à l'isoflurane. Le réveil de vécuronium s'est produit spontanément (groupe témoin; C) ou a été rehaussé avec de la néostigmine, 0,04 mg/kg PC, IV, administrée lorsque des réponses 2 (N2) ou 4 (N4) à une stimulation de quatre impulsions «train-of-four¼ (TOF) ont d'abord été observées. La durée du BNR a été significativement écourtée pour N2 et N4 par rapport à C. La période du BNR complet a été égale pour tous les groupes; les différences ont été observées durant la phase de réveil de BNR. La durée du réveil rehaussée à la néostigmine a été significativement écourtée pour N4 par rapport à N2, mais la durée globale de BNR n'a pas été réduite. Le réveil du BNR a été plus rapide avec la néostigmine. Il n'y a pas d'avantage clinique à retarder l'administration de la néostigmine une fois que 2 réponses à TOF sont présentes.(Traduit par Isabelle Vallières).

Pillar[6]MaxQ functions as an in vivo sequestrant for rocuronium and vecuronium.

The binding affinity of pillar[6]MaxQ toward a panel of neuromuscular blockers and neurotransmitters was measured in phosphate buffered saline by isothermal titration calorimetry and 1H NMR spectroscopy. In vivo efficacy studies showed that P6MQ sequesters rocuronium and vecuronium and reverses their influence on the recovery of the train-of-four (TOF) ratio.

Denervation stage differentially influences resistance to neuromuscular blockers in rat gastrocnemius.

BACKGROUND: Muscle denervation was common in clinical surgery patients, which was mostly caused by trauma, paraplegia, and other factors. Denervated muscle in patients could lead to significant differential reaction to neuromuscle blockers due to the time of denervation and affected muscle area. We tested the hypothesis that resistance to non-depolarizing muscle relaxants (NDMRs) changes with time, and is related to the expression of immature and total acetylcholine receptors (AChRs). MATERIALS AND METHODS: The study evaluated the effect change of neuromuscular blockers in tibial nerve transected rat model. To determine 50% effective dose of NDMRs and succinycholine at 1, 7, 14, 28, and 35 days after denervation, action potential amplitude was monitorted by intracellular recording method. The messenger DNA that encodes the AChR-γ and AChR-ε subunits and the protein of the -γ and -ε subunits were quantified in the gastrocnemius by reverse transcription-polymerase chain reaction and western blotting respectively. Receptor number and pharmacodynamic changes was analyzed by correlation and regression analysis. RESULTS: Increased AChR-γ correlated with total AChRs, suggesting that the up-regulated AChRs may contain the immature isoform. The 50% effective dose of vecuronium and atracurium increased 1.2- to 1.5-fold at all time periods and correlated significantly with AChRs and AChR-γ. CONCLUSIONS: After denervation, resistance to NDMRs occurred earlier, was more marked from 14 days, and changes in resistance to NDMRs in skeletal muscle after nerve injury is dependent on the level of expression of immature and total AChRs. Denervation time should be of concern when such patients undergo surgery.

Efficacy of Atracurium-Vecuronium Combination in Patients Undergoing Laparoscopic Surgery: A Randomized Controlled Study.

INTRODUCTION: Deep neuromuscular blockade (d-NMB) is an essential requirement for carboperitoneum during laparoscopy surgery. However, sustaining d-NMB till the completion of surgery delays the reversal of the residual block. Therefore, there is a merit in exploring the effect of synergistic vecuronium-atracurium combination on the duration-of-action of d-NMB during "laparoscopic" surgery when we compare intubating bolus non-depolarizers (atracurium, vecuronium) administered alone. This study aims to evaluate whether the synergistic effect atracurium-vecuronium combination increases duration-of-action of d-NMB "laparoscopic" surgery settings. METHODS: Forty-eight patients (18-60 years, American Society of Anesthesiologists physical status- II/III, either sex) undergoing laparoscopic cholecystectomy were randomly allocated to receive vecuronium (vecuronium group, n = 16) or atracurium (atracurium group, n = 16) or vecuroniumatr-acurium combination (vecuronium-atracurium combination group, n = 16) and analyzed for the effects on the duration-of-action (primary objective); onset-of-action, reversibility, and quality of intubating conditions (secondary objectives) profile of neuromuscular blockade in patients undergoing laparoscopic cholecystectomy. RESULTS: Duration-of-action of neuromuscular blockade was significantly longer in patients who received atracurium-vecuronium combination (53.9 ± 9.7 minutes) versus atracurium-alone (41.1 ± 3.8 minutes) or vecuronium-alone (43.5 ± 9.2 minutes) (P = 0.000). No difference was found for the time to onset-of-action (vecuronium [198.1 ± 34.9 seconds], atracurium [188.5 ± 50.6 seconds], or atracurium-vecuronium combination [196.3 ± 46.3 seconds] [P = 0.829]); time for the reversal of muscle relaxation effect (vecuronium [559.9 ± 216.2 seconds], atracurium [584.7 ± 258.3 seconds], and atracurium-vecuronium combination [555.0 ± 205.4 seconds] [P = 0.925]); and quality-of-intubating conditions (vecuronium group [9.6 ± 1.3]; atracurium group [10.0 ± 0.0]; atracurium-vecuronium group [10.0 ± 0.0] [P = 0.182]). CONCLUSION: The synergistic effect of the atracurium-vecuronium combination leads to an increased duration-of-action of d-NMB during laparoscopic cholecystectomy without impacting onset-of-action, quality of intubating conditions, and reversal of muscle relaxant effect.

Diabetes mellitus affects the duration of action of vecuronium in dogs.

OBJECTIVE: To compare the duration of action of vecuronium in diabetic dogs with a control group. STUDY DESIGN: Prospective clinical study. ANIMALS: Forty client-owned diabetic (n = 20) and non-diabetic dogs. METHODS: Dogs were considered free from other concurrent disease based on clinical examination and laboratory data. After pre-anaesthetic medication with acepromazine and methadone, anaesthesia was induced with intravenous (IV) propofol and maintained with isoflurane-nitrous oxide in oxygen. Neuromuscular blockade (NMB) was achieved with vecuronium, 0.1 mg kg(-1) IV and its effects recorded by palpation (pelvic limb digital extension) and electromyography (m. tibialis cranialis) of responses (twitches; T) to repeated train-of-four (TOF) nerve stimulation. Time to onset of NMB was the period between vecuronium injection and loss of fourth twitch (T4) in the TOF pattern recorded by EMG and palpation. Duration of NMB was defined as the time from drug administration to return of T1 by palpation (T1(tactile) ) and EMG (T1(EMG) ). Times to return of T2-4 were also recorded. Time from induction of anaesthesia to vecuronium injection was recorded. Heart rate, non-invasive mean arterial pressure, body temperature, end-tidal isoflurane and end-tidal CO(2) concentrations were recorded at onset of NMB and when T1(EMG) returned. Loss and return of palpable and EMG responses for diabetic and non-diabetic dogs were compared using t-tests and Mann Whitney U-tests. RESULTS: There were significant (p < 0.05) differences between diabetic and non-diabetic dogs for the return of all four palpable and EMG responses. Times (mean ± SD) for return of T1(tactile) were 13.2 ± 3.5 and 16.9 ± 4.2 minutes in diabetic and non-diabetic dogs respectively. There were no differences between diabetic and non-diabetic dogs in the time to onset of vecuronium with EMG or tactile monitoring. CONCLUSIONS AND CLINICAL RELEVANCE: The duration of action of vecuronium was shorter in diabetic dogs as indicated by both tactile and EMG monitoring.

Observations of the potency and duration of vecuronium in isoflurane-anesthetized horses.

OBJECTIVE: To evaluate the potency and duration of three subparalyzing doses of vecuronium (VEC) in isoflurane-anesthetized horses. STUDY DESIGN: Prospective experimental study. ANIMALS: Thirteen healthy adult horses undergoing arthroscopic surgery. METHODS: During isoflurane anesthesia, horses received one of three doses of vecuronium (25, 50, or 100 µg kg(-1)). Neuromuscular transmission was monitored with acceleromyography (AMG) with train-of-four (TOF) stimulation of the radial nerve. Maximal depression of the first twitch (T1), and onset time were recorded for each dose. Recovery time to a TOF ratio >90% was also evaluated. RESULTS: Vecuronium 25 µg kg(-1) produced no observable T1 depression in four horses. VEC 50 µg kg(-1) (n = 5) produced a maximal T1 depression of [median (min, max)] 41 (20, 71) % in four horses, and no neuromuscular block was seen in the fifth. VEC 100 µg kg(-1) was given to four horses and produced a T1 depression of 73 (64, 78) %. Of the four horses in which VEC 50 µg kg(-1) produced a measurable neuromuscular block, three recovered spontaneously 43 (40, 52) minutes after VEC administration; a fourth subject received edrophonium to reverse residual block at the end of the surgery. Spontaneous recovery after VEC 100 µg kg(-1) occurred by 112 minutes in one horse, and had to be facilitated by edrophonium in the remaining three horses, more than 2 hours after VEC had been given. CONCLUSIONS AND CLINICAL RELEVANCE: A dose of 100 µg kg(-1) VEC in isoflurane anesthetized horses failed to produce complete paralysis. The partial neuromuscular block lasted at least 2 hours after this dose had been administered. Edrophonium was required to reverse the neuromuscular block in three of four horses. It is likely that more than 100 µg kg(-1) VEC would be necessary for complete neuromuscular blockade in horses, and that this dose will last >2 hours.

Required dose of sugammadex or neostigmine for reversal of vecuronium-induced shallow residual neuromuscular block at a train-of-four ratio of 0.3.

Residual shallow neuromuscular block (NMB) is potentially harmful and contributes to critical respiratory events. Evidence for the optimal dose of sugammadex required to reverse vecuronium-induced shallow NMB is scarce. The aims of the present study were to find suitable doses of sugammadex and neostigmine to reverse a residual vecuronium-induced NMB from a time of flight (TOF) ratio of 0.3-0.9 and evaluate their safety and efficacy. In total, 121 patients aged 18-65 years were randomly assigned to 11 groups to receive placebo, sugammadex (doses of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg), or neostigmine (doses of 10, 25, 40, 55, or 70 µg/kg). The reversal time of sugammadex and neostigmine to antagonize a vecuronium-induced shallow residual NMB (i.e., TOF ratio of 0.3) and related adverse reactions were recorded. Several statistical models were tested to find an appropriate statistical model to explore the suitable doses of sugammadex and neostigmine required to reverse a residual vecuronium-induced NMB. Based on a monoexponential model with the response variable on a logarithmic scale, sugammadex 0.56 mg/kg may be sufficient to reverse vecuronium-induced shallow residual NMB at a TOF ratio of 0.3 under anesthesia maintained with propofol. Neostigmine may not provide prompt and satisfactory antagonism as sugammadex, even in shallow NMB.

Magnesium sulfate enhances non-depolarizing muscle relaxant vecuronium action at adult muscle-type nicotinic acetylcholine receptor in vitro.

AIM: To investigate the effect of magnesium sulfate and its interaction with the non-depolarizing muscle relaxant vecuronium at adult muscle-type acetylcholine receptors in vitro. METHODS: Adult muscle-type acetylcholine receptors were expressed in HEK293 cells. Drug-containing solution was applied via a gravity-driven perfusion system. The inward currents were activated by brief application of acetylcholine (ACh), and recorded using whole-cell voltage-clamp technique. RESULTS: Magnesium sulfate (1-100 mmol/L) inhibited the inward currents induced ACh (10 µmol/L) in a concentration-dependent manner (IC(50)=29.2 mmol/L). The inhibition of magnesium sulfate was non-competitive. In contrast, vecuronium produced a potent inhibition on the adult muscle-type acetylcholine receptor (IC(50)=8.7 nmol/L) by competitive antagonism. Magnesium sulfate at the concentrations of 1, 3, and 6 mmol/L markedly enhanced the inhibition of vecuronium (10 nmol/L) on adult muscle-type acetylcholine receptors. CONCLUSION: Clinical enhancement of vecuronium-induced muscle relaxation by magnesium sulfate can be attributed partly to synergism between magnesium sulfate and non-depolarizing muscle relaxants at adult muscle-type acetylcholine receptors.

Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.

1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 µmol/L)-, cisatracurium (0.32 µmol/L)- and vecuronium (0.36 µmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 µmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.

Sugammadex reverses neuromuscular block induced by 3-desacetyl-vecuronium, an active metabolite of vecuronium, in the anaesthetised rhesus monkey.

BACKGROUND AND OBJECTIVE: 3-Desacetyl-vecuronium is an active metabolite of the neuromuscular blocking agent (NMBA) vecuronium, which might lead to residual paralysis after prolonged administration of vecuronium in critically ill patients with renal failure. This study investigated the ability of sugammadex to reverse 3-desacetyl-vecuronium-induced neuromuscular block (NMB) in the anaesthetised rhesus monkey. METHODS: Experiments were performed in anaesthetised female rhesus monkeys. After bolus intravenous injection of vecuronium (n = 8) or 3-desacetyl-vecuronium (n = 8) 10 µg kg(-1) (ED90), a continuous infusion of the same NMBA was started to maintain the first twitch of the train-of-four (TOF) at 10% of baseline value. The infusion was stopped and NMB recovered spontaneously. The procedure was repeated, but immediately after stopping the infusion, an intravenous bolus dose of sugammadex 0.5 or 1.0 mg kg(-1) was given. For each NMBA, four placebo experiments were performed, in which the second recovery from NMB was also spontaneous. For all experiments, time to recovery of the TOF ratio to 90% was retrieved. RESULTS: After administration of sugammadex for reversal of 3-desacetyl-vecuronium-induced NMB, recovery was significantly faster than spontaneous recovery. Mean time to recovery of TOF to 90% was 3.2 min (sugammadex 0.5 mg kg(-1)) and 2.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (17.6 min). For vecuronium-induced NMB, mean time to recovery of TOF to 90% was 17.1 min (0.5 mg kg(-1)) and 4.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (23.4 min). CONCLUSION: Sugammadex rapidly and effectively reversed 3-desacetyl-vecuronium-induced NMB in the rhesus monkey, at a lower dose than that needed to reverse vecuronium-induced NMB.

Assessment of the potential for displacement interactions with sugammadex: a pharmacokinetic-pharmacodynamic modelling approach.

BACKGROUND: Sugammadex is a γ-cyclodextrin that binds with high affinity to the neuromuscular blocking agents (NMBAs) rocuronium (bromide) and vecuronium (bromide) by encapsulation. Cyclodextrins are known to form inclusion complexes with other compounds. OBJECTIVES: We utilized a previously developed pharmacokinetic-pharmacodynamic model to identify potential clinically relevant displacement interactions with sugammadex. The potential for sugammadex to capture other drug molecules, thereby reducing their efficacy, is not discussed here. METHODS: Isothermal titration calorimetry (ITC) was used to determine the binding affinity (estimated by association rate constant [k(ass)]) between sugammadex and 300 commonly prescribed drugs. The screening included drugs commonly used in or shortly after anaesthesia, commonly prescribed drugs such as antidepressants and cardiovascular drugs, drugs (both steroidal and nonsteroidal) acting on steroidal receptors (such as the corticosteroids hydrocortisone, prednisolone and dexamethasone), and the selective estrogen receptor modulator toremifene. The model took into account the population pharmacokinetic-pharmacodynamic relationships of sugammadex, rocuronium and vecuronium, the binding affinities of the NMBAs and other compounds as determined by ITC, and the relationship between the free concentration of NMBA with sugammadex in the presence of a third complexed compound. Using the model, the critical concentrations of a concomitantly administered compound required to result in a train-of-four (TOF) ratio of <0.9, indicating reoccurrence of neuromuscular blockade, for each plasma concentration of sugammadex and NMBA were calculated. For compounds with a k(ass) value of ≥ 2.5 × 104 mol/L likely to be administered during sugammadex reversal, the combinations of k(ass) and maximum plasma drug concentration (C(max)) were entered into a graph, consisting of a critical line established using a conservative approach, and those compounds above this critical line potentially resulting in a TOF ratio <0.9 were subsequently identified. Clinical validation was performed in a post hoc analysis of data from ten sugammadex studies, in which the impact of various drugs administered perioperatively on neuromuscular recovery was assessed for up to 1 hour after sugammadex administration. RESULTS: ITC analysis demonstrated that the binding affinity of rocuronium and vecuronium for sugammadex was very high, with k(ass) values of 1.79 × 107 mol/L and 5.72 × 106 mol/L, respectively. Only three compounds (flucloxacillin, fusidic acid and toremifene) were found to have critical combinations of k(ass) and C(max), and thus the potential for displacement. Sugammadex was administered to 600 patients for reversal of rocuronium- or vecuronium-induced blockade in the ten analysed studies, in which 21 co-administered drugs were selected for analysis. No reoccurrence of blockade occurred in any patient. CONCLUSION: Of 300 drugs screened, only three (flucloxacillin, fusidic acid and toremifene) were found to have potential for a displacement interaction with sugammadex, which might potentially be noticed as a delay in recovery of the TOF ratio to 0.9. A clinical study found no evidence of a clinically relevant displacement interaction of flucloxacillin with sugammadex; these findings confirm the highly conservative nature of the modelling and simulation assumptions in the present study.

Preoxygenation with 20º head-up tilt provides longer duration of non-hypoxic apnea than conventional preoxygenation in non-obese healthy adults.

PURPOSE: Failed airway is the anesthesiologist's nightmare. Although conventional preoxygenation can provide time, atelectasis occurs in the dependent areas of the lungs immediately after anesthetic induction. Therefore, alternatives such as positive end-expiratory pressure (PEEP) and head-up tilt during preoxygenation have been explored. We compared the conventional preoxygenation technique (group C) with 20º head-up tilt (group H) and 5 cmH(2)O PEEP (group P) in non-obese individuals for non-hypoxic apnea duration. METHODS: A total of 45 patients were enrolled (15 in each group). After 5 min of preoxygenation, intubation was performed after induction of anesthesia with thiopentone and succinylcholine. After confirming the tracheal intubation by esophageal detector device and capnogram, all patients were administered vecuronium to maintain neuromuscular blockade and midazolam to prevent awareness. Post-induction, patients in all groups were left apneic in supine position with the tracheal tube exposed to atmosphere till the SpO(2) dropped to 93% or 10 min of safe apnea was achieved. RESULTS: The demographic data were comparable. Non-hypoxic apnea duration was higher with group H (452 ± 71 s) compared to group C (364 ± 83 s, P = 0.030). Group P did not show significant increase in the duration of non-hypoxic apnea (413 ± 86 s). There were no adverse outcomes or events. CONCLUSIONS: Preoxygenation is clinically and statistically more efficacious and by inference more efficient in the 20º head-up position than with conventional technique in non-obese healthy adults. Although application of 5 cmH(2)O PEEP provides longer duration of non-hypoxic apnea compared to conventional technique, it is not statistically significant.

[The relationship between the intraoperative hypothermia and the residual neuromuscular of single intubation dose of vecuronium].

OBJECTIVE: To study the relationship between the intraoperative hypothermia and the residual neuromuscular of single intubation dose of vecuronium. METHODS: The designed patients were from July to December in 2009. There are 36 male and 44 female cases. Their age was 19 to 59 years. The induction and sustaining are routine method. There were no additional muscle relaxant. Intraoperative nasopharyngeal temperature (T) < 36°C for the intraoperative hypothermia (LBT group) or non-intraoperative hypothermia group (NBT group). The patients turn back the PACU with tracheal intubation. Measured TOFr immediately after extubation. RESULTS: The incidence of residual neuromuscular single intubation dose of vecuronium was 28.7%. The incidence of postoperative residual neuromuscular was 43.2% (16/37) in the LBT group. The incidence of postoperative residual neuromuscular was 16.3% (7/43) in the NBT group. LBT group compared with the NBT group the incidence of postoperative residual neuromuscular was significant differences (P < 0.05). CONCLUSION: The incidence of residual neuromuscular increases. When patients in the surgery exist low body temperature.