Sugammadex And Neostigmine Dose-finding Study For Reversal Of Vecuronium-induced Shallow Neuromuscular Block

Objective1,To investigate the suitable dose of sugammadex or neostigmine for reversal of vecuronium-induced residual NMB to achieve a TOF ratio of 0.9 from a TOF ratio of 0.3.2.To determine the incidence of reoccurrence of neuromuscular block within the first 60 min,of muscle weakness in the post-anesthesia care unit and of adverse events during the studyMethodsThe study consisted of 121 patients who underwent routine elective surgery in our hospital between July 2018 and June 2019.Inclusion criteria were:age 18-65 years,American Society of Anesthesiologists(ASA)physical status Ⅰ-Ⅲ,body mass index 18.5-25.0 kg/m2,and undergoing general anesthesia with an expected duration of at least 1 h.Exclusion criteria were:expected difficult airway,neuromuscular disease,significant hepatic or renal dysfunction,a family history of malignant hyperthermia,allergy to any of the drugs used in this trial,taking medication that might interfere with NMB or the antagonist,and glaucoma.Patients who were pregnant or breastfeeding were not included,nor were those who had participated in another study within the previous 30 days.In total,121 patients were randomly assigned to one of 11 groups to receive placebo,sugammadex 0.125,0.25,0.5,1.0,or 2.0 mg/kg,or neostigmine 10,25,40,55,or 70 μg/kg combined with half doses of atropine.On arrival in the operating room,an intravenous cannula was inserted in a forearm vein of the patient,on the side opposite to that used for the electromyograph.Monitoring of vital signs was started,such as electrocardiography,SpO2 level and noninvasive blood pressure.Anesthesia was induced and maintained with targetcontrolled infusion of propofol 3-5 ug/ml using the Marsh pharmacokinetic model and remifentanil at 4-6 ng/ml using the Minto pharmacokinetic model.Patients were artificially ventilated by face mask until intubation of the trachea to maintain normocapnia and oxygen saturation of more than 96%.Body temperature was maintained at above 36.0℃.Neuromuscular monitoring was according to international consensus guidelines9.The adductor pollicis muscle response to ulnar nerve stimulation was monitored by a neuromuscular transmission module via a S/5 GE Datex Light monitor(GE Datex Medical Instrumentation,Inc.,Tewksbury,MA).The piezoelectric probe of the acceleromyograph was attached to the tip of the thumb,with a hand adapter that ensured preload of the thumb.After immobilizing the forearm and degreasing the skin,surface skin electrodes were placed over the ulnar nerve proximal to the wrist.Following a 5-s tetanic train of 50 Hz to stabilize the signal,the stimulation was switched to TOF mode(70-mA current;0.2-ms pulse duration,2 Hz frequency).Calibration of the EMG monitoring was then commenced to determine the individual supramaximal nerve stimulation.After the signal was stable,repetitive TOF stimulation was applied at the ulnar nerve wrist point every 20 s until the patient recovered from anesthesia.Skin temperature was measured at the site of the neuromuscular measurements and maintained at above 32.0℃.Vecuronium 0.1 mg/kg was administered as an i.v.bolus after stabilization of the EMG twitch response.When the TOF ratio disappeared,the trachea was intubated.During surgery,0.02 mg/kg of vecuronium was administered to maintain an NMB depth according to clinical need.When surgery was coming to an end,spontaneous recovery from the NMB was allowed to a TOF ratio of 0.3.Study medications,dosed according to randomization,or placebo were administered as an i.v.bolus within 10 s into the forearm vein.Neuromuscular monitoring was continued for at least 30 min after the TOF ratio reached 0.9.Reoccurrence of NMB was defined as the reappearance of a TOF ratio less than 0.8.After the patient had recovered from anesthesia,the trachea was extubated.Patients were kept in the post-anesthesia care unit(PACU)for a minimum of 60 min under close surveillance for any signs of reoccurrence of muscle weakness or other adverse events.In the PACU,every 15 min until discharge,patients were required to open their eyes for 5 s,perform a 5-s head-lift test,a 5-s leg-lift test and swallow saliva to check for clinical evidence of any muscle weakness.In addition,a test for general muscle weakness was performed using the Medical Research Council Scale.10 Meanwhile,patients’ level of consciousness was assessed using Ramsay scores if they were uncooperative.Oxygen saturation,heart rate,noninvasive blood pressure and respiratory rate were routinely monitored,and oxygen was delivered via a nasal cannula.After discharge from the PACU,the patients were monitored for 24 h to detect any late adverse events.ResultBased on the mono-exponential model with the response variable on a logarithmic scale,sugammadex was estimated to be 1.79 mg/kg for an average recovery time of 2 min in 50%of patients and 0.42 mg/kg for an upper limit of 5 min for 95%of patients.In neostigmine group,the dose was calculated to be 27μg/kg for an upper limit of 5 min for 95%of patient,but for an average recovery time of 2min,the dose was not estimable.The overall incidence of re-paralysis was 19.2%in neostigmine group,but zero in sugammadex group.ConclusionIn conclusion,Sugammadex 0.5 mg/kg and neostigmine 32 μg/kg can satisfactorily reverse vecuronium-induced shallow residual neuromuscular block at a TOF ratio of 0.3.The reliability of reversal acceleration was improved by increasing the dose of sugammadex,but this result was not valid for neostigmine.The higher the administered dose of neostigmine,the higher the incidence of reoccurrence of NMB,which occurred when exceeding 40 μg/kg at a TOF ratio of 0.3.