The study was approved by the Hospital Institutional Review Board and registered with the Clinical Trial Registry of China (ChiCTR-1800017696).
Consecutive patients diagnosed as MG grade I~II of Osserman classification scheduled to undergo right sided VATS thymectomy were enrolled in this study between May 2016 and May 2018. The diagnosis was confirmed by the presence of circulating antibody to the acetylcholine receptor, typical clinical and laboratory findings (ptosis, diplopia, limb weakness, and a decremental conduction response on electrical stimulation of the nerve supply to the deltoid muscle). Written informed consent was obtained from patients the day before the operation. Exclusion criteria included suspected difficult intubation, BMI >30 kg.m-2, age less than 18 or over 60 years old, hepatic or renal dysfunction, cardiovascular dysfunction, neurologic disorder, operational time over 4 hours, intraoperative blood loss over 1000 ml, history of chronic pulmonary disease, chronic medication with calcium channel blocker or magnesium, history of known allergy to magnesium sulphate or any other study drugs, and coexisting autoimmune diseases, such as hyperthyroidism, rheumatoid arthritis, scleroderma or lupus.
The selected patients were randomly assigned to magnesium sulfate or normal saline (control) group. A random sequence was kept within a sealed opaque envelope by an assistant not involved in this study. On the morning of the surgery, the assistant opened a sealed envelope and prepared magnesium sulfate (60mg.kg-1 diluted in 50ml normal saline) or 50ml normal saline according to the group allocation. The anaesthetist was blinded to the study drug.
Anticholinesterase medication and/or steroid drug was continued as the patient’s routinely treatment regimen until the morning of surgery. No premedication was given to the patients. Once upon the patient arrived operative room, anesthesia monitoring, including SpO2, ECG, noninvasive blood pressure, bispectral index (BIS™ sensor; Medtronic, Minneapolis, MN, USA) monitoring was applied. Bispectral index was recorded using BISx Power LinkTM by Philips Medical Systems (Royal Philips Electronics, Eindhoven, The Netherlands). After checking the patient’s information with the surgeon and operative circulating nurse, an 18 intravenous cannula and a left radial artery line were placed under local anesthesia with 2% lidocaine, and then the noninvasive blood pressure monitoring was changed to invasive continuous blood pressure monitoring. All the monitoring data were retrieved from an automatic anesthesia information system which was linked to the patient’s physiological monitor and was recorded.
Anesthesia was induced with 4µg.kg-1 fentanyl and propofol target controlled infusion (TCI) with Marsh model built- in pump (Fresenius Kabi AG, Bad Homburg, Germany) started with effect-site concentration (Ce) 2µg.ml-1 and aimed for patient’s unconsciousness with BIS value at 40-60. The patients were ventilated with face masks and kept end tidal carbon dioxide between 30-45 mmHg. After BIS value was kept between 40-60 for 10 minutes with relative stabilized propofol concentration, the TOF monitoring at the adductor pollicis muscle (ISx Power LinkTM by Philips Medical Systems) was started with electric stimulation (amplitude 50mA, interval time 20 seconds). For TOF monitoring, 2 surface electrodes were placed on cleaned skin overlying the ulnar nerve at the wrist. After the basal TOF was recorded, the observational drug (magnesium sulfate or normal saline) was given in 5 minutes. Five minutes later after observational drug infusion was finished, the TOF was recorded. If the TOF was larger than 10%, 0.05mg.kg-1 rocuronium and repeated dose of rocuronium in a 3 minutes interval was given intravenously until the TOF was less than 10%. After the TOF less than 10%, the DLT was intubated with direct video laryngoscopy. The intubation was performed by an experienced anaesthetist. If the tracheal intubation was not successfully completed within 20 s, it was recorded as a failed attempt. Mean blood pressure (MAP) and heart rate (HR) were recorded before intubation (Pre-intubation), and after intubation (Post-intubation), the maximum values of MAP and HR within 3 minutes after intubation were also recorded.
The intraoperative anesthesia was maintained with propofol TCI and remifentanil 2~4µg.kg-1 according to clinical need and BIS values (40-60). Before skin incision, local anesthesia was performed with 0.5% ropivacaine 10ml. During the operation, we did not give any NMB. After the end of operation, if the TOF was less than 90% or the anaesthetist was not satisfied with recovery of the respiratory function, neostigmine 0.05mg.kg-1 and calcium chloride 1g were given to the patient. 15~30 minutes before the end of operation, 40mg parecoxib was administered for prevention of postoperative pain, and 4mg ondansetron plus 5 mg dexamethasone was administered for prevention of postoperative nausea and vomiting (PONV). During the operation, 5mg.kg-1.h-1 Ringer's lactate solution was given, and no urine catheter was used. Epinephrine was used to maintain blood pressure normal if necessary. All thymectomy was conducted with right sided VATS thymectomy with three holes. Before closing the chest ports, negative suction of chest cavity combined with lung recruitment maneuvers was used to re-expand the right collapsed lung. No postoperative chest duct drainage was left.
The primary observational outcome of this study was the cumulative rocuronium dose during the induction. The secondary outcome was intubation condition for DLT placement. The DLT intubation condition quality was evaluated based on Copenhagen Consensus Conference scoring system: ease of laryngoscopy, vocal cord position and/or movement and response to intubation or cuff inflation (cough or diaphragmatic movement), and further classified as excellent, fair or difficult [11,12]. Other outcomes including intubation stimulation induced MAP and HR change (Post-intubation vs. Pre-intubation), propofol concentration when intubation, time from last dose of rocuronium administration to TOF returned to 90%, the needed time for extubation based on the decision of the anaesthetist (measured from the moment of the end of the operation). After extubation, 0-100mm visual analogue score (VAS) , postoperative Riker sedation and agitation scale and PONV were recorded. For 0-100mm VAS, we classified the patients’ postoperative pain intensity as none, mild, moderate, or severe. The following cut points on the pain VAS were determined: no pain (0–4 mm), mild pain (5–44 mm), moderate pain (45–74 mm), and severe pain (75–100 mm) [13]. For Riker sedation and agitation scales, we further divided the patients into three categories according to the scale: over sedated (scales 1 - 2), non-agitated (scales 3 - 4) and agitated (scales 5 - 7) [14,15].
We estimated the sample size based on the primary outcome (cumulative rocuronium dose used for intubation). In our pilot study, the mean difference of the initial rocuronium dose between magnesium sulfate group and normal saline group was 0.14mg.kg-1 with a pooled variance (SD) of 0.11. To obtain an alpha value of 0.05 and a test power of 80%, about 12 subjects were needed in each group. Anticipating about 20% dropout rate, we roughly estimated that 30 patients were needed.
Continuous variables presented as mean (SD) or number (%) were compared by Student t-test, F-test, Chi-square test or Fisher’s exact test. Categorical variables are presented as the number of patients and were compared by Chi-square test or Fisher’s exact test. A P value <0.05 was considered significant. Data Analyses were accomplished using MedCalc for Windows, version 11.4.2.0 (MedCalc Software, Mariakerke, Belgium).