Participants and Study Design
The study was performed after receiving written informed consent from all participants. All study procedures were approved by the Clinical Research Ethics Committee of the Affiliated Hospital of Xuzhou Medical University, Jiangsu, China (the reference number: XYFY2017-KL005-01, approval date: December 18, 2017). The present trial was prospectively registered prior to the first patient enrolment at http://www.chictr.org.cn (the registration number is ChiCTR-IPD-17011145, Principal investigator: D.Y. Q., date of registration: April 13, 2017).
Patient Management
Sixty-nine American Society of Anesthesiologists grade I and II patients, aged 30-65 years, undergoing laparoscopic partial gastrectomy with carbon dioxide pneumoperitoneum, were enrolled in this study. Patients with hypermagnesemia, with known allergy to magnesium sulfate, unstable blood pressure (hypertension or hypotension), cardiac dysfunction (NYHA grade Ⅲ and Ⅳ), morbid obesity, and severe hepatic, renal or endocrine were excluded from the study. The Ethical Committee of the affiliated hospital of Xuzhou medical college approved the study (No: XYFY2017-KL005-01) and written informed consent was obtained from all participants. The study was registered at Chinese Clinical Trial Registry; the registration number is ChiCTR-IPD-17011145.
Peripheral, central venous, and arterial cannulations were performed on the patients, under local anesthesia on arrival at the operation theatre. Electrocardiogram, oximetry, intra-arterial blood pressure, and central venous pressure were monitored. The participants were premedicated with midazolam, 1-2 mg intravenously, 10 minutes before the induction of anesthesia. The anesthesia was induced intravenously using etomidate 0.25 mg/kg and sufentanil 0.5 μg/kg. Endotracheal intubation was facilitated by administering the muscle relaxant cisatracurium 0.3 mg/kg intravenously. The initial tidal volume was 8-10 ml/kg at a respiratory rate of 12 breaths per minute. Ventilation was adjusted to maintain the end-tidal carbon dioxide at 35 to 45 mmHg. After 10 minutes of stable cardiovascular variables, HR, MAP, CO, CVP and SVR were measured using the FloTrac/Vigileo Monitoring System. The persons who prepared and dispensed the drugs did not participate in the monitoring of hemodynamic parameters. Immediately before the pneumoperitoneum, the participants were assigned (using a computer derived random number sequence) to one of the three groups. Group L received magnesium sulfate 30 mg/kg in 20 ml of normal saline over 5 min intravenously as a bolus dose followed by 15 mg/kg/h in 20 ml of normal saline as continuous maintenance infusion for 1 h; group H received magnesium sulfate 50 mg/kg in 20 ml of normal saline over 5 min as a bolus dose followed by 30 mg/kg/h in 20 ml of normal saline as continuous maintenance infusion for 1 h; and group S (control group) received 20 ml 0.9% saline infusion as bolus dose followed by 20 ml/h continuous maintenance infusion for 1 h, immediately before the induction of pneumoperitoneum.
Anesthesia in all the groups was maintained by propofol (4 - 6 mg/kg/h) , remifentanil (0.25 - 0.35 μg/kg/min) and cisatracurium (0.1 - 0.12 mg/kg/h) administered intravenously. During the maintenance, bispectral index (BIS) values, determined by ConviewTM Depth of Anesthesia Monitor (Pearlcare Medical, Zhejiang, China), were maintained at 45 - 60. During the surgery, we adjusted the pumping rate of propofol and remifentanil based on BIS, heart rate, and blood pressure, our study controlled according to the BIS value, When the BIS value was above 60 or below 45, propofol infusion rate would be adjusted by 0.5mg/ kg/h each time. If the BIS value was maintained between 45-60, but the blood pressure fluctuates more than 20% of the basal level, remifentanil infusion rate would be adjusted by 0.02ug/kg/min each time. In addition, the degree of muscle relaxation was monitored with the TOF-GUARD muscle relaxometer (Organon Teknika, Turnhout, Belgium). Esophageal temperature was maintained using a heated blanket. Stopped pumping cisatracurium at the beginning of suture. The propofol and remifentanil infusions were stopped at the end of surgery. Patients were routinely sent to the PACU followed by intravenous administration of atropine sulfate 0.02 mg/kg and neostigmine 0.04 mg/kg for reversal of muscle relaxation, and the staffs worked in PACU monitored and removed the tracheal tube when the TOF ratio > 90%.
In cases of acute and severe hemodynamic fluctuations, the following medical interventions were performed: during the operation, we maintained the BIS value between 45 and 60 and excluded the effects of insufficient analgesia, for hypotension (MAP < 60 mmHg), an intravenous bolus dose of 50 ug phenylephrine was administered; and for hypertension (MAP > 110 mmHg) an intravenous bolus dose of 5 mg urapidil was administered. The data from the subjects who required vasoactive drugs during the surgery were excluded from the subsequent analysis.
The primary and secondary outcome
The primary outcome is the difference in SVR between different groups. The secondary outcome is the differences of other indicators between groups, such as CO, MAP, HR, CVP, vasopressin and postoperative pain score.
FloTrac/Vigileo Monitoring System
The system is a minimally invasive continuous CO monitoring system based on arterial pressure waveform analysis. The catheter inserted into the radial artery was connected to the transducer of third-generation FloTrac/Vigileo system, which updated the MAP, HR, and CO every 20 seconds. The SVR can be continuously measured or calculated based on the patients’ information about age, gender, height , weight and the data on central venous pressure (CVP).
Surgical technique
The operations were performed in a standard group by a single surgeon. Carbon dioxide pneumoperitoneum was established in the patient in supine position, using a Verres needle. The pneumoperitoneal pressure was maintained at 15 mmHg throughout the laparoscopic procedure. According to the surgical requirements, all the patients were positioned in a head-up tilt of about 30°. To avoid potential severe hypotension as a result of anesthesia induction, all patients received 8-10 ml/kg compound electrolyte solution before the induction of anesthesia. Intraoperatively, the intravenous infusion of lactate ringer solution or compound electrolyte solution was 6 ml/kg/h. In order to fully observe the effect of magnesium sulfate on pneumoperitoneum, if the pneumoperitoneum duration in a participant was less than two hours, then the data of the corresponding participant were removed from the final analysis.
Postoperative analgesia
In this trial, patients were not given regional analgesia and PCA analgesia pumps which are consisted mainly of sufentanil, dezocine and tropisetron were used after the patient left the PACU. We evaluated the VAS score 5 min and 20min after extubation. When the score is >5, we used fentanyl 0.05 mg iv for analgesia .
Evaluation of the outcome variables
The hemodynamic parameters of the three groups were recorded using the FloTrac/Vigileo monitoring system. The recording of the hemodynamic data for each participant in each group was initiated after the induction of anesthesia and achievement of hemodynamic stability. The baseline values for all parameters were recorded at this point (T1). The study parameters measured included HR (beats/min), MAP (mmHg), CO (L/min), CVP(cmH2O) and SVR (dyn/s/cm5) at following intervals: Ten minutes after the induction of anesthesia in the supine position (T1); at the initiation of pneumoperitoneum (T2),and 5 (T3), 10 (T4), 30 (T5), and 60 (T6) minutes post-pneumoperitoneum in the reverse Trendelenburg position; 10 minutes after exsufflation in the supine position (T7). Blood samples for assessing serum magnesium and vasopressin concentrations were collected from the radial artery. The serum levels of vasopressin and magnesium were recorded at T1, T3, and T7. The dose of intraoperative remifentanil and fentanil, operation time, and pneumoperitoneum time were simultaneously recorded. Vasopressin levels were measured by radioimmunoassay (GC-911 Gamma radioimmunoassay counter, USTC ZONKIA, Anhui, china). We evaluated the extubation time (the time from the end of the operation to the extubation) and visual analogue scale (VAS) at 5 min and 20 min after extubation. The incidence of adverse reactions 24 h after the operation were also recorded.
Statistical analysis
A sample size calculation was performed using PASS (Version 11.0; NCSS, USA) using a one-way analysis of variance. According to preliminary testing, we assumed that the mean SVR in Group S, Group L, Group H respectively are 2043, 1893, 1697, and the variability (SD) of the SVR of the three groups are 304, 297, 322. On the basis of a 0.05 level of significance with a power of 0.90, we sought to enroll at least 21 patients per group in the investigation to achieve sufficient statistical power. To compensate for the lack of 10% follow-up data, we aimed to recruit 23 patients per group.
Quantitative data confirming to the normal distribution were described as means ± standard deviation and the data of the non-normal distribution were represented by the median and the interquartile range. The data among the three study groups were analyzed by one-way analysis of variance (ANOVA) with post hoc least significant difference (LSD) test as appropriate. The Kruskal-Wallis test was used to analyze not normally distributed variables. For serially measured values, repeated-measures ANOVA and post hoc LSD tests were used to assess the trends in changes of serial values and interaction of trends between the groups. Comparison of continuous variables with baseline values were analyzed using student’s t-test in each group. Categorical variables were analyzed using chi-square (c2) or and Fisher definite probability tests. P value < 0.05 was considered statistically significant. Statistical analysis was performed using statistical software SPSS16.0 (SPSS, Chicago, USA).