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).
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, 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 was maintained in all groups 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 for 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 sented 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 < 25%.
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).
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.
In this trial, patients were not given regional analgesia and PCA analgesic pumps
which consisted mainly of sufentanil, dizocine and tropisetron were used after the
patient leaving PACU. We evaluated the VAS score 5 min and 20min after extubation.
When the score >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.
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 conforming 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
(2) 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).