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:
DECEMB
ER
18, 2017). The present trial was prospectively registered prior to the first patient enrolment
at <a href="http://www.chictr.org.cn">http://www.chictr.org.cn</a> (the registration number is ChiCTR-IPD-17011145, Principal investigator: D.Y. Q.,
date of registration: April 13, 2017).</p>
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), poor left ventricular
function, morbid obesity, and severe hepatic, renal, endocrine, or cardiac dysfunction
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, 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) and remifentanil
(0.25 - 0.35 μg/kg/min) 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. In addition, the degree of muscle relaxation was monitored with the TOF-GUARD
muscle relaxometer (Organon Teknika, Turnhout, Belgium), and the intraoperative train-of-four was maintained
at <25%. When the myokymia was restored to 25% during the operation, 0.05 mg/kg cisatracurium
was administered intravenously. Esophageal temperature was maintained using a heated
blanket. The propofol and remifentanil infusions were stopped at the end of surgery,
followed by intravenous administration of atropine sulfate 0.02 mg/kg and neostigmine
0.04 mg/kg for reversal of muscle relaxation, and extubation.
In cases of acute and severe hemodynamic fluctuations, the following medical interventions
were performed: for bradycardia (heart rate <45 beats/min), an intravenous bolus dose
of 0.6 mg atropine was administered; for hypotension (MAP < 60 mmHg), the rate of
infusion of intravenous fluid was increased and/or 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,
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°. Before the first hemodynamic measurement, 8-10 ml/kg
of compound electrolyte solution was given intravenously to maintain the stroke volume
variation at less than 13%. Sodium lactate ringer solution and hydroxyethyl starch
(6 ml/kg/h, crystallographic ratio 1: 1) were intravenously infused based on the loss
of body fluids during the operation. 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.
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), 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, 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 were described as means ± standard deviation. 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. 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) test. P value < 0.05 was considered statistically significant. Statistical analysis was performed
using statistical software SPSS16.0 (SPSS, Chicago, USA).