Clinical trial NCT02100280
Conditions: Neuromuscular Blockade
Keywords: Neuromuscular blockade Sugammadex Laparoscopic surgery IL-6
Sponsor: Seoul National University Bundang Hospital
Start date: 2014-06-29; Completion date: 2017-06-16
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a multicenter, randomized, controlled, double-blinded, and parallel design study. A total of 96 patients were decided to be recruited considering a 10% dropout rate. Patients are randomized to receive a deep block or a moderate block. The randomization numbers are generated using a computer-generated randomization code (1) and are sealed in the opaque envelope until they are handed over to the anesthesiologist in charge of anesthesia management after the induction of anesthesia. Patients, surgeons reporting the scale of surgical status, and another researcher analysing the cytokines levels are blinded to the patient group. Patients aged 18-65 yr, ASA 1 or 2, and are scheduled for elective laparoscopic gastrectomy are included. Patients with severe respiratory or cardiac disease, hepatic or renal function impairment, on medications affecting neuromuscular function, and with known allergy to the drugs to be used are excluded.

Detailed description:
Induction and maintenance of anesthesia

Premedication is done with midazolam 0.03 mg/kg IV at reception area. Anesthesia is induced and maintained with intravenous propofol, remifentanil, and rocuronium. The dose of propofol is adjusted to maintain BIS value to 40-60, remifentanil to maintain blood pressure within 20% of preoperative value, and rocuronium to maintain PTC 1-2 (deep block) or TOF1-2 (moderate block). The monitoring consists of ECG, NIBP, pulse oximetry, temperature, ETCO2, BIS, and neuromuscular monitoring with acceleromyography (TOF-Watch SXTM, Organon Ltd., Dublin, Ireland).

Management and monitoring of neuromuscular block

After induction of anesthesia, continuous neuromuscular monitoring is started after calibration and stabilization of the signal as recommended by good clinical research practice; 50 Hz tetanic stimulation for 5 s, calibration, stabilization for at least 2 min 2. After stabilization, rocuronium 0.6 mg/kg is administered IV within 5 s for tracheal intubation. Maintenance dose of 0.1-0.2 mg/kg rocuronium is administered as needed for the maintenance of PTC1-2 (deep block) or TOF1-2 (moderate block). At the end of surgery, sugammadex 4 mg/kg for deep block group or neostigmine 50 ㎍/kg with glycopyrrolate 10 ㎍/kg for moderate block group are administered IV for reversal of neuromuscular block.

Evaluation of surgical conditions

A 5-point surgical rating scale (1 = excellent, 2 = good, 3 = acceptable, 4 = poor, 5 = extremely poor) is rated by the surgeon who is in charge of the patient's operation and is blind to the patient's group assignment. Intraoperative patient movement reported by surgeon, checked by restoration of spontaneous respiration or sudden increase in PIP, and any other movement are also recorded.

Measurement of cytokines and acute phase reactants

Blood samples are collected from the antecubital vein of the arm not used for IV infusion preoperatively, at the end of peritoneal closure, and 1, 2, \& 48 hr after the end of operation for analysis of TNF-α, IL-1β, 6, 8 and CRP. The blood samples are collected at test tubes and sent to the laboratory on ice. Cytokines are analyzed with enzyme-linked immunosorbent assay and CRP is determined by an institutional chemistry analyzer.

Postoperative pain measurement

Postoperative pain is evaluated by verbal numerical rating scale (VNRS, 0 = no pain, 10 = the severest pain imaginable) at postoperative 1, 2, 6, 24, and 48 hr. Postoperative pain is controlled by IV patient controlled analgesia using fentanyl. If patient complain of severe pain (VNRS score of 7 or more), additional analgesics can be used according to the attending physician. The amount of fentanyl used and additional analgesic drugs used are reported.

Arms: arm 1: After induction of anesthesia, continuous neuromuscular monitoring is started after calibration and stabilization of the signal as recommended by good clinical research practice; 50 Hz tetanic stimulation for 5 s, calibration, stabilization for at least 2 min 2. After stabilization, rocuronium 0.6 mg/kg is administered IV within 5 s for tracheal intubation. Maintenance dose of 0.1-0.2 mg/kg rocuronium is administered as needed for the maintenance of post tetanic count 1-2 (deep block). At the end of surgery, sugammadex 4 mg/kg are administered IV for reversal of neuromuscular block. arm 2: After induction of anesthesia, continuous neuromuscular monitoring is started after calibration and stabilization of the signal as recommended by good clinical research practice; 50 Hz tetanic stimulation for 5 s, calibration, stabilization for at least 2 min 2. After stabilization, rocuronium 0.6 mg/kg is administered IV within 5 s for tracheal intubation. Maintenance dose of 0.1-0.2 mg/kg rocuronium is administered as needed for the maintenance of train of four count 1-2 (moderate block). At the end of surgery neostigmine 50 ㎍/kg with glycopyrrolate 10 ㎍/kg are administered IV for reversal of neuromuscular block.
Interventions: intervention 1: deep block
Intervention descriptions: intervention 1: sugammadex 4 mg/kg are administered IV for reversal of neuromuscular block

Protocol documents:
Prot_SAP_000.pdf: 
Effect of deep neuromuscular block on stress response during 
laparoscopic gastrectomy
Trial registration: NCT02100280
Material and methods
This prospective, randomized, and controlled study was done after approval of 
the institutional review board of Seoul National University Bundang Hospital 
(Seongnam, South Korea) and registration at clinicaltrials.gov (NCT02100280). 
Adult (≥18 yrs) patients, whose American Society of Anesthesiologists (ASA) 
physical status I or II, scheduled for elective laparoscopic gastrectomy who 
provided written informed consent were included. Patients with renal or hepatic 
dysfunction, history of neuromuscular disease, allergy for neuromuscular blocker, 
or family history or malignant hyperthermia were excluded. Patients were 
randomly assigned to groups moderate and deep using a computer-generated 
random numbers (Random Allocation Software, version 2.0). All of the primary 
and secondary outcome variables were checked by blinded investigator to patient 
group.
When patients arrived at the reception area, premedication was done with 
midazolam 
0.03 
mg 
kg-1.AnaesthesiawasinducedandmaintainedwithIVpropofol,remifentanil,androcuronium.
Thedoseofpropofolwasadjustedtomaintainbispectralindex(BIS; 
A-2000 
BIS™ 
monitor; Aspect Medical Systems, Inc., Natick, MA, USA) value of 40-60, 
remifentanil to maintain blood pressure and heart rate within 20% of preoperative 
value, and rocuronium to maintain train-of-four (TOF) 1-2 (moderate group) or 
post-tetanic count (PTC) 1-2 (deep group). The monitoring was composed of 
electrocardiography, noninvasive blood pressure, pulse oximetry, esophageal 
temperature, end tidal CO2,BIS,andacceleromyography(TOF-Watch-SX; MSD BV, 
  
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Oss, The Netherlands).
The neuromuscular monitoring and management were done according to Good 
Clinical Research Practice guidelines.6 After induction of anaesthesia, continuous 
neuromuscular monitoring was started after calibration and stabilization of the 
signal as recommended in Good Clinical Research Practice guidelines; 50 Hz 
tetanic stimulation for 5 s, calibration, and stabilization for at least 2 min. After 
stabilization, rocuronium 0.6 mg / kg IV was administered for trachealintubation. 
Maintenance dose of 0.1 - 0.2 mg / kg rocuronium was administered as needed 
for the maintenance of TOF1-2(moderateblock) or PTC1-2(deepblock). At the end 
of surgery, reversal of neuromuscular block was done according to current 
guidelines using IV neostigmine up to 50 ㎍ /  kg with glycopyrrolate in 5:1 
ratio in moderate group and IV sugammadex 2-4mg / kg in deep group.
Blood samples were collected from the antecubital vein of the arm not used for 
IV infusion at preoperatively, at the end of peritoneal closure, and at 2 and 
48hrs after the end of operation for analysis of TNF-α, IL-1β, IL-6, IL-8, and 
C-reactive protein (CRP) (Table 1). The blood samples were collected at the 
serum sepersting tubes and were leave at room temperature for more than 30 
minutes and centrifuged at 3,000 r.p.m for 10 minutes. Transfer the separated 
serum to Micro Tube 1.0ml each, and stored (less than -20 ℃) in Deepfreezer. 
Cytokines were analysed with enzyme-linked immunosorbent assay kit(R&D 
Systems, Minneapolis, Minnesota, USA) and CRP was determined by an 
institutional chemistry analyser(Beckman Coulter, Brea, Califonia, USA).
Intraoperative patient movement, the requirements for muscle relaxation by 
surgeon, the amount of rocuronium used, time from administration of reversal 
agent to TOF ration of 0.9, operation time, and anesthesia time were recorded. 
A 5-point surgical rating scale (1 = excellent, 2 = good, 3 = acceptable, 4 = 
  
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poor, 5 = very poor) was rated by surgeon at the end of surgery. At 
post-anaesthesia care unit (PACU), symptoms or signs of residual paralysis were 
evaluated; hypoxemia (SpO2 < 95%), inability to maintain head elevation for 5 
s, or diplopia. 
Postoperative pain was evaluated using verbal numerical rating scale (VNRS, 0 = 
no pain, 10 = the severest pain imaginable) at postoperative 1, 2, 6, 24, 48 hr. 
Postoperative pain was controlled by IV patient controlled analgesia using 
fentanyl. If patient complained of severe pain (VNRS score of 7 or more), 
additional analgesics could be used by the attending physician. The amount of 
fentanyl used and additional analgesic drugs used were reported. Complications 
related to anticholinesterase, such as nausea or vomiting, dry mouth, and delayed 
gas out were also evaluate at the same time.
Statistica analysis
The primary outcome variable was the level of IL-6. To detect the difference in 
the IL-6 level of 10 pg/ml with α = 0.05 and β = 0.2, 43 patients per group 
were needed. This calculation was based on a between subject standard deviation 
of change of 16.3 pg/ml for IL-6 level from the previous study.3 Considering the 
10% dropout rate, a total of 48 patients per group were decided to be recruited. 
Data were expressed as mean (SD) or median (range) and P < 0.05 were 
considered statistically significant. The interval data (cytokines levels) were 
analyzed by unpaired t-test, ordinal data (surgical rating scale, postoperative pain) 
by Mann-Whitney U test, and nominal data by test of Fisher’s exact test as 
appropriate. 
The 
comparison 
of 
data 
within 
the 
group 
was 
done 
by 
repeated-measures ANOVA.
  
  
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