Clinical trial NCT03576118
Conditions: Pneumoperitoneum
Keywords: biotrauma laparoscopic surgery neuromuscular block sugammadex
Sponsor: Ajou University School of Medicine
Start date: 2018-11-05; Completion date: 2019-09-19
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purposes of this study is to investigate the effects of moderate vs. deep neuromuscular block on respiratory mechanics and biotrauma in patients with intraoperative protective lung ventilation for laparoscopy.

Detailed description:
Mechanical ventilation results in the disruption of the alveolar-capillary barrier and increased permeability, a hallmark of experimental ventilator-induced lung injury. These mechanical forces also induce an increase in the concentrations of inflammatory cytokines.

The benefits of deep neuromuscular blocks for laparoscopic procedures are controversial and most of the studies undertaken have only sought to improve surgical conditions. Theoretically, deep neuromuscular block permits a lower abdominal insufflation pressure, which leads to better respiratory mechanics and gas exchange. The investigators examined the effects of moderate vs. deep neuromuscular block on respiratory mechanics and biotrauma in patients with intraoperative protective lung ventilation for laparoscopy. The investigators hypothesized that deep neuromuscular block (PTC 1 or 2) and low pressure pneumoperitoneum (8 mmHg) would improve respiratory mechanics and reduce inflammatory processes associated with biotrama during mechanical ventilation compared with moderate neuromuscular block (TOF count 1 or 2 ) and standard pressure pneumoperitoneum (12-15 mmHg).

Arms: arm 1: Deep neuromuscular relaxation and low pressure pneumoperitoneum arm 2: Moderate neuromuscular relaxation and standard pressure pneumoperitoneum
Interventions: intervention 1: Deep neuromuscular block intervention 2: Moderate neuromuscular block
Intervention descriptions: intervention 1: Deep neuromuscular block using high dose rocuronium and 8 mmHg pneumoperitoneum intervention 2: Moderate neuromuscular block using moderate dose rocuronium and 12-15 mmHg pneumoperitoneum

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Study Protocol 
 
Title: Effects of moderate versus deep neuromuscular block on respiratory mechanics and biotrauma 
during protective lung ventilation for robotic gynecologic surgery 
NCT No: NCT03576118 
Document date: 2019-08-01 
 
 
 
 
 


2 
 
This study was approved by Ajou University Hospital Institutional Review Board (AJIRB-MED-OBS-
18-115) and is registered at http://clinicaltrials.gov (NCT03576118). Between May 2018 and November 
2019, 74 patients aged 25-80 years undergoing robotic gynecologic surgery with Trendelenburg 
position were enrolled. Written informed consent was obtained from all participants before 
randomization. The exclusion criteria were operation time <1 h, uncontrolled cardiovascular morbidity, 
cerebrovascular and respiratory diseases, neuromuscular disorder, prior abdominal surgery and morbid 
obesity (body mass index >30 kg/m2).  
 
Interventions 
Patients were randomly allocated to either moderate NMB group or deep NMB group using a computer-
generated randomization (http://www.random.org). Moderate NMB group (n = 37) was maintained with 
train of four (TOF) count of 1-2 combined with IAP at 12 mmHg during surgery and then reversed 
using IV neostigmine of 50 μg/kg and glycopyrrolate of 10 μg/kg after surgery. Deep NMB group (n = 
37) was maintained with post-tetanic count (PTC) of 1-2 combined with IAP at 8 mmHg and then 
reversed using IV sugammadex of 4 mg/kg. Study intervention was conducted by an independent 
investigator who did not involve in the outcome assessment. The anesthetic provider, patients, and 
outcome assessors were blinded to the group assignment throughout the study period.  
 Standard monitoring included pulse oximeter, electrocardiogram, noninvasive blood pressure, and 
bispectral index (BISTM Quattro Sensor; Covidien, Mansfield, MA, USA). Acceleromyography (TOF-
Watch-SX; MSD BV, Netherlands) was applied to monitor the response of the adductor pollicis muscle.    
Anesthesia was implemented with total intravenous anesthesia using target-controlled infusion (TCI) 
of propofol and remifentanil. Anesthesia was induced with propofol of 4.0~6.0 μg/mL and remifentanil 
of 3.0~4.0 ng/mL as target concentration. After consciousness loss, the TOF-Watch-SX was calibrated 
and stabilized (<5% variation in the TOF ratios). IV rocuronium of 0.6 mg/kg was administered, and 
then tracheal intubation was done after confirmation of relaxation. A 20-G radial arterial catheter was 
inserted for continuous monitoring of hemodynamics and blood sampling. Mechanical ventilation was 


3 
 
composed of volume-controlled mode at a constant flow with a tidal volume 8 ml/kg of ideal body 
weight, and at an I:E ratio of 1:2 (FiO2=0.5). Respiratory rate is set to an end-tidal carbon dioxide 
tension (ETCO2) between 30 and 40mm Hg with 5 cmH2O PEEP and an inspiratory pause of 10%. 
Anesthesia was maintained using propofol and remifentanil TCI to achieve the BIS value of 40-60 and 
mean arterial pressure (MAP) within 20% of baseline. Rocuronium (0.3 to 0.4 mg/kg/hr) or saline are 
continuously infused and titrated according to the group assignment until the end of the fascia suturing. 
After dressing, the NMB was reversed, and extubation was done after confirming TOF ratio >0.9. 
Lactate Ringer’s solution or normal saline was infused at a rate of 6 mL/kg/h.  
Trendelenburg position was performed at 30°. PP was controlled through the limit of CO2 insufflator. 
IV patient-controlled analgesia was administered with fentanyl at a rate of 0.4 µg/kg/hr for 48 hr as 
patient’s need. 
 
Data collection 
The primary end point was the levels of inflammatory cytokines; pro-inﬂammatory cytokines including 
tumor necrosis factor (TNF)-α, TNF receptor (TNFR)-1, interleukin (IL)-1β, and IL-6, and anti-
inﬂammatory cytokines including IL-4 and IL-10. Blood samples were collected at 3 time points; after 
induction (baseline), the end of PP, and 24 hr after surgery. The collected blood samples were transferred 
to EDTA tubes and sent to the laboratory in a container. They were centrifuged at 3600 rpm for 30 min. 
Then, the supernatant serum of 1.5 mL was gathered into an Eppendorf tube and frozen at −80°C for 
later analysis. Levels of the cytokines were measured by using commercially available ELISA kit (R&D 
systems, Minneapolis, Minnesota, USA). Each sample was analyzed in triple and excluded when at 
least one was not determined, and the average value was calculated. 
Respiratory parameters including peak inspiratory pressure (Ppeak) and plateau pressure (Pplat) were 
measured at 5 time points; after induction (baseline), 15 min and 60 min after PP, the end of PP and the 
end of surgery. Hemodynamics such as heart rate (HR) and MAP and parameters relating with arterial 
blood gas analysis (pH, PaO2 and PaCO2) were measured at abovementioned 5 time points and in post-


4 
 
anesthesia care unit. The abdominal and shoulder pains were measured using numeric rating scale (NRS, 
0-10) including the numbers of patients requesting analgesics and antiemetics. White blood cell (WBC) 
count was measured at preoperative and 24 hr after surgery. C-reactive protein (CRP, normal range 
≤0.5 mg/dL) and chest x-ray were evaluated at 24 hr after surgery.  
 
Statistical Analysis 
Sample size are determined based on the findings of a previous study, where the mean ± SD of IL-6 
was 45 ± 8.6 pg/L in mechanical ventilation after conventional pneumoperitoneum. We considered a 
15% reduction of IL-6 to be clinically relevant. With a significant level of 5 % and a power of 90%, 36 
subjects were required in each group. We included 37 patients per group to allow for possible dropouts. 
Values are expressed as mean ± SD (or standard error) or medians (range) or numbers (proportion). 
Normality of distribution was assessed with the Kolmogorov-Smirnov test. Parametric data and 
nonparametric data were analyzed by using the independent t test and the Mann–Whitney U test, 
respectively. Categorical variables were evaluated by using the chi-square test or Fisher’s exact test. 
Repeated-measured variables were analyzed by using a linear mixed model with a Bonferroni-
correction. A P value <0.05 was considered statistically significant. Statistical analysis was conducted 
using SAS (version 9.3, SAS Inc., Cary, NC, USA) and R package (version 3. 6.1).