This trail was approved by the ethics committee of the Ruijin Hospital affiliated to the Shanghai Jiaotong University School of Medicine (No. 2020-007-1) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at chictr.org.cn (ChiCTR2000034621, Principal investigator: Fang Ke, Date of registration: 12, July, 2020).
In this study, patients undergoing surgery for colorectal cancer were enrolled on an elective date from August 2020 to February 2021. Patients had an American Society of Anesthesiologists (ASA) grade I-III physical status classification, were between 18–80 years of age, and had a body mass index (BMI) between 18–26kg/m2. Patients suffering from neuromuscular junction diseases, severe heart, lung, liver, or kidney insufficiency, severe blood system disease, coagulation dysfunction, thrombocytopenia, or hemophilia were excluded from the study.
Participants were randomly divided into two groups: a deep neuromuscular blockade group (D Group) or a moderate neuromuscular blockade combined with TAPB group (M Group). A random number table method was adopted using Excel to allocate participants to the groups, and the grouping results were only known by the anesthesiologist. Throughout the operation, the patient’s blood pressure, electrocardiogram, pulse oxygen saturation, and Narcotrend (Monitor Technik, Bad Bramstedt, Germany) were routinely monitored. Oxygen was inhaled through a mask, and peripheral veins were catheterized for fluid administration.
A neuromuscular blockade monitor (E-NMT, GE Company, Finland) was used to stimulate the ulnar nerve and observe the contraction reaction of the adductor pollicis muscle. TOF counting with a frequency of 2Hz, current of 60mA, at 20-s intervals was adopted. Every 10min, PTC was monitored in the D Group.
Propofol (2mg/kg) and sufentanil (0.3µg/kg) were given for anesthesia induction. After the patient lost consciousness, TOF count monitoring was performed, ensuring the basic values were 90–110% for three consecutive times. The D Group was given rocuronium (0.6mg/kg, Esmeron®, N.V. Organon, Netherlands) through intravenous injection, while the M Group was given rocuronium (0.4mg/kg) intravenously. Continuous monitoring of neuromuscular blockade was conducted, and endotracheal intubation was performed when the TOF count was 0.
After endotracheal intubation, the researchers implemented TAPB according to the patient’s group. The M Group received ultrasound-guided bilateral TAPB using ultrasound (Edge, Sonosite®, Fuji Film, Japan) and in-plane techniques. The patients lay supine, exposing the abdominal area between the costal margin and iliac crest. The ultrasound probe was placed transversely between the costal margin and the iliac crest, near the front or middle axillary line. Three layers of abdominal muscles were identified, including the external oblique muscle, the internal oblique muscle, and the transverse abdominal muscle. After the needle (Stimuplex® D, 0.71*120mm 22G*, B Braun Melsungen AG, Germany) was inserted between the internal oblique and transverse abdominal muscles, it was withdrawn to ensure that the needle tip was not in a blood vessel. Then local anesthetic (20ml of 0.375% ropivacaine, Naropin®, AstraZeneca) was injected into each side.
Within 10 min of TAPB administration, the surgeon entered the room and prepped and draped the patient. Pneumoperitoneum was established five minutes after the operation commenced. Then, the surgeon (observer) measured the distance from the sacral promontory to the umbilical skin, while pneumoperitoneum pressure was controlled at 12 mmHg.[5, 16] During the operation, the surgeon scored the surgical space conditions according to a five-point ordinal scale ranging from 1 (extremely poor conditions) to 5 (optimal conditions) (Table 1).  The data were recorded by the anesthesiologist. The surgeon didn't know the group allocation.
The surgical rating score
Extremely poor conditions: the surgeon is unable to work because of coughing or because of the inability to obtain a visible laparoscopic field because of inadequate muscle relaxation. Additional neuromuscular blocking agents must be given
Poor conditions: there is a visible laparoscopic field, but the surgeon is severely hampered by inadequate muscle relaxation with continuous muscle contractions, movements, or both with the hazard of tissue damage. Additional neuromuscular blocking agents must be given
Acceptable conditions: there is a wide visible laparoscopic field but muscle contractions, movements, or both occur regularly causing some interference with the surgeon’s work. There is the need for additional neuromuscular blocking agents to prevent deterioration
Good conditions: there is a wide laparoscopic working field with sporadic muscle contractions, movements, or both. There is no immediate need for additional neuromuscular blocking agents unless there is the fear of deterioration
Optimal conditions: there is a wide visible laparoscopic working field without any movement or contractions. There is no need for additional neuromuscular blocking agents
Anesthesia was maintained by target control infusion (TCI) and desflurane. The TCI(Perfusor® Space Infusion Pump, B.Braun Melsungen AG.) effect compartment concentration(Marsh model) of propofol was 1 µg/ml, and remifentanil was sustainedly infused at 0.1µg/kg/min. Desflurane (6%) was inhaled continuously, and the minimum alveolar concentration (MAC) was maintained between 0.7 and 1.0. The depth of anesthesia was maintained in the Narcotrend range of 30–50. A single dose of sufentanil (0.2µg/kg) was given before incision. Neuromuscular blockade was monitored and maintained by continuously infusing rocuronium (initial rate of 3µg/kg/min). The TOF count in the D Group was maintained at 0 with PTC ≥ 1. The PTC was measured every 10 min during the operation. When PTC was > 15, the infusing rate of rocuronium was increased, and when PTC was < 1, infusing rate was decreased. If TOF count occurred during the period, a single dose of rocuronium (5mg) was administered. The TOF count in the M Group was maintained within 1–3. The rocuronium infusing rate was increased when TOF count was 3 and decreased when TOF count was 1 (Fig. 1). When systolic blood pressure decreased by > 30% or mean arterial pressure (MAP) <65mmHg for more than three minutes, phenylephrine (20µg) or ephedrine (5mg) was injected intravenously once.
The infusion of muscle relaxants ceased and a single dose of sufentanil (0.3µg/kg) were given10 min before the end of the operation. Then the patients were transferred to the post-anesthesia care unit as the standard procedure at author’s institution. In this study, all patients were routinely antagonized. When the TOF count recovered to 0.1, neostigmine (40µg/kg, Xinyi, China) and atropine (20µg/kg, Xinyi, China) were given to antagonize the residual effects of the muscle relaxants. Coughing and swallowing reflexes were recovered when the patient regained consciousness. The endotracheal tube was removed after TOF ratio ༞0.9, establishing a steady breathing frequency of 10–20 breathes per minute and PetCO2 was ≤ 45mmHg. Time to extubation, total time in PACU and other adverse events (apnea, desaturation) were recorded.
Oxycodone was used for patient-controlled-analgesia (PCA), the background dose was 1 mg/h, bolus dose was 1 mg/time, locked for 30 minutes. The postoperative visual analogue scale (VAS) and bolus time follow-up were performed by a specialized anesthetic nurse. The specialized anesthetic nurse didn't know the group allocation.
The primary outcome measure was the distance from the sacral promontory to the umbilical skin and the surgeon's subjective score of the surgical space conditions. Secondary outcome measures included the dosage of various narcotic drugs, the patient’s hemodynamic parameters during different periods of the operation, and patient pain scores (VAS) after the operation.
The purpose of this clinical trial was to verify that the surgical space conditions of the M Group were not inferior to that of the D Group. Therefore, the sample size estimation formula for a non-inferior, parallel (1:1) clinical trial was: Nc= (Z1−α+Z1−β) σ2(1 + 1/K)/(µT-µC+∆)2. According to the results of our pilot study, the mean µT value of the distance from the sacral promontory to the umbilical skin in the M Group was 16.03cm, and the mean µC value in the D Group was 15.66cm. The non-inferiority limit was set as ∆ = 1.5 cm. Assuming that the standard deviation (σ) was the same for both groups at 2.4, and α = 0.025, β = 0.10, and K = 1, then according to the formula, nc=35. Considering a drop-out rate of 10% in each group, the number of cases in each group should be no less than 39. Thus, 40 cases were included in each of the two groups in this study, which fulfills the requirements of the statistical tests.
Measurement data were summarized as mean ± standard deviation (‾x ± s). Categorical data were summarized as numbers and percentages(%). Comparisons between the two groups were analyzed by student t-test for measurement data, Chi-square test was used for categorical data (or Fisher’s exact test if expected count less than five), and Wilcoxon rank-sum test was used for ranked data. Bilateral 95% confidence intervals were calculated of the difference in surgical space measurements between the groups. Whether the effect of moderate neuromuscular blockade combined with TAPB on surgical space measurements was not inferior to that of deep neuromuscular blockade was judged according to the preset non-inferior effect limit of 1.5cm. If the lower boundary of the 95% confidence interval for (µT - µC) did not cross − 1.5 cm, noninferiority of the M group to the D group would be established. A P value of < 0.05 was considered statistically significant. Statistical analysis was performed with SPSS20.0 software.