This study was approved by the Institutional Review Board of Zhongshan Hospital, Fudan University (B2019-074R)) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prospectively prior to patient enrollment at http://www.chictr.org/cn/(registration number: ChiCTR1900023050, Principal investigator: Chao Liang, Date of registration: 08/05/2019). The study protocol was performed in accordance with the relevant guidelines and has been reported in line with Consolidated Standards of Reporting Trials (CONSORT) Guidelines.
Study Population
Patients 20–70 years of age, of American Society of Anesthesiologists physical status (ASA PS) 1 or 2, and diagnosed with solitary pulmonary nodules without chronic pain (with no pain medications routinely used) were deemed suitable to undergo 3-port single-intercostal VATS performed by surgeons. The exclusion criteria included pre-existing infection at the block site, history of chronic pain, significant coagulopathy, contraindication to techniques or drugs used in the protocol, and conversion to open thoracotomy.
Randomization And Patient Grouping
According to a computer-generated randomization list, patients were assigned in blocks of three, with a sealed envelope technique, to one of three groups: Group C (General anesthesia with patient-controlled intravenous analgesia [PCIA]), Group T (General anesthesia with patient-controlled epidural analgesia [PCEA]), or Group E (general anesthesia with continuous ESPB and PCIA).
Method Of Anesthesia And Analgesia
On arrival at the operating room, routine monitoring, including invasive blood pressure, pulse oxygen saturation (SpO2), and electrocardiography, was performed. In group T, the patient was placed in a left lateral decubitus position, and a thoracic epidural catheter (19G; Pajunk GmbH Medizintechnologie, Germany) was inserted at the thoracic (T) T7 to T8 epidural space by an experienced anesthesiologist, before induction. In group E, before induction, the patient was placed in a left lateral decubitus position, and a high-frequency linear ultrasound transducer was placed in a longitudinal orientation, 3 cm lateral to the T5 spinous process. Three muscles superficial to the hyperechoic transverse process shadow were identified as follows: trapezius, rhomboid major, and erector spinae. Under ultrasound guidance, an 8-cm 22-gauge block needle was inserted in-plane in a caudad-to-cephalad direction, until the tip was laid on the surface of the transverse process. The correct needle tip position was confirmed by visualizing the linear fluid spread that separated the erector spinae muscle from the transverse process. Then, 30 mL of 0.375% ropivacaine was injected deep into the erector spinae muscle, and a thoracic epidural catheter was subsequently inserted. After confirmation and assessment of the sensory block to pinprick, general anesthesia induction was initiated.
General anesthesia was induced with propofol Target controlled infusion(TCI) (target plasma concentration was set at 4.0 µg ml− 1), remifentanil (0.2 µg kg− 1min− 1), sufentanil (0.2 µg kg− 1), and rocuronium bromide (0.6 mg kg− 1). Patients were intubated using a double-lumen tube to achieve lung isolation, and then correct positioning was confirmed by fibreoptic bronchoscopy. After induction, ropivacaine (0.1875%, 5 mL) was injected into the epidural space of the patients in group T every 5 minutes, a total of 3 times, and ropivacaine (0.1875%, 5 mL) was injected into the epidural space every hour during surgery. One-lung ventilation was initiated when the operation was started. Anaesthesia was maintained with sevoflurane (0.8 MAC). During the surgical procedure, 5 µg of sufentanil was administered intravenously in both groups to maintain the systolic BP changes within 20% of the baseline. This dose was repeated every 10 min until the blood pressure returned to the required limits. Rocuronium was administered as required.
All patients in three groups using the same electronic analgesia pump (AM380; ACE Medical Co. Ltd, Gyeoggi, Korea). In group C, the drugs used for PCIA were sufentanil (1µg/kg) and ramosetron (0.6 mg), which were diluted in 0.9% normal saline to a final volume of 250 mL. The analgesia pump settings were as follows: background dose, 0 mL/h; self-controlled additional dose, 4 mL/time; and lockout time, 6 minutes. In group T, the drugs administered for PCEA were ropivacaine (0.12%) and sufentanyl (0.6 µg/mL), diluted in 0.9% normal saline to a final volume of 250 mL. The analgesia pump settings were as follows: background dose, 3 mL/h; self-controlled additional dose, 4 mL/time; and lockout time, 10 minutes. In group E, the drugs administered for continuous ESPB analgesia was ropivacaine (0.2%) diluted in 0.9% normal saline to a final volume of 250 mL. The analgesia pump settings were as follows: background dose, 7 mL/h; self-controlled additional dose, 0 mL/time; and lockout time, 40 minutes. A PCIA pump (with settings same as for group C) was also used in group E to evaluate postoperative sufentanil consumption.
Intraoperative and postoperative sufentanil consumption in each group was recorded. During the preoperative preparation, patients were educated to evaluate their pain using the visual analog scale (VAS) with scores ranging from 0 to 10 (0 = no pain, 10 = worst pain), VAS scores at rest and during coughing immediately out of post-anaesthesia care unit (PACU), at postoperative 6h, 12h, and 24h, were recorded. Before the day of surgery, patients were asked by the investigators to complete the Quality of Recovery-15 (QoR-15) questionnaire as a measure of baseline (relatively healthy) status. They were then asked to again fill the questionnaire 24h postoperatively. Opioid-related adverse events after the operation, such as nausea and vomiting, dizziness, hypotension, pruritus, and respiratory symptoms, were also recorded.
Statistical analysis
The primary endpoint of this study was intraoperative sufentanil consumption. The secondary endpoints were postoperative sufentanil consumption; VAS scores at rest and during coughing immediately out of the PACU, at postoperative 6h, 12h, and 24h; QoR-15 at preoperative and postoperative 24h; and postoperative opioid-related adverse events.
Normality testing was conducted using the Kolmogorov–Smirnov test. All data were reported as mean (standard deviation [SD] ), median (inter-quartile range), or number (percentage) as appropriate. Normally distributed continuous variables were compared using the one-way analysis of variance (ANOVA). Non-normally distributed continuous variables were compared using the non-parametric Kruskal –Wallis test. Categorical variables were analyzed using the Chi-square test and Fisher’s exact test.
All data were processed using IBM SPSS Statistics 21.0 (IBM Inc., New York, NY). A two-sided p-value < 0.05 was considered statistically significant.
In a pilot study of 45 patients, the mean (SD) intraoperative sufentanil consumption was 38.0 (9.8), 23.0 (6.0), and 25.3 (6.0) in Groups C, T, and E, respectively. A sample size of 31 participants in each group was calculated using the one-way ANOVA to show a 20% difference in the mean intraoperative sufentanil consumption for an expected SD of 10, with a statistical power of 90% and an alpha error level of 0.05. To allow for attrition, the sample size was enlarged to 120.