This study was approved by the Institutional Review Board of Zhongshan Hospital, Fudan University (B2019-074R) and written informed consent was obtained from all individuals 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 the guidelines of the Consolidated Standards of Reporting Trials.
Study population
Patients aged 20–70 years, with an American Society of Anesthesiologists physical status (ASA PS) of 1 or 2 and a diagnosis of solitary pulmonary nodules without chronic pain or with no pain medications routinely used were deemed suitable to undergo 3-port single-intercostal VATS, as performed by surgeons. The exclusion criteria were 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 to one of three blocks, 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 were performed. In group T, the patients were 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, the patients were placed in a left lateral decubitus position before induction, 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 (AstraZeneca AB) 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, induction of general anesthesia was initiated.
General anesthesia was induced with propofol (Corden Pharma S.P.A) target-controlled infusion (TCI) (target plasma concentration was set at 4.0 μg/ml), remifentanil (Jiangsu Nhwa Pharmaceutical Co., Ltd) (0.2 μg/kg/min), sufentanil (Yichang Renfu Pharmaceutical Co. Ltd) (0.2 μg/kg), and rocuronium bromide (0.6 mg/kg). Patients were intubated using a double-lumen tube to achieve lung isolation; correct positioning was confirmed using fibreoptic bronchoscopy. After induction, ropivacaine (0.1875%, 5 mL) was injected into the epidural space of the patients in group T every 5 min for a total of three times; 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. Anesthesia was maintained with sevoflurane (Shanghai Hengrui Pharmaceutical Co., Ltd.) (0.8 MAC). During the surgical procedure, 5 μg of sufentanil was administered intravenously to both groups for maintaining systolic blood pressure 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 the three groups were administered the same electronic analgesia pump (AM380; ACE Medical Co. Ltd., Gyeoggi, Korea). In group C, the drugs used for PCIA were sufentanil (1 μg/kg) and ramosetron (Chongqing Lummy Pharmaceutical Co., Ltd.) (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 min. In group T, the drugs administered for PCEA were ropivacaine (0.12%) and sufentanil (0.6%), 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 min. In group E, the drugs administered for continuous ESPB analgesia were 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 min. A PCIA pump, with the same settings as for group C, was also used in group E to evaluate postoperative sufentanil consumption.
The intraoperative and postoperative sufentanil consumption in each group was recorded. During the preoperative preparation, patients were instructed to evaluate their pain using the following: visual analog scale (VAS), with scores ranging from 0 to 10 (0 = no pain, 10 = worst pain); and VAS scores at rest and during coughing immediately out of the post-anesthesia care unit (PACU) at 6 h, 12 h, and 24 h postoperatively. Before the day of surgery, the investigators asked patients to complete the Quality of Recovery-15 (QoR-15) questionnaire as a measure of baseline (relatively healthy) status. They were then asked to repeat the questionnaire 24 h postoperatively. Opioid-related adverse events, such as nausea, 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 the following: postoperative sufentanil consumption; VAS scores at rest and during coughing immediately out of the PACU at 6 h, 12 h, and 24 h postoperatively; QoR-15 at 24 h pre- and postoperatively; and postoperative opioid-related adverse events.
Normality testing was conducted using the Kolmogorov–Smirnov test. All data are reported as mean (standard deviation [SD]), median (inter-quartile range), or number (percentage), as appropriate. Normally distributed continuous variables were compared using a 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). Statistical significance was defined as a two-sided P-value < 0.05.
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 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 increased to 120.