Trial design and inclusion and exclusion criteria
This prospective, randomized clinical study was approved by the institutional ethics committee of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (2020080419244502), and registered in the Chinese Clinical Trial Registry (ChiCTR2100044060). Written informed consent was obtained from all patients. A total of 115 patients with lung cancer with an American Society of Anesthesiologists (ASA) physical status of I or II, aged 18 to 64 years old, who were selected for UVATS between March 2021 and July 2021 were recruited into this study (Fig. 1). All patients were able to communicate well and understood how to evaluate their pain score at rest or during coughing. The major exclusion criteria were as follows: infection at the site of injection for ultrasound-guided PVB or RLB; peripheral neuropathy; coagulation disorder; morbid obesity (body mass index (BMI) more than 40 kg/m2); allergy to ropivacaine; greater than first-degree heart block; hypertension; bradycardia (heart rate (HR) less than 60 beats per min); pregnancy; clinically significant cardiovascular, pulmonary, hepatic or renal disease; psychiatric illness that would interfere with the pain score assessment; and analgesic drug use within 1 week before surgery. During the preoperative interview, patients were taught how to evaluate their pain score using the numerical rating scale (NRS).
Randomization and block procedures
Before the study, every patient was trained on how to use the patient-controlled intravenous analgesia (PCIA) pump and instructed on using the NRS, with a score of 0 indicating no pain and a score of 10 indicating the worst imaginable pain. Upon arrival in the nerve block room, the patient was placed in a lateral decubitus position with the operative side up, and standard ASA monitoring, including five-lead electrocardiography and monitoring of the HR, respiratory rate (RR) and pulse oxygen saturation (SpO2), was applied. All patients received oxygen through a mask. Sedation and analgesia were provided by intravenous administration of midazolam (1 to 2 mg) and sufentanil (5 to 10 μg), which were titrated to patient comfort during the whole nerve block procedure. For all patients, a high-frequency linear ultrasound transducer (4–13 MHz, Esaote MyLab 25 Gold, Genoa, Italy) was used to identify the order of the laminae of thoracic vertebrae and paravertebral spaces. After confirmation of satisfactory ultrasound visualization of both potential block sites, patients were randomized using a computer-generated list and opaque, sealed envelopes to one of two treatment groups: (1) ultrasound-guided PVB (group P) or (2) ultrasound-guided RLB (group R). Patients were blinded to the treatment group allocation (Fig. 2).
Under ultrasound guidance, after a skin wheal was raised using 2 ml of 1% lidocaine, an 80-mm, 22-gauge block needle (Stimuplex® D Plus; B Braun, Melsungen, Germany) was inserted in-plane in a caudad-to-cephalad direction. In addition, 0.5% ropivacaine was injected at the appropriate level(s) after negative aspiration (15 mL for each level on the operative side) (Fig. 3). For both PVB and RLB, a two-level injection technique was performed at T3 and T5. The nerve block was considered successful if, within 30 min, the patient experienced decreased sensation to pinprick at least from the ipsilateral third to sixth thoracic dermatomes at the level of the anterior axillary line.
Intraoperative and postoperative management
General anesthesia was induced with 0.05 mg/kg midazolam, 1.5–2.5 mg/kg propofol, 0.2–0.4 μg/kg sufentanil and 0.6 mg/kg rocuronium. General anesthesia was maintained with desflurane, sufentanil and rocuronium. Intraoperative sufentanil was administered at the discretion of the blinded anesthesia team based on cardiovascular responsiveness to noxious stimuli in order to maintain systolic blood pressure within ±20% of baseline. When the patient’s systolic blood pressure increased by more than 20% from the baseline value, 0.1 μg/kg sufentanil was administered intravenously. After 10 min, if the systolic blood pressure was still higher than 120% of the baseline value, 0.1 μg/kg sufentanil was again administered intravenously. Ten minutes later, if the systolic blood pressure was still higher than 120% of baseline after two consecutive sufentanil boluses, 0.5 mg of nicardipine was administered until the systolic blood pressure decreased to baseline ±20%. During the operation, the velocity of fluid infusion was maintained at 6 mL/(kg.h).
After disinfecting the skin in the surgical area, a 5-cm-long incision in the fourth or fifth intercostal space at the anterior axillary line was made (Fig. 4). At the conclusion of the surgical procedure, a chest drain was placed at the edge of the incision (Fig. 4). At the end of the surgery, an intravenous analgesic pump was applied. The PCIA protocol was programmed with 2.5 μg/kg sufentanil diluted to 100 mL (bolus, 1.5 mL; lockout time interval, 10 min; 1 h limit, 9 mL without any baseline infusion). PCIA was administered when the NRS score was ≥4 or at the request of the patient. After surgery, patients were extubated, taken to the postanesthesia care unit (PACU) and received by a nurse anesthetist blinded to the randomization. In addition, a standard PACU care procedure was followed.
Outcomes
The primary outcome was the NRS score within the 48-h period after surgery. The intraoperative sufentanil consumption and total postoperative sufentanil consumption within the 48-h period were also recorded, along with the time at which the patient first required analgesics after nerve block. Before the nerve block procedure (baseline) and at 3 h, 6 h, 12 h, 24 h, 36 h and 48 h after surgery, the patient’s mean arterial pressure (MAP), HR, and NRS scores at rest and during coughing were all assessed. Adverse events, such as bradycardia (HR less than 60 beats per min), hypotension (systolic blood pressure less than 90 mmHg or more than 20% lower than baseline), hypoxemia (SpO2 less than 90%), respiratory depression (RR less than 10 breaths per min lasting for more than 10 min), pruritus, neurotoxicity, backache, nausea and vomiting, were recorded after surgery. Bradycardia was treated with intravenous boluses of 0.5 mg of atropine. Hypotension was treated with 6 mg of ephedrine and 6 ml/kg normal saline; the same doses were repeated as required. Hypoxemia was treated with inhalation of oxygen through a face mask. Respiratory depression was treated with naloxone and oxygen until the respiratory rate was greater than 15 breaths per min.
In addition, adverse events related to block procedures were recorded. Pneumothorax and/or hydropneumothorax were indicated when patients presented with dyspnea. Physical exam revealed notably decreased breathing sounds and hyperresonance to percussion of the ipsilateral chest [16, 17]. In addition, video-assisted thoracoscopy confirmed that local anesthetic liquid had been injected into the chest cavity. After the nerve block procedure, new symptoms, such as weakness, pain, tingling, paresthesia or numbness in the skin of the corresponding innervated area, indicated nerve injury. Thoracic nerve root pain is often described as burning or sharp, stemming from the back and traveling to other parts of the body connected to the damaged nerve. If the patient had the symptoms described above, further MRI scans or CT scans was performed [18,19,20]. In this study, bleeding complications included the occurrence of vascular puncture, active bleeding, or hematoma formation caused by paravertebral block or retrolaminar block [21]. Bleeding complications were identified when blood was drawn back into the syringe during the nerve block operation or a chest wall hematoma was observed under thoracoscopy. The criteria for nerve block-related superficial soft tissue infection were swelling along the needle placement track, local tenderness along the needle placement track, fever (> 38.0 °C), and leukocytosis (> 12/nl or C-reactive protein (CRP) > 20 mg/l) [22]. The criteria for nerve block-related abscess or deep tissue infection were evidence of an abscess or fluid collection consistent with an infectious process by imaging or surgical exploration within 30 days after peripheral nerve block needle placement, fever (> 38.0 °C), positive culture from surgical exploration or puncture, leukocytosis (> 12/nl or CRP > 20 mg/l), local tenderness, focal back pain, and neurological deficit [22].
Statistical analysis
The primary outcome was the pain score at rest within the 48-h period after surgery. In our preliminary study conducted in 10 adult patients (5 in each group), the mean NRS score at rest within the 48-h postoperative period was 2.0 ± 1.6 and 3.8 ± 1.9 in group P and group R, respectively. We hypothesized that ultrasound-guided PVB would reduce the NRS score compared with RLB. PASS version 11.0.7 (PASS, NCSS, LLC, USA) for Windows was used to calculate the sample size. Student’s t-test was selected, and the group allocation ratio was equal. The hypothesized means of the NRS scores were 2.0 and 3.8, and the standard deviations (SDs) were 1.6 and 1.9, respectively. Then, we calculated that a sample of 27 patients would provide 90% power at a two-sided alpha level of 0.05. Ultimately, we recruited 30 patients in each group for a total of 60 patients considering the possibility of dropout and loss to follow-up.
Continuous variables are presented as the mean ± SD or median (25th to 75th percentiles), and categorical data are presented as numbers and percentages. Normality was tested by Kolmogorov-Smirnov analysis. Student’s t-test or Mann-Whitney U test was used for analysis of the NRS score, intraoperative sufentanil consumption, total postoperative sufentanil consumption and duration of analgesia. For analysis of the MAP and HR data, repeated-measures ANOVA with Bonferroni correction was used. To analyze rescue flurbiprofen axetil, the incidence of adverse effects, Fisher’s exact test was used. All data were processed by IBM SPSS Statistics 21.0 (IBM, Inc., New York, NY). A 2-sided p value less than 0.05 was considered statistically significant.
