The study was approved by the Medical Ethics Committee of the Affiliated Hospital of Qingdao University and was performed between May 2018 and Sep 2018. Informed written consent was signed by every patient prior to enrollment in this study. Our study was registered with Chinese Clinical Trial Registry (ChiCTR1800016379). All study procedures were completed at the affiliated hospital of Qingdao university, a tertiary care, teaching hospital located in Qingdao, China. The surgical procedures performed included VATS lobectomy and systematic mediastinal lymphadenectomy.
The inclusion criteria included the following: patients with lung tumors who were undergoing VATS lobectomy, aged 18-70 years, of both genders, American Society of Anesthesiologists physiological statusⅠto Ⅲ. The exclusion criteria were used: body mass index ≥30 kg/m2, anatomical abnormalities of the thoracic spine identified by chest computed tomography, spontaneous pneumothorax in the medical history, known allergy or hypersensitivity against amino-amide local anesthetics (LA), use of nonsteroidal anti-inflammatory drugs 2 weeks before surgery, coagulopathies in the medical history. Seventy-five patients scheduled for VATS lobectomy completed. 54 patients undergoing elective VATS lobectomy were randomized by computer to either PVB/GA (n=27) or GA (n=27). Two PVB patients who was with failed PVB and converted to open surgery did not participate in the final analysis. Three GA patients dropped out after randomization. We finally analyzed patients undergoing PVB/GA (n=25) or GA (n=24) .Perioperative data were collected by anesthesia personnel (residents, nurse anesthetists and attendings).
Thoracic paravertebral block technique
We performed ultrasound-guided two-shot paravertebral blocks with 20 ml of 0.375% ropivacaine (AstraZeneca AB, PS05070, Sweden) at the thoracic interspace T4-5 and T7-8. We used long-axis (transverse approach) in-plane techniques for thoracic paravertebral nerve block. Using the ultrasound system (SonoSite M-Turbo, SonoSite Inc., Bothell, WA) to determine the thoracic paravertebral space (TPVS) of T4 and T7 levels in the lateral position, we visualized that the needle tip (Stimuplex D Plus, 0.71 × 80 mm, 22G × 3 ⅛,” B.Braun Melsungen AG, Germany) was between the superior costotransverse ligament and the pleura and placed it inside the TPVS, 20 ml of 0.375% ropivacaine (each injection point) was administered after negative aspiration under direct ultrasound imaging .
Intraoperative and postoperative management
On the day of surgery, investigators generated the randomization sequence using a computerized program. The allocation was concealed until shortly before anesthesia. An anesthesiologist who was not involved in this study placed the assignment numbers in opaque sealed envelopes to conceal the randomization sequence. All cases were allocated at random to one of two group: a control group (group GA), receiving general anesthesia and postoperative patient-controlled intravenous analgesia (PCIA), and a treatment group (group PVB), receiving thoracic paravertebral anesthesia combined general anesthesia and postoperative PCIA. Medical Ethics Committee approval and written informed consent were obtained. All patients were conducted by same anesthesiologist who had considerable prior experience with use of PVB.
In both groups, induction of anesthesia was performed with propofol (1-2 mg/kg), sufentanil (0.4-0.5μg/kg), and cisatracurium (0.15-0.2 mg/kg) for muscle paralysis. After tracheal intubation, maintenance of anesthesia was performed with sevoflurane (1%) in a mixed oxygen/air fresh gas, and cisatracurium as needed in both groups. Analgesia was assured by the ropivacaine solution (0.375%) in the PVB group and by sufentanil as needed in the GA group.
Flurbiprofen 50 mg was intravenous injection at 30 minutes before the end of surgery in the both groups. When the surgery is finished, all patients were transferred to the postanesthesia care unit (PACU). All patients who were awake were connected with the PCIA pump with sufentanil and ondansetron. Sufentanil was inserted with 1-2μg/h. A bolus of 2 mL was allowed at every 15 minutes up to a maximal dose of 10μg/h.
All patients were treated with IV flurbiprofen in 50-100 mg increments for a Visual Analog Scale (VAS) score of 4/10 or greater or patient request for analgesia. Patients were monitored in the PACU until they met discharge criteria.
Our primary end point was pain scores at rest and on cough. A VAS was used to assess pain intensity at 1, 4, 24 and 48 h after completion of surgery. The secondary outcomes were plasma concentrations of MMP-9, postoperative complications and postoperative hospital stay. Postoperative complications including pneumonia, atelectasis, air leak, atrial fibrillation, hypotension and postoperative nausea and vomiting (PONV).
Blood samples were obtained 10 min before anesthesia (T0), at the end of surgery (T1), and at 12 h after operation (T2). Blood was collected into EDTA tubes and centrifuged at 4000 g for 15 min at 4℃ immediately after sampling. Thereafter, plasma was stored at -70℃ until all the samples were collected. Plasma concentrations of MMP-9 were measured with commercially quantitative sandwich ELISA kits (Wuhan USCN Business Co., Ltd, Wuhan, China). Standards were prepared, and the appropriate volume of sample or standard was added to a 96-well polystyrene microtitre plate, and incubated for 1hr at 37℃. Unbound material was removed. Detection Reagent A (biotin-conjugated antibody specific to target protein) was added to each well, and the incubation was continued for 37℃. After washing with wash buffer 3 times, Detection Reagent B (avidin conjugated HRP) was added to each well, and the incubation was continued for 0.5 hr at 37℃. After washing with wash buffer 5 times, TMB substrate was added to each well, and the incubation was continued for 10-20 mins at 37℃. Once 50μl stop solution was added to each well, and the absorbance at 450 nm was measured.
Seven known concentrations, ranging from 0.156 to 10 ng/ml was measured for MMP-9. Samples values was used for further statistical analysis. The concentration of target protein in the samples is then determined by comparing the O.D. of the sample to the standard curve.
Demographic information (age, sex, body mass index, and the American Society of Anesthesiologists grade) and pertinent surgical information (operation time, estimated blood loss, type of surgery, histology and stage of tumor) were recorded.
Prospectively collected data included pain scores at 1, 4, 24 and 48 h after completion of surgery, complications (pneumonia, atelectasis, air leak, atrial fibrillation, hypotension, PONV), and length of stay. Both groups received PCA using a mixture of 1μg/mL sufentanil and 0.08mg/mL ondansetron with the pump set to deliver doses of 1-2μg/h intravenous sufentanil with a 15-min lockout time. If the VAS score is greater than 3, 50-100 mg of flurbiprofen was injected intravenously. Nausea and vomiting were treated with intravenous 8 mg ondansetron. Ambulation early after VATS lobectomy was a postoperative ERAS element. The patients were made to walk along the bedside, if possible, walk around the ward always accompanied by family member and the nursing staff on the following day after surgery. Oral liquid on the first day after surgery, and a semi-liquid diet after flatus passage were started at postoperative day 1. The early postoperative intake of solids was initiated at postoperative passage of flatus. All patients were subjected to enforced early mobilization. Perioperative management was similar in both groups.
The sample size calculation was based on mean VAS scores (2.53±0.83) from our hospital in the pilot study. To have a greater than 90% power with an overall 2-sided typeⅠerror rate of 5%, and consider withdrawal and loss of follow-up (cases of 10%), at least 22 patients were required in each group.
Continuous variables were expressed as the mean (± 1 standard deviation) or median (95 % confidence interval (CI)) when data were not normally distributed and were compared between the two groups using the Mann-Whitney U test. P < 0.05 was considered significant for all data. Data were analyzed by use of the statistical package for the social sciences (SPSS 23.0).