Ethics approval and consent to participate
This study was approved by the Institutional Ethics Committee of Zhoushan Hospital (Ref. 2017–008) and was registered in the Chinese Clinical Trial Registry (ChiCTR-IPR-17011249) on April 27, 2017. Our study adhered to CONSORT guidelines. Written consents to participate were obtained from all participants after enrollment.
Clinical trial course
From April to August 2017, we screened all patients scheduled for thoracoscopic lobectomy for clinical stage I or II NSCLC. The inclusion criteria for participants of this study were aged 18 to 75 years, with an American Society of Anesthesiologists physical status of I or II. The exclusion criteria of this study were severe pulmonary dysfunction or difficulty intubation of double-lumen tube (DLT).
Patients were randomly allocated to two groups (1:1) based on computer-generated random numbers. Allocation details were sealed in sequentially numbered opaque envelopes. All patients, surgeons and research staff performing follow-up were fully blinded to group allocation. The anesthetists were not blinded and were not involved in study follow-up.
To avoid interference with the trial intervention, we used a standardized perioperative management protocol (including thoracic anesthesia, fluid management, surgical approach, and postoperative care). No patients received premedication. All patients were fasted 6 h to solids and 2 h to clear liquids. In the operating room, a radial arterial line was inserted for measuring the arterial pressure and sampling the arterial blood gas. For induction, patients received midazolam (0.05 mg/kg), sufentanil (5 μg/kg), propofol (1.5 mg/kg), and cisatracurium (0.2 mg/kg). After induction, an appropriate size of DLT was intubated, and the correct position of DLT was confirmed by fiberoptic bronchoscope in both supine and lateral positions. The fraction of inspired oxygen (FiO2) was initially set at 60%, and in cases of saturation of pulse oxygenation (SpO2) less than 92%, FiO2 was increased to 100%. Anesthesia was maintained with 1.0 to 2.5% sevoflurane, remifentanil, and cisatracurium. The protocol for ventilation was as follows: tidal volume of 8 ml/kg per ideal body weight during two-lung ventilation (TLV) and 6 ml/kg per ideal body weight during OLV, and respiratory rate of 12/min without positive end-expiratory pressure. All patients received 4 mL/kg/h Ringer’s lactate solution throughout the intraoperative period. In the postoperative period, maintenance fluids (2 mL/kg/h) were continued until patients were able to tolerate adequate oral intake. All operations were performed by an experienced thoracic surgical team specialized in video-assisted thoracoscopic surgery. At the end of the surgery, the tracheal tube was removed, and patients were transferred to the postanesthesia care unit. Ultrasound-guided unilateral thoracic paravertebral nerve block (T5–6 and T6–7) was used by injecting 10 mL of ropivacaine 0.25% for postoperative analgesia. All patients received additional analgesic treatment with paracetamol 1 g 4 times daily.
In the HPC group (n = 38), HPC was applied after confirmation of the DLT position in the correct positions and before incision. HPC was applied on the nondependent lung by intermittent ventilation. Three cycles were performed, each consisting of 5-min of no ventilation and opening to atmosphere followed by 3-min of ventilation. The protocol for ventilation was as follows: tidal volume of 6 ml/kg per ideal body weight, respiratory rate of 12/min, FiO2 of 60%, sevoflurane of 1.5% and intermittent two-lung ventilation when SpO2 < 92%. The non-operated lung received continuous ventilation. In the control group (n = 38), patients received TLV after confirmation of the DLT position and before incision.
The primary outcome was lung oxygenation expressed by the PaO2/FiO2 ratio. Secondary outcomes included the following: intraoperative adverse events, pulmonary function, postoperative pulmonary complications, and duration of hospital stay.
Arterial blood gases were evaluated at 30 min after OLV and at 7 day after surgery. The occurrence of intraoperative adverse events, such as tachycardia, bradycardia, hypotension, hypertension, and oxygen desaturation were recorded by the clinical anesthesiologists. Hypotension and bradycardia were defined as a decrease from baseline value by 20%. Hypertension and tachycardia were defined as an increase from baseline value by 20%. Oxygen desaturation was defined as a SpO2 value of < 92%. We used a portable spirometer (Spirobank, GTM, Medical International Research, Rome, Italy) to measure the pulmonary function of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) before surgery and repeated this measurement at 7 day after surgery. Every pulmonary function test was performed three times with the patient in a semirecumbent position, and the average value was recorded. Postoperative pulmonary complications were defined as pneumonia, atelectasis, pleural effusions, and prolonged air leak > 7 days. The duration of hospital stay was counted from the day of operation to the day of discharge.
Sample size calculation was based on the primary outcome of the PaO2/FiO2 ratio. A previous study showed that the means ± standard deviation (SD) value of PaO2/FiO2 during OLV was 192 ± 67 mmHg . Our hypothesis was that the HPC would improve the PaO2/FiO2 ratio by 25%. Assuming a power of 80% and a level of significance of 0.05, it was estimated that 31 patients would be required for each group. To account for a 10% dropout rate, we included 35 patients in each group.
Statistical analyses were conducted using the SPSS 20.0 statistical software (IBM Corporation, Armonk, NY, USA). Quantitative data were expressed in the means ± SD or medians (interquartile range, IQR) and compared with independent t-test or Mann-Whitney U test, respectively. Categorical data were expressed as a frequency or percentage and compared with the Fisher’s exact test or the chi-square test. Variables with repeated measures were analyzed using a linear mixed model with a patient indicator as a random effect and group, time, and group-by-time as fixed effects. P values less than 0.05 were considered to be statistically significant.