Study Design
Patients scheduled for elective laparoscopic esophagectomy at the First Affiliated Hospital of Anhui Medical University (Anhui, China) were included in the study. The study protocol had received prior approval from the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 20190385), and this trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR1900026190). Before participation in the study, all patients provided informed consent.
Study Population
Patients with esophageal cancer in our hospital were considered for enrollment. The inclusion criteria were as follows: American Society of Anesthesiologists' (ASA) physical status I or II, requirement for OLV during operation, and 49–77 years old. Exclusion criteria were preexisting hypoxemia, diagnosed major obstructive or restrictive pulmonary disease [preoperative forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) <70% of the predicted value], pulmonary infection before surgery, body mass index (BMI) of less than 20 or more than 35, and use of immune modulators.
Randomization and Blinding
The randomized numbers were generated by a research coordinator using block sizes on a 1 : 1 ratio. This ensured that each group had an equal number of subjects. Then, the research coordinator sealed the numbers in opaque envelopes. During OLV, the anesthesia assistant opened the envelopes, set the breathing parameters and covered the breathing parameters using opaque paper. The anesthesia assistant did not participate in the next study. One anesthesiologist collected the specimens, and another anesthesiologist recorded the breathing parameters. Both physicians were blinded to the allocation.
Study Protocol
Standard monitoring devices were applied after admission to the operating room. Before induction of anesthesia, an artery catheter was inserted into the left radial artery. Anesthesia induction was performed with 2.0 mg/kg propofol, 0.05 mg/kg midazolam, 4 µg/kg sufentanil and 0.9 mg/kg rocuronium. A double-lumen endotracheal tube (Broncho-Cath® 35 F or 37 F; Covidien, Ireland) was inserted into the left main bronchus. Anesthesia was maintained with 6–8 mg/kg propofol, 0.1–0.3 µg/kg remifentanil per minute, and 5.0–10.0 µg/kg rocuronium per minute. A forced-air warming system (3M Company, Shanghai, China) was used to keep the patients warm.
After intubation, conventional two-lung ventilation (TLV) with a tidal volume of 8 mL/kg of ideal body weight (IBW) was performed for 15 minutes. Then, all patients were turned to the left lateral position, and OLV was initiated. During OLV, the patients were randomly divided into 2 groups. In the control group (group A), OLV with a routine tidal volume (Vt=8 mL/kg IBW) and volume-controlled ventilation mode was used. In the lung-protective ventilation group (group B), OLV with a low tidal volume (Vt=5 mL/kg IBW) and 5 cm H2O PEEP was chosen. With both TLV and OLV, mechanical ventilation was performed with an inspiratory to expiratory ratio of 1:2, 100% oxygen, and an I respiratory rate to maintain an end-tidal CO2 (ETCO2) of 35–40 mmHg.
Observational Indexes
Peak airway pressure (Ppeak), plateau airway pressure (Pplat) and blood gas analyses were evaluated at three stages: during TLV before surgery, 30 minutes after OLV and during TLV at the end of surgery. Furthermore, the driving pressure (ΔP) was recorded. ΔP was defined and calculated as follows: ΔP=Pplat–PEEP [16].
Bronchoalveolar lavage was performed after induction of general anesthesia and at the end of the surgical procedures. BALF was aspirated from the left lung after instillation of 10 mL of sterile isotonic saline. Then, the recovered BALF was centrifuged at 700 g for 10 minutes at 4°C, and the supernatant was stored at -80°C. The cell pellets were resuspended in ice-cold sterile isotonic saline for staining and counting.
Blood samples were obtained before induction of general anesthesia and at the end of the surgical procedures. Five milliliters of arterial blood samples was centrifuged at 800 g for 5 minutes. The upper plasma was separated and stored at -80°C.
MT, IL-18 and IL-1β concentrations in the plasma and BALF were determined by commercial ELISA kits (Cusabio, Wuhan, China). We performed the assays according to the manufacturer’s instructions. The limitations for MT, IL-18 and IL-1β were 0.1 pg/mL, 2.2 pg/mL and 7.8 pg/mL, respectively.
The primary outcomes were pulmonary complications, including pulmonary infection, acute lung injury or acute respiratory distress syndrome and reintubation or invasive mechanical ventilation. In addition, secondary outcomes, including anastomotic fistula, incision infection, ICU stay and death before hospital discharge, were recorded.
Statistical Aanalysis
According to previous studies, the cell numbers in the BALF increased more than 30% after OLV [5].We assumed that the cell numbers in the BALF increased at least 25% with a power of 80% and an α of 5%, and thus, 12–14 patients in each group were needed. Data are presented as the mean ± SD or number of patients. One-way ANOVA with a post hoc Bonferroni test was used to analyze normally distributed data. Non-normally distributed data were analyzed by chi-square tests. All statistical analyses were performed with SPSS 19, and a P value of <0.05 was considered significant.