This single-center study was conducted by the Department of Anesthesiology, Peking University Hospital of Stomatology in Beijing, China. Ethics approval was received from the Biomedical Ethics Committee of Peking University Hospital of Stomatology (Number: PKUSSIRB-201734029) in December 2017. The trial is registered with the Chinese Clinical Trial Registry (Number: ChiCTR1800015347). This was a prospective trial with two parallel arms to test the hypothesis of whether maintenance of anesthesia with sevoflurane leads to fewer PPCs within 7 days compared to maintenance of anesthesia with propofol.
Randomization and blinding
Randomization was performed by an independent statistician, and random numbers generated by SAS 8.0 software were used to assign participants randomly (1:1) to either intravenous propofol or inhalational sevoflurane for maintenance of anesthesia. The codes were kept in sealed envelopes. Before surgery, these envelopes were provided to the attending anesthesiologist by a researcher not involved in patient care. Patients and surgeons did not know about the grouping during surgery and follow-up. In addition, the physicians who conducted follow-up examinations after surgery were blinded to the group allocation.
The study population comprised 220 patients between March 26, 2018, and March 25, 2019. Written informed consent was obtained before randomization from each patient. Patients with oral and maxillofacial cancer surgery were eligible for participation in the study if they were 19 to 79 years of age, were scheduled to undergo oral and maxillofacial cancer resection and free flap (fibula or forearm) reconstruction surgery with an expected duration of at least 4 h, and had a preoperative pulmonary complication risk index (Canet score) of 26 points or more. The Canet score is a risk score for pulmonary complications, with a score of 26-44 representing moderate risk and that of 45 or greater representing high risk. 13
Patients were ineligible if they refused to participate in the clinical trial or had a body mass index of 35 or higher, severe chest wall malformation, acute phase of chronic obstructive pulmonary disease (AECOPD), uncontrolled asthma (Asthma Control Test ≤ 18), 14 pulmonary artery stenosis, pulmonary hypertension and congestive heart failure, complex heart deformities, severe liver (Child-Pugh grade C) or kidney dysfunction (requirement of renal replacement therapy), or a history of mental illness.
All patients were managed according to the same anesthesia protocol. Routine hemodynamic monitoring (continuous 5-lead electrocardiogram, pulse oximetry, and noninvasive blood pressure), as well as the bispectral index (BIS) (Covidien, USA), was performed and cannulation of the dorsalis pedis for monitoring of invasive arterial pressure was completed immediately after anesthesia induction.
Anesthesia induction was carried out in both groups with 0.1 mg/kg penehyclidine hydrochloride, 0.05 mg/kg midazolam, 0.3 μg/kg sufentanil, 2 mg/kg propofol, and 0.6 mg/kg rocuronium. The parameters were volume-controlled ventilation, tidal volume (Vt) of 8 ml/kg (ideal weight), and fraction of inspiration O2 (FiO2) of 0.4–0.5; the respiratory rate was adjusted to maintain an end-tidal carbon dioxide concentration (ETCO2) between 35 and 45 mmHg.
In the propofol group, anesthesia was maintained by propofol as a target-controlled infusion (2 to 6 μ g /ml), while in the sevoflurane group, sevoflurane was applied with end-tidal concentrations of 2 to 5%. Analgesia was administered by applying target-controlled infusion of remifentanil up to 6 ng/ml and or boluses of sufentanil 0.2 to 0.5 μg/kg in accordance with patient needs. Muscle relaxation was achieved by intermittent injection of rocuronium bromide. The depth of anesthesia was to maintain a BIS between 40 and 60. In patients who underwent surgery for more than 4 h, cefuroxime sodium 1.5 g was used 30 min before surgery and for the fourth hour during surgery. At the end of surgery, whether the prophylactic tracheotomy is needed according to patient's range of tumor resection, repair method and neck mobility. All patients with endotracheal intubation or tracheotomy returned to the post-anesthesia care unit (PACU) after they showed spontaneous respiration.
Postoperative patients who underwent tracheotomy (decannulation on the fifth day) or endotracheal intubation (extubation the next morning) were observed for a night in the PACU. Low-flow supplemental oxygen and dexmedetomidine sedation (the dose of 1 μg/kg was pumped for 10 min, and then maintained at 0.3 μg/kg/h until the total dose reached 200 μg) were routinely provided. All patients were treated with intravenous patient-controlled analgesia (PCA) (48 h). The target was to maintain a Visual Analogue Scale (VAS) score of 3 or less. 15 A nonsteroidal anti-inflammatory drug (flurbiprofen axetil) was administered when considered necessary, and without contraindications. If there were no special circumstances, patients returned to the ward the next morning.
Patients in the ward inhaled hydrocortisone up to discharge (4 mg hydrocortisone + 100 ml normal saline, tid) and a vibrating sputum clearance device (TC Juhnson) was used until the sixth day after surgery. Patients with forearm flaps were treated with cefuroxime sodium (1.5 g bid) until the fifth day after surgery. Cefuroxime sodium (1.5 g bid) and ornidazole (0.5 g bid) were used up to 6 days for patients with fibula flaps after surgery.
The primary outcome was the difference in the occurrence of PPCs within the first 7 days after surgery between the two groups (tracheotomy and non-tracheotomy patients)
- The difference in the occurrence of PPCs between two groups of tracheotomy patients within the first 7 days after surgery
- The difference in the incidence of PPCs between two groups of non-tracheotomy patients within the first 7 days after surgery
- Main types and grading of PPCs
- The time to onset of PPCs (from the end of surgery to the first diagnosis of PPCs)
- The incidence of postoperative extrapulmonary complications, length of stay (LOS) in the hospital after surgery, and 30-day mortality.
Patient follow-up and outcome assessment
Patients were followed up once a day until postoperative day 7. PPCs were deﬁned as previously described: pulmonary infection, pleural effusion, atelectasis, pneumothorax, bronchospasm, pulmonary edema, pulmonary embolism, respiratory failure, and acute respiratory distress syndrome (ARDS).16,17 They were classified according to diagnostic criteria (Additional file 1) and assessed using the Clavien-Dindo classification, whereby grade 0 indicated no complication and grade V indicated death. PPCs of grade II or higher were used to calculate the incidence of PPCs (Additional file 2). The diagnosis of a PPC was made by the attending medical team (anesthesia, ICU, or respiratory medicine team). The physician who diagnosed PPCs considered physical examination results, conventional monitoring findings, laboratory results, X-ray findings, and others. All radiologic diagnoses were based on reports of attending radiologists not involved in the present study. Furthermore, surgical complications (vascular crisis or hematoma), extrapulmonary complications, hospital stay, and mortality at 30 days were also recorded. Cardiologic complications were defined as atrial fibrillation, cardiac failure, myocardial ischemia, and cardiac arrest. Hypotension was defined systolic blood pressure < 90 mmHg or a decrease of more than 30% from baseline. Hematoma or vascular crisis were defined as the need for urgent surgical re-exploration due to clinical evidence of vascular flap compromise or hematoma. Postoperative delirium (POD) was assessed with the confusion assessment method for the intensive care unit (CAM-ICU).18
The sample size was calculated based on previous studies. The incidence of PPCs after a free flap surgery in the propofol group was 26%, compared to 54% in the sevoflurane group. 2 Considering that clinical research mostly involves studies with a small sample, the power is increased as much as possible to increase the credibility of the results. Therefore, in this study, 95% power was considered. In order to detect differences, it was necessary to include 90 patients per group with an alpha risk of 2.5% and a beta risk of 5% in a two-tailed comparison. The ratio of the two groups was 1:1. Considering a dropout rate of about 20%, 110 pairs were enrolled.
Categorical variables were analyzed using the chi-squared test, continuity correction chi-squared test, or Fisher exact test based on sample size or frequency. The independent t-test was used for normally distributed continuous variables, and Mann-Whitney U test was used for non-parametric continuous variables. The relative risk and the 95% confidence interval of the differences were calculated for the primary outcome. Univariate logistic regression analysis was used to determine relevant baseline covariates associated with the primary outcome. If P values were less than 0.10 and were clinically relevant, then adjusted analyses were performed using a multivariate logistic regression model. Furthermore, the time to occurrence of the PPCs was compared using the Kaplan-Meier estimator, and the differences between groups were tested by the log-rank test. All analyses were performed using SPSS version 21.0. A two-sided P value of less than 0.05 was considered to indicate statistical significance.