We did this prospective, double-blind, randomized, placebo-controlled, single-center, clinical trial in the department of anesthesiology of Peking University Hospital of Stomatology, a tertiary academic hospital in Beijing, China. The ethics was approved by Peking University Hospital of Stomatology Biomedical Ethics Committee (Number: PKUSSIRB-201735060) on January 26, 2018. The trial was registered with Chinese Clinical Trial Registry, www.chictr.org.cn (Number: ChiCTR1800016153) on May 15, 2018. This manuscript reporting adhered to CONSORT guidelines.
Written informed consent was obtained from all participating patients or their next of kin or legal representative who must understand the recruiter’s description of the trial. The main aim of the study was to evaluate the supremacy of the intervention. Entitled patient were enlisted and arbitrarily designed to benefit one of the interventions, DEX or placebo (normal saline).
Randomization and blinding
A biostatistician from Peking University Third Hospital, who was independent of data management and statistical analyses, generated random numbers (in a 1:1 ratio) using the SAS 9.2 software (SAS Institute, Cary, NC, USA). The results of randomization were sealed in sequentially numbered envelopes. Throughout the survey period, enlisted patients were unpremeditated chosen to obtain DEX or placebo. A survey anesthesiologist, according to the arbitrarily series those not taking part in the survey applied the survey medicine.
The investigators, health-care team members (including the attending anesthesiologists, surgeons, nurses and the physicians for postoperative follow-up) and patients were blind to the treatment group assignment throughout the study period. In case of emergency, (such as development of severe adverse events, persistent hemodynamic instability or rapid deterioration of the patient’s clinical status), the attending anesthesiologist could request to unmask the allocation, and adjust or even stop study drug infusion if necessary. These non-blind situations were documented, but the final analyses were performed on the intention-to-treat population.
Patients were included if they (1) were scheduled for oral and maxillofacial surgery with fibular free flap reconstruction that was expected to exceed 3 h under general anesthesia, (2) were 51 years old or over, (3) took tracheotomy before the end of the surgery, (4) had an intermediate to high risk of developing PPCs judged by Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score (cumulative ARISCAT risk score were 26 or greater) (Additional file 1).
Patients were excluded if they met the following criteria: (1) body mass index of 35 or higher, (2) allergic to DEX, (3) recent sedatives-taking history, (4) sick sinus syndrome, or severe sinus bradycardia(< 50 beats per min[bpm]), or second degree or greater atrioventricular block without pacemaker, (5) previous lung surgery history, or severe chest wall malformation, or acute exacerbation of chronic obstructive pulmonary disease (AECOPD), or uncontrolled asthma (Asthma control test ≤18), or pulmonary artery stenosis, or pulmonary hypertension, (6) complex heart deformities, congestive heart failure, or known preoperative left ventricular ejection fraction less than 30%, (7) serious hepatic dysfunction(Child-Pugh class C), or serious renal dysfunction(requirement of renal replacement therapy), (8) a history of mental illness, (9) refused to participate in the clinical trial.
Interventions, anesthesia and perioperative management
The study drug DEX, dexmedetomidine hydrochloride injection 2 ml: 0.2 mg (manufactured by Yangtze River Pharmaceutical (Group) Co., Ltd., Jiangsu, China), was diluted with normal saline to 50 mL (the final concentration of DEX was 4 μg/mL) by a nurse, who did not participate in the rest of the study, before administration. The study drug (diluted DEX) and placebo drug(normal saline)were all provided as clear aqueous solution in the same 50 ml injection syringes and dispensed according to the randomization results. The two drugs were given as an initial dose of 0.1 ml/kg (0.4 μg/kg of DEX in the treatment group) over 10 min followed by a maintenance dose of 0.1 ml/kg/h (0.4 μg/kg/h of DEX in the treatment group) from the beginning of anesthesia induction on the day of surgery until 0600 h on the first day after surgery.
All patients followed the similar anesthesia and perioperative management regimen. Half an hour before the beginning of the surgery, prophylactic antibiotics (mostly cefuroxime 1.5 g, the second-generation cephalosporin) were routinely administered and apply once more at the fourth hour within the operation time when the surgery time was longer than 4 hours. After surgery, routine antibiotics with cefuroxime 1.5 g twice a day and ornidazole 0.5 g twice a day for 6 days were administered. The choice and the duration of antibiotics treatment were decided according to the Guiding Principles of Clinical Use of Antibiotics (2015 edition) which was published by Chinese National Health and Family Planning Commission in 2015.
Perioperative monitoring included continuous 5-lead electrocardiogram, pulse oxygen saturation, noninvasive blood pressure, Train-of-Four ratio (TOF, T4/T1) for measuring the level of neuromuscular blockade, Bispectral Index (BIS) (Covidien, USA) value, end-tidal carbon dioxide concentration (EtCO2), airway pressure, axillary temperature, urine output. Intra-arterial pressure was also monitored through cannulation of the arteria dorsalis pedis (on the opposite of the surgical leg) immediately after anesthesia induction.
All patients were performed general anesthesia with nasotracheal intubation. Anesthesia was induced in both groups with 0.05 mg/kg midazolam, 0.3 μg/kg sufentanil, 2 mg/kg propofol, and 0.6 mg/kg rocuronium, and maintained with target-controlled infusion (TCI) of propofol (2 to 6 μg/ml plasma concentration) and remifentanil (0.5 to 6 ng/ml plasma concentration), without inhalational sevoflurane and nitrous oxide. During operation, in accordance with hemodynamic state, surgical steps and TOF ratio, additional analgesia was administered by applying boluses of sufentanil 0.1 to 0.5 μg/kg and muscle relaxation was achieved by intermittent injection of rocuronium 10 mg each time. BIS value was maintained between 40 and 60.
Volume-controlled mechanical ventilation was established with the fraction of inspiration O2 (FiO2) from 0.4 to 0.6, the tidal volume from 6 to 8 ml/kg (ideal weight), the positive end-expiratory pressure (PEEP) 5 cm H2O. The respiratory rate was adjusted to maintain EtCO2 between 35 and 45 mmHg.
Fluid management was performed according to routine practice with crystalloids - sodium lactate ringer’s injection and/or colloids - 6% hydroxyethyl starch (HES) 130/0.4 sodium injection. Packed red blood cells were transfused while the hemoglobin level was lower than 7 g/dl.
Before the end of the surgery, all patients underwent tracheotomy after spontaneous breathing recovery (TOF ratio > 0.9). After surgery, all patients were transferred to the postoperative care unit (PACU) and supervised until 0830 h on the first day after surgery before sent back to the general wards.
During the postoperative period, intravenous patient-controlled analgesia with sufentanil 1.0 ~ 1.5 μg/kg and tropisetron 10 mg was provided for up to 48 h. All patients were given aerosol inhalation with ambroxol 60 mg and hydrocortisone 4 mg three times a day before discharge and mechanical vibration sputum expectoration (TC Juhnson) three times a day for 5 days. Usually on the fifth day after surgery, the tracheostomy tube was removed after the oral and maxillofacial surgeons evaluating the situation of the airway and operation area. Other treatments including early mobilization (routinely on the fourth postoperative day), anticoagulant therapy (routinely 5 days, with aspirin or low molecular heparin), enteral and parenteral nutrition were administered according to routine practice.
The adverse events (bradycardia and hypotension) were monitored and documented throughout the period of study drug infusion. Bradycardia was defined as heart rate less than 50 beats/min or a decrease of more than 20% from baseline. Hypotension was defined as systolic blood pressure less than 90 mmHg or a decrease of more than 20% from baseline. Intervention for bradycardia included administration of medication (atropine mostly) or adjustment of study drug infusion, or both. Intervention for hypotension included intravenous fluid bolus, or administration of vasoactive drugs (ephedrine, methoxamine, etc.) or adjustment of study drug infusion. All interventions were recorded.
The postoperative daily follow-up period was 7 days. Research members who were trained before the study and not involved in the clinical care of patients did the outcome assessment.
The primary outcome was the incidence of PPCs within 7 days after surgery. PPCs was defined as any preselected complication occurred, which included respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, aspiration pneumonitis, pulmonary edema, pulmonary embolism, and acute respiratory distress syndrome. The diagnostic criteria of each individual PPCs were similar with those used in the previous studies [1,2,3](Additional file 2). We chose the Clavien-Dindo Classification  to categorize PPCs into five major groups (Additional file 3). In our study, PPCs of grade II or above were considered to calculate the incidence of PPCs. The diagnosis of PPCs was made by the attending medical team (anesthesiologists, Intensive Care Union physicians, or respiratory physicians). The physicians diagnosed PPCs according to patients’ medical history, clinical physical examination, conventional monitoring value, laboratory results, image examination, and so on. If a PPC occurred, the date of earliest diagnosis and the evidences according to which the diagnosis was made were documented.
The secondary outcomes were as follows: (1) the time to first diagnosis of PPCs - indicated the time from end of surgery to first diagnosis of PPCs within 7 days after surgery; (2) the number of PPCs - indicated the number of diagnosed individual PPCs within 7 days after surgery; (3)the dose-effect relationship between DEX and PPCs; (4) the incidence of postoperative extrapulmonary complications - defined as complications other than PPCs that occur during operation and within 7 days after surgery, and require therapeutic intervention, included delirium – assessed by the Confusion Assessment Method for the ICU (CAM-ICU) , anemia - defined as hemoglobin less than 9 g/dL, extrapulmonary infection; (5) the unexpected need for secondary surgery (hematoma or vascular crisis exploration); (6) the adverse events (bradycardia, hypotension) during the period of study drug infusion; (7) length of stay in hospital after surgery; (8) 30-day all-cause mortality.
Sample size and statistical methods
We used the excellent effect test of two groups of independent sample rate to calculate the sample size. According to the literature data , the sample size was calculated according to the incidence of postoperative pulmonary complications. The incidence was 3.89% in the experimental group (DEX group) and 17.99% in the control group. The class I error of hypothesis test was 0.025, the class II error was 0.2, and the proportion of sample size between the test group and the control group was 1:1. The sample size was calculated by Stata 10.0 software According to the bilateral test formula of sample size: n = 2 × (U α + U β) 2 × P (1-P) / δ 2, δ was set to 0.01. The sample size of the test group was 64 and that of the control group was 64. Taking into account the dropout rate of 20%, each group requires a sample size of 76.8, so we planned to enroll 160 patients (80 for each group) in all.
We analysed outcome data and safety in the intention-to-treat population. Statistical analyses were performed on SPSS version 24.0 software (SPSS, Chicago, IL, USA) and P values less than 0.05 were considered to be of statistical significance. Statistical description was provided for baseline data such as demographic variables, medical history, perioperative medications, and perioperative management. For primary outcome (the incidence of PPCs with 7 days after surgery), the effect of the intervention was reported as number and percentage and estimated with relative risk and 95% confidence interval and the χ2 test for hypothesis testing. For secondary outcomes, continuous variables with normal distribution were analyzed using an unpaired t test; continuous variables with abnormal distribution or ranked data were analyzed by Mann-Whitney U test; categorical variables were analysed with the χ2 test, continuity correction χ2 test or Fisher exact test. Time-to-event results were calculated with the Kaplan-Meier estimator, and the differences between groups were assessed by the log-rank test. And, Cox regression was used for survival analysis. For dose-effect relationship, receiver operating characteristic (ROC) curve was used for calculating the P and cutoff values.