Patients intubated for less than 24 h in the respiratory ICU and aged 18 years or older were eligible for this trial if they had an estimated survival time > 2 weeks. Patients were excluded if they had: ventilation parameters with positive end-expiratory pressure (PEEP) > 10 cmH2O or fraction of inspired oxygen (FiO2) > 0.8; hemodynamic instability; history of severe pulmonary bullae with pneumothorax; positive cuff leak test, which means patients with upper airway obstruction, it is difficult to push the secretion up to the oropharynx [14, 15] or had been included in other clinical studies. During the study, patients that were withdrawn from mechanical ventilation after less than 72 h, or those whom refused treatment were also excluded.
Trial design and randomization
This was a prospective, single-center, randomized, clinical control trial conducted in the Respiratory ICU at Beijing Chao-Yang Hospital, Capital Medical University (ClinicalTrials.gov, NCT02032849). This study was approved by the Ethics Committee of Beijing Chao-Yang Hospital (2014-KE-106) and informed consent was obtained from the patients or their surrogates.
Randomization was performed using random numbers generated by the random number generator in the SPSS 23.0 statistical software (IBM Corp., Armonk, NY, USA). The enrolled patients (n = 241) were randomly assigned to either the RFEM group (n = 120) or the SSD group (n = 121). Allocation concealment was conducted using sequentially numbered opaque sealed envelopes. This was an unblinded trial because the physicians were aware of the treatment assigned to every participant. However, during the entire study period, the endpoint judgement and the statisticians were blinded.
All patients enrolled in this study underwent endotracheal intubation along with a subglottic suctioning catheter (TaperGuard™ Evac Oral Tracheal Tube; Medtronic, USA). Clearance of subglottic secretions was performed every 6 h, and the secretion amounts were recorded.
Rapid-flow expulsion maneuver (RFEM)
A manual resuscitator was attached to endotracheal tube and the cuff deflated during the initiation of exhalation, the rapid flow produced by the manual resuscitator passing the space around the deflated cuff was used to remove subglottic secretions to the oropharynx. The operational procedure is completed by two operators (respiratory therapists or ICU nurses), described in Additional file 1: S1, and Additional file 2: Video S1 showed how RFEM works.
Subglottic secretion drainage (SSD)
A pressure of − 100 mmHg with a 15-s duration was applied through a subglottic secretion drainage catheter connected to the sputum collector to carefully suction oral and tracheal secretions while subjects were placed in a semi-recumbent position . If the catheter became blocked, 5 ml of normal saline was instilled through the drainage lumen to maintain its patency .
Data collection, quality control and VAP prevention-bundle
After informed consent was obtained from the study patients or surrogates, baseline data were recorded: age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score at ICU admission, comorbidities, causes of tracheal intubation and laboratory examinations. Ventilator parameters were also recorded at randomization.
Daily data for a VAP-monitoring form were recorded for each enrolled patient and checked by five respiratory therapists. The diagnosis of VAP was initially made according to the VAP diagnostic criteria (Additional file 1: S2) by two blindly assigned ICU physicians. If the results were inconsistent, a microbiologist would participate to establish the diagnosis. Clinical data were recorded on paper case record forms then double-entered into an electronic database and validated by the trial staff.
Other measures were taken to prevent VAP in the two groups, including raising the head of the bed, oral care using chlorhexidine, rational use of sedative and analgesic drugs, maintenance of cuff pressure within 25–30 cmH2O, replacement of ventilator tubes only when visible stains or failure occurred, early limb rehabilitation exercise, and daily evaluation of extubation.
The incidence of VAP was the primary endpoint of the study. Patients enrolled in the study were followed-up prospectively for the occurrence of VAP until they received a tracheotomy, were successfully weaned from mechanical ventilation, discharged from the hospital, or died. The per protocol population contains patients who had PEEP below 10 cmH2O or FiO2 below 0.8 at study randomization. These patients were included in the intention-to-treat analysis.
The secondary endpoints included, mechanical ventilation duration, time from intubation to VAP, length of and cost of ICU stay, and mortality while in ICU. The daily volume of subglottic secretions cleared and the need for tracheotomy and reintubation were also recorded.
The safety of RFEM was assessed by recording episodes of pneumothorax, unplanned extubation and changes in vital signs during the maneuver process. Incidence of the post-extubation laryngeal dyspnea in both groups was also evaluated as a safety factor.
Sample size calculation
The primary endpoint was evaluated using a non-inferiority analysis. Sample sizes of 120 participants per group achieve 80% power to detect a non-inferiority margin difference between the group proportions of 0.10, with a one-sided test significance level of 0.05, and a loss to follow-up rate of 10%. Based on the incidence rates of VAP in patients requiring mechanical ventilation in our ICU prior to this study and the results of previous studies [17,18,19], the SSD group proportion is 15%, and the RFEM group proportion is 16.7%.
SPSS 23.0 software (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The level of significance for all statistical tests was 0.05 (two-tailed). The measurement data were presented as means ± SD (standard deviations) or medians and quartile distribution (skewed distribution). Differences between groups were analyzed using the analysis of variance or nonparametric test (skewed distribution). Count data were presented as frequencies and percentages, and differences between groups were tested using the χ2 test or Fisher’s exact test. VAP-free survival curves in the two groups were displayed graphically according to the Kaplan–Meier method and analyzed using the log-rank test. Univariate and multivariate logistic regression was used to analyze the risk factors for the prevalence of VAP.