This was a prospective, randomized controlled trial performed at the endoscopy center, First Medical Center of Chinese PLA General Hospital. This study was approved by the Ethical Committee of Chinese PLA General Hospital (#2019-088-01), and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry (ChiCTR1900023151, Principal investigator: Changsheng Zhang, Date of registration: May 14th, 2019). This manuscript adheres to the applicable CONSORT guidelines.
Study population
From Jun. 1st, 2019 to Aug. 1st, 2019, 60 patients aged 20-65 years were enrolled in this study. Inclusion criteria included patients meeting criteria for American Society of Anesthesiology (ASA) Class I or II who were scheduled for endoscopic submucosal dissection (ESD) or peroral endoscopic myotomy (POEM) under general anesthesia. Patients were excluded if they had one or more of the following criteria: a history of asthma, known allergy to study drugs, anticipated difficult intubation, history of documented chronic organ failure, hypertension, ischemic heart disease, atrioventricular block, incomplete or partial heart blocks, application of vasoactive drugs perioperatively.
Study procedures
Patients were randomly allocated to the standard awake intubation care group (Group S-AIC) or novel awake intubation care group (Group N-AIC) in a double-blind fashion based on a computer-generated code. The anesthesiologists participating in this study had at least five years of experience as attending physicians at our institution. In this study, topical anesthesia administration to the upper airway was performed alone by an anesthesia nurse to ensure that the anesthesiologist, the clinical investigator, and the data analyst were all blinded to the study grouping.
After arriving in the operation room, venous access was obtained with an 18-gauge cannula placed in the left forearm. Electrocardiogram, pulse oximetry, and noninvasive blood pressure (cuff placed on the right upper arm) were continuously monitored. The standard of care for awake intubation at our institution is to perform topical anesthesia using tetracaine sprays of both the oropharyngeal mucosa and the tracheal mucosa based on a sedation index (Bispectral index [BIS] values between 80-85). The patient is then intubated with a laryngoscope, rigid laryngoscope, or fiberoptic scope. Thus, in Group S-AIC, moderate sedation of the patient was provided with intravenous midazolam (0.03 mg/kg) and fentanyl (2 μg/kg) boluses. After adequate sedation was achieved, patients received oropharyngeal tetracaine (Chengdu Tiantaishan Pharmaceutical Co., Ltd, China) spray three times every two minutes (See supplemental video). First, the soft palate was sprayed. Then, the radix linguae were sprayed while the patient was instructed to pronounce ha. Finally, the epiglottis was sprayed with the guidance of delicate video laryngoscopy. The total volume of tetracaine (1%) used for oropharyngeal spray was 0.5ml. In Group N-AIC, patients received oral administration of dyclonine hydrochloride mucilage (10 mg/10ml, Yangtze River Pharmaceutical Co. Ltd, China) for topical anesthesia of the oropharyngeal mucosa using the same sedation index. The first 2 ml were slowly swallowed as a test-dose to rule out possible allergic reaction. After two minutes, the remaining 8ml were administered and kept in the oropharynx for three minutes before swallowing.
The degree of oropharynx mucosal numbness was evaluated two minutes after both study procedures. After obtaining adequate pharyngeal anesthesia, needle cricothyroidotomy was performed in both groups, and 2 ml of tetracaine (2%) were injected to provide topical anesthesia of the subglottic tracheal mucosa. Three minutes later, all patients were instructed to swallow all the secretions and drug residues in the mouth and were intubated with a video laryngoscope while spontaneously breathing. The total time and number of attempted intubations were recorded.
After tube insertion, a cuff pressure between 24 and 28 cm H2O was maintained using an aneroid manometer to provide an adequate seal of the airway. Patients were instructed to place themselves in the left lateral position with the tube in place. General anesthesia induction was achieved by initiating target-controlled infusion (TCI) of propofol (Marsh model, target effect-site concentration of 2-4 μg/kg·min) and remifentanil (Minto model, target effect-site concentration of 3-4 ng/kg·min). The propofol and remifentanil targets were adjusted to maintain target BIS values between 40-60 during the entire procedure. All patients were mechanically ventilated to maintain end-tidal CO2 (EtCO2) between 32 and 36 mmHg during the surgery.
Patients’ hemodynamic parameters, mean arterial pressure (MAP) and heart rate (HR), were recorded at the following time points: 10min after arriving in the endoscope room (T0), before the needle cricothyroidotomy (T1), immediately after intubation (T2), 5 min after intubation (T3), 3min after left lateral positioning (T4), and immediately after extubation (T5). The degree of oropharyngeal mucosal numbness was defined as invalid, slight numbness, numbness, or significant numbness. The severity of nausea during laryngoscopy was assessed using a verbal numerical rating scale of 0-10 (0=no feeling of nausea, 10=severe nausea). The best view obtained by video laryngoscope in each subject was described as that which visualized the glottis or the epiglottis. The amount of secretions before intubation was classified as few, medium or heavy secretions, and the amount of suctioning required before intubation was recorded. The patient’s tolerance of endotracheal tube presence was assessed by the anesthesiologist during the patient self-positioning into left lateral decubitus as good, medium, or bad. Bucking response and presence of sore throat were recorded at extubation. The severity of sore throat at 24 hours and 48 hours after surgery was assessed using a verbal numerical rating scale of 0-10 (0=no sore throat, 10=worst sore throat imaginable).
Statistical analysis
We anticipated enrolling 30 subjects (27+10% possible dropouts) in both groups. Sample size calculations showed that 27 patients were needed in both groups in order to detect a difference in MAP immediately after intubation between the two groups of 7.7mmHg (standard deviation 9.8mmHg) with a power of 0.8 and a two-sided p value of less than 0.05.
The statistical analysis was conducted using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, Version 17.0 for Windows). Results are expressed as means and standard deviations, medians and ranges, or numbers and percentages. The comparison of normally distributed continuous variables between the groups was performed using t-test. For time-dependent changes, repeated measures analysis of variance was applied. Normality of data was checked by measures of skewness and Kolmogorov Smirnov tests of normality. Nominal categorical data between the groups were compared using the chi-squared test or Fisher’s exact test as appropriate. Ordinal categorical variables and non-normal distribution of continuous variables were compared using the Mann-Whitney U-test. A p value of less than 0.05 was considered statistically significant.