This randomized, controlled and double-blinded clinical trial was approved by our Institutional Ethics Committee. Patients undergoing gynecological procedures under general anesthesia with endotracheal intubation were recruited, and informed consents were obtained. They were aged 18-60 years old with the American Society of Anesthesiologists (ASA) physical status class I to II. Exclusion criteria included: 1) previous history of oral, pharyngeal, cervical spinal or thyroid surgery; 2) previous history of symptomatic gastric reflux, postoperative sore throat, pulmonary disease, or allergy to any local anesthetics; 3) previous history of or suspected difficult airway; 4) a nasogastric tube needed for postoperative management; 5) upper respiratory tract infection in the last month; and 6) smoking.
Totally 104 patients were screened and 4 patients refused to participate. Therefore, 100 patients were finally included. According to a computer-generated random number table, they were assigned to receive one of the following media to inflate the cuffs of the endotracheal tubes: 1% tetracaine (Group T, N=25), 2% lidocaine (Group L, N=25), 0.9% normal saline (Group N, N=25) or air (Group A, N=25).
A standard protocol was used for anesthesia induction: midazolam 0.05 mg/kg, fentanyl 4 μg/kg, propofol 2 mg/kg. Tracheal intubation was facilitated by rocuronium 0.6 mg/kg or vercuronium 0.1 mg/kg. Endotracheal intubation tubes with low-pressure and high-volume cuffs (Medical Devices Co., Ltd. Guangzhou peacekeeping force, Guangzhou, China) were used in this study. The size of the tube for each patient was determined by the attending anesthesiologist assigned for each case and intubations were performed by anesthesiologists who had more than 3 years of practicing experience and were blinded to group allocation. Stylet for endotracheal intubation was used in every subject. According to the randomization table, all the endotracheal tubes and the corresponding inflation media were freshly prepared by the same nurse anesthetist who was not involved in intraoperative anesthesia management or postoperative follow-up. The cuff of the ETT was slowly inflated with the assigned inflation medium to occlude the leak around the tube by the minimal occlusive volume technique. Briefly, a small volume of inflation medium was injected into the cuff by the same nurse anesthetist, until no leak was heard during the peak airway pressure of the ventilation cycle by the anesthesiologist in charge of each patient. The volume of injected inflation medium was recorded and intra-cuff pressure was measured with a manometer. During this process, the cuff and the connected syringe or manometer were covered by black paper, which made them invisible to anesthesiologist in charge. The anesthesia maintenance was performed at the discretion of the anesthesiologist in charge of each patient, either with sevoflurane inhalation or propofol infusion. Depolarizing muscle relaxants or long-acting opioids, such as sufentanil, were avoided.
The deliveries of anesthetics would be stopped after the final stitch was completed. Once the extubation criteria were met (adequate spontaneous ventilation and response to verbal command to open her eyes), ETT would be removed.
The postoperative follow-ups were conducted by certified registered nurse anesthetists blinded to the randomization. The primary outcome was the severity of the post-intubation sore throat measured by the Visual Analogue Scale (VAS) score at 6 hours after extubation. The secondary outcomes were incidences of ETT-induced emergence phenomena, which were defined as complications related to endotracheal intubation including tube intolerance, coughing on tube, restlessness, hoarseness, and laryngospasm, as well as the VAS scores at 24 and 48 hours after extubation. Duration of intubation was also recorded. The flow chart was presented as figure 1.
In Vitro Study
For the in vitro test, ID 6.5# tubes with low-pressure and high-volume cuffs (Medical Devices Co., Ltd. Guangzhou peacekeeping force, Guangzhou, China) were prepared and divided into two groups. 1% tetracaine and 2% lidocaine was used to inflate the cuff, respectively. The intra-cuff pressure was set at 14 mm Hg, guided by the results from our human study. Each ETT was then placed in a magnetically stirred bath of 100 ml normal saline at 37℃. Samples (1 ml) of the bath contents were drawn every 30 minutes for 300 minutes. The concentration of local anesthetic in the samples was measured by High Perform Liquid Chromatography (Agilent 4860, Santa Clara, CA), according to our well established protocol. This diffusion test would be repeated for 5 times for each local anesthetic.
The animal study was approved by our institutional Animal Experimental Ethics Committee. Dogs were anesthetized with intramuscular (i.m.) injection of 5 mg/kg ketamine. Then peripheral vein was catheterized. 0.1 mg/kg midazolam, 0.05 μg/kg sufentanil and 2.5 mg/kg propofol were given and tracheal intubation was facilitated with rocuronium at the dose of 0.6 mg/kg. At this stage, the dogs were divided into 2 groups (N=6 per group) randomly, according to the type of media received for inflating the ETT cuff (normal saline or air). The cuff was inflated by minimal occlusive volume technique as previously described, and the intra-cuff pressure was also measured by manometer. The dogs were kept in supine position during the 4-hour intubation and anesthesia was maintained by continuous midazolam and remifentanil infusion. After the tube was removed, the trachea underneath the cuff was harvested for pathological investigation by a trained pathologist. The lesions of the trachea were scored according to severity and distribution (19). Scores for severity were: none=0, minimal=1, mild=2, moderate=3, marked=4 and severe=5. Scores for distribution were: none=0, focal=1, locally extensive=2, multifocal=3, multifocal and coalescent=4 and diffused=5. The pathology score was the sum of the severity and distribution scores.
Power calculation for the human study was based on our preliminary data. A minimum of 90 patients had to be included to detect a 2-point decrease in VAS with a two-sided significance level of 0.05 and power of 80%. Considering potential loss during follow-up, sample size of 25 for each group was determined.
Data analysis was performed using GraphpadPrsim Software (version 5.01, GraphPad Software, Inc., La Jolla, CA). Quantitative data between groups were analyzed by one-way analysis of variance (ANOVA) test, followed by Student-Neumann-Keuls test when indicated, except for age. Age was analyzed by Kruskal-Wallis test, followed by Nemenyi test when necessary. VAS score for sore throat was analyzed by the Kruskal-Wallis test, followed by the Mann-Whitney U test when indicated at each time point. The incidences of intubation-related complications were compared by the Pearson Chi-square test. All the reported P values were two-detailed and P value less than 0.05 was considered statistically significant.