This study was approved by the hospital ethics committee of the Eye, Ear, Nose and Throat Hospital of Fudan University, Shanghai, China (2013005) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (NCT03918889, Principal investigator: Rui Xu, date of registration: March 28, 2019). We did a prospective, randomized, double-blind, single-center clinical trial in department of anesthesiology in the Eye, Ear, Nose and Throat Hospital of Fudan University. This manuscript adheres to the applicable CONSORT guidelines.
Patients were randomly allocated to either group dexmedetomidine (group D) (n = 43) or group midazolam (group M) (n = 43). Randomized group allocation was performed using a computerized randomization table created by one staff member who was not involved in the patients’ anesthesia or recovery care. The randomization result was kept sealed in an envelope, only the nurse who prepared the anesthetics could open the envelope in order to prepare allocated drug. A total of 83 medical records were analyzed, 43 from group D and 40 from group M. The patients, the nurse in post anesthesia care unit (PACU), and attending anesthesiologist were blinded to the study medicine administration.
We enrolled 86 adult patients with American Society of Anesthesiologist physical status (ASA) Ⅲ or Ⅳ, aged 25–70 years, male, scheduled for partial or total laryngectomy.
Patients with cardiac disease, neuropsychiatric diseases, pharyngeal paraganglioma, uncontrolled hypertension (i.e., systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 mmHg), take β-adrenoreceptor blockers, long-term (> 6 months) abuse of alcohol, opioids or sedative-hypnotic drugs, dexmedetomidine or midazolam allergies, undergo awake fiberoptic intubation, operation time shorter than 1 h or longer than 4 h, patient who had tracheotomy history were excluded.
Drugs including sedative, analgesic, antiemetic and anti-itching drugs were not given before operation. After arrived at operation room, electrocardiogram, pulse oximetry, blood pressure, bispectral index, end-tidal carbon dioxide and temperature were continuously monitored and recorded. General anesthesia was induced with sufentanil 0.2 µg/kg, propofol 2.5 mg/kg, after confirmation of adequate muscle relaxation with the administration of cisatracurium 0.2 mg/kg iv, an endotracheal tube with internal diameter of 7 mm was inserted into the trachea. Endotracheal tube cuff pressure was maintained at 25 cmH2O measured using a calibrated handheld Portex Cuff Inflator Pressure Gauge (Portex Limited, Hythe, Kent, UK). Prior to the start of surgery, sufentanil 0.1 µg/kg was given. Either dexmedetomidine (Precedex; Henrui Pharmaceutical, China) (group D, n = 43) infusion at 0.5 µg/kg for 10 min before tracheotomy, then adjusted to 0.3 µg/kg/h or midazolam (Midazuolun injection; Enhua Pharmaceutical, China) (group M, n = 43) infusion at 0.05 mg/kg ten minutes before tracheotomy, then adjusted to 0.02 mg/kg/h was administered in a blind mode. Anesthesia was maintained with 1-1.3 minimum alveolar concentration end-tidal concentration of sevoflurane in 30% oxygen/air mixture to keep bispectral index between 45 and 55. The maintenance infusion rate of cisatracurium is 1-1.5 µg/kg/min and tmaintenance infusion rate of sufentanil was 0.002 µg/kg/min according to clinical needs. Granisetron 6 mg was administered at the end of surgery for prevention of postoperative nausea and vomiting (PONV). Endotracheal secretions were removed before tracheostomy tube insertion. Topical tetracaine hydrochloride gel was applied to the tracheostomy tube in order to enhance toleration.
After surgical procedures were finished, sevoflurane was discontinued, 100% oxygen was administered at 6 l/min and then patients were transferred to PACU. Neostigmine 0.04 mg/kg and atropine 0.02 mg/kg were given to reverse residual neuromuscular block. After spontaneous ventilation returned, confirmation patient had fully recovered from muscle relaxation and after patients opened eyes, patients were weaned from mechanical ventilation. Nurses who assessed subjects were blinded to the medicine intervention. If there was any adverse event, an attending anesthesiologist managed it. In case of bradycardia (heart rate (HR) < 45 beats/min), 0.5 mg atropine was administered, if systolic blood pressure (SBP) decreased to less than 90 mmHg, ephedrine 6 mg was used.
Cough grading was based on modified 4-point Minogue scale. Grade 1 equates to no cough; grade 2 (mild) represents coughing once or twice; grade 3 (moderate) means fewer than 4 non-sustained coughs lasting 1–2 s each or overall coughing lasting less than 5 s; grade 4 (severe) was at least 4 coughs lasting at least 2 s, or overall coughing duration was more than 5s9. The patients’ level of sedation was assessed by ramsay sedation scale (RSS):1 = the patient is anxious and restless or agitated, or both; 2 = the patient is cooperative, tranquil, and oriented; 3 = the patient responds to commands only; 4 = the patient exhibits a brisk response to a loud auditory stimuli or a light glabellar tap; 5 = the patient exhibits a sluggish response to a loud auditory stimulus or a light glabellar tap; 6 = the patient exhibits no response10. In addition, the nurse also assessed postoperative pain score by visual analogue scale (VAS) (0–10; 0 = no pain, 10 = worst pain). If pain score was above 5, sufentanil 0.1 µg/kg was given to patients immediately as rescue analgesic, consumption of analgesics was recorded.
HR, SBP, diastolic blood pressure(DBP) and pulse oximetry(SpO2) were recorded before induction(T1), after drug administration(T2), after intubation(T3), after medicine intervention(T4), at moment of laryngectomy(T5), completion of surgery(T6), at the point of awareness(T7), at departure from PACU(T8), 2 h after surgery(T9), 24 h after surgery(T10), 48 h after surgery(T11). Duration of surgery, respiratory recovery time, duration of PACU stay was also recorded. Incidence of adverse events including bradycardia, hypotension (< 30% decrease from baseline), hypertension(> 30% increase from baseline), vomiting, pale lip, delirium, subcutaneous emphysema, hematoma were noted by a nurse who was blinded to medicine intervention. The incidence of pneumonia in the 72 hours after surgery was also collected.
The primary endpoint was incidence and severity of cough. The secondary outcome measures were hemodynamic responses, postoperative pain scores, sedation scores, respiratory recovery time, duration of PACU stay, and incidence of adverse events.
PASS15 was used to calculate sample size. On basis of preliminary study, incidence of no cough in group M was about 65%, and group D was about 25% higher than group M. The proportion in group D is assumed to be 0.65 under the null hypothesis and 0.90 under alternative hypothesis. The proportion in group M is 0.65. The test statistic used is one-sided Z-Test with unpooled variance. The significance level of the test is 0.025. Group sample sizes of 40 in group D and 40 in group M achieve 80% power to detect a difference between the group proportions of 0.25. Assuming a dropout rate of 8%, final sample size was determined to be 43 patients each group, with a power of 80% and an alpha level of 0.05.
The t test was used for between-group comparisons of HR, SBP, DBP, and SpO2. Repeated-measures ANOVA was used for within-group comparisons. The χ2 test or the Fisher exact test was used to analyze coughing severity, sedation, pain scores and adverse events. A p-value of 0.05 or less was considered statistically significant.