2.1 Study Participants
This prospective and randomized controlled trial was registered with the China Clinical Research Information Service (registration number, ChiCTR1900026097). The trial protocol was approved on August 8, 2019 by the Ethics Committee of the Eye & ENT Hospital, Fudan University (approval no. 2019057). Written informed consent was obtained from all patients before randomization and surgery. There were 70 men eligible for participation who were 35–65 years of age, had a BMI of 19–30 kg/m2 and an American Society of Anesthesiologists (ASA) grade I or II were scheduled to undergo elective VPL (oncology classification: cT1NM–cT3NM) between September 2019 and June 2020. Patients were excluded if they had abnormal coagulation function, history of cardiopulmonary and cerebrovascular diseases, history of head and neck chemoradiotherapy and/or neck surgery, history of allergy to anesthetic drugs, or were enrolled in another study. The operations were performed using a similar technique by otolaryngologist who had each performed more than 30 times of VPL procedures.
2.2 Study Interventions
On arrival in the operating room, the patients received routine monitoring, including electrocardiography, non-invasive blood pressure, and pulse oxygen saturation. Subsequently, a 20-G intravenous cannula was inserted and patients were intravenously injected with sufentanil 0.2 µg/kg, propofol 2–3 mg/kg, rocuronium 0.6 mg/kg, and remifentanil 0.5–1 µg/kg for the induction of general anesthesia, followed by orotracheal intubation. Intraoperatively, anesthesia was maintained with 2.5–3.5% sevoflurane in oxygen at an age-adjusted minimum alveolar concentration of 0.9–1.1, remifentanil 0.1 µg/kg/min (dosage adjusted in accordance with blood pressure and heart rate (HR)), dexmedetomidine 1 µg/kg, and a total intraoperative dosage of sufentanil of 0.5 µg/kg. Initial respiratory parameters were set as follows: pressure-controlled ventilation; inspiratory pressure, 10–15 cm H2O; respiratory frequency, 10 bpm; ratio of inspiratory time to expiratory time, 1:1.5–1:2.0; fraction of inspired oxygen, 0.5. The parameters were adjusted to maintain a tidal volume of 7–8 ml/kg and an end-tidal CO2 pressure of 35–45 mmHg. Body temperature was monitored and maintained at 36.0–37.0 °C throughout surgery.
At the end of surgery, 2% lidocaine hydrochloride (1.5 mg/kg) was dripped into the balloon-type silica gel tracheostomy tube (TOT) before placement upon completion of surgery. The balloon pressure of the endotracheal TOT was consistently 40 cm H2O (manometer, Covidien, Germany). Postoperatively, residual muscle relaxants were antagonized with neostigmine 0.02 mg/kg and atropine 0.01 mg/kg. Patients received postoperative self-controlled analgesia with sufentanil 0.04 µg/kg/h, dexmedetomidine 0.08 µg/kg/h, and granisetron 2 µg/kg/h.
Patients were randomly assigned to receive vasopressor or normal saline by computer-generated allocations in concealed opaque envelopes into one of the two groups 35 patients each. The random allocation sequence was generated by an investigator not involved in the study. In the controlled hypertension group (Group H), the patients received intravenous administrations of ephedrine 6 mg (maximum dose not exceeding 30 mg) intermittently or continuous infusion of phenylephrine 10 min before the closure of the operative incision (Ta). The target mean arterial pressure (MAP) was maintained between 90 and 110 mmHg. Ephedrine was administered when the HR was < 60 bpm, while phenylephrine was administered when the HR was > 60 bpm. In the normal saline group (Group N), the patients were intravenously injected with a placebo comprising normal saline 0.1 ml/kg at Ta.
2.3 Study Outcomes
The HR and MAP were recorded at the time of arrival in the operating room (the mean of three measurements was used as the baseline value), Ta, after drug administration (Tb) (at the time of the highest MAP), at the time of leaving the postanesthesia care unit (PACU) (T1), 6 hours postoperatively (T2), and 24 hours postoperatively (T3). The bleeding score of the surgical field was recorded at Ta and Tb. Operation duration (defined as the time from the creation of the skin incision to the suturing of the cervical wound) and recovery duration (defined as the time from the end of surgery to the ability to open the eyes in response to calling) were also recorded. The amount of fluid administered and the cumulative dosage of vasoactive drugs (ephedrine and phenylephrine) were also recorded.
The primary endpoint of the study was the drainage (ml) (defined as the volume aspirated from the suction pipe above the balloon of the TOT plus the negative pressure drainage). The secondary outcomes were intraoperative bleeding score, postoperative incisional bleeding score, coughing score, nausea and vomiting score, and frequency of bloody sputum aspiration were recorded at T1, T2, and T3. Any new cardiovascular and cerebrovascular complications, hematoma and reoperation that occurred were also recorded.
The intraoperative bleeding score of the surgical field was assessed based on a four-point scale where 0 indicated no bleeding (excellent operative field), 1 indicated minimal bleeding (sporadic suction), 2 indicated diffuse bleeding (repeated suction), and 3 indicated considerable bleeding (continuous suction) [6]. The degree of postoperative incisional bleeding was recorded using a system in which nine equal squares were drawn on the gauze pad under the TOT, and 0 indicated no blood or almost no blood on the pad, 1 indicated that only one square was soaked with blood, and 9 indicated that all nine squares were soaked with blood [7]. Nausea and vomiting was scored as 0, no nausea and vomiting; 1, only nausea, no vomiting; 2, transient vomiting with nausea; 3, vomiting requiring treatment; 4, uncontrollable vomiting [8]. The number of coughs per patient was continuously monitored for 15 min postoperatively; coughing was assessed using a four-point scale as 1, no coughing; 2, minimal coughing (one to two times); 3, moderate coughing (three to four times), or 4, severe coughing (≥ five times) [9]. The intraoperative bleeding score was assessed by the surgeon who was blinded to the study groups. Each postoperative score was evaluated by a nurse anesthetist who was blinded to the experimental groups.
2.4 Statistical Analysis
The number of patients in each group was based on our preliminary study and a statistical power of 80% and an estimate of a 30% improvement in volume of drainage, in the first 24 hours postoperatively in Group N compared with Group H with a 5% significance level. Statistical analyses were performed using SPSS 19.0 (Chicago, IL, USA). MAP and HR were expressed as mean (standard deviation, SD) and the significance was examined by two-way analysis of variance after repeated measures and results at the same time point were compared using post hoc Bonferroni test. Age, body weight, BMI, duration of surgery, recovery time, temperature and fluid infusion were analyzed using Student's t-test. The coughing score and nausea and vomiting score were analyzed using the chi-square test. The volume of drainage, degree of intraoperative bleeding, postoperative incisional bleeding and frequency of sputum aspiration were presented as median (interquartile range, IQR) and were compared using the Kruskal-Wallis test. P < 0.05 was considered statistically significant.