Comparison of dexmedetomidine vs. remifentanil combined with sevoflurane during radiofrequency ablation of hepatocellular carcinoma: a randomized controlled trial

Ethical approval for this randomized prospective controlled study was provided by the ethics committee of the Third Affiliated Hospital of Sun Yat Sen University, Guangzhou, China, on 5 May 2015. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-OPC-15006613, http://​www.​chictr.​org.​cn/​edit.​aspx?​pid=​11243&​htm=​4) on 16 June 2015. The checklist from the CONSORT 2010 Statement was used (Additional file 1).

The study involved patients who were scheduled to undergo elective RFA for HCC under general anesthesia in our hospital between June 2015 and October 2015. The inclusion criteria were American Society of Anesthesiologists physical status classification I–II, Child–Pugh class A or B, age between 18 and 65 years, and a single tumor of size ≤5 cm or not more than three tumor nodules ≤3 cm. The exclusion criteria were: prior treatment for liver cancer (such as transarterial chemoembolization and liver resection); recent α₂ agonist use; being allergic to any of the drugs used in this study; operation time <30 min or >3 h; history of serious impairment in respiratory, cardiovascular (heart block, myocardial ischemia, or uncontrolled high blood pressure), renal, or central nervous functions; long-term use of psychiatric or neurological drugs; and severe hearing disability. The patients were allowed to quit the study at any time.

After obtaining informed consent from all participants, trained staff used a computer-generated randomization code to randomize the patients into a remifentanil group (REMI group) or a dexmedetomidine group (DEX group) in a 1:1 ratio. For ethical reasons, patient safety, and drug dosing, the anesthesiologists in charge were not blinded to the study drugs, but group allocation was concealed from the patients and data analysts.

Patients received no premedication. Heart rate (HR), peripheral arterial oxygen saturation (SpO₂), non-invasive blood pressure, and bispectral index were monitored continuously (MP60, Philips, Boeblingen, Germany). In the DEX group, 200 μg dexmedetomidine diluted to a concentration of 4 μg mL^− 1 was administered as a 0.4 μg kg^− 1 bolus infusion 15 min before the induction of anesthesia and continued at a rate of 0.2 μg kg^− 1 h^− 1 until 10 min before the end of the surgery. In the REMI group, 1 mg remifentanil diluted to a concentration of 20 μg mL^− 1 was administered continuously at a rate of 3 μg kg^− 1 h^− 1 from 15 min before the induction of anesthesia until the end of the surgery.

General anesthesia was induced with propofol (1.5 mg kg^− 1), fentanyl (3.0 μg kg^− 1), and cisatracurium (0.2 mg kg^− 1). After tracheal intubation, anesthesia was maintained at a bispectral index of 45–55 with sevoflurane inhalation. At 5 min before the end of surgery, tropisetron was administered at a dose of 0.1 mg kg^− 1 (maximum total dose, 5 mg). Sevoflurane was stopped at the end of the surgery (the end of the last RFA procedure).

On occasion, bolus doses of dopamine (2 mg) were administered to avoid hypotension (defined as a >30% decrease in mean arterial pressure [MAP] from the baseline value [before anesthesia induction]) [24, 25]. Atropine was administered at doses of 0.25 mg to avoid bradycardia (defined as HR < 50 beats per minute). These doses were repeated as necessary. Serious drug-related adverse events should be avoided, such as allergic reactions and refractory hemodynamic events (refractory hypotension and bradycardia were defined as hypotension or bradycardia that persisted for at least 10 min despite administering more than three doses of dopamine or atropine). If these events occurred intraoperatively, the anesthesiologist had immediately to terminate the drug infusion, take the necessary measures, and record the circumstances.

After the surgery, patients were transferred to a post-anesthesia care unit (PACU). Immediately when the patients awoke, they were extubated and questioned about their pain intensity and comfort. Pain intensity was assessed with a visual analog scale (VAS; 0–10 cm, handheld slide-rule type). If the VAS score was 3 or more, a bolus of 2 mg (body weight < 60 kg) or 3 mg (body weight > 60 kg) morphine [26‐28] was administered intravenously. VAS scores were obtained every 5 min until pain relief, which was defined as a VAS score of <3. If the respiratory rate was <12 breaths/min, SpO₂ was < 95%, or a serious adverse event (such as an allergic reaction, vomiting, or severe pruritus) related to morphine administration occurred, the morphine infusion was stopped. After the patients were transferred back to the ward, appropriate analgesics were administered if the patients complained of serious pain with VAS scores ≥3. Liver function was tested at least three times in the first three days after the surgery.

The primary outcome (endpoint) was postoperative pain intensity, which was assessed by VAS scores. These scores were assessed every 5 min starting from the time of extubation in the PACU and were assessed daily during the first 3 postoperative days when the patients had returned to the ward. A trained investigator blinded to the group assignment performed the assessments for all patients.

Secondary outcomes (endpoints) included analgesic requirement, liver function, patient comfort, and hemodynamic changes. The intraoperative anesthetic requirement, which was the concentration of inhaled sevoflurane, was monitored every 15 min after the start of surgery, and the total dosage of sevoflurane was recorded. Postoperative analgesic administration, including that in the PACU and the ward, was also recorded. Preoperative liver function and the peak or nadir of liver-function data in the first three postoperative days were recorded, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), total bilirubin (TBIL), prothrombin time (PT), and PT activity (PT%). Sedation–agitation scale (SAS) scores (Table 1) [29] were recorded every 5 min in the PACU. We also documented the time to emergence, which was defined as the interval between the end of the surgery and a response to a verbal command to open the eyes, which was assessed every 3 min, as well as the time to extubation. Patients’ general condition and comfort after the surgery were evaluated by assessing the rates of disorientation (patients were asked where they were), sore throats, hoarseness, headache, dizziness, discomfort, cold, nausea, vomiting, and intraoperative awareness. Hemodynamic data (HR and MAP) were monitored continuously and recorded at the following time points: before the administration of remifentanil or dexmedetomidine (baseline); 5, 10, and 15 min after their administration; at the time of intubation; 1, 2, and 5 min after intubation; at the start of the surgery; 15, 30, 45, and 60 min after the start of the surgery; when the patient was transferred to the PACU; 5 min after transfer to the PACU; at the time of extubation; and 1 and 5 min after extubation.

The primary outcome was the incidence of pain, defined as a VAS score ≥3. Our pre-experimental data indicated that this incidence would be 10% in the DEX group and 40% in the REMI group. The following formula [30] was used to determine the sample size: n = 15.7 / h² where h = ∣Φ₁ − Φ₂∣, where Φ₁ is the arcsine transformation for the DEX group and Φ₂ is the arcsine transformation for the REMI group, assuming α = 0.05, β = 0.2, and a 20% dropout rate. Therefore, the study required 47 patients in each group.

Data were expressed as mean ± standard deviation, median and interquartile range, or proportions, and were analyzed using the SPSS v20.0 software package (SPSS, Chicago, IL, USA). Parametric data were analyzed using analysis of variance, and nonparametric data were analyzed using the Mann–Whitney U-test. MAP, HR, and sevoflurane concentration were evaluated using repeated-measures analysis of variance and the t-test. Time to emergence and time to extubation were compared using the Mann–Whitney U-test. Fisher’s exact test was used to analyze proportions. A two-sided P < 0.05 was considered statistically significant.

VAS scores and the incidence of postoperative pain (VAS score ≥ 3) did not significantly differ between the two groups at any time point (P > 0.05; Table 3). The analgesic requirement did not significantly differ between the two groups within the time frame of the focus after the surgery (P > 0.05; Table 3). The incidence of postoperative pain at 48 h after surgery in the REMI group was significantly different from the incidence at the end of surgery (8.51% vs. 27.66%, P = 0.030). There were no significant differences at other time points in the same group (P > 0.05; Table 3).

Immediately after extubation, the general condition of the patients, in terms of disorientation, sore throat, hoarseness, headaches, dizziness, discomfort, cold, nausea, vomiting, and intraoperative awareness, was similar in both groups (P > 0.05; Table 4). Liver function was assessed on the first 3 postoperative days. The peak ALT, AST, and TBIL levels were slightly higher in the DEX group, while the nadir ALB and PT% activity and peak PT levels were slightly lower in the REMI group, but the differences were not statistically significant (P > 0.05; Table 5). All of the liver functions tested were significantly worse postoperatively than preoperatively (P < 0.05).

Repeated-measures analysis of variance revealed significant variation in HR and MAP over time within each group (Fig. 2a, b). HR was significantly lower in the DEX group than in the REMI group at 1 min after intubation (70.62 ± 12.93 vs. 75.38 ± 15.46, P = 0.018), 30 min after the start of surgery (59.21 ± 8.26 vs. 67.76 ± 12.90, P < 0.001), and during recovery (P < 0.005; Table 6). Hypotension (34.04% vs. 23.40%, P = 0.362) and bradycardia (34.04% vs. 40.43%, P = 0.670) (requiring treatment with dopamine or atropine) occurred in both groups, but their incidence did not differ between the two groups (Table 7). Refractory hypotension (4.26% vs. 4.26%, P = 1.000) and bradycardia (4.26% vs. 2.13%, P = 1.000) also occurred in both groups, but their incidences were not significantly different (Table 7).

At each measured time point during the surgery, the concentration of inhaled sevoflurane was significantly lower in the DEX group than in the REMI group (Fig. 2c). Anesthesia time did not significantly differ between the two groups, but there were significant differences in the total dosage of sevoflurane (22.77 ± 11.18 vs. 17.58 ± 11.22 mL, P = 0.017) and the sevoflurane dosage related to anesthesia time (16.41 ± 5.74 vs. 11.56 ± 5.20 mL h^− 1, P < 0.001; Table 8). Delayed emergence was defined as a time to emergence of over 30 min. Although there were more patients with delayed emergence in the DEX group (12.77% vs. 4.26%), the difference was not statistically significant (P = 0.267; Table 9). Time to emergence, time to extubation, and the number of patients with a postoperative SAS score of ≥5 did not significantly differ between the two groups (Table 9).