Intraoperative and Postoperative Dexmedetomidine Combined With Sufentanil and Dezocine-based Patient-Controlled Intravenous Analgesia Increases Female Patients' Global Satisfaction Degree After Thoracoscopic Surgery: A Randomised Double-blind Controlled Trial

Background(cid:0)There are no studies on the use of dexmedetomidine combined with sufentanil and dezocine-based patient-controlled intravenous analgesia (PCIA) in females undergoing thoracic surgery. We postulate that introducing dexmedetomidine to a combination of dezocine-based PCA drugs and sufentanil will increase female patients' global satisfaction degree. Methods(cid:0)One hundred fty-two female patients with physical classication type I or II according to the American Society of Anesthesiologists undergoing thoracoscopic surgery were arbitrarily classied into two categories, either receiving sufentanil and dezocine-based PCIA (group C) or incorporating dexmedetomidine with sufentanil and dezocine-based PCIA (group D). The patients' global satisfaction degree, postoperative nausea and vomiting (PONV), PCA bolus, rescue analgesia requirements, drug-related adverse effects, rest and coughing visual analogue scale (VAS) ratings, and Ramsay sedation scores (RSS) were measured at 6, 12, 24, 36 and 48 h after surgery. Results(cid:0)Compared with the C group, the patient satisfaction degree was signicantly higher; pain scores at rest and coughing were signicantly different at 6, 12, 24, 36 and 48 h postoperatively; less rescue analgesia and PCA bolus were required; and a lower incidence of PONV was found in the D group. There were non-signicant trends for the sedation scores and drug-related adverse effects in both groups. Conclusions(cid:0)Dexmedetomidine combined with sufentanil and dezocine increased female patients' global satisfaction degree after thoracoscopic surgery. This effect could be linked to the improvement in postoperative analgesia and reduction in postoperative nausea and vomiting; the combined treatment did not increase drug-related adverse effects in female patients.


Introduction
With the emergence of enhanced recovery after surgery (ERAS), adequate pain control has been reported to enhance surgical results leading to decreased morbidity, hospitalisation and convalescence, and it is generally accepted that adequate pain management is a requirement for early postoperative rehabilitation [1] . Patients undergoing thoracic surgery experience serious pain with major effects from respiratory movements during the postoperative period [2][3] . The most widely used analgesic approach continues to be patient-controlled intravenous analgesia (PCIA). Opioids are analgesics that are frequently used for PCIA. While increased dosages of opioid pharmaceutical products may improve postoperative pain, undesirable drug-related consequences, including pruritus, vomiting, nausea and respiratory distress, often occur [4] .
Dezocine is a serotonin-norepinephrine reuptake inhibitor and functions as a partial μ-receptor agonist and κ-receptor antagonist [5] . Small doses of dezocine combined with morphine increase the effectiveness of postoperative analgesia for thoracotomy [6] . Dexmedetomidine is a highly selective α 2 adrenergic receptor agonist that hypnotic, sedative, analgesic and anxiolytic actions and does not cause respiratory depression. Dexmedetomidine can also increase the analgesic e cacy of opioids [7][8][9][10][11][12] . However, the mechanisms of the effect of dexmedetomidine when combined with opioids remain unclear.
In this randomised, placebo-controlled, double-blind study, we hypothesised that the addition of dexmedetomidine to sufentanil and dezocine-based PCA drug mixtures would improve female patient satisfaction. The secondary goal was to assess the analgesic potency and undesirable outcomes of dexmedetomidine 48 h after thoracoscopic surgery.

Methods
Patients and data collection A total of 152 female patients who were 30-60 years of age, were American Society of Anesthesiologists (ASA) class I-II, and presented for three-trocar video-assisted thoracoscopic surgery from February 24, 2020, to April 2, 2020, were enrolled. The Shanghai Jiaotong University Shanghai Chest Hospital (KS1865) Academic Review Board authorised the research procedure for surgeries involving general anaesthesia. We registered this research at Chictr.org (ChiCTR2000030429). Written informed consent was obtained from all participants.

Inclusion criteria
The female patients were selected as follows: 1) capacity to comprehend Chinese verbal and written, 2) American Society of Anesthesiologists physical status I to II, 3) age 30 to 60 years, 4) scheduled for threetrocar VATS under general anesthesia, and 5) received 48 h continual PCIA after surgery.

Exclusion criteria
The exclusion criteria were as follows: 1) age under 30 or over 60 years, 2) refusal to participate, 3) use of psychiatric medications and alcohol abuse, 4) history of cardiovascular disease, 5) acute or chronic liver or kidney disease, 6) cognitive impairment, and 7) pregnancy or lactation.

Randomisation
Patients were randomised with a 1:1 equal allocation ratio to sufentanil and dezocine-based PCIA (group C) or combined dexmedetomidine with sufentanil and dezocine-based PCIA (group D). A clinical trial statistician provided randomisation by centre using a random circle permutation. After written informed consent, the anaesthetist began randomisation of the patients using the online database. Later, in the procedure room, the randomised treatment was started.

Blinding
The patients and the research team were not informed as to whether the patients were assigned to the sufentanil and dezocine-based PCIA group (group C) or the combined dexmedetomidine with sufentanil and dezocine-based PCIA group (group D) until the end of the study. The blinding could be disrupted in case of emergency if the patients' health or safety were at risk.

Methods of Anaesthesia
According to the clinical research center protocol, when the patient arriveed at the anaesthesia preparation room, a peripheral vein was opened using a catheter, and right internal jugular central venous catheterisation was performed. When the participants were released to the operating room, in addition to a normal evaluation via pulse oximetry, non-invasive blood pressure (NIBP) and electrocardiography (ECG), the arterial pressure was assessed using a radial artery catheter in all patients. During surgery, surface electrodes for the bi-spectral index were placed on the front of the patients; BIS was maintained between 40 and 50. For both groups, a standardised anaesthetic method was used. Induction and upkeep of anaesthesia were the responsibility of the participating anaesthesiologists who were blinded to group assignments. Ten minutes before the induction of anaesthesia, 0.5 μg/kg dexmedetomidine (DEX ) was in group D or normal saline in group C was added to a 20-ml syringe for administration over ten min. Anaesthesia was subsequently induced at an effect-site concentration (Ce) of 4 μg/ml with sufentanil (0.5 μg/kg), cisatracurium (0.2 mg/kg), 50 mg urbiprofen, and 2% propofol using a target-controlled infusion (TCI). The patients were intubated with a DLT in the lateral position, which required no operation. The correct position was con rmed with the use of a breoptic bronchoscope (FOB). Throughout the initial two-lung ventilation (TLV) and one-lung ventilation (OLV) cycles, the tidal volume was 7 ml/kg, which maintained PetCO 2 at 35-45 mmHg (I/E = 1:2, f = 12). Anaesthesia was maintained using cisatracurium (0.12 mg/kg/h), remifentanil (0.1-0.3 μg/kg/min) and 2% propofol, with Ce at 2-3 μg/ml titrated to maintain BIS between 40 and 50; the mean arterial blood pressures (MAPs) and heart rates (HRs) were 20% less than the baseline values. The nasopharyngeal temperature was maintained at ≥36.5°C. FOB was used to validate the correct DLT location after the patient was placed in a lateral decubitus position once more. Using 100% oxygen, anaesthesia induction and OLV were introduced and sustained. At the end of the operation, the inspired concentration of oxygen was decreased by 50% and the positive end expiratory pressure was increased to 5 cmH 2 O after the lung recruitment manoeuvre. At the end of surgery, intravenous infusion of all anaesthetics were stopped, a palonosetron hydrochloride injection (0.25 mg for a single injection ) was given to prevent nausea and vomiting, and the analgesia pump was connected. Then, the operative times and the incidences of hypotension, atrial brillation and sinus bradycardia were recorded. After surgery, patients were transferred to a post anaesthesia care unit (PACU).

Postoperative PCIA strategy
In the PCIA protocol, the sufentanil and dezocine levels were determined based on body weight in the study timeframe. As per the study design, the PCIA base regimen was 1.5 μg/kg sufentanil and 0.3 mg/kg dezocine diluted to 100ml with 0.9% normal saline. In the D group, in addition to the sufentanil and dezocine, 3.0 μg/kg dexmedetomidine was added to the PCIA pump. The PCIA was set to a background infusion rate of 2 ml/h, lock-out interval of 15 min and 0.5 ml bolus on demand. All study patients received a 0.5 ml i.v. of PCIA solution while connected to a PCIA pump. The PCIA was set to a continuous background infusion of 0.03 μg/kg/h sufentanil with a bolus of 0.02 μg/kg sufentanil and allowed a continuous background infusion of 0.06 μg/kg/h dexmedetomidine with a bolus of 0.03 μg/kg dexmedetomidine. The PCA was used continuously for the rst 48 h postoperatively. If patients complained of extreme discomfort, higher than a VAS level of 5, Once released to the general ward, the physicians advised them to push the PCA button, and if comfort was not achieved, then the nurse would administer a rescue analgesic of 50 mg urbiprofen intravenously.

Primary outcome
The primary endpoint measures was the satisfaction degree in the two groups within 48 h after surgery. The satisfaction degree scores were from 1 to 4 (4 = very satis ed, 3 = satis ed, 2 = moderately satis ed, and 1 = not satis ed).

Secondaryoutcomes
The secondary endpoint measures were postoperative nausea and vomiting (PONV), PCA bolus, requirement for rescue analgesia, drug-related adverse effects, the visual analogue scale (VAS) pain scores at rest and while coughing, and the Ramsay sedation score (RSS) at 6, 12, 24, 36 and 48 h postoperatively.
The nausea and vomiting (PONV) ratings were on a 4-point scale (1 = without nausea and vomiting, 2 = nausea without vomiting, 3 = less than twice vomiting, 4 = extreme vomiting more than twice), [13] and the sedation score was on a 6-point sedation scale (1 = fully awake; 2 = cooperative, calm; 3 = response only to verbal commands; 4 = vigorous response to light stimulation while asleep; 5 = sleeping without light reaction; 6 = unarousable). The degree of resting and coughing pain from the operation was assessed at 6, 12, 24, 36 and 48 hrs. A graphical analogue scale, numerical analogue scale or numerical ranking scale from 0 to 10 (0 indicates no pain at all and 10 re ects the worst pain known) was used to measure pain severity. [7] The 48-h analgesia pump PCA bolus and rescue analgesia were recorded, and the occurrences of nausea and vomiting, pruritus, hypotension (MAP < 60 mmHg), sinus bradycardia (HR < 60 beats/min), excessive sedation (RSS ≥3), hypoxaemia (SpO 2 < 93%), and respiratory depression (respiratory rate < 8 bpm) were recorded for 48 h postoperatively.

Statistical analysis
Quantitative variables are reported as the mean ± standard deviation. Categorical data are de ned in terms of frequencies and fractions. The statistical study was carried out using SPSS version 22 (SPSS, Chicago, IL). The χ 2 test or Fisher's exact test was performed to compare all categorical variables. Continuous variables were tested with the non-parametric Mann-Whitney U test or t-test depending on the distribution of the data. Two-sided p-values < 0.05 were considered as statistically signi cant The sample size was estimated based on an anticipated 20% drop in the satisfaction degree ratio for 48 h postsurgery. For an 80% power (α= 0.05, β= 0.2), the sample size needed for each group was estimated to be 69, with a dropout rate of 10%. There were 76 patients per group for the nal sample size.

Results
A total of 152 female patients were included in this study, but nine were omitted. Eventually, data from 143 patients were entered for nal examination (Fig 1). There were no major variations between the demographic information of the groups (Table 1), namely, height, age, weight, ASA grade, operating period, intraoperative sufentanil and remifentanil intake, or right/left lobectomy resection (P>0.05, Table  1).
The patients in group D had a slightly greater degree of satisfaction than the patients in group C (p<0.05, Table 6). Table 2 displays the rescue analgesia and the PCA pump bolus. Post-operative rescue analgesia showed major differences between the groups. The D group required less rescue analgesia within 48 h postoperatively compared with the C group (P<0.05, Table 2). In the D group (P<0.05, Table 2), the amounts of the cumulative boluses, actual PCA boluses, and unsuccessful boluses within 48 h were smaller than those in the C group.
Compared with the C group, the Ramsay score had no signi cant differences at 6, 12, 24, 36 and 48 h postoperatively (P > 0.05, Table 3), and the VAS scores at rest and while coughing were lower at 6, 12, 24, 36 and 48 h postoperatively in the D group (P < 0.05, Table 3).
Compared with the C group, the incidence of nausea and vomiting and rescue antiemetics within 48 h postoperatively were signi cantly lower in the D group (p < 0.05, Table 4). We found no respiratory depression during 48 h after surgery (P > 0.05, Table 5).  Values are means ± SD or numbers (%), *Statistically signi cant (P <0.05). Values are means ± SD, *Statistically signi cant (P <0.05).

Discussion
In this randomised controlled study, dexmedetomidine introduced to a sufentanil and dezocine-based PCA drug blend increased female patients' postoperative global satisfaction degree, reduced the severity and frequency of vomiting and nausea and the requirement for rescue analgesia, minimised the consumption of analgesic, and decreased postoperative pain scores without increasing the incidence of clinically relevant hypertension, hypotension, excessive sedation, sinus bradycardia, hypoxaemia or respiratory depression during the rst 48 h after thoracoscopy.
Opioids, such as sufentanil and morphine, are commonly used with postoperative analgesia and various forms of treatment. Nevertheless, opioid-related adverse effects, such as addiction, respiratory depression, diarrhoea, constipation, pruritus and sedation, compel us to seek novel medications that are suitable as postoperative analgesics to minimise the use of opioids and reduce their negative impacts and have suitable postoperative analgesics. Multimodal analgesia of medications has proven successful [14] .
Dezocine is a combined agonist and antagonist of combined opioid receptors, and an increasing amount of research has demonstrated that dezocine use with opioids may decrease opioid intake and the adverse effects correlated with opioids. For instance, Wu et al [6] reported that low dezocine levels could improve postoperative analgesia, nausea and pruritus following thoracotomy. Furthermore, Yu et al [15] showed that dezocine provides a substantial postoperative antihyperalgesic and analgesic impact for up to 48 h on patients receiving elective open gastrectomy. Dexmedetomidine is an agonist of the highly selective receptor α 2 . Dexmedetomidine is quite appropriate for use as a part of multimodal analgesia because of its analgesic, sedative, hypnotic, and anti-sympathetic effects. Patient-controlled analgesia paired with dexmedetomidine is used to reduce the side effects associated with opioids [16][17] .
Patients experience serious pain after thoracoscopic surgery. Effective postoperative analgesia can reduce pain scores, the PCA bolus, and the need for rescue analgesia and increase the overall level of comfort of from analgesic in female patients in the 48 h after surgery. Such ndings showed that introducing dexmedetomidine to sufentanil and PCA based on dezocine could improve the analgesic effects, providing female patients with a better analgesic experience.
PONV is undeniably quite stressful, and even a slight episode will dramatically decrease the degree of patient satisfaction, postpone hospital discharge and increase the utilisation of medical services, particularly for high-risk female patients [18] . This research found that PONV occurrence could be decreased by the addition of dexmedetomidine to sufentanil and dezocine-based PCA. Previous research has indicated that perioperative use of dexmedetomidine could minimise the occurrence of nausea and vomiting [19][20] . This anti-nausea property may be explained by the direct anti-nausea and anti-vomiting functions of α 2 receptor agonists. Furthermore, PONV may be decreased by the anti-sympathetic qualities of dexmedetomidine.
The research presented herein revealed no substantial difference in the degree of sedation between the two groups. Dexmedetomidine has sedative qualities and acts on the subcortical system to generate sedation and enhance the quality of postoperative sleep [21][22][23] . Hence, dexmedetomidine is known to offer sedation without a respiratory disturbance, and the Ramsay sedation scores (RSS) did not indicate unnecessary sedation either. Dexmedetomidine sedation is close to normal sleep, suggesting that the formulation of 0.06 μg/kg/h dexmedetomidine used in our research procedure did not produce severe sedation of therapeutic importance but may have improved the level of satisfaction of the female patients.
In this clinical trial study, there were some limitations. Firstly, we assessed the degree of satisfaction using the patients' rating on a scale; this method was subjective. Secondly, because of the time constraints, the sample size was not large enough. In addition, discrepancies in hospitalisation length and medical billing were not assessed and will be examined in future research. Finally, a long-term analysis on the improvement in degree of satisfaction many months later is needed, as research has demonstrated that there may be a correlation between acute postoperative pain and the likelihood of developing chronic pain [24] .
In conclusion, combining dexmedetomidine with a sufentanil and dezocine-based PCA drug mixture could improve female patients satisfaction degree in the rst 48 h of after thoracoscopic surgery, providing good analgesic e cacy, less postoperative nausea and vomiting, and no increase in postoperative adverse events.

Conclusion
Dexmedetomidine combined with sufentanil and dezocine-based increased female patients' global satisfaction degree after thoracoscopic surgery. This effect could be linked to the improvement in postoperative analgesia and reduction in postoperative nausea and vomiting, and did not increase drugrelated adverse effects in female patients. CONSORT ow diagram