In this non-inferiority randomized controlled trial in patients undergoing gynecological laparoscopic surgery, under ERAS protocol, OFA with esketamine and dexmedetomidine was non-inferior to OA with sufentanil and remifentanil in pain scores calculated as the area under the curve for the first 48 hours postoperatively. Furthermore, we found that no differences in the intraoperative HR and MAP and the number of rescue analgesia required between two groups, which supports our primary outcome. Meanwhile, lower incidence of PONV and preliminary improvement of PSQ were advantages of OFA which compared to OA. However, in terms of postoperative recovery time, OFA had certain disadvantage.
Although minimally invasive surgery, such as laparoscopic surgery, has become an important part of ERAS in gynecologic surgery, postoperative pain caused by laparoscopic surgery still creates difficulties for anesthesia management in ERAS context. Opioid is gradually replaced by non-opioid medications because of opioid-related disadvantages. In this study, all patients were under ERAS protocol after discussing with surgeon and nurses team. We applied TIVA combined with ultrasound-guided TAP block and non-steroidal anti-inflammatory drug (NSAID) flurbiprofen axate, which was administered for postoperative rescue analgesia. In this context, we purely researched application of opioid and non-opioid medications in gynecological laparoscopic surgery. Patients’ postoperative VAS scores while coughing at different time points were evaluated and recorded. Use of the area under the curve is a common approach to the analysis of continuous variables because of its superiority in precision and bias [13]. In Petersen’s study, they used AUC based on VAS scores while coughing at 0, 2, 4, 6, 8, and 24 hours postoperatively in patients undergoing laparoscopic cholecystectomy in day-case surgery to evaluate postoperative pain [9]. In our study, patients’ postoperative hospital days were longer, as well as postoperative pain is a continuous process, so we recorded VAS scores while coughing at 0, 12, 24, 36 and 48 hours postoperatively. Compared to VAS at a single time point, AUCVAS can better reflect the overall level of pain for a period of time. Therefore, the result of AUCVAS was effective and intuitional. AUCVAS was no differences in two groups, as well as there was no difference in the number of postoperative rescue analgesia required in two groups, and no differences were found in VAS scores from T6-T10, therefore we think that analgesic effect of OFA was not inferior to that of OA.
In our study, we administered esketamine and dexmedetomidine for OFA. In a previous placebo-controlled trial [14], esketamine functioned as a longtime analgesic role. An evidence-based review confirmed that as part of ERAS protocol, esketamine improved prognosis of patients [15]. In Massoth’s study, opioid-free protocol as esketamine 0.15 mg/kg for induction and a continuous infusion of dexmedetomidine 0.3 µg/kg/h + esketamine 0.15 mg/kg/h for maintenance of anaesthesia in patients undergoing gynecological laparoscopic surgery was feasible and easy to perform [7].
PONV is another difficulty to be solved in the ERAS context. To reduce PONV, we adopted ERAS protocol which included preoperative carbohydrate loading, limiting fasting of clear liquids, intaking caffeine, chewing gum and postoperative early mobilization [16]. The side-effects of opioids include nausea, vomiting and constipation [17]. In terms of anesthesia, avoidance of intraoperative opioids and volatile anesthetics may be related to reduction of PONV [8]. With the return of patients’ water intake and upcoming PONV pathophysiological climax (24h postoperatively), PONV occurs more frequently and intensively [18]. In our study, incidence of PONV in group OFA was lower than that of in group OA in a period of 48h after surgery (10.1%, 28.9%, respectively, P = 0.04). Compared to Christina’s study, the incidence of PONV in both groups in our study was lower, the result might preliminarily demonstrate the advantages of ERAS protocol in PONV prophylaxis. However, considered that the simple size of our study was small, this result need to be interpreted with caution. Moreover previous research has proved that dexmedetomidine may reduce the occurrence of PONV while producing sedation and analgesia [19]. Therefore, we can assume that under ERAS protocol, OFA technique in this study has positive effects in reduction of PONV.
PSD, which is related to type of surgery, duration of surgery, methods of anesthesia, anesthesia agents and other factors, has gradually drawn attention. Postoperative pain and opioids have significant effects on postoperative sleep quality. Opioids can lead to postoperative sleep disturbance, which may be related to the regulation mechanism of endogenous opioid activity [20]. Propofol, the interoperative sedative, can reduce the long-term postoperative sleep quality, it may be correlated with the occurrence of postoperative sleep disorders [21]. Esketamine and dexmedetomidine have been proven to improve of sleep quality [22, 23]. PSQI is widely used to assess patients’ sleep condition and provide reference for perioperative management. On the premise of no difference in PSQI before surgery between two groups in this study, we found that 1 month after surgery, PSQI of two groups had no significant difference. But in group OFA, compared to preoperative period, postoperative sleep quality of patients was improved, so we considered that OFA technique may play a role in this. The results of our study can only show that OFA has certain improvement effect on PSD in the short-term period after surgery, but the long-term effect on PSD needs further research.
Times of awakening and orientation recovery in group OFA were longer than those in group OA in this study. Although several studies found that delayed recovery may lead to serious postoperative complications, in this study delayed recovery does not have apparent anesthesia related adverse reactions, the reason may be that our population was ranged from 18–65 years old, which reduced the possibility that elder patients are more susceptible to postoperative complications due to delayed recovery. Furthermore, dexmedetomidine has certain effect on delayed recovery, but its role is gentle and the efficacy is close to the physiological effect of sleep, It is also safe for elder patients [24]. Meanwhile, esketamine was considered does not prolong awakening time in minimally invasive surgery, but the dose-dependent of this drug need to be noticed [25].
Esketamine has the effect of sympathetic activation that can increase heart rate, blood pressure and cardiac output [26], whereas dexmedetomidine plays the opposite role. Add into account the as well as subtle differences of analgesic effect between OFA and OA technique, these factors may lead to our study results regarding MAP and HR. Although MAP in group OFA (84.38 ± 11.08) was higher than that in group OA (79.00 ± 8.92) at T2 (P = 0.022), no differences were found in total trends of intraoperative hemodynamic variables in both groups. We consider that OFA technique can maintain period of intraoperative anesthesia as smoothly as OA.
There are several limitations in the study. Firstly, although there was significant difference in incidence of PONV between two groups, we didn’t collect the history of PONV and motion sickness, which are also risk factors of PONV. In addition, the number of rescue antiemetics after surgery was not recorded, hence in subsequent study, we will focus on PONV and prepare to observe and record more comprehensive data, even consider testing PONV related blood indicators such as histamine and 5-hydroxytryptamine or serotonin if necessary [27]. Moreover, we think that the sample size was not enough, and the range of age was narrow. Nowadays, more elder patients receive surgery and anesthesia, and the subsequent trauma and stress will bring more serious complications and seriously affect postoperative recovery. In order to carry out OFA technique more comprehensively, we should enroll elder patients, and conduct larger sample and multi-center trial. Thirdly, we should research VAS scores at rest and during movement of patients separately. VAS is a subjective indicator, which would change in accordance to patients’ feeling and understanding of pain. Hence, perhaps combining with serological test, which is related to postoperative pain can be more objective and reliable. In addition, we should prolong the duration of postoperative follow-up, an one-month PSQI follow-up would not completely reflect postoperative sleep quality, and risk factors of PSD should be preoperatively certain. Change of sleep quality is gradual, and a longtime follow-up is necessary.