Opioid-Free General Anesthesia with Dexmedetomidine-Esketamine-Lidocaine Versus Opioid-Based General Anesthesia with Sufentanil-Remifentanil for Breast Benign Patients Undergoing Lumpectomy

Background: Opioid-free anesthesia (OFA) is being implemented in breast benign lumpectomy due to increased awareness of opioid adverse effects and the national opioid crisis. The objective of this study was to examine the effect of Dexmedetomidine-Esketamine-Lidocaine OFA technique in breast benign lumpectomy and assess its impact on subjective pain, intraoperative hemodynamic parameters, adverse events versus standard opioid-based technique (OA). Methods: In this prospective, randomized study, sixty breast benign patients, aging from 20 to 60 years with American Society of Anesthesiologists physical status I or II, were scheduled to undergo lumpectomy. The patients were randomized to receive either OFA (OFA group) or opioid-based (OA group) anesthesia. Dexmedetomidine-Esketamine-Lidocaine or Sufentanil-Remifentanil was administered for induction and maintenance in OFA group or OA group, respectively. Intravenous urbiprofen axate 50 mg was administered 10 minutes before the end of surgery, and dezocine 5 mg was given to patient showing visual analog scale (VAS) pain score ≥ 4 at any point of time for postoperative rescue analgesia in both groups. Intraoperative hemodynamic parameters at the time points of entering operating room (T 0 ), immediately after induction of anesthesia (T 1 ), immediately after intubation (T 2 ), 1 minute after surgical incision (T 3 ), 5 minutes after surgical incision (T 4 ), and 10 minutes after surgical incision (T 5 ), number of vasoactive drugs required, awakening time and recovery time of orientation, postoperative pain VAS at 2 h, 12 h, and 24 h after recovery, number of postoperative rescue dezocine analgesia required, and incidence of adverse events were recorded. Results: The mean arterial pressure and heart rate at T 1 , T 2 , T 3 , T 4 , T 5 were signicantly lower in OA group than OFA group. The incidences of application of rescue ephedrine (1 of 30 [3.3%] versus 12 of 30 [40%], P=0.001)


Introduction
Nowadays, opioids have been widely used in general anesthesia since they have low stress responses, stabilize the circulatory system and alleviate the pain of the cancer patients [1] . However, they are associated with severe side effects. Some of these side effects such as respiratory depression, postoperative nausea and vomiting (PONV) are obvious; some are of a more clandestine nature. For example, hyperalgesia caused by opioids are of concern yet often go unnoticed [2] [3] . Furthermore, the opioid epidemic and chronic long-term opioid usage have been attributed, in part, to the use of opioids in the perioperative period [4] .
To begin addressing these issues, opioids-free technique is receiving increasing attention in anesthesiologists [5] , which has been reported widely in orthopedic surgery, breast surgery and gastrointestinal surgery [6] [7][8] . There are multiple regimens to achieve an opioid-free perioperative analgesic management. Multimodal analgesia involves the use of sympatholytic drugs and non-opioide analgesics. These drugs can reduce or avoid the use of opioids in the postoperative period. Common nonopioid analgesics, which can be given intravenously in the intra-operative period, include alpha-2 agonists (clonidine and dexmedetomidine), beta blockers (esmolol), gabapentinoids (gabapentine and pregabaline), lidocaine (lidocaine hydrochloride), magnesium (magnesium sulfate), N-methyl D-aspartate (NMDA) receptors (ketamine, esketamine) and dexasone (dexamethasone) [9] . It has been shown that all these drugs with their analgesic effect if given together are changing the pathophysiologic process that is involved in nociception.
There is no consensus about how to achieve OFA in the literatures and between centers. The combination of Dexmedetomidine-Esketamine-Lidocaine has never been reported in OFA and clinicians uncertain about whether it is bene cial or harmful. Thus, the objective of this study is to examine the use of a OFA protocol which consisted with Dexmedetomidine-Esketamine-Lidocaine in breast benign lumpectomy and assess its impact on subjective pain, intraoperative hemodynamic parameters and adverse events.
Further, we raise awareness for our novel OFA protocol to improve safety and quality of care for our patients.

Materials And Methods
This prospective, randomized trial was approved by the Institutional Ethics Committee (2020KY071) and was registered at the Chinese Clinical Trial Registry (ChiCTR2100044230). A written informed consent was obtained from all patients enrolled in the study.
Patients with American Society of Anesthesiologists (ASA) physical status classes I or II, aged 20 60 years and scheduled for breast benign lumpectomy between December 2020 and July 2021 were considered eligible to participate in this prospective, randomized clinical trial. Major exclusion criteria were: hypertension; ischemic heart disease; psychiatric disorders; a history of signi cant hepatic, renal, or cardiac disease; preoperative heart rate (HR) less than 50 beats/min with/without cardiac conduction or rhythm abnormalities; chronic pain treatment or chronic steroid therapy; allergy to the study drugs; refusal to participate in the study; and inability to comprehend VAS. Those who were transferred to a mastectomy because of the malignant pathology were subsequently excluded from the study. Patients were randomized using computer-generated random numbers to received OFA group or OA group anesthesia (n = 30, each group).
Before the study procedure, all the patients were instructed on using a 10 cm visual analog scale (VAS; with "0" mark corresponding to no pain and "10" mark representing the worst imaginable pain). Investigator assessing the postoperative parameters, and the data analyst were blinded to the study. The anesthetist providing anesthesia was not blinded to the study drugs administered.
OFA was de ned as the administration of no opioids either pre-or intraoperatively until wound closure, and rescue opioids were only given when the patients were fully awake and had been administered nonopioid analgesics previously. OA was de ned as the administration of any opioid during the pre-or intraoperative period. Postoperative opioids (after OFA or OA) were de ned as the administration of opioid from the time of wound closure until discharge from the hospital. After induction of anesthesia, laryngeal mask airway was placed in all patients. Intravenous urbiprofen axate 50 mg for multimodal analgesia and ondansetron 4 mg for preventing postoperative nausea and vomiting were administered 10 minutes before the end of surgery in both groups. Dexmedetomidine, esketamine, lidocaine, remifentanil, and propofol were stopped at the end of the surgery. Atropine 10 µg.kg − 1 and neostigmine 50 µg.kg − 1 were administered to reverse muscle relaxation. Laryngeal mask airway extubation was performed once the patient was conscious and spontaneous ventilation of the patient was adequate, and the patients were transferred to the postanesthesia care unit (PACU).
Non-invasive blood pressure was assessed at least at 3 min of interval during anesthesia. Hypotension (MAP < 60 mmHg) was treated with ephedrine 6 mg intravenously and bradycardia (heart rate < 45 bpm) was treated with atropine 0.5 ~ 1 mg intravenously. Hypertension (MAP > 120mmHg) was treated with urapidil 5 ~ 10 mg intravenously. Any patient showing VAS ≥ 4 at any point of time was administered intravenous dezocine 5 mg slowly for postoperative rescue analgesia.
The following demographic data were recorded: age, BMI, duration of surgery, amount of bleeding, current or recent motion sickness, or previous PONV. Noninvasive blood pressure and heart rate were recorded at the time points of entering operating room (T 0 ), immediately after induction of anesthesia (T 1 ), immediately after intubation (T 2 ), 1 minute after surgical incision (T 3 ), 5 minutes after surgical incision (T 4 ), and 10 minutes after surgical incision (T 5 ). The cases of receiving ephedrine, urapidil, and atropine were recorded. The time of awakening, recovery time of orientation, cases of increased oral secretion were recorded while patients in PACU. Postoperative pain was assessed at 2 h, 12 h, and 24 h postoperatively using the VAS score. The incidence of adverse events during the rst 24 h postoperatively, such as postoperative nausea and vomiting and the number of antiemetics administered after PONV, were also recorded.
We calculated that a sample size of 36 patients per group would maintain 90% power at 5% signi cance level (two-sided) to detect a difference of 0.35 in the postoperative pain VAS at 2 h after recovery between the two groups, with a SD of 0.43 and an estimated 10% dropout.
Statistical analysis was performed with SPSS V.26.0 (IBM Corp, Armonk, New York, USA) for Windows and GraphPad Prism 8 (GraphPad Software, La Jolla, California, USA) for Windows. Continuous data were tested for normality using the Kolmogorov-Smirnov test. Normally distributed data which were presented as mean ± SD were compared using Student's T test. Nonnormally distributed data which were presented as median [interquartile range] were compared using the Mann-Whitney U test. Categorical data which were presented as n (%) were compared using the χ² test or Fisher's exact test, as appropriate. Twotailed P < 0.05 value was considered to be statistically signi cant.

Results
Seventy-two patients undergoing breast benign lumpectomy were identi ed. Four of them were cancelled of scheduled surgery, three declined to participated, ve changed to a mastectomy, and the remaining sixty patients were equally randomized to either OFA group (n = 30) or OA group (n = 30) [ Figure 1].
The demographic pro le of the two study groups were summarized in Table 1. Statistical analysis revealed nonsigni cant differences between the two study groups as regards age, height, weight, the duration of surgery, the amount of bleeding, current or recent motion sickness and previous PONV (P > 0.05). Data are presented as mean ± SD or number (%).
As regards changes in the mean arterial blood pressure and heart rate, they were signi cantly lower in OA group compared to those in OFA group [ Figures 2 and 3].
Compared with OFA group, the incidences of application of rescue ephedrine, atropine were statistically higher in OA group, whereas the incidence of rescue urapidil showed no signi cant difference between the two studied groups [ Table 2]. As regards pain VAS scores at 2 h, 12 h, and 24 h after recovery, and number of rescue dezocine analgesia required, there were no statistically signi cant difference between the two studied groups (P > 0.05) [ Table 3]. Awakening time and recovery time of orientation at the end of surgery were signi cantly longer in patients of OFA group than those in OA group (P < 0.01) [ Table 4]. Values are presented as mean ± SD. P < 0.05 was considered statistically signi cant.*Signi cant to the OFA group.
The incidences of nausea and vomiting, application of rescue ondansetron, were statistically higher in OA group than those in OFA group, whereas the incidences of increased oral secretion and dizziness showed no signi cant difference between the two studied groups [ Table 5].

Discussion
This prospective randomized study exploring the use of an OFA regime in women undergoing breast benign lumpectomy demonstrated similar clinical outcomes to conventional OA when comparing pain scores, as well as postoperative rescue analgesic required. In fact, this study demonstrated that not only can patients achieve equivalent outcomes without intraoperative opioids, but also can achieve better hemodynamic stability and lower incidences of postoperative nausea and vomiting.
OFA is based on the use of drugs that do not interact signi cantly with opioid receptors µ, κ and δ. Nmethyl-D-aspartate antagonists such as ketamine and esketamine, α2 agonists such as clonidine, dexmedetomidine, and acetaminophen, nonsteroidial anti-in ammatory urbiprofen axate and local anaesthetics lidocaine are the major medicines used [9] [10] . Dexmedetomidine is a highly selective α2adrenergic agonist that blocks sympathetic nervous system activity by directly acting on spinal preganglionic sympathetic neurons. It is widely used for sedation, anxiolysis, and analgesia to reduce the requirement of anesthetics during general anesthesia [11] [12] . Ketamine and esketamine act on N-methyl-Daspartate receptors to provide superior analgesia and prevent opioid induced hyperalgesia [13][14] [15] .Lidocaine is known to have anti-in ammatory and immunomodulatory effects in patients undergoing abdominal surgery, which can reduce postoperative ileus, nausea, and vomiting and improve the rate of recovery of bowel function, thereby shortening the hospital stay [16] . Previous studies had shown that the combination of dexmedetomidine-ketamine-lidocaine in OFA reduced intraoperative stress, postoperative pain, and opioid-related complications [17][18] , but the total intravenous anesthesia composed of dexmedetomidine-ketamine-lidocaine for OFA in lumpectomy had rarely been reported. Esketamine is an optical isomer of ketamine. Its pharmacological characteristics are similar to racemic ketamine, but it has more advantages in clinical application. The hypnotic and analgesic effect is twice than that of ketamine.
Beyond that, it has higher bioavailability, shorter elimination half-life, and fewer side effects [19] [20] . Taking together, we choosed the combination of dexmedetomidine-esketamine-lidocaine for OFA in breast benign lumpectomy.
In this study, MAP and HR of OFA group were higher than those of OA group at all time points, con rming that opioids can effectively inhibit various stress responses, but the incidences of hypotension and bradycardia subsequently increased signi cantly. The intraoperative uctuation range of MAP and HR in OFA group was smaller than that in OA group, which may be due to the following reasons: (1) dexmedetomidine can active α2 adrenergic receptor, which leads to a decrease in sympathetic out ow and an increase in vagal activity. Besides, dexmedetomidine may also have a certain peripheral ganglion block effect, which further enhances its antisympathetic effect [11] [21] ; (2) The sympathetic excitatory effect of esketamine partly counteracts the cardiovascular inhibitory effect of propofol [22] .
Previous studies had led to con icting results regarding the effect of OFA on postoperative analgesia.
Indeed, some studies reported a reduction in postoperative analgesia score [23] [24] , whereas others showed a similar postoperative pain score [25][26] . These discrepancies could be due to the different methods of compound anesthesia and the differences in postoperative multimodal analgesia. A meta-analysis including 1304 patients showed that OFA provide similar analgesia or opioid consumption in the postoperative period [27] . In our study, there was no difference in pain scores between the OFA group and the OA group at each time point after surgery, suggesting that both anesthesia methods can provide effective analgesia in breast benign lumpectomy.
Previous studies had shown that compared with pain and other complications, postoperative nausea and vomiting were the last thing patients want to experience [28] . Breast benign lumpectomy is common in young women who are at high risk of postoperative nausea and vomiting due to no previous opioid use or smoking history. Up to 50% of patients with traditional OA will experience postoperative nausea and vomiting [29] . Ziemann-Gimmel et al found that total intravenous OFA was associated with a large reduction in relative risk of PONV in patients undergoing bariatric operations [30] . This was comparable to our nding, which showed a signi cant reduction in PONV by 43%. However, the comparison of reduction has to be interpreted with caution because of the different patient populations observed.
Awakening time and recovery time of orientation were prolonged in the OFA group in this study. The use of dexmedetomidine might have delayed recovery [31] . This nding was consistent with previous research [32] . But in that research, patients in OFA experienced high incidences of hypoxemia and bradycardia. The high dosage (1.2 ± 2 µg.kg − 1 .h − 1 ) of dexmedetomidine might be the main reason of causing those side effects. Establishing arti cial pneumoperitoneum and the addition of dexmedetomidine in this speci c situation contributing to unexpected cardiovascular changes might be another reason for causing those adverse effects. By contrast, the dosage of dexmedetomidine (0.1 ~ 0.2 µg.kg − 1 .h − 1 ) used in our study was low and our study did not establish arti cial pneumoperitoneum, which explaining the low incidences of adverse events.
This study is not without limitations. Firstly, the collection of postoperative nausea and vomiting measures was not standardized, and we did not assess the quality of postoperative recovery. Another limitation is the lack of validated nociception monitor. Finally, our de nition of OFA (multimodal anesthesia including dexmedetomidine, esketamine and lidocaine) is not de nitive, and other ways to administer OFA have to be explored [33] .
The combination of Dexmedetomidine-Esketamine-Lidocaine OFA technique may be an alternative anesthesia for breast benign lumpectomy. It can provide effective anesthesia, better hemodynamic stability, equivalent postoperative analgesia, lower incidences of postoperative nausea and vomiting compared with OA. It is suitable for special patients with opioid tolerance, high risk of postoperative nausea and vomiting, obesity and other special patients, and also provides more options for clinical anesthesia program. However, it did result in some adverse events, such as longer awakening time and longer recovery time of orientation, so the dosage of combination drug still needs to be further optimized.
Declarations Figure 1 Flowchart of the study Figure 2 Changes in mean arterial pressure during perioperative period in OFA group or OA group. P <0.05 was considered statistically signi cant. *Signi cant to the OFA group.