Effect of intravenous lidocaine combined with dexmedetomidine on postoperative nausea and vomiting after laparoscopic total hysterectomy CURRENT STATUS: POSTED

A few studies have manifested that intravenous (IV) lidocaine or dexmedetomidine decreased the incidence of postoperative nausea and vomiting (PONV). We investigated whether lidocaine plus dexmedetomidine infusion could better reduce the incidence of PONV than placebo after laparoscopic total hysterectomy. This prospective, randomized controlled study enrolled 126 women undergoing elective laparoscopic total hysterectomy with general anesthesia. They divided into the following two groups: patients in the lidocaine combined with dexmedetomidine group (group LD) received lidocaine (1.5 mg/kg loading, 1.5 mg/kg/h infusion) and dexmedetomidine (0.5 μg/kg loading, 0.4 μg/kg/h infusion), respectively. Patients in the control group (group CON) received the equal volume of saline. The primary outcome was the incidence of nausea, vomiting and PONV for the first 48 hours after surgery. The secondary outcomes included intraoperative propofol and remifentanil consumption, postoperative fentanyl requirement, Ramsay sedation score, and the incidence of bradycardia during post-anesthesia care unit (PACU) stay period.

respectively). Propofol and remifentanil total dose in the intraoperative period was significantly lower in group LD compared with group CON (P<0.01 and P<0.01). However, the level of sedation and incidence of bradycardia during the PACU stay period were markedly increased in group LD compared with group CON (P<0.01 and P<0.01).

Conclusion
Lidocaine plus dexmedetomidine infusion markedly decreased the occurrence of nausea, vomiting and PONV within the 2 to 24 hours after laparoscopic total hysterectomy with general anesthesia. However, it increased the incidence of bradycardia and the level of sedation during the PACU stay period.

Background
Nausea and vomiting after surgery is one of unpleasant, trouble, and the most common side effects with general anesthesia, especially use of a large amount of opioids. Despite the advances in surgical techniques, anesthetic, and management of anesthesia, PONV, as well as postoperative pain, are very crucial problem for anesthesiologists and surgeons after surgery. With the development of enhanced recovery after surgery (ERAS), laparoscopic surgery is widely used for gynecological patients because of some advantages, including postoperative pain relief, accelerated recovery after surgery, and an improved cosmetic effect [1]. However, subjects undergoing gynecological laparoscopic surgery are high-risk factors of PONV. It was reported that the incidence of PONV in highrisk patients with no prophylaxis was likely to reach up to 70% to 80% [2,3,4]. The occurrence of nausea and vomiting after surgery may result in more discomfort and dissatisfaction for patients, disorder of electrolyte, and prolonged the time of hospitalization. Currently, although a large amount of prophylactic measures are also effective in women. However, given the higher baseline risk, such as gynecological laparoscopic surgery, a single prophylactic measure is often not sufficient to achieve a satisfactory PONV prophylaxis.
Dexmedetomidine is a highly selectively alpha 2-adrenergic agonist, which has been described as having sedation, anxiolysis, analgesia, and much less respiratory depression.
As an anesthetic adjuvant, it has been widely used during the anesthesia period because of several benefit effects, such as reducing catecholamine release [5], sparing-opioids [6] and improving the quality of recovery [7,8]. It was revealed that systemic administration of dexmedetomidine may enhance the analgesic effect of opioids and reduce opioids requirement during the perioperative and postoperative period [9,10], and reduction of opioids consumption and requirement during the intraoperative and postoperative period may result in decreasing of opioid-related adverse reactions including PONV. Recently, some studies have pointed that perioperative dexmedetomidine administration could reduce the incidence of PONV [11,12]. Additionly, a lot of studies showed that IV lidocaine has some beneficial effects, such as analgesic, anti-hyperalgesic, and anti-inflammatory properties [13,14]. Recent meta-analysis showed that the perioperative lidocaine administration reduced risk of nausea but not vomiting overall during the first 48 hours after the operation [15]. Therefore, we hypothesized that the combination of lidocaine and dexmedetomidine would further reduce the incidence of nausea, vomiting, and PONV after laparoscopic total hysterectomy compared to placebo. The primary purpose of the present study was to examine the effect of a combined application of dexmedetomidine plus lidocaine on nausea, vomiting, and PONV within 48 hours after laparoscopic total hysterectomy undergoing general anesthesia.

Methods
The Ethics Committee of the Affiliated Anqing Hospital of Anhui Medical University (Ethics Committee reference number: AQ042) approved the present study. This prospective, randomized controlled study was registered at www.clinicaltrial.gov (NCT03788018). The present study was conducted from January 2018 to December 2018 at the Affiliated Anqing Hospital of Anhui Medical University. Patients were required to sign the informed consent at least one day before surgery. 126 patients with American Society of Anesthesiologists (ASA) physical statusⅠand Ⅱ, 40-55 years of age, and scheduled for elective laparoscopic total hysterectomy undergoing general anesthesia were enrolled.
The exclusion criteria in the current study included preoperative atrioventricular block and bradycardia, history of allergy to local anesthetics, severe respiratory disease, impaired kidney or liver function. In addition, history of preoperative opioids medication and psychiatric were excluded from this study.

Assigned groups and randomization
Patients were randomized by a nurse of PACU independent of the study who obtained random numbers (random numbers generated by a computer), and patient allocation ratio was 1:1. Assignments were concealed in sealed envelopes. Patients were allocated into two groups, including group LD and group CON. Patients received IV bolus infusion of lidocaine (2%) 1.5 mg/kg and dexmedetomidine 0.5 µg/kg diluted with normal saline to 20 ml in group LD, respectively, over 10 minutes before induction of anesthesia, followed by a continuous IV infusion at rate of lidocaine 1.5 mg/kg [16] and dexmedetomidine 0.4 µg/kg [17] made up to 20 mL every hour until 30 min before the end of operation, respectively. Patients received 20 ml normal saline and 20 ml normal saline in group CON, respectively, over 10 minutes before induction of anesthesia, followed by a continuous IV infusion 20 ml normal saline and 20 ml normal saline every hour until 30 min before the end of surgery, respectively. Investigators, clinicians and patients were all fully blinded to treatment allocation. The drug solutions were prepared by an anesthesiologist who was not participated in the administration of the trial.

Anesthesia protocol
All surgical procedures for laparoscopic total hysterectomy were implemented by two high-experienced surgeons. All patients received intramuscular phenobarbital (0.1 g) 30 minutes before surgery. Basic non-invasive arterial pressure (NIBP), heart rate (HR), electrocardiogram (ECG), end-tidal CO 2 (PetCO 2 ), peripheral pulse oximeter (SPO 2 ), trainof-four (TOF), and Bispectral Index (BIS) monitors were attached to all the subjects for monitoring the vital sign, neuromuscular block, and the depth of anesthesia. Arriving at the operation room, patients were received the ringer's lactate (1 mL/kg/h) to maintain its patency. All the patients were preoxygenated with 100% oxygen via facemask for 3 to 5 minutes before induction of anesthesia to obtain sufficient oxygenation. Anesthesia was induced with target-controlled infusion (TCI) of propofol and remifentanil. The target predicted plasma concentration of propofol was 3.0 μg/mL [18]. This predicted plasma propofol concentration was kept stable for 3 minutes and then remifentanil TCI begun. The target predicted plasma concentration of remifentanil was 5.0 ng/ml [19]. Cis-atracurium 0.15 mg/kg was injected intravenously when the patients lost consciousness, and an endotracheal tube (ETT) with an internal diameter of 6.5 mm (female) was inserted into the trachea after adequate muscle relaxation. Mechanical ventilation was performed using fabius machine. Tidal volume was set 6-8 mL/kg, and respiratory rate was set 10-13 beat/min (bpm) to keep the PetCO 2 between 35 and 45 mmHg during the intraoperative period. A supplemental dose of cis-atracurium was administered intermittently to maintain muscle relaxation during the anesthesia period. The depth of anesthesia was maintained by adjusting predicted propofol and remifentanil TCI according to BIS values and hemodynamic variables within 20% of preoperative values. BIS was kept between 45 and 60 during the anesthesia period. The ringer's lactate solution was infused at a rate of 6-8 mL/kg/h during the intraoperative period. 30 minutes before the end of surgery, Fentanyl 1μg/kg was administered intravenously, and then patients were connected to an IV patient-controlled analgesic system (IVPCA) with 0.3 µg/kg/h fentanyl and granisetron hydrochloride 6 mg (100 ml of total volume) to deliver a bolus of 0.075 µg/kg of the above analgesics with a lockout time of 15 minutes. Atropine (0.5 mg) and neostigmine (1 mg) was given by intravenously to reverse neuromuscular block when the patients restored spontaneous respiration. Patients were extubated when TOF ratio at least 0.9. The patients were transported to the PACU after their endotracheal tube were extubated in the operating room to continue treatment. All patients were continued to observe for 2 hours during the PACU stay period. The Ramsay sedation score and incidence of bradycardia during the PACU stay period were recorded. The operations were performed by two highexperienced surgeon under a CO 2 pneumoperitoneum, and the pressure of pneumoperitoneum was kept between 10 mmHg and 12mmHg for all patients. At the end of surgery, 10 mL of 0.75% ropivacaine was injected the abdominal trocar sites by one surgeon for providing wound infiltration analgesia after surgery.

Outcomes variables
Our primary outcome was the incidence of nausea, vomiting and PONV during the first 48 hours after surgery. The secondary outcomes included Ramsay sedation score, the incidence of bradycardia, postoperative cumulative fentanyl requirment, and propofol and remifentanil total dose during the anesthesia period. The intensity of pain after the operation was estimated with a 10-cm VAS in the PACU and the ward (0 for no pain, 10 for the most imaginable pain). If the VAS>3, an additional 25 µg of fentanyl was treated intravenously until the VAS<3. Sedation levels of subjects during the PACU stay period were evaluated with the Ramsay sedation scale (1: agitated and uncomfortable, 2: cooperative and orientated, 3: can follow simple directions, 4: asleep but strong response to stimulation, 5: asleep and slow response to stimulation and 6: asleep and no response to stimulation).

Sample size calculation
According to Geng ZY [20] study, a sample size of 58 patients per group was needed to confirm a 50% reduction in the incidence of PONV with a power of 80% and a significance level of 0.05. Therefore, we enrolled 126 cases to account for drop outs in the present study.

Statistical Analysis
All the statistical analyses in the present study were performed using SPSS statistics v.17 (IBM Corp., Armonk, NY, USA) software. Data are presented as the number (percentage) of subjects or mean±standard deviation. Categorical data were analyzed using the χ 2 test or the Fisher's exact test as appropriate. Continuous data in the two groups were analyzed using the independent t-test. A P value of less than 0.05 was considered statistically significant.  There were no significant differences between the two groups with respect to age, BMI, blood loss, intraoperative fluid infusion volume, duration of anesthesia, duration of surgery, history of smoking, history of PONV, and history of motion sickness (Table 1).

Results
Propofol and remifentanil total dose was much lower in group LD compared with group CON during the intraoperative period (P 0.01 and P 0.01). The level of sedation was significantly higher during the PACU stay period in group LD compared to group CON (P 0.01). The incidence of bradycardia was much higher in group LD than group CON during the PACU stay period (P 0.01). But, severe bradycardia (heart rate [HR] <40 bpm) was not happen in group LD. The cumulative requirement of fentanyl during the first 48 hours after surgery was significantly reduced in group LD compared to group CON (P 0.01, P 0.01, P 0.05, respectively). Extubation time was longer in group LD than group CON (P 0.01) ( Table 2).
The incidence of nausea, vomiting and PONV during the 0 to 2 hours after surgery was slightly lower in group LD than group CON (P=0.634, P=0.619, P=0.439, respectively), but this difference was not statistically significant between the group LD and group CON. The occurrence of nausea, vomiting and PONV within 2 to 24 hours after the operation was significantly decreased in group LD compared with group CON (P 0.05, P 0.01, P 0.01, respectively). The incidence of nausea, vomiting and PONV at 24 to 48 hours after surgery was also not significant differences between the two groups (P=0.311, P=0.369, P=0.429, respectively) ( Table 3).

Discussion
This trial demonstrated that IV lidocaine combined with dexmedetomidine markedly reduced the incidence of nausea, vomiting and PONV within the postoperative 2 to 24 hours compared to placebo after laparoscopic total hysterectomy with general anesthesia.
However, the statistical difference was not observed for the occurrence of nausea, vomiting, and PONV between the 0 to 2 hours and 24 to 48 hours after surgery in group LD and group CON.
Several measures have been attempted to decrease the incidence of nausea, vomiting and PONV, but they were not able to completely eliminate it. Ahn E et al. indicated that lidocaine administration was significantly lower incidence of nausea compared with the control group with laparoscopic colectomy, it most likely attributed to intravenous lidocaine decreased the total amount of fentanyl [21]. Samimi S et al. revealed that lidocaine1.5mg/kg bolus intravenously 30 minutes before incision and constant rate infusion of lidocaine 2mg/kg/h until 1 hour after the end of procedure decreased the incidence of PONV [22]. However, the incidence of vomiting was not significant difference between treatment group and control group. The results of the meta-analysis by Weibel S et al. showed that IV lidocaine administration reduced nausea compared with control group during the perioperative period [15]. Additionally, Bielka K et al. found that dexmedetomidine infusion at rate of 0.5 μg/kg/h from induction of anaesthesia to extubation was reduced the incidence of PONV in patients after laparoscopic cholecystectomy (OR 5, 95% CI 1.1-26, p=0.005) [23]. Meta-analyses of clinical trials had similar results, that is, dexmedetomidine infusion during the anesthesia period decreased the incidence of PONV [24]. Suzuki T et al. have revealed that patients who were received dexmedetomidine administration had much lower incidence of PONV than those who were received NLA [25]. Geng ZY et al. also revealed that intraoperative dexmedetomidine infusion reduced the incidence of nausea early postoperative period but not vomiting in patients who received gynaecological laparoscopic surgery with general anesthesia [20].
In a study by Bakan M et al. showed that intravenous lidocaine and dexmedetomidine infusion for laparoscopic cholecystectomy reduced the incidence of PONV undergoing patients requiring tracheal intubation for general anesthesia [26]. In our study, we observed that lidocaine plus dexmedetomidine infusion significantly reduced the incidence of nausea, vomiting and PONV during the first 2 to 24 hours after surgery undergoing laparoscopic total hysterectomy with general anesthesia. Several identified independent risk factors for PONV for instance female, history of smoking, history of motion sickness or PONV, and laparoscopic surgery especially gynecological laparoscopic surgery in the current study were not comparable significance between the two groups. The incidence of nausea, vomiting and PONV during the initial 2 to 24 hours after surgery was markedly lower in group LD compared with group CON. It may be associated with lidocaine plus dexmedetomidine administration had much less intraoperative remifentanil requirement, postoperative fentanyl consumption, and pain intensity during the first 2 to 24 hours after surgery. Moreover, Postoperative pain relief also might be decrease catecholamine release. Because high level of catecholamine in serum may be induce PONV. In the present study, our results were explained by several reasons. First, dexmedetomidine had sympatholytic and opioid-sparing effects, which reduced catecholamine concentrations and opioid consumption. Second, lidocaine plus dexmedetomidine infusion could provide better pain relief after surgery, and significantly decrease postoperative fentanyl consumption. This was similar results by Xu et al. who found that lidocaine combined with dexmedetomidine infusion resulted in greater analgesic and opioid-sparing effects compared to lidocaine and dexmedetomidine infusion alone in patients undergoing abdominal hysterectomy [27]. Third, lidocaine combined with dexmedetomidine administration probably much better inhibited stress response by intubation, operation, and pneumoperitoneum, which may be associated with lower catecholamine concentrations. Finally, we speculated that lidocaine combined with dexmedetomidine infusion might be have better anti-inflammatory effect. Although dexmedetomidine possess the hypnotic and sedative effect, bradycardia was the most common side effect of dexmedetomidine administration, especially a large dose of dexmedetomidine. Therefore, we chose a relatively lower dose (0.5 μg/kg loading, 0.4 μg/kg/h infusion) for decreasing the incidence of bradycardia and facilitating recovery after the operation. In our study, severe bradycardia was not observed during the combined infusion of lidocaine plus dexmedetomidine. Lidocaine constant rate infusion (CRI) is associated with sedation [28].
The results of our study demonstrated that the incidence of bradycardia and level of sedation were much higher in group LD than group CON during the PACU stay period.
Meanwhile, we also found that lidocaine combined with dexmedetomidine infusion prolonged extubation time after surgery. Hence, lidocaine plus dexmedetomidine infusion reduced the incidence of nausea, vomiting and PONV, but increased the incidence of bradycardia and level of sedation during the PACU stay period, and prolonged extubation time.
Our study has several limitations. On the one hand, our sample was relatively small, and we were also not compared effects of intravenous lidocaine, dexmedetomidine alone on the incidence of nausea, vomiting and the overall incidence of PONV. On the other hand, although we speculated that combined application of lidocaine plus dexmedetomidine further inhibited stress response and inflammatory response, we were not detected levels of catecholamine and inflammatory factor such as IL-1, IL-6, and TNF-α in serum.

Conclusions
Lidocaine combined with dexmedetomidine administration may be provide better reduction of nausea, vomiting and PONV for the first 2 to 24 hours after the operation in patients undergoing laparoscopic total hysterectomy requiring tracheal intubation for propofol and remifentanil total intravenous anesthesia (TIVA). However, it increased the incidence of bradycardia and level of sedation during the PACU stay period.

Availability of data and materials
The datasets generated and/or analyzed during the current study are available from corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
No funding was received.

Authors'contributions
SQX, XJ, SBW, and YHL conceived of the study and drafted the study protocol. SQX, XJ, SBW, SHH, and QL all participate in the study design and coordination of the study. SQX, XJ, and SHH contribute to data collection. SBW is the principal investigator and has overall responsibility for the study. SQX, XJ performed the statistical analysis for the study protocol. SQX, XJ and SBW draft and revised the manuscript. SQX, XJ, SBW and YHL critically revised the manuscript. All authors have read and approved the final manuscript. Tables Table 1 Demographic baseline characteristics of the study group patients Values are in mean ± SD, number, number (%).
Abbreviations: BMI, body mass index; PONV, postoperative nausea and vomiting; CON, control; LD, lidocaine plus dexmedetomidine. Table 2 Clinical baseline characteristics of the study group patients Values are in mean ± SD, number (%).
Abbreviations: PONV, postoperative nausea and vomiting; CON, control; LD, lidocaine plus dexmedetomidine. a Significantly difference from group CON. a P0.05 compared to group CON Figure 1 CONSORT flow diagram for the study .

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