{"paper_id":"393d0498-5f23-42ff-a72c-c34810f7bf61","body_text":"R E S E A R C H A R T I C L E Open Access\nEffects of intravenous lidocaine,\ndexmedetomidine, and their combination\non IL-1, IL-6 and TNF- α in patients\nundergoing laparoscopic hysterectomy: a\nprospective, randomized controlled trial\nSiqi Xu 1, Shenghong Hu 1, Xia Ju 1, Yuanhai Li 2, Qing Li 3 and Shengbin Wang 1*\nAbstract\nBackground: Surgical-related inflammatory responses have negative effects on postoperative recovery. Intravenous\n(IV) lidocaine and dexmedetomidine inhibits the inflammatory response. We investigated whether the co-\nadministration of lidocaine and dexmedetomidine could further alleviate inflammatory responses compared with\nlidocaine or dexmedetomidine alone during laparoscopic hysterectomy.\nMethods: A total of 160 patients were randomly allocated into four groups following laparoscopic hysterectomy:\nthe control group (group C) received normal saline, the lidocaine group (group L) received lidocaine (bolus infusion\nof 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D) received\ndexmedetomidine (bolus infusion of 0.5 μg/kg over 10 min, 0.4 μg/kg/h continuous infusion), and the lidocaine plus\ndexmedetomidine group (group LD) received a combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min,\n1.5 mg/kg/h continuous infusion) and dexmedetomidine (bolus infusion of 0.5 μg/kg over 10 min, 0.4 μg/kg/h\ncontinuous infusion). The levels of plasma interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF-α)\nat different time points were the primary outcomes. Secondary outcomes included hemodynamic variables,\npostoperative visual analogue scale (VAS) scores, time to first flatus, and incidence of nausea and vomiting after\nsurgery.\nResults: The levels of plasma IL-1, IL-6, and TNF- α were lower in groups D and LD than in group C and were\nlowest in group LD at the end of the procedure and 2 h after the operation ( P < 0.05). The VAS scores were\ndecreased in groups D and LD compared with group C ( P < 0.05). The heart rate (HR) was decreased at the end of\nthe procedure and 2 h after the operation in groups D and LD compared to groups C and L ( P < 0.001). The mean\nblood pressure (MBP) was lower at 2 h after the operation in groups L, D, and LD than in group C ( P < 0.001). There\nwas a lower incidence of postoperative nausea and vomiting (PONV) in group LD than in group C ( P < 0.05).\n(Continued on next page)\n© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,\nwhich permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if\nchanges were made. The images or other third party material in this article are included in the article's Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons\nlicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nThe Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the\ndata made available in this article, unless otherwise stated in a credit line to the data.\n* Correspondence: shbw1965@126.com\n1Department of Anesthesiology, The Affiliated Anqing Hospital of Anhui\nMedical University, Anqing 246000, China\nFull list of author information is available at the end of the article\nXu et al. BMC Anesthesiology            (2021) 21:3 \nhttps://doi.org/10.1186/s12871-020-01219-z\n\n(Continued from previous page)\nConclusions: The combination of lidocaine and dexmedetomidine significantly alleviated the inflammatory\nresponses, decreased postoperative pain, and led to fewer PONV in patients undergoing laparoscopic hysterectomy.\nTrial registration: ClinicalTrials.gov ( NCT03276533), registered on August 23, 2017.\nKeywords: Lidocaine, Dexmedetomidine, Interleukin, Tumor necrosis factor- α, Laparoscopic hysterectomy\nBackground\nLaparoscopic procedures are widely adopted for\ngynecological patients due to certain benefits, including\ndecreased intensity of pain after surgery, improved post-\noperative recovery of intestinal function, and improved\ncosmetic effects [ 1]. However, tissue injury induced by\nsurgical trauma stimulates the systemic inflammatory\ncascade to elicit the release of a large number of inflam-\nmatory cytokines [ 2]. High levels of inflammatory cyto-\nkines not only affect wound healing but may also be\nassociated with a large number of complications, such as\npostoperative pain, fatigue, and cognitive dysfunction\n[3–5]. Dexmedetomidine, a highly selective alpha 2-\nadrenergic agonist, can lead to hypnosis, sedation, anal-\ngesia and minimal respiratory depression [ 6]. As an\nanesthetic adjuvant, in view of reducing catecholamine\nrelease [ 7], sparing opioids [ 8], and improving the qual-\nity of recovery during the anesthesia period [ 9, 10], dex-\nmedetomidine has been widely used in the clinical\nsetting. Animal and clinical studies have revealed that\nthe systemic administration of dexmedetomidine may\nexert anti-inflammatory effects [ 11, 12]. The systemic\nadministration of lidocaine has been increasingly used\nfor surgical patients due to its potential beneficial effects,\nincluding opioid-sparing [ 13], analgesic [ 14] and anti-\ninflammatory properties [ 15]. Our previous study indi-\ncated that dexmedetomidine plus lidocaine infusion may\nfurther decrease the intensity of postoperative pain,\nlower the requirement of fentanyl after surgery, and ac-\ncelerate bowel function recovery than lidocaine or dex-\nmedetomidine infusion alone [ 16]. Although intravenous\nlidocaine and dexmedetomidine infusion alone may\nexert anti-inflammatory efficacy, the degree to which the\ncombination of lidocaine and dexmedetomidine infusion\ninhibits the inflammatory response has not been evalu-\nated. Therefore, we hypothesized that the co-\nadministration of lidocaine and dexmedetomidine could\nfurther decrease the levels of plasma TNF- α, IL-6, and\nIL-1 compared with lidocaine and dexmedetomidine\nalone after laparoscopic hysterectomy.\nMethods\nThe research approach was approved by the Ethics\nCommittee of Anqing Municipal Hospital and registered\nat www.clinicaltrials.gov (Number: NCT03276533, regis-\ntration date: 08/23/2017). All methods were performed\nin accordance with the relevant guidelines and regula-\ntions in our present study. All subjects provided\ninformed consent at least 12 h before surgery. The inclu-\nsion criteria of our trial included American Society of\nAnesthesiologists (ASA) physical status I and II, age\nbetween 40 and 65 years, and undergoing laparoscopic\nhysterectomy with general anesthesia. The exclusion cri-\nteria included a history of allergy to local anesthetics,\npreoperative atrioventricular block and bradycardia,\nimpaired kidney or liver function, underlying severe\nrespiratory disease, and a history of opioid use and psy-\nchiatric disease. Patients were randomized into four\ngroups (groups L, D, LD, and C) by a nurse in the posta-\nnesthesia care unit (PACU) who did not participate in\nthe study according to computer-generated random\nnumbers and sealed envelopes. Patients in group L re-\nceived a bolus infusion of lidocaine (2%; 1.5 mg/kg over\n10 min before the induction of anesthesia), and then\nlidocaine was infused at a rate of 1.5 mg/kg/h, which was\nceased 30 min before the end of the operation [ 17]. Pa-\ntients in group D received a bolus infusion of dexmede-\ntomidine (0.5 μg/kg over 10 min before the induction of\nanesthesia), and then dexmedetomidine was infused at a\nrate of 0.4 μg/kg/h, which was ceased 30 min before the\nend of operation [ 16]. Patients in group LD received a\nbolus infusion of lidocaine (2%; 1.5 mg/kg) and dexme-\ndetomidine (0.5 μg/kg) over 10 min before the induction\nof anesthesia, and then lidocaine and dexmedetomidine\nwere infused at a rate of 1.5 mg/kg/h and 0.4 μg/kg/h, re-\nspectively, which were ceased 30 min before the end of\nthe operation. Patients in group C received the same vol-\nume of normal saline (40 mL) 10 min before the induc-\ntion of anesthesia, and then normal saline (0.9%) was\ncontinuously infused in an equal volume (40 mL/h), and\nceased 30 min before the end of the operation. Study\nparticipants, including anesthesiologists, clinicians, and\nsubjects, were blinded to the treatment assignments.\nThe drug solutions in each group were provided by a\nnurse in the PACU who did not participate in the trial.\nThe primary endpoints in our study included the\nlevels of plasma IL-1, IL-6, and TNF- α at different\ntime points. The secondary endpoints included intra-\noperative propofol and remifentanil consumption, HR,\nMBP, VAS scores, time to first flatus, incidence of\nnausea and vomiting after the operation, and rescue\nanalgesics (fentanyl).\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 2 of 9\n\nBasal vital signs, including MBP, peripheral oxygen satur-\nation (SPO2), electrocardiogram (ECG), HR and pressure of\nend-tidal CO2 (PetCO2), were established for each patient.\nAll subjects received Ringer’s lactate (4–6m L / k g / h )f o rc o m -\npensatory capacity after arriving at the operating room. To\nreserve sufficient oxygenati on, before the induction of\nanesthesia, all patients were given continuously oxygen\n(100%) for 3 to 5 min via a facemask. The induction of gen-\neral anesthesia in all four groups was implemented with a\ntarget-controlled infusion (TCI) of plasma remifentanil and\npropofol. The initial TCI level of plasma propofol was set as\n3.0 μg/mL [18]. The initial TCI level of plasma remifentanil\nwas set as 5.0 ng/mL [19] 3 min after propofol infusion, and\nthen cis-atracurium (0.15 mg/kg) was administered intraven-\nously. Mechanical ventilation was implemented with an\nanesthesia machine (Aespire View, Datex-Ohmeda, USA).\nRespiratory parameters were adjusted to set PetCO2 between\n35 mmHg and 45 mmHg. To maintain muscle relaxation\nduring the anesthesia period, a supplemental dose of cis-\natracurium was injected intermittently. During the surgery,\nBIS values were maintained between 50 and 60 by adjusting\nthe TCI concentrations of plasma propofol during the\nanesthesia period in all patients. The hemodynamic variables\nwere maintained within 20% of the preoperative baseline\nvalues by adjusting the infusi on plasma concentrations of\npropofol and remifentanil. When patients had MBP < 60\nmmHg or HR < 50 beats/min, ephedrine (6 mg) or atropine\n(0.5 mg) was intravenously administered, respectively. Fen-\ntanyl (1 μg/kg) was given intravenously 30 min before the\nend of surgery to alleviate the intensity of pain after surgery,\nand patient-controlled intravenous analgesia (PCIA) with\n0.3 μg/kg/h fentanyl (a total regimen of 100 ml) was con-\nnected to each patient to deliver a bolus of fentanyl\n(0.075μg/kg) with a 15-min lockout interval. Propofol and\nremifentanil infusions were terminated at the end of the pro-\ncedure, and ondansetron (0.1 mg/kg) was injected to prevent\nnausea and vomiting after the operation. Neostigmine\n(20 μg/kg) and atropine (10 μg/kg) were injected intraven-\nously to reverse neuromuscular blockade when spontaneous\nrespiration sufficiently recovered. The endotracheal tube was\nremoved when the train-of-four (TOF) ratio was at least 0.9\nand patients were able to open their eyes according to verbal\ninstructions. The patients were transferred to the PACU by\nan anesthesiologist 5 min after the endotracheal tube was re-\nmoved. All patients were observed for 2 h in the PACU. The\nsurgical procedure was completed by the same operative\nt e a m ,a n dt h et a r g e tp r e s s u r eo fc a r b o nd i o x i d e( C O2)\npneumoperitoneum was maintained between 10 mmHg and\n12 mmHg during the perioperative period.\nThe levels of plasma IL-1, IL-6, and TNF- α were mea-\nsured at different time points, including baseline, the\nend of surgery, and 2 and 24 h after the operation. Blood\nsamples from each patient were placed in tubes and cen-\ntrifuged within 30 min, and plasma was separated and\nstored at − 70 °C until analysis. Enzyme-linked immuno-\nsorbent assay kits (KANU BIOLOGICAL TECHNOL-\nOGY CO., Ltd., Shanghai, China) were used to test the\nlevels of cytokines.\nA 10-cm visual analogue scale (VAS) was used to as-\nsess the intensity of pain after the operation during the\nfirst 24-h period (0 = no pain; 10 = most imaginable\npain). A total of 25 μg of fentanyl was injected when the\npostoperative VAS score was > 3 and until the VAS\nscore was ≤3.\nThe MBP and HR were recorded at baseline, at the\nend of surgery, and 2 h after the operation. Intraopera-\ntive propofol and remifentanil consumption, the operat-\ning time, the anesthesia time, VAS scores, the incidence\nof nausea and vomiting, rescue analgesics, and time to\nfirst flatus were recorded after surgery.\nSample size calculation\nBased on our pilot study, we chose the levels of plasma\nIL-1, IL-6, and TNF- α as the primary outcome. This\nstudy was powered to detect a difference in the plasma\nlevels of IL-1, IL-6, and TNF- α among the four arms\nwith a β value set at 20% and α value set at 5% from\nPASS software. The mean and SD values of plasma IL-1,\nIL-6, and TNF-α a tt h ee n do fs u r g e r yi na l lf o u rg r o u p sw e r e\nas follows:XCon =2 . 6p g / m L ,XLido= 2.4 pg/mL,XDex = 2.3 pg/\nmL, X Lido + Dex=2 . 1p g / m L , SCon =0 . 5p g / m L , SLido= 0.5 pg/\nmL, SDex = 0.4 pg/mL, SLido + Dex= 0.3 pg/mL;XCon =2 2 . 2p g /\nmL, XLido = 20.9 pg/mL, XDex = 19.0 pg/mL, XLido + Dex =\n17.7 pg/mL, S Con =5 . 9p g / m L , SLido = 5.3 pg/mL, S Dex =\n4.8 pg/mL, S Lido + Dex =4 . 7p g / m L ; a n dX Con =4 1 . 6p g /\nmL, XLido = 39.9 pg/mL, XDex = 37.8 pg/mL, XLido + Dex =\n32.9 pg/mL, S Con =7 . 2p g / m L , SLido =8 . 4p g / m L , SDex =\n8.9 pg/mL, S Lido + Dex = 7.9 pg/mL. Therefore, 32, 33,\nand 22 subjects for each group were respectively obtained,\nand considering a possible 20% dropout rate, we\nultimately intended to recruit a total of 40 subjects\nfor each arm.\nStatistical analysis\nWe used SPSS v.17 (IBM Corp., Armonk, NY, USA)\nsoftware to complete the statistical analyses in the\npresent study. Data are expressed as the number or\nmean ± standard deviation. The χ2 test or Fisher ’s exact\ntest, as appropriate, was used for categorical data ana-\nlysis. One-way analysis of variance (ANOVA) was used\nfor continuous data analysis in all four groups. Repeated\nmeasures design analysis of variance was applied to\ncompare differences in plasma IL-1, IL-6, and TNF- α\nand MBP and HR at different time points in all four\ngroups. If group differences were found by ANOVA to\nbe significant, Tukey ’s post- hoc test was performed for\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 3 of 9\n\nfurther analysis. Statistical significance was defined as a\nP value < 0.05.\nResults\nA total of 176 subjects were recruited for our trial, and\nsixteen patients were excluded, (nine patients with a his-\ntory of preoperative bradycardia and seven patients who\ndid not agree to participate in the study). Eventually, 160\nsubjects completed the present study. Data obtained\nfrom forty subjects in each arm were analysed (Fig. 1).\nNo significant differences were observed in any of the\nfour arms in regard to ASA physical status, age, BMI,\nduration of the operation, weight, or duration of\nanesthesia (Table 1).\nIntraoperative consumption of remifentanil and propofol\nThe consumption of remifentanil and propofol was signifi-\ncantly decreased in groups L, D, and LD compared to group\nC( a l lP < 0.001). The consumptionof remifentanil and pro-\npofol was lowest in group LD during the intraoperative\nperiod (P < 0.001). There were no significant differences in\nthe intraoperative consumption of propofol and remifentanil\nbetween groups L and D (P =0 . 7 4 0a n dP =0 . 0 9 7 )( T a b l e2).\nPostoperative VAS scores at rest\nThe VAS scores in groups L, D, and LD were signifi-\ncantly decreased compared to those in group C at 2\nand 6 h after the operation ( P = 0.022, P = 0.028, P <\n0.001, P < 0.001, P < 0.001, and P < 0.001, respectively).\nThe VAS scores in group LD were lower than those\nin the other three groups at 2, 6, and 12 h after sur-\ngery ( P < 0.01). There were no significant differences\nin postoperative VAS scores between groups L and D\n(P =0 . 0 5 4 ,P = 0.168, P = 0.144, P = 0.839, respectively)\n(Table 3).\nTime to first flatus\nThe time to first flatus in groups L and LD was shorter\nthan that in groups C and D ( P = 0.005, P = 0.012, P <\n0.001, and P = 0.001, respectively). There was no significant\ndifferences in the time to first flatus between groups C and\nD( P =0 . 9 9 2 )( T a b l e2).\nIncidence of nausea and vomiting after the operation\nThe number of patients who experienced nausea and\nvomiting in group LD (25%) was less than that in\ngroup C (52.5%) during the first 24 h after the\nFig. 1 CONSORT flow diagram for the study\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 4 of 9\n\noperation ( P = 0.012). There were no differences with\nrespect to PONV in groups L (42.5%) and D (32.5%) com-\npared to group C (52.5%) ( P = 0.370 and P = 0.070). The\nincidence of PONV was lowest in group LD (Table 2).\nThe levels of plasma TNF- α, IL-6, and IL-1 at different time\npoints\nThe levels of plasma TNF- α, IL-6, and IL-1 were not sig-\nnificantly different between the four groups at baseline.\nCompared to baseline, the levels of plasma TNF- α, IL-6,\nand IL-1 were significantly elevated at the end of the op-\neration and 2 h after surgery (all P < 0.001). Compared to\ngroup C, the levels of plasma TNF- α, IL-6, and IL-1\nwere significantly decreased at the end of the operation\nand 2 h after surgery in groups D and LD (all P < 0.05).\nThe levels of plasma TNF- α, IL-6, and IL-1 were lower\nat the end of the operation and 2 h after surgery in\ngroup LD than in groups L and D (all P < 0.05). The\nlevels of plasma TNF- α, IL-6, and IL-1 were not signifi-\ncantly different during the perioperative period or during\nthe first 24 h after surgery between groups L and D. The\nlevels of plasma TNF- α, IL-6, and IL-1 were not signifi-\ncantly different at 24 h after surgery in all four groups\n(Table 4).\nMBP and HR at different time points\nThe MBP was significantly decreased in groups L, D,\nand LD at 2 h after surgery compared with group C\n(P =0 . 0 3 4 , P = 0.005, and P < 0.001, respectively).\nCompared with group L, the MBP was significantly\nlower at 2 h after surgery in group LD ( P = 0.044). HR\nwas significantly lower in groups D and LD at the\nend of surgery and 2 h after surgery than in groups C\nand L (all P < 0.001) (Table 5).\nDiscussion\nA significant finding from our trial was that the intraop-\nerative combination of lidocaine and dexmedetomidine\ninfusion further reduced inflammatory responses com-\npared with lidocaine or dexmedetomidine infusion alone\nin patients following laparoscopic hysterectomy. Patients\nwho received lidocaine plus dexmedetomidine infusion\nwere associated with lower levels of plasma IL-1, IL-6,\nand TNF- α at the end of the operation and 2 h after sur-\ngery, lower VAS scores after surgery, and less intraoper-\native consumption of remifentanil and propofol\ncompared with patients who received lidocaine or dex-\nmedetomidine infusion alone. The co-administration of\nlidocaine and dexmedetomidine also resulted in a lower\nincidence of PONV.\nSurgical-related tissue damage induces stress responses\nin the body, and further promotes the release of peri-\noperative inflammatory cytokines, including IL-1, IL-6,\nand TNF- α [20]. The harmful inflammatory responses\ncaused by surgical procedures have negative effects on\npostoperative outcomes in surgical patients and increase\nmorbidity and mortality. The suppression of periopera-\ntive inflammatory responses is associated with less post-\noperative pain and improves postoperative outcomes.\nTherefore, it is important to effectively alleviate peri-\noperative inflammatory responses for patients following\nsurgery, especially major surgery. Animal experiments\nTable 1 Characteristics of patients\nVariable Group C\n(n = 40)\nGroup L\n(n = 40)\nGroup D\n(n = 40)\nGroup LD\n(n = 40)\nP value\nAge (years) 47.2 ± 4.8 48.1 ± 5.6 47.8 ± 4.9 47.3 ± 5.4 0.848\nWeight (kg) 59.9 ± 6.7 59.2 ± 6.3 57.8 ± 5.7 58.9 ± 6.2 0.541\nBMI 24.6 ± 2.6 24.3 ± 2.3 23.8 ± 2.4 24.0 ± 2.2 0.402\nAnesthesia time (min) 118.3 ± 9.2 120.7 ± 7.2 118.6 ± 7.7 120.2 ± 7.9 0.478\nOperation time (min) 99.6 ± 10.4 101.0 ± 11.1 98.9 ± 8.5 100.2 ± 11.5 0.827\nASA physical status (I / II) 21/19 18/22 23/17 20/20 0.729\nTable 2 Doses of propofol, remifentanil, rescue anesthetic, first flatus time, and incidence of PONV\nIndex Group C\n(n = 40)\nGroup L\n(n = 40)\nGroup D\n(n = 40)\nGroup LD\n(n = 40)\nP value\nPropofol dose (mg) 702.6 ± 56.3 650.3 ± 46.8 * 640.0 ± 39.0* 554.0 ± 35.3*#★ < 0.001\nRemifentanil dose (microg) 965.4 ± 87.7 835.8 ± 59.3 * 799.2 ± 68.9* 550.6 ± 62.1*#★ < 0.001\nRescue anesthetic (microg) 33.8 ± 22.3 21.3 ± 19.2 * 0.0 ± 0.0*# 0.0 ± 0.0*# < 0.001\nFirst flatus time (hours) 23.1 ± 3.8 20.4 ± 3.3 *★ 22.8 ± 3.4 19.9 ± 3.4 *★ < 0.001\nPONV (percentage) 21 (52.5) 17 (42.5) 13 (32.5) 10 (25) * 0.036\nData are presented as mean ± standard deviation (SD)\nC control, L lidocaine, D dexmedetomidine, LD lidocaine and dexmedetomidine combination\n*P < 0.05 versus group C, #P < 0.05 versus group L, ★P < 0.05 versus group D\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 5 of 9\n\nTable 3 VAS scores at rest during the first 24 h after operation\nVAS scores Group C\n(n = 40)\nGroup L\n(n = 40)\nGroup D\n(n = 40)\nGroup LD\n(n = 40)\nP value\n2 h after surgery 3.3 ± 0.7 2.9 ± 0.6 * 2.5 ± 0.6 * 1.8 ± 0.6 *#★ < 0.001\n6 h after surgery 3.4 ± 0.8 3.0 ± 0.8 * 2.6 ± 0.7 * 1.7 ± 0.6 *#★ < 0.001\n12 h after surgery 2.7 ± 0.6 2.5 ± 0.8 2.2 ± 0.8 * 1.6 ± 0.7 *#★ < 0.001\n24 h after surgery 2.0 ± 0.7 1.7 ± 0.7 1.5 ± 0.6 * 1.3 ± 0.6 *# < 0.001\nData are presented as mean ± standard deviation (SD)\nC control, L lidocaine, D dexmedetomidine, LD lidocaine and dexmedetomidine combination\n*P < 0.05 versus group C, #P < 0.05 versus group L, ★P < 0.05 versus group D\nTable 4 Comparison of plasma IL-1, IL-6, and TNF- α levels at different time points\nCytokines Groups T 0 T1 T2 T3\nIL-1(pg/ml) Group C 1.27 ± 0.35 2.72 ± 0.56 △ 3.18 ± 0.57△ 1.53 ± 0.36\nGroup L 1.36 ± 0.27 2.56 ± 0.52 △ 2.97 ± 0.53△ 1.51 ± 0.31\nGroup D 1.38 ± 0.33 2.41 ± 0.48 △ 2.83 ± 0.59△ 1.55 ± 0.37\nGroup LD 1.35 ± 0.36 2.02 ± 0.45 △ 2.36 ± 0.47△ 1.56 ± 0.34\naP 0.599 0.519 0.290 0.907\nbP 0.431 0.035 0.030 0.396\ncP 0.744 < 0.001 < 0.001 0.221\ndP 0.993 0.519 0.656 0.805\neP 0.995 < 0.001 < 0.001 0.594\nfP 0.958 0.04 0.001 0.985\nIL-6 (pg/ml) Group C 11.33 ± 2.57 23.98 ± 6.37 △ 26.05 ± 7.26△ 12.65 ± 3.18\nGroup L 10.95 ± 2.46 23.03 ± 5.87 △ 23.18 ± 5.07△ 12.00 ± 3.11\nGroup D 10.40 ± 2.94 20.60 ± 5.03 △ 21.75 ± 4.91△ 11.43 ± 3.34\nGroup LD 10.65 ± 2.66 17.15 ± 4.82 △ 18.30 ± 5.31△ 11.18 ± 3.11\naP 0.992 0.870 0.115 0.798\nbP 0.408 0.037 0.005 0.317\ncP 0.669 < 0.001 < 0.001 0.168\ndP 0.792 0.211 0.681 0.851\neP 0.958 < 0.001 0.001 0.654\nfP 0.975 0.031 0.038 0.985\nTNF-α (pg/ml) Group C 12.55 ± 2.21 44.28 ± 6.89 △ 76.10 ± 10.65△ 14.78 ± 3.49△\nGroup L 12.80 ± 2.28 41.18 ± 8.55 △ 73.13 ± 9.31△ 14.30 ± 2.66\nGroup D 12.93 ± 2.35 38.80 ± 9.84 △ 69.45 ± 8.75△ 13.80 ± 2.96\nGroup LD 13.13 ± 2.64 33.78 ± 6.92 △ 62.95 ± 11.33△ 13.43 ± 3.53\naP 0.965 0.326 0.550 0.909\nbP 0.894 0.016 0.019 0.520\ncP 0.700 < 0.001 < 0.001 0.233\ndP 0.995 0.562 0.363 0.896\neP 0.928 < 0.001 < 0.001 0.609\nfP 0.982 0.032 0.023 0.952\nData are presented as mean ± standard deviation (SD)\nT0 baseline, T1 at the end of surgery, T2 2 h after surgery, T3 24 h after surgery, C control, L lidocaine, D dexmedetomidine, LD lidocaine and\ndexmedetomidine combination\n△P < 0.05 compared with T 0, aP for group C versus group L, bP for group C versus group D, cP for group C versus group LD. dP for group L versus group D, eP for\ngroup L versus group LD, fP for group D versus group LD\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 6 of 9\n\nsuggest that dexmedetomidine administration exerts\nsome degree of protection for organs such as the lung\n[21], kidney [ 22], and brain [ 23]. The effects are associ-\nated with the anti-inflammatory property of dexmedeto-\nmidine. Kang et al. [ 24] found that dexmedetomidine\nreduced the levels of IL-1 β and TNF- α at the end of\nperitoneal closure and 1 h after the operation in patients\nundergoing laparoscopic cholecystectomy. Dong et al.\n[25] revealed that systemic dexmedetomidine infusion\ndecreased the levels of IL-1, IL-6, TNF- α, and C-reactive\nprotein (CRP) at 1 h before the end of surgery and 24 h\nafter surgery. The results of the present study indicated\nthat dexmedetomidine infusion resulted in lower plasma\nIL-1, IL-6, and TNF- α concentrations at the end of the\noperation and 2 h after surgery as well as lower VAS\nscores at 2, 6, 12 and 24 h after surgery compared with\nnormal saline infusion. Furthermore, the infusion of\nlidocaine combined with dexmedetomidine significantly\ndecreased the levels of plasma IL-1, IL-6, and TNF- α at\nthe end of the operation and 2 h after surgery and allevi-\nated pain at 2, 6, and 12 h compared to the infusion of\ndexmedetomidine alone. This suggests that lidocaine\nplus dexmedetomidine infusion further suppresses the\nsecretion of inflammatory cytokines and improves the\npostoperative intensity of pain compared with dexmede-\ntomidine infusion alone and that postoperative pain re-\nlief may be associated with lower levels of plasma IL-1,\nIL-6, and TNF- α. Anti-inflammatory and analgesic ef-\nfects of combination regimen decrease postoperative\npain intensity and requirement of opioids, which reduce\nadverse effects associated with opioids, including PONV,\ndelayed recovery of intestinal function, etc. Furthermore,\nit may be decrease cost and time of hospital and im-\nprove patient satisfaction in the clinical practice.\nLidocaine, an amide local anesthetic, is used for\nlocal anesthesia and to treat ventricular arrhythmias\nin the clinical setting. Currently, clinical studies have\nshown that intravenous li docaine administration\ndecreases opioid consumption [ 26] and postoperative\npain [ 27] and accelerates bowel function recovery\n[28]. Sridhar et al. [ 29] showed that intravenous\nlidocaine was associated with low levels of CRP and\nIL-6 during the post-operat ive period following se-\nlective open abdominal surgeries. Song et al. [ 30]r e -\nvealed that intravenous lidocaine infusion attenuated\nt h ei n i t i a t i o no fa ne x c e s s ive inflammatory response\nduring laparoscopic surgery and was associated with\nlow levels of serum IL-6 and IL-8. Our results dem-\nonstrated that intravenous lidocaine did not signifi-\ncantly decrease the levels of plasma IL-1, IL-6, and\nTNF-α compared to intravenous normal saline. The\ncause of the inconsistent results may be associated\nw i t ht h ed o s a g eo fl i d o c a i n e ,t y p eo fs u r g e r y ,a n d\nduration of continuous lidocaine infusion. The levels\nof plasma IL-1, IL-6, and TNF- α in group LD were\nlower than those in groups L and D. This suggested\nthat the combination of lidocaine and dexmedetomi-\ndine infusion further alleviated inflammatory re-\nsponses resulting from surgical trauma compared\nwith lidocaine or dexmedetomidine infusion alone.\nThis effect is attributed to following factors. (1)\nLidocaine combined with dexmedetomidine may fur-\nther attenuate the surgical stress response. (2) Lido-\ncaine and dexmedetomidine may exert anti-\ninflammatory properties by different mechanisms of\naction. (3) The combination of lidocaine and dexme-\ndetomidine infusion may exert additive anti-\ninflammatory effects. Our results also showed that\nlidocaine infusion was associated with lower VAS\nscores at 2 and 6 h after surgery, and a shorter time\nto first flatus. This finding suggests that lidocaine in-\nfusion may decrease early postoperative pain and fa-\ncilitate faster bowel functi on in patients undergoing\nlaparoscopic hysterectomy.\nAs an adjuvant drug, dexmedetomidine has been re-\nlated to attenuating the MBP and HR and the re-\nsponse to surgical procedures. Several studies have\ndemonstrated that the most common side effect of\ndexmedetomidine administration is bradycardia, which\nmay or may not be accompanied by a transient in-\ncrease in MAP [ 31–33]. Hence, we selected a smaller\ndose (0.5 μg/kg loading, 0.4 μg/kg/h infusion) in the\npresent study to decrease ad verse effects, including\nbradycardia, hypertension, and hypotension, and to\navoid delayed recovery after the operation.\nHemodynamic variables were stable at 2 h after sur-\ngery in groups D and LD. HR significantly decreased\nin groups D and LD compared to group C at the end\nof the operation and 2 h after surgery. Although lido-\ncaine plus dexmedetomidine infusion and dexmedeto-\nmidine infusion alone increased the incidence of\nbradycardia in the present study, we found that HR <\nTable 5 Comparison of MAP and HR at different time points\nVariables Groups T 0 T1 T2\nMAP (mmHg) Group C 79.2 ± 8.2 73.9 ± 4.3 △ 77.1 ± 5.1\nGroup L 78.6 ± 8.5 73.3 ± 5.1 △ 74.2 ± 4.7 △*\nGroup D 81.4 ± 7.1 72.2 ± 5.9 △ 73.6 ± 4.4 △*\nGroup LD 80.1 ± 6.2 71.1 ± 4.5 △ 71.5 ± 4.6 △*#\nHR (bpm) Group C 74.3 ± 9.0 66.9 ± 6.3 △ 71.8 ± 5.7\nGroup L 72.6 ± 8.5 66.3 ± 6.6 △ 68.6 ± 7.7\nGroup D 74.8 ± 9.1 60.4 ± 5.2 △*# 60.9 ± 5.4 △*#\nGroup LD 73.8 ± 9.2 60.0 ± 5.0 △*# 60.2 ± 4.8 △*#\nData are presented as mean ± standard deviation (SD)\nT0 baseline, T1 at the end of surgery, T2 2 h after surgery, C control, L lidocaine,\nD dexmedetomidine, LD lidocaine and dexmedetomidine combination\n△P < 0.05 compared with T 0, *P < 0.05 versus group C, #P < 0.05 versus group L\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 7 of 9\n\n50 bpm rarely occurred during the intraoperative\nperiod or during the PACU stay period after surgery.\nPONV is prevalent in patients following gynecological\nlaparoscopic surgery. The present study showed that pa-\ntients who received lidocaine plus dexmedetomidine had\na lower incidence of PONV than those receiving normal\nsaline. The possible reasons include lower postoperative\npain intensity and inflammatory cytokines.\nOur study had several limitations. On the one hand,\nwe only recorded a few inflammatory cytokines, includ-\ning IL-1, IL-6, and TNF- α, and did not perform clinical\nmeasurements associated with inflammatory responses.\nOn the other hand, we only observed the levels of\nplasma IL-1, IL-6, and TNF- α at the end of surgery and\n2 and 24 h after surgery. These time points may not ef-\nfectively reflect the levels of plasma IL-1, IL-6, and TNF-\nα caused by surgical insult in a time –dependent manner.\nFinally, we only focused on the intraoperative effects of\nlidocaine combined with dexmedetomidine following\nlaparoscopic hysterectomy. This was a short study and\nlacked recovery profile assessments, such as patient\nsatisfaction.\nConclusions\nThe intraoperative combination of lidocaine and dexme-\ndetomidine infusion further alleviated inflammatory re-\nsponses, decreased postoperative pain, and led to fewer\nPONV in patients undergoing laparoscopic hysterectomy\nthan either drug alone. Moreover, the improvement in\npostoperative pain and PONV may be associated with\nthe suppression of inflammatory cytokines.\nThe future perspectives\nThe development of ERAS and minimization of opioid\nor free opioid use may improve the recovery quality of\npatients. The inflammatory response may be associated\nwith perioperative neurocognitive disorders (PNDs). The\nco-administration of lidocaine and dexmedetomidine\nmay provide better anti-inflammatory and analgesic ef-\nfects than lidocaine or dexmedetomidine alone. There-\nfore, the effects of the combination regimen on PNDs\nand the feasibility of the method for minimizing opioid\nor free opioid use were the points of concern.\nAbbreviations\nIV: Intravenous; ASA: American Society of Anesthesiologists; IL-1: Interleukin-1;\nIL-6: Interleukin-6; TNF- α: Tumor necrosis factor- α; MBP: Mean blood pressure;\nHR: Heart rate; CO 2: Carbon dioxide; PONV: Postoperative nausea and\nvomiting; PACU: Postanesthesia care unit; SPO 2: Peripheral pulse oximeter;\nECG: Electrocardiogram; PetCO 2: Pressure of end-tidal CO 2; TCI: Target-\ncontrolled infusion; PCIA: Patient-controlled intravenous analgesia; TOF: Train\nof four; VAS: Visual analogue scale; SD: Standard deviation; ANOVA: One-way\nanalysis of variance; CRP: C-reactive protein; MAP: Mean arterial pressure\nAcknowledgements\nNot applicable.\nAuthors’ contributions\nSQX contributed to study design, data collection, statistical analysis,\ndrafting the manuscript, and revised the manuscript. SHH contributed to\ndata collection and revised the manuscript. XJ contributed to data\ncollection and study design. YHL was engaged in the design of the study\nand helped to the revision of the manuscript. QL participated in the\ndesign of the study and was responsible for clinical coordination. SBW\ndesigned the study, revised the manuscript, and interpreted the data. All\nauthors read and approved the final manuscript.\nFunding\nThis study was supported by Clinical Research Fund of Anhui Medical\nUniversity (2019xkj224).\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available\nfrom the corresponding author on reasonable request.\nEthics approval and consent to participate\nThe study was approved by the Ethics Committee of Anqing Municipal\nHospital on 10, August, 2017. Written informed consent was obtained from\neach participant.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthor details\n1Department of Anesthesiology, The Affiliated Anqing Hospital of Anhui\nMedical University, Anqing 246000, China. 2Department of Anesthesiology,\nThe First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.\n3Department of Gynaecology and Obstetrics, The Affiliated Anqing Hospital\nof Anhui Medical University, Anqing 246000, China.\nReceived: 10 September 2020 Accepted: 14 December 2020\nReferences\n1. Aarts JW, Nieboer TE, Johnson N, Tavender E, Garry R, Mol BW, et al. Surgical\napproach to hysterectomy for benign gynaecological disease. Cochrane\nDatabase Syst Rev. 2015;8:CD003677.\n2. Li Y, Wang B, Zhang LL, He SF, Hu XW, Wong GT, et al. 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Anesth Analg. 2002;94:1434 –40.\n32. Feld JM, Hoffman WE, Stechert MM, Hoffman IW, Ananda RC. Fentanyl or\ndexmedetomidine combined with desflurane for bariatric surgery. J Clin\nAnesth. 2006;18:24–8.\n33. Talke P, Lobo E, Brown R. Systemically administered alpha2-agonist-induced\nperipheral vasoconstriction in humans. Anesthesiology. 2003;99:65 –70.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nXu et al. BMC Anesthesiology            (2021) 21:3 Page 9 of 9","source_license":"CC0","license_restricted":false}