Effects of remifentanil on hemodynamics, liver function and ICAM-1 expression in liver cancer patients undergoing surgery

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1 872 Effects of remifentnil on hemodynmics, liver function nd ICAM-1 expression in liver cncer ptients undergoing surgery QI JIANG 1*, XIULING SONG 2*, ZHENG CHEN 3, CONGHUI WANG 1 nd HUIYU LUO 1 Deprtments of 1 Anesthesiology nd 2 Endocrinology, Xingyng No. 1 People's Hospitl, Hubei University of Medicine, Xingyng, Hubei ; 3 Deprtment of Heptobiliry Surgery, Gungdong Province Key Lbortory of Mlignnt Tumor Epigenetics nd Gene Regultion, Reserch Center of Medicine, Sun Yt Sen Memoril Hospitl, Sun Yt Sen University, Gungzhou, Gungdong , P.R. Chin Received Februry 3, 2017; Accepted My 2, 2017 DOI: /ol Abstrct. The objective of the present study ws to investigte the effects of remifentnil on hemodynmics, liver function, nd expression of intercellulr dhesion molecule 1 (ICAM 1) in ptients with liver cncer undergoing surgery. A totl of 60 ptients who underwent liver cncer resection in The First People's Hospitl of Xingyng, Hubei University of Medicine from Jnury 2014 to Jnury 2016 were selected, including 33 mles nd 27 femles, with n verge ge of 54.12±4.77 yers. Ptients were rndomly divided into the control group nd experimentl group (n=30 ech). The control group nd experimentl group were nesthetized with propofol/isoflurne nd remifentnil/propofol, respectively. In ddition to generl prmeters, the following prmeters were nlyzed: men systolic blood pressure nd men distolic blood pressure were obtined before tretment, during nesthesi induction nd intubtion, during blockde of trction reflexes in surgery, nd before extubtion t the end of surgery. The recovery time from nesthesi withdrwl to spontneous brething, time of eye opening, time of extubtion, nd level of consciousness were recorded. Liver expression of ICAM 1 ws mesured with SABC stining, nd the expression of sprtte minotrnsferse (AST), lnine minotrnsferse (ALT), nd totl bilirubin (TBIL) were recorded on the first, third, fifth, nd seventh dy fter surgery. According to hemodynmic prmeters, ptients in the experimentl group experienced more stble condition thn ptients in the control group (P<0.05). In ddition, the recovery time of the experimentl group ws shorter thn tht of the control group (P<0.05). Mrkers of liver function Correspondence to: Dr Huiyu Luo, Deprtment of Anesthesiology, Xingyng No. 1 People's Hospitl, Hubei University of Medicine, 15 Jiefng Rod, Xingyng, Hubei , P.R. Chin E mil: h715zf@163.com * Contributed eqully Key words: remifentnil, ischemi reperfusion injury, hemodynmics, liver function (AST, ALT nd TBIL) of the two groups fter surgery were higher thn those before surgery, nd the increses of the experimentl group were significntly lower thn those of the control group. ICAM 1 expression in the experimentl group ws significntly lower thn in the control group (P<0.05). In conclusion, nesthesi with remifentnil better mintined the stbility of hemodynmics, plyed protective role ginst heptic ischemi reperfusion injury, nd reduced ICAM 1 expression. Introduction At present, resection is n importnt tretment option for liver cncer. However, intropertive liver dmge is often inevitble. Ischemi reperfusion injury in liver surgery is common pthophysiologicl consequence in ptients (1). Ptients with liver cncer my lredy experience certin degree of liver dysfunction before surgery. Therefore, choosing n pproprite nesthetic is key for minimizing further dmge to the liver during this type of surgery. On the surfce of heptocytes, heptic sinusoidl endothelil cells nd vsculr endothelil cells express vrious dhesion molecules, mong which intercellulr dhesion molecule 1 (ICAM 1) is primrily expressed in liver tissue. The expression of ICAM 1 cn serve s biomrker of the extent of liver dmge, where higher expression indictes more severe liver dmge (2). In the present study, remifentnil ws used for generl nesthesi of ptients undergoing liver cncer surgery, to investigte the effects of remifentnil on liver function nd ICAM 1 expression, s well s blood pressure vrition in ptients. The findings my serve s reference for selecting pproprite nesthesi during surgery. Ptients nd methods Ptients. A totl of 60 ptients who underwent liver cncer resection in The First People's Hospitl of Xingyng, Hubei University of Medicine (Xingyng, Chin) were rndomly selected from Jnury 2014 to Jnury 2016, including 33 mles nd 27 femles with verge ge of 54.12±4.77 yers. All selected ptients were designted s clss I or clss II ccording to the Americn Society of Anesthesiologists

2 JIANG et l: REMIFENTANIL IN LIVER CANCER 873 Physicl Sttus clssifiction system, nd Clss A ccording to the Child Pugh clssifiction of liver disese. The ptients were rndomly divided into the control group nd experimentl group, with 30 cses in ech group. There were 17 mles nd 13 femles in the control group, with verge ge of 54.87±3.76 yers, nd 15 mles nd 15 femles in the experimentl group, with n verge ge of 53.43±4.12 yers. There were no significnt differences in preopertive liver function tests between ptients, nd surgery ws completed by the sme group of physicins in The First People's Hospitl of Xingyng, Hubei University of Medicine. Ptients hd no history of mentl disese, neurologicl disese, or serious crdiovsculr disese; no recent dministrtion of nrcotic nlgesics nd sedtive hypnotics; nd no history of using drugs tht cn cuse liver dmge, such s benzodizepines nd opioids. This study ws pproved by the Ethics Committee of Xingyng No. 1 People's Hospitl. Signed written informed consents were obtined from ll prticipnts before the study. Anesthesi. Ptients in the control group were nesthetized with propofol/isoflurne, wheres ptients in the experimentl group were dministered remifentnil/propofol (Yngze Phrm, Tizhou, Chin). Ptients were connected to the electrocrdiogrm monitor, nd received oxygen flow through fce msk fter entering the operting room. Physiologicl indictors such s blood pressure, hert rte (HR), nd finger oxygen sturtion were monitored. After estblishing the upper extremity venous ccess, ctheter ws plced in the right internl jugulr vein for mesuring the centrl venous pressure while keeping the venous ccess open. Anesthetics such s remifentnil, propofol, nd midzolm (Yngze Phrm) were dministered to ptients t the dose of 4 µg/kg, 2.5 mg/kg, nd 0.05 mg/kg, respectively, for nesthesi induction before nesthesi to fcilitte intubtion. Ptients in the control group were nesthetized with propofol/isoflurne. Following the protocol, propofol ws dministered intrvenously t dose of mg/kg/h, nd 2 3% isoflurne ws simultneously dministered by inhltion. The dministrtion of isoflurne nd propofol ws stopped 15 nd 5 min, respectively, before surgery ws finished. During surgery, the concentrtion of isoflurne ws djusted in time in ccordnce with the depth of nesthesi nd chnges of ptient hemodynmic prmeters. Ptients in the experimentl group were nesthetized with remifentnil/propofol t dose of µg/kg/min nd 7 10 mg/kg/h, respectively. The doses of remifentnil nd propofol were djusted ccording to hemodynmic chnges during surgery. Infusion of remifentnil nd propofol ws stopped 5 min before surgery ws finished. Ptients in the two groups were extubted fter wke up, recovery of spontneous brething, nd ctivtion of cough nd swllowing reflexes. Finlly, ptients were sent to the intensive cre unit. ICAM 1 mesurement. Heptic blood flow ws controlled during surgery in ptients in the two groups when liver tissues were hrvested. The obtined liver tissues were mrked nd stored in liquid nitrogen. The SABC stining technique ws used to determine the expression of ICAM 1 in liver tissue. Briefly, smples were first prepred nd cut into 5 µm prffin embedded sections. The sections were then ffixed on microscope glss slides using n dhesive. After drying, the sections were dewxed nd hydrted. After endogenous enzymes were inctivted t 20 C for 10 min, the sections were wshed three times with distilled wter, nd then immersed in citrte buffer. The buffer ws heted until it boiled, nd ws then left to stnd for 10 min without heting. After repeting the heting/cooling cycle two times, the sections were rinsed two times with PBS, followed by the ddition of ntigen retrievl buffer to expose the ntigen. The sections were then rinsed two times with PBS, followed by ddition of BSA blocking buffer, nd incubtion for 20 min. Rbbit nti rt ICAM 1 monoclonl ntibody ws dded nd incubted t 4 C. After wrming the sections to room temperture, they were rinsed with PBS, followed by the ddition of SABC regent, nd incubtion. The sections were plced in kit nd developed t 20 C, followed by wshing, counterstining, dehydrtion, clering, nd mounting. The sections were then observed under light microscope (BX-42; Olympus, Tokyo, Jpn). ICAM 1 ntibody, DAB chromogenic regent, nd other immunohistochemistry regents were purchsed from Wuhn Boster Biologicl Technology, Ltd. (Wuhn, Chin). Observtionl indictors. The generl prmeters of ptients (preopertive) were mesured nd recorded, such s sex, ge, men HR, men rteril pressure (MAP), nd liver function mrkers including sprtte minotrnsferse (AST), lnine minotrnsferse (ALT), nd totl bilirubin (TBIL). The men systolic blood pressure (SBP) nd men distolic blood pressure (DBP) were obtined before tretment, during nesthesi induction nd intubtion, during blockde of trction reflexes in surgery, nd before extubtion t the end of surgery. The recovery time from nesthesi withdrwl to spontneous brething, time of eye opening, time of extubtion, s well s the level of consciousness were recorded. The level of consciousness ws grded ccording to the Observer's Assessment of Alertness/Sedtion Scle. Ptients received score of 5 if they replied redily to nme cll nd were fully wke, score of 4 if they replied sluggishly to nme cll with slow speech rte, score of 3 if they replied only to loud nme cll with blurred speech nd dull eyes, score of 2 if they did not reply to nme cll nd only responded to mild prodding or shking, nd score of 1 if they were in lethrgic stte nd did not respond to mild prodding nd shking. In ddition, the levels of liver function mrkers, AST, ALT, nd TBIL were mesured in ll ptients t the first (D1), third (D3), fifth (D5), nd seventh (D7) dy fter surgery. Sttisticl nlysis. SPSS 19.0 sttisticl softwre ws used for dt nlysis (IBM SPSS, Armonk, NY, USA). Numericl dt re presented s men ± stndrd devition. A Chi squred (χ 2 ) test ws used for ctegoricl dt. The t test for two independent smples ws used for intergroup comprisons. Repeted mesures nlysis of vrince ws employed for intrgroup comprisons. P<0.05 ws considered to be sttisticlly significnt. Results Generl prmeters (preopertive). There were no significnt differences in sex, ge, HR, MAP, AST, ALT, or TBIL between the control group nd experimentl group (P>0.05; Tble I).

3 874 Tble I. Generl prmeters of ptients (preopertive). Sex Age HR MAP AST ALT TBIL Group (mle/femle) (yers) (per min) (mm Hg) (µmol/l) (µmol/l) (µmol/l) Control 17/ ± ± ± ± ± ±7.93 Experimentl 15/ ± ± ± ± ± ±8.44 P Vlue P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 HR, hert rte; MAP, men rteril pressure; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; TBIL, totl bilirubin. Tble II. Hemodynmic dt of the two groups t different time points. During nesthesi During blockde of Before extubtion Blood Before induction nd trction reflexes t the end of Group pressure surgery intubtion in surgery surgery Control SBP (mm Hg) ± ± ±17.27,c ±12.54,c DBP (per min) 78.47± ± ±11.75,c 86.49±10.17,c Experimentl SBP (mm Hg) ± ± ±13.12 b,c ±12.89 b,c DBP (per min) 77.68± ± ±9.82 b,c 72.19±9.48 b,c P<0.05, compred with dt during nesthesi induction nd intubtion within the group; b P>0.05, compred with dt during nesthesi induction nd intubtion within the group; c P<0.05, compred with dt in the other group t the sme time point. SBP, systolic blood pressure; DBP, distolic blood pressure. Tble III. Recovery dt of the two groups. Recovery time of Time of Level of Group spontneous brething eye opening Extubtion time consciousness Control 8.81± ± ± ±0.67 Experimentl 5.42± ± ± ±0.31 P<0.05, compred with the experimentl group. Hemodynmic dt. In the control group, SBP nd DBP were significntly higher during blockde of trction reflexes in surgery nd before extubtion t the end of surgery compred with the vlues during nesthesi induction nd intubtion (P<0.05). However, in the experimentl group, SBP nd DBP were comprble t these time points (P>0.05). Compring the two groups, SBP nd DBP during blockde of trction reflexes in surgery nd before extubtion t the end of surgery were lower in the experimentl group thn in the control group (P<0.05; Tble II). Recovery time. In the comprison of recovery time of spontneous brething, time of eye opening, extubtion time, nd level of consciousness (Tble III), the experimentl group ws better thn the control group, nd the differences were sttisticlly significnt (P<0.05). Liver function. The levels of the liver function mrkers (AST, ALT, nd TBIL) of the two groups of ptients were significntly higher fter surgery compred with those before surgery (P<0.05). The levels of AST, ALT, nd TBIL on the first, third, nd fifth dy fter surgery were higher in the control group thn in the experimentl group, nd the differences were sttisticlly significnt (P<0.05). On the seventh dy, the levels of the three mrkers returned to norml in both groups, nd there were no significnt differences between the two groups (Tble IV). ICAM 1 expression. The expression of ICAM 1 ws 54.31% in the control group, which ws significntly higher thn in the experimentl group (37.66%) (P<0.05; Fig. 1). Discussion According to globl sttistics, liver cncer rnked third mong cncer deths in 2002 (3). Primry liver cncer is not only common mlignnt tumor, but lso one of the leding cuses of deth. According to yer 2000 sttistics, the number

4 JIANG et l: REMIFENTANIL IN LIVER CANCER 875 Tble IV. The levels of liver function mrkers. Group Mrker D0 D1 D3 D5 D7 Control AST 41.28± ±29.19,c ±34.62,c 90.63±23.64,c 47.41±13.64 ALT 47.13± ±32.75,c ±34.51,c 99.82±25.77,c 49.63±14.96 TBIL 15.24± ±8.1,c 24.14±8.69,c 27.59±10.67,c 16.17±7.81 Experimentl AST 39.52± ±26.39 b,c ±25.19 b,c 72.47±19.78 b,c 40.42±10.56 ALT 45.21± ±31.46 b,c ±30.31 b,c 75.97±20.73 b,c 42.55±11.87 TBIL 15.87± ±7.88 b,c 22.97±8.13 b,c 18.77±9.64 b,c 15.93±8.11 P<0.05, compred with D0 within the control group; b P<0.05, compred with D0 within the experimentl group; c P<0.05, compred with the sme dy in the other group. AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; TBIL, totl bilirubin. Figure 1. ICAM 1 expression in the two groups by SABC stining. ICAM 1, intercellulr dhesion molecule 1. * P<0.05. of cses of liver cncer in Chin ccounted for 55% of the globl cse number, indicting tht Chin hs become country with high incidence of liver cncer. Moreover, the number of cses is incresing. The number of new cses ech yer hs reched pproximtely 350,000 (4). Presently, there re effective wys to tret liver cncer, including surgery, rdiotherpy nd chemotherpy, liver trnsplnttion, biologicl therpy, nd Chinese medicine (5). Surgery with resection offers the only chnce to cure liver cncer, thus prtil heptectomy is currently the preferred method of tretment for liver cncer (6). Opertive blood loss is mjor risk fctor ssocited with opertive mortlity fter prtil heptectomy. For effective bleeding control, temporry occlusion of heptopetl blood flow is highly necessry. However, this procedure my result in ischemi reperfusion injury of heptocytes. For ptients with poor liver function, reperfusion injury my directly ffect postopertive liver function recovery nd liver regenertion, which re ssocited with postopertive liver filure nd incresed mortlity (7,8). Thus, prevention or reduction of liver ischemi reperfusion injury during surgery hs importnt clinicl significnce for ptients undergoing liver cncer surgery. Estblishing procedures to prevent or reduce heptic ischemi reperfusion injury hs become reserch focus for reserchers nd clinicins over the world. It ws reported tht dministrtion of n pproprite nesthetic drug during surgery reduced liver reperfusion injury to certin extent by improving liver tolernce to ischemi (9,10). Remifentnil is potent opioid receptor gonist chrcterized by fst onset nd rpid metbolism. It is rpidly met bolized to n inctive metbolite by plsm nd tissue esterses, which is independent of the liver nd kidney, thus it hs been widely used in liver surgery nesthesi (11). In ddition, it ws recently reported tht remifentnil plys role in reducing ischemi reperfusion injury (12). In this control study, it ws found tht ptients receiving remifentnil during liver surgery experienced smller increse in the levels of the liver function mrkers on the first, third, nd fifth dy fter surgery, compred with ptients in the control group. Moreover, the experimentl group (dministered remifentnil) ws better thn the control group (dministered isoflurne) in terms of recovery time of spontneous brething, time of eye opening, extubtion time, nd level of consciousness. This showed tht dministrtion of remifentnil during surgery reduced liver ischemi reperfusion injury, plyed protective role in postopertive liver function, nd to some extent promoted recovery of liver function. In ddition, remifentnil ws obviously dvntgeous for postopertive recovery. ICAM 1 is single chin trnsmembrne glycoprotein with core peptide moleculr weight of 55 kd. It is member of the immunoglobulin superfmily. When inflmmtion occurs, inflmmtory fctors re relesed, which cn induce endothelil cells nd other cells to express ICAM 1 on the cell surfce, thus enhncing surfce dhesion. In the present study, it ws found tht the level of ICAM 1 in the experimentl group ws lower thn tht in the control group, nd the difference ws sttisticlly significnt. This showed tht the dministrtion of remifentnil reduced the relese of certin cytokines nd proinflmmtory fctors in liver ischemi reperfusion, resulting in reduced inflmmtory response of the liver, nd protected liver cells to some extent. Most ptients with liver cncer re middle ged nd older, who show ge relted low responses in utonomic reflexes, nd hve poor bility to djust their response to vrious stimuli such s cutting, trction, nd clipping during surgery. Therefore, these ptients tend to experience lrge fluctutions in hemodynmics, nd it is difficult to mintin stble stte. For older ptients whose hemodynmics re unstble during surgery, selecting n pproprite nesthesi is highly importnt for reducing nesthesi complictions (13). In the present study, it ws found tht when using remifentnil nesthesi during surgery, ptients experienced smller fluctutions in blood pressure thn ptients in the control group. This showed tht remifentnil cn better mintin blood pressure

5 876 stbility when ptients re sedted during surgery, nd thus the stbility of the circultory system. In conclusion, remifentnil cn better mintin blood pressure stbility of older ptients during surgery, nd the stbility of the circultory system. In ddition, remifentnil cn reduce the relese of liver relted cell dhesion molecules nd inflmmtory fctors, thus reducing liver ischemi reperfusion injury to protect liver function. References 1. Kto R, Ross S nd Foëx P: Fentnyl protects the hert ginst ischemic injury vi opioid receptors, denosine A1 receptors nd KATP chnnel linked mechnisms in rts. Br J Anesth 84: , Ymnouchi K, Yng K, Okudir S, Eguchi S, Furui J nd Knemtsu T: [D Al2, D Leu5] enkephlin (DADLE) protects liver ginst ischemi reperfusion injury in the rt. J Surg Res 114: 72 77, Prkin DM, Bry F, Ferly J nd Pisni P: Globl cncer sttistics, CA Cncer J Clin 55: , Prkin DM, Bry F, Ferly J nd Pisni P: Estimting the world cncer burden: Globocn Int J Cncer 94: , Thoms MB, O'Beime JP, Furuse J, Chn AT, Abou Alf G nd Johnson P: Systemic therpy for heptocellulr crcinom: Cytotoxic chemotherpy, trgeted therpy nd immunotherpy. Ann Surg Oncol 15: , de Boer MT, Molenr IQ nd Porte RJ: Impct of blood loss on outcome fter liver resection. Dig Surg 24: , Clvien PA, Selzner M, Rüdiger HA, Grf R, Kdry Z, Rousson V nd Jochum W: A prospective rndomized study in 100 consecutive ptients undergoing mjor liver resection with versus without ischemic preconditioning. Ann Surg 238: , discussion , Bng NR, Homer Vnnisinkm S, Grhm A, Al Mukhtr A, White SA nd Prsd KR: Ischemic preconditioning in trnsplnttion nd mjor resection of the liver. Br J Surg 92: , Müller C, Dünschede F, Koch E, Vollmr AM nd Kiemer AK: Alph lipoic cid preconditioning reduces ischemi reperfusion injury of the rt liver vi the PI3 kinse/akt pthwy. Am J Physiol Gstrointest Liver Physiol 285: G769 G778, Bedirli N, Ofluoglu E, Kerem M, Utebey G, Alper M, Yilmzer D, Bedirli A, Ozlu O nd Psoglu H: Heptic energy metbolism nd the differentil protective effects of sevoflurne nd isoflurne nesthesi in rt heptic ischemi reperfusion injury model. Anesth Anlg 106: , Lötsch J: Phrmcokinetic phrmcodynmic modeling of opioids. J Pin Symptom Mng 29: S90 S103, Kim HS, Cho JE, Hong SW, Kim SO, Shim JK nd Kwk YL: Remifentnil protects myocrdium through ctivtion of nti poptotic pthwys of survivl in ischemi reperfused rt hert. Physiol Res 59: , Kim TY, Kim DK, Yoon TG, Lim JA, Woo NS, Chee HK, Shin JK, Song MG nd Kim SH: Myocrdil injury in remifentnil bsed nesthesi for off pump coronry rtery bypss surgery: An equipotent dose of sevoflurne versus propofol. Anesth Intensive Cre 39: , 2011.