A comparison of the effects of midazolam, propofol and dexmedetomidine on the antioxidant system: A randomized trial

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE 9: , 2015 A comprison of the effects of midzolm, propofol nd dexmedetomidine on the ntioxidnt system: A rndomized tril CHAO HAN 1*, WEILIANG DING 2*, WENJIE JIANG 1*, YU CHEN 3, DONGYUAN HANG 1, DAMING GU 1, GUOJUN JIANG 4, YONGFEI TAN 4, ZHIJUN GE 5 nd TIELIANG MA 2 1 Deprtment of Anesthesiology; 2 Centrl Lbortory, The Affilited Yixing Hospitl of Jingsu University, Yixing; 3 Deprtment of Anesthesiology, Jingsu Province Hospitl, Nnjing; Deprtments of 4 Criticl Cre Medicine nd 5 Crdic nd Thorcic Surgery, The Affilited Yixing Hospitl of Jingsu University, Yixing, Jingsu , P.R. Chin Received July 17, 2014; Accepted Mrch 18, 2015 DOI: /etm Abstrct. Previous studies on the ntioxidnt ctivity of sedtives hve predominntly been in vitro investigtions tht re lcking clinicl dt, resulting in conclusion without cogency. The im of the present prospective, rndomized study ws to use single sedtive drugs for nesthesi induction to compre their ntioxidnt properties. The effects on the ntioxidnt system of midzolm, propofol nd dexmedetomidine were ssessed using oxidtive stress indictors nd micronuclei (MN). Forty nine ptients undergoing esophgel cncer rdicl prosttectomy were selected. Midzolm, propofol nd dexmedetomidine were used to induce nesthesi. Venous blood smples were obtined prior to nd t 2 nd t 24 h fter surgery, nd oxidtive stress indictors were detected using the pproprite kits. The cytokinesis block micronucleus cytome ssy ws executed nd the frequencies of MN, nucleoplsmic bridges nd nucler buds were exmined. It ws found tht the use of the three sedtives, respectively, led to mrked increse in the levels of free rdicl indictors t 2 h fter surgery, which then decresed t 24 h fter surgery. Furthermore, lower levels of oxidtive stress were found following the use of propofol nd dexmedetomidine compred with those following midzolm dministrtion, nd similr results were obtined regrding Correspondence to: Dr Tieling M, Centrl Lbortory, The Affilited Yixing Hospitl of Jingsu University, 75 Tongzhengun Rod, Yixing, Jingsu , P.R. Chin E mil: mtieling@foxmil.com Professor Zhijun Ge, Deprtment of Crdic nd Thorcic Surgery, The Affilited Yixing Hospitl of Jingsu University, 75 Tongzhengun Rod, Yixing, Jingsu , P.R. Chin E mil: stff789@yxph.com * Contributed eqully Key words: midzolm, propofol, dexmedetomidine, oxidtive stress, micronucleus the level of MN. It is suggested tht propofol nd dexmedetomidine exhibit superior ntioxidnt function to midzolm. Introduction Oxidtive stress is defined s stte in which the production of rective oxygen species (ROS) overcomes the endogenous ntioxidnt defenses of the host, which leds to lipid, protein nd DNA dmge. Lipid peroxidtion, which is the min method by which free rdicls induce cellulr dmge, cn cuse decreses in membrne fluidity nd permebility, nd membrne protein denturtion. Oxidtive stress cn lso led to DNA dmge, which is ssocited with chromosome berrtions nd micronucleus formtion (1). Micronuclei (MN) result from chromosoml frgments or lgging chromosomes during cell division, which re not included in the min nucleus, existing independently in the cytoplsm. MN re min biologicl mrker of chromosoml instbility (2). An ssocition hs been proposed between incresed oxidtive stress nd poor outcomes in the criticlly ill, suggesting potentil role for ntioxidnt strtegies in the intensive cre unit (ICU) (3). Limiting levels of oxidtive stress my prevent cellulr deth, decrese inflmmtion nd reduce morbidity nd mortlity rtes (4); therefore, the ntioxidnt properties of sedtive drugs should be tken into considertion s n importnt prt of ICU remedy strtegies, prticulrly when mechnicl ventiltion is required. Previously, Kng et l (5) clssified the ntioxidnt potentil of vrious drugs used in the periopertive period; however, to the best of our knowledge, comprison of the effects on the ntioxidnt system of dexmedetomidine, propofol nd midzolm, which re most frequently used in the ICU, hs yet to be documented. The im of the present study, therefore, ws to investigte the ntioxidnt properties of the three sedtive drugs. Numerous clinicl studies hve reveled the involvement of ROS in severe invsive surgeries, such s thorcotomy, open hert surgery nd orgn trnsplnttion (6 10). In the present study, clinicl model ws designed in which single sedtive drug ws used for nesthesi induction nd mintennce to chieve definite depth of nesthesi in esophgel

2 2294 HAN et l: ANTIOXIDANT EFFECTS OF MIDAZOLAM, PROPOFOL AND DEXMEDETOMIDINE cncer rdicl prosttectomy. Venous blood smples obtined prior to surgery (T0) nd t 2 h (T1) nd 24 h (T2) fter surgery were tested to confirm the levels of ROS genertion (superoxide nion, hydrogen peroxide nd hydroxyl rdicl), the ctivity of endogenous ntioxidnt enzymes [superoxide dismutse (SOD), glutthione peroxidse (GSH Px) nd ctlse (CAT)] nd the levels of lipid peroxidtion product [mlondildehyde (MDA)] (11,12). DNA dmge ws detected using the cytokinesis block micronucleus cytome ssy (CBMN) (2). Mterils nd methods Study subjects. The study ws pproved by the Ethics Committee of the Affilited Yixing Hospitl of Jingsu University (Yixing, Chin) nd written informed consent ws obtined from ech of the prticipnts. Forty nine ptients of Society of Anesthesiologists physicl sttus Ⅰ Ⅱ, who were undergoing esophgel cncer rdicl prosttectomy, were rndomly divided into three groups: Midzolm (M group, n=16), propofol (P group, n=16) nd dexmedetomidine (D group, n=17). Ptients with liver or renl dysfunction or hemosttic disorders were excluded. The dministrtion of ntioxidnts, including vitmins C nd E, edrvone, ebselen, resvertrol nd other Chinese herbs tht hve been suggested to possess ntioxidnt properties, ws not permitted during the periopertive period. Anesthesi. All p tients received 0.5 mg tropine intrmusculrly s premediction 30 min prior to entering the operting thetre. In the M group, nesthesi induction ws performed through the intrvenous injection of midzolm (0.3 mg/kg), fentnyl (5 µg/kg) nd vecuronium bromide (0.15 mg/kg), nd mintined by intrvenous infusion of midzolm ( µg/kg/min) nd fentnyl (0.05 µg/kg/min). In the P group, nesthesi ws induced by intrvenous injection of propofol (1 mg/kg), fentnyl (5 µg/kg) nd vecuronium bromide (0.15 mg/kg), nd mintined by intrvenous infusion of propofol ( µg/kg/min) nd fentnyl (0.05 µg/kg/min). In the D group, nesthesi ws induced by intrvenous injection of dexmedetomidine (0.5 µg/kg), fentnyl (5 µg/kg) nd vecuronium bromide (0.15 mg/kg), nd mintined by intrvenous infusion of dexmedetomidine ( µg/kg/min) nd fentnyl (0.05 µg/kg/min). All ptients received trchel intubtion nd underwent mechnicl ventiltion with 100% oxygen (tidl volume, 8 10 ml/kg; respirtory frequency, 10 14/min) with the im of chieving n end tidl crbon dioxide level of mmhg during the surgicl procedure. An extr fentnyl dose (5 µg/kg) ws dministered to the ptients 3 min before the surgery. The Cerebrl Stte Index (CSI) monitor, n electroencephlogrm bsed monitor tht hs similr performnce to the Bispectrl Index in terms of predicting the clinicl stte of the ptient ssessed by the Observer's Assessment of Alertness/Sedtion scle (9), ws used to monitor the depth of nesthesi during the surgery. The CSI vlue ws mintined t ~50 by djusting the dose of the sedtive drugs. Vsopressors were dministered to regulte men rteril pressure (MAP) t bsl level. The vsoctive gents nd corresponding dose rnges were dopmine (6 30 µg/kg/min) nd nitroglycerin (1 5 µg/kg/min). Post opertive mngement. Following surgery, the ptients were dmitted to the Post Anesthesi Cre Unit (PACU) for monitoring. In ddition to ntimicrobil, expectornt, ntcid nd nutrition therpy, intrvenous morphine infusion (15 25 µg/kg/h) ws used for postopertive nlgesi. The ptients were extubted when there ws no indiction of bleeding nd the ptient ws observed to be lert, crdiovsculrly stble nd normothermic, with n rteril oxygen tension of >74 mmhg, n inspired oxygen concentrtion of <40% nd positive end expirtory pressure of <5 cmh 2 O. Prior to the ptients being dischrged from the wrd, three criteri hd to be met: i) Consciousness; ii) spontneous brething without n endotrchel tube; nd iii) stble hemodynmics without vsoctive drug dministrtion. Study protocol. The MAP, hert rte (HR), oxygen sturtion nd fluid volume were continuously monitored during the surgicl procedure nd in the PACU. The time until recovery of consciousness, trchel extubtion time nd length of PACU sty were recorded. Venous blood smples were obtined prior to the surgery (T0) nd t 2 h (T1) nd 24 h (T2) fter the surgery. The smples were then centrifuged t 1,000 x g for 15 min t room temperture nd the se rum smples were stored t 80 C until nlysis. Biochemicl nlysis. In this study, oxidtive stress indictors were divided into three ctegories: Free rdicl indictors (superoxide nion, hydrogen peroxide nd hydroxyl rdicl), free rdicl dmge indictors (MDA) nd endogenous ntioxidnt indictors (SOD, GSH Px nd CAT). All procedures were performed ccording to the instructions provided with the kits from Jincheng Bioengineering Reserch Institute (Nnjing, Chin): Superoxide nion, A052; hydrogen peroxide, A064 1; hydroxyl rdicl, A018; MDA, A003 1; SOD, A001 1; GSH Px, A005; nd CAT, A CBMN. Blood smples were drwn from the subjects. A smple of whole blood (0.5 ml) ws dded to 4.5 ml RPMI 1640 culture medium nd phytohemgglutinin, which ws required for lymphocyte stimultion. Cytochlsin B (6 µg/ml; Sigm Aldrich, St. Louis, MO, USA) ws dded fter 44 h of culture to block cytokinesis, which fcilitted the identifiction of lymphocytes tht hd divided in culture. As such, cells tht hd undergone the first mitotic division were recognized s binucleted cells nd were selectively screened for the presence of MN, nucleoplsmic bridges (NPBs) nd nucler buds (NBUDs) (7). Cell hrvesting, hypotonic tretment, fixtion nd slide preprtion were performed following stndrd procedures. The presence of MN ws scored blindly in 1,000 binucleted cells, in ccordnce with stndrd criteri, nd the frequency ws expressed s the number of binucleted cells contining one or more MN/NPBs/NBUDs per 1,000 cells (2). Sttisticl nlysis. Ctegoricl vribles re presented s percentges nd continuous vribles re expressed s the men ± stndrd devition. Differences between vribles were nlyzed using the Student's t test (continuous vribles) nd the χ 2 test (ctegoricl vribles). Dt nlysis ws performed using SPSS for Windows softwre version 14.0 (SPSS, Inc.,

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 9: , Tble I. Demogrphics nd clinicl chrcteristics. Chrcteristic M group P group D group Age (yers) 70.4± ± ±5.2 Gender (mle/femle) 12/4 12/4 12/5 Weight (kg) 61.17± ± ±8.83 Surgery durtion (h) 2.4± ± ±0.3 Blood loss (ml) 249±45 228±36 242±34 Fluid blnce in surgery (ml) 1,356±74 1,418±88 1,462±93 Use of vsoctive gents (n) Intropertive fentnyl requirement (mg) 0.68± ± ±0.05 Postopertive morphine requirement (mg) 64.6± ± ±3.3 Time until recovery of consciousness (h) 2.5± ± ±0.5 Trchel extubtion time (h) 4.6± ± ±0.9 Length of sty in the PACU (h) 43.4± ± ±5.1 Compred with M group, P<0.05. Results re presented s the men ± stndrd devition. M group, midzolm group; P group, propofol group; D group, dexmedetomidine group; PACU, Post Anesthesi Cre Unit. Chicgo, IL, USA). P<0.05 ws considered to indicte sttisticlly significnt difference. Results Ptient chrcteristics. The clinicl chrcteristics of the ptients re summrized in Tble I. The groups were similr in terms of ge, gender, weight, surgery durtion, blood loss, fluid volume, use of vsoctive gents, dose of intropertive fentnyl, dose of postopertive morphine nd length of sty in the PACU; however, the time until consciousness ws recovered nd trchel extubtion time in the M group were significntly longer thn the results for the other two groups (P<0.05). All ptients in the periopertive period were in stedy stte, nd no postopertive complictions were observed. The blood pressure, HR nd other vitl signs of the ptients of the three groups exhibited no significnt differences (P>0.05) (Fig. 1). Levels of free rdicl, free rdicl dmge nd endogenous ntioxidnt indictors. To ssess the levels of oxidtive stress, free rdicl indictors (superoxide nion, hydrogen peroxide nd hydroxyl rdicl) were detected in the plsm t different time points. The results showed tht the levels of the three indictors were incresed significntly 2 h fter surgery, but then returned to levels pproching those prior to the surgery. Furthermore, compred with the M group, the levels of the three indictors were significntly lower in the P nd D groups (Tble II). The levels of MDA showed similr trends to the free rdicl indictors; however, the level of MDA in the D group ws significntly lower thn tht in the P group t T2, while the levels in the P nd D groups were both lower thn tht observed in the M group (Tble III). With regrd to the endogenous ntioxidnt indictors (SOD nd GSH Px), the levels t T1 were found to be lower thn the presurgery vlues in the three groups. Furthermore, Figure 1. Results for the (A) men rteril blood pressure nd (B) hert rte (B) t different time points in the three groups. M group, midzolm group; P group, propofol group; D group, dexmedetomidine group; PACU, Post Anesthesi Cre Unit. the levels of SOD nd GSH Px were significntly higher in the P nd D groups compred with those in the M group. Notbly, the level of CAT did not exhibit ny significnt chnges mong the three groups (Tble IV). In these cses, it ws concluded tht more desirble effects were found in the P nd D groups.

4 2296 HAN et l: ANTIOXIDANT EFFECTS OF MIDAZOLAM, PROPOFOL AND DEXMEDETOMIDINE Tble II. Levels of superoxide nions, hydroxyl rdicls nd hydrogen peroxide. Indictor T0 T1 T2 Superoxide nion (U/l) M group 109.0± ± ±41.9 b P group 103.7± ±34.2,c 117.3±32.3 b,c D group 112.8± ±37.7,c 113.0±39.0 b,c Hydroxyl rdicl (U/ml) M group 336.5± ± ±78.3 b P group 339.7± ±82.6,c 353.4±82.9 b,c D group 347.3± ±77.2,c 363.4±79.1 b,c Hydrogen peroxide (mmol/l) M group 35.4± ± ±8.3 b P group 33.6± ±16.1,c 36.2±7.9 b,c D group 35.4± ±10.8,c 35.7±6.4 b,c Compred with T0, P<0.05; b compred with T1, P<0.05; c compred with M group, P<0.05. Results re presented s the men ± stndrd devition. M group, midzolm group; P group, propofol group; D group, dexmedetomidine group. Tble III. Levels of mlondildehyde. Group T0 T1 T2 M 5.1± ± ±1.4 b P 5.2± ±0.9,c 6.8±1.1 b,c D 5.1± ±1.3,c 5.3±1.2 b,c,d Compred with T0, P<0.05; b compred with T1, P<0.05; c compred with M group, P<0.05; d compred with P group, P<0.05. Results re presented s the men ± stndrd devition. M group, midzolm group; P group, propofol group; D group, dexmedetomidine group. Chromosoml instbility of lymphocytes in the ptients. In order to exmine the oxidtive dmge of the lymphocytes from the blood smples, the CBMN ssy ws utilized to detect the frequencies of MN, NPBs nd NBUDs t T0, T1 nd T2. It ws found tht the micronucleus nd NPB frequencies exhibited time dependent effect, with increses t T1 nd decreses t T2; however, no significnt differences mong the three time points were found for the NBUD frequency. It ws further noted tht the micronucleus frequency ws significntly lower in the P nd D groups thn tht in the M group t T1 nd T2 (Tble V). We therefore speculted tht propofol nd dexmedetomidine cused less dmge thn midzolm. Discussion Although previous in vitro study demonstrted tht the mjority of sedtive drugs exhibit ntioxidnt ctivity (5), the ppliction of sedtive drugs hs, for long time, been minly bsed on the phrmcology nd phrmcokinetic properties of the drugs, without considering their ntioxidnt ctivity nd effect on progress nd prognosis. Previous studies on the ntioxidnt ctivity of sedtives re predominntly in vitro investigtions (5) tht re lcking clinicl dt, resulting in conclusion without cogency. In the present study, specific mjor surgery (esophgel cncer rdicl prosttectomy) nd stndrdized remedy strtegies were selected s clinicl model of oxidtive stress. Vrious sedtive drugs were then used in generl nesthesi; the chnges in the levels of oxidtive stress indictors were detected nd the ntioxidnt ctivities of the sedtives were evluted. A number of different mechnisms cn led to the increse in free rdicl levels cused by surgicl trum: Mitochondril DNA dmge nd cytochrome oxidse system dysfunction; hypoxnthine conversion to xnthine nd xnthine conversion to uric cid ctlyzed by xnthine oxidse; increses in the levels of cytokines, such s tumor necrosis fctor nd interleukin 1, during the surgicl procedure nd following neutrophil nd mcrophge stimultion, cusing respirtory burst; nd oxygen derived free rdicls induced by ctecholmine relese during the periopertive period. In the present study, it ws found tht the levels of free rdicl indictors (superoxide nion, hydrogen peroxide nd hydroxyl rdicl) were mrkedly incresed t 2 h fter surgery nd decresed t 24 h fter surgery, suggesting tht surgery induced oxidtive stress nd incresed the levels of free rdicls. We therefore speculted tht the respirtory burst ws the min mechnism of oxidtive stress. Kng et l (5) found tht midzolm exhibited ntioxidnt properties, but more recent studies hve demonstrted tht the clinicl concentrtion of midzolm does not hve free rdicl scvenging cpcity (13). Previous studies investigting

5 EXPERIMENTAL AND THERAPEUTIC MEDICINE 9: , Tble IV. Levels of SOD, GSH Px nd CAT. Prmeter T0 T1 T2 SOD (U/ml) M group 43.4± ± ±5.2 P group 46.5± ±7.5,c 45.1±5.7 b,c D group 47.1± ±3.9,c 44.4±5.5 b,c GSH Px U M group 37.8± ± ±6.1 P group 39.8± ±8.9,c 33.3±9.6 b,c D group 38.0± ±7.8,c 38.1±8.2 b,c CAT U/ml M group 6.3± ± ±1.0 P group 6.4± ± ±1.1 D group 6.2± ± ±1.2 Compred with T0, P<0.05; b compred with T1, P<0.05; c compred with M group, P<0.05. Results re presented s the men ± stndrd devition. M group, midzolm group; P group, propofol group; D group, dexmedetomidine group; SOD, superoxide dismutse; GSH-Px, glutthione peroxidse; CAT, ctlse. Tble V. Frequencies of micronuclei, nucleoplsmic bridges nd nucler buds in 1,000 cells. Prmeter T0 T1 T2 Micronuclei M group 19.3± ± ±4.2 b P group 17.0± ±4.2,c 25.1±3.3 b,c D group 18.4± ±3.3,c 24.4±3.2 b,c Nucleoplsmic bridges M group 7.3± ± ±4.3 b P group 6.8± ± ±4.0 b D group 7.9± ± ±4.2 b Nucler buds M group 5.6± ± ±3.3 P group 5.3± ± ±2.1 D group 5.9± ± ±1.2 Compred with T0, P<0.05; b compred with T1, P<0.05; c compred with M group, P<0.05 (Mnn Whitney U test). Results re presented s the men ± stndrd devition. M group, midzolm group; P group, propofol group; D group, dexmedetomidine group. the effects of sedtives on free rdicls hve shown tht propofol cn not only directly rect with free rdicls (14), but lso enhnce heme oxygense expression nd generte ntioxidnt ctivities (15), s its moleculr structure is similr to tht of the endogenous ntioxidnt vitmin E. Nishin et l (16) found tht the clinicl concentrtion of dexmedetomidine hd no effect on the chemotxis nd phgocytosis of neutrophils nd the production of the superoxide nion; however, Tniguchi et l (17) suggested tht dexmedetomidine could reduce the inflmmtory cell response nd inhibit the relese of pro inflmmtory cytokines nd the genertion of oxygen free rdicls. In the present study it ws found tht the levels of superoxide nion, hydrogen peroxide nd hydroxyl rdicl in the P nd D groups were lower 2 h fter the surgery thn those in the M group, suggesting tht propofol nd dexmedetomidine re stronger rdicl scvengers. MDA, which is product of lipid peroxidtion, is the most commonly used indictor of oxidtive stress. Lipid peroxidtion, which is the primry mechnism by which free rdicls induce cellulr dmge, cn cuse decreses in membrne fluidity nd permebility, nd membrne protein denturtion. Hydroxyl rdicls induce the peroxidtion of unsturted ftty cids nd form lipid peroxidtion chin rection (18); only when two lipid rdicls rect to form non rdicl product or when the rdicls re quenched by n ntioxidnt molecule, such s α tocopherol (vitmin E), is the chin rection terminted (19). Propofol cn reduce lipid peroxidtion due to its similr moleculr structure to vitmin E (20). The present results lso showed tht the levels

6 2298 HAN et l: ANTIOXIDANT EFFECTS OF MIDAZOLAM, PROPOFOL AND DEXMEDETOMIDINE of MDA in the P nd D groups t 2 h fter surgery were lower thn those in the M group, demonstrting tht propofol nd dexmedetomidine cn significntly reduce lipid peroxidtion during surgery when compred with midzolm. At 24 h fter surgery, the level of MDA in the D group ws the lowest mong the three groups, suggesting tht dexmedetomidine exerts the strongest protection ginst lipid peroxidtion; however, the mechnism hs yet to be elucidted. Surgicl stress cn cuse decrese in the ntioxidnt enzyme ctivities of the body (21). A previous study showed tht propofol nd dexmedetomidine could enhnce the SOD ctivity of humn blood, with similr effects exhibited by both drugs (22). Another investigtion found tht propofol ws more potent enhncer of SOD ctivity thn midzolm (23). In the present study, the levels of SOD nd GSH Px in the M group t 2 h fter surgery were mrkedly lower thn those in the P nd D groups, suggesting tht surgicl trum would decrese the ctivities of SOD nd GSH Px nd tht propofol nd dexmedetomidine could enhnce the ctivities of the two indictors. The levels of CAT did not show ny differences mong the groups, indicting tht surgicl trum nd incresed free rdicl production hve few effects on the level of CAT. This my be result of GSH Px replcing the role of CAT in higher orgnisms, nd prticulrly in humns (24). It hs previously been shown tht the ctive metbolites (ctive oxygen ions, peroxides, free rdicls nd other ROS mterils) generted by oxidtive stress ttck the body nd led to n increse in the micronucleus frequency (25). In the present study, therefore, the CBMN ssy ws used to ssess the oxidtive DNA dmge of the peripherl blood lymphocytes of the ptients, nd to further to evlute the effects of the three sedtives. It ws found tht the micronucleus nd NPB frequencies were significntly higher t T1 thn those t T0, nd were lower t T2 thn tht t T1, showing tht the levels of oxidtive DNA dmge were higher following surgery but decresed with time. Furthermore, it ws found tht the micronucleus frequencies of the P nd D groups t T1 nd T2 were lower thn the frequency of the M group, suggesting tht propofol nd dexmedetomidine hd superior ntioxidnt function. Since it is the NPBs, not the NBUDs, tht eventully form MN (25), no significnt differences were found in the frequency of NBUDs. In conclusion, the dministrtion of propofol or dexmedetomidine leds to lower levels of oxidtive stress nd more desirble effects on the ntioxidnt system following surgery thn midzolm. Furthermore, dexmedetomidine exerts longer cting ntioxidnt effects thn propofol; however, the effects of sedtives on the ntioxidnt system, tretment of diseses nd disese outcome require further clinicl studies. Acknowledgements This study ws supported in prt by the Medicl Reserch Project of the Helth Deprtment of Jingsu Province (no. Z201218) nd the Six Tlent Peks Progrm of Jingsu Province (no. WSN 024, 2013). References 1. Møller P, Loft S, Lundby C nd Olsen NV: Acute hypoxi nd hypoxic exercise induce DNA strnd breks nd oxidtive DNA dmge in humns. FASEB J 15: , Fenech M: Cytokinesis block micronucleus cytome ssy. Nt Protoc 2: , Collier BR, Gildi A, Dossett LA, Dyer L, Fleming SB nd Cotton BA: Impct of high dose ntioxidnts on outcomes in cutely injured ptients. JPEN J Prenter Enterl Nutr 32: , Christmn JW, Blckwell TS nd Juurlink BH: Redox regultion of nucler fctor kpp B: therpeutic potentil for ttenuting inflmmtory responses. Brin Pthol 10: , Kng MY, Tsuchiy M, Pcker L nd Mnbe M: In vitro study on ntioxidnt potentil of vrious drugs used in the periopertive period. 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