Bacterial Translocation in Thoracic and/or Head Trauma

Transcription

1 ORİJİNAL ARAŞTIRMA Bacterial Translocation in Thoracic and/or Head Trauma Erhan AYAN, MD, a Murat DEMİR, MD, a Alper AKDAĞ, MD, b Oğuz KÖKSEL, MD, a Gülden ERSÖZ, MD, b Ali ÖZDÜLGER, MD a Departments of a Thoracic Surgery, b Infection Diseases, Mersin University Faculty of Medicine, Mersin Ge liş Ta ri hi/re ce i ved: Ka bul Ta ri hi/ac cep ted: This study was approved by the Mersin University Institutional Ethics Committee for Animal Studies with document number /13 and was funded by the Mersin University Scientific Research Projects unit. Ya zış ma Ad re si/cor res pon den ce: Erhan AYAN, MD Mersin University Faculty of Medicine, Department of Thoracic Surgery, Mersin, TÜRKİYE/TURKEY erhanayan10@hotmail.com ABS TRACT Ob jec ti ve: Bac te ri al trans lo ca ti on (BT) is among the cri ti cal com po nents in the prog - ress of mul tip le or gan fa i lu re. We per for med this study to in ves ti ga te whet her BT with such se ri - o us comp li ca ti ons oc curs fol lo wing iso la ted blunt tho ra cic tra u ma or mul tip le tra u mas inc lu ding blunt tho ra cic and he ad tra u ma com po nents. Ma te ri al and Met hods: In this study, 48 Wis tar rats we re ran domly di vi ded in to fo ur gro ups (n= 12) as con trol (C), tho ra cic tra u ma (TT), he ad tra u ma (HT) and he ad+tho ra cic tra u ma (HTT) gro ups. Fol lo wing sac ri fi ce at 24 ho urs af ter tra u ma mul tip le spe ci mens from me sen te ric lymph no des, sple en, li ver, lung, and ile um and blo od samp les we - re col lec ted from all rats and we re eva lu a ted for bac te ri al growth af ter ino cu la ti on on to 5% blo od agar. Re sults: When com pa red to ot her gro ups, the in ci den ce of BT in the HTT gro up was sig ni fi - cantly hig her (p= 0.003). Alt ho ugh the ra te of BT in the TT gro up se e med hig her than C and the HT gro ups, the dif fe ren ce was not sig ni fi cant. Conc lu si on: TT con cur rent with HT re sul ted in a sig ni fi cantly hig her ra te of BT. Furt her stu di es to cla rifty the cor re la ti on bet we en inf lam ma tory res pon ses fol lo wing he ad and TTs and BT are im por tant in the sen se to re du ce mor tal con se qu en - ces of this phe no me non sig ni fi cantly in the ne ar fu tu re. Key Words: Bac te ri al trans lo ca ti on; tho ra cic in ju ri es; he ad in ju ri es ÖZET Amaç: Bak te ri yel trans lo kas yon (BT), çok lu or gan yet mez li ği ge liş me sin de kri tik kom po - nent ler den bi ri dir. Bu ça lış ma nın ama cı, izo le künt to raks trav ma sı ile künt to raks trav ma sı ve ka - fa trav ma sı nı da içe ren mul tipl trav ma la rı, bak te ri yel trans lo kas yon ge liş me si açı sın dan kar şı laş tır mak tır. Ge reç ve Yön tem ler: Ça lış ma mız da 48 adet Wis tar cin si sı çan rast ge le, kon trol (C), to raks trav ma sı (TT), ka fa trav ma sı (HT), ka fa + to raks Trav ma sı (HTT) ol mak üze re 4 gru ba ay - rıl dı. Tüm sı çan lar, trav ma dan son ra ki 24. sa at te öl dü rül dü; me zen te rik lenf bez le ri, da lak, ka ra ci - ğer, ak ci ğer ve kan ör nek le rin de bak te ri yel üre me ge li şip ge liş me di ği %5 lik kan lı agar be si ye ri ne ekim le ri ya pı la rak de ğer len di ril di. Bul gu lar: HTT gru bu di ğer grup lar la kar şı laş tı rıl dı ğın da bak te - ri yel trans lo kas yo nun bu grup ta an lam lı de re ce de da ha faz la ol du ğu gö rül müş tür (p= 0.003). TT gru bun da ki üre me HT ve kon trol gru bu na gö re da ha faz la ol mak la bir lik te,ara da ki fark is ta tis tik - sel açı dan an la mı de ğil dir. So nuç: TT ile bir lik te HT ol du ğun da BT nin be lir gin ola rak da ha yük sek oran da ger çek leş ti ği gö rül müş tür. Mul tipl trav ma lar dan son ra ge li şen yan gı sal ya nıt ile BT ara sın - da ki ko re las yo nun ya pı la cak ça lış ma lar la ay dın la tıl ma sı sa ye sin de bu ol gu la rın ölüm cül so nuç la rı - nın ya kın ge le cek te cid di oran da azal tı la bi le ce ği ne ina nı yo ruz. Anah tar Ke li me ler: Bak te ri yel trans lo kas yon; to ra sik ya ra lan ma lar; ka fa trav ma sı Turkiye Klinikleri J Med Sci 2009;29(4): Cop yright 2009 by Tür ki ye Kli nik le ri ne-third of patients admitted to hospitals following a blunt thoracic trauma may develop pulmonary contusion that can progress to pneumonia, Acute lung injury (ALI) or adult respiratory distress Turkiye Klinikleri J Int Med Med Sci 2009;29(4) Sci 2008, 4 859

2 Ayan ve ark. syndro me (ARDS), which still ha ve an ove rall morta lity ra te of 10-25%, des pi te con si de rab le ad van ces in in ten si ve ca re ma na ge ment in re cent ye ars. 1,2 Se ve ral pre vi o us stu di es ha ve shown in de ta il that a se ri o us inf lam ma tory res pon se de ve lops in the first ho urs fol lo wing tra u ma, which norma li zes by the end of the 7 th day. 1,3,4 It has be en repor ted that to cle arly elu ci da te the pat ho ge ne sis of post-con tu si on pne u mo ni a, ALI and ARDS, so me ot her co-fac tors which may con tri bu te to this inf - lam ma tory res pon se ne ed to be in ves ti ga ted as well. 5,6 The pas sa ge of in tes ti nal bac te ri a and/or the ir en do to xins ac ross the in tes ti nal bar ri er is re fer red to as bac te ri al trans lo ca ti on (BT). 7 The phe no me - non of BT can oc cur fol lo wing many con di ti ons such as ab do mi nal tra u ma, ab do mi nal com part - ment syndro me, mal nut ri ti on, ma lig nan ci es, burns, he morr ha gic shock and ex po su re to ra di a ti on Thus, re gar ding tra u ma as a pos sib le ca u se of mor ta li ti es such as sep sis and multiple organ failure (MOF), we de sig ned this study to as sess whet - her BT oc cured fol lo wing iso la ted TT and/or HT inc lu ding TT. MA TE RI AL AND MET HODS All ex pe ri ments we re per for med in ad he ren ce to the Na ti o nal Ins ti tu tes of He alth Gu i de li nes on the Ca re and Use of La bo ra tory Ani mal s. The ap pro - val of the Et hics Com mit te e was ob ta i ned be fo re the on set of the study. In this study, forty-eight al bi no Wis tar rats we ig hing bet we en g we re ran do mi zed in - to fo ur gro ups as C (n= 12), TT; n= 12, HT; n= 12 and HTT; n= 12. The animals were given a water suspension including cfu/ml Escherichia coli in addition to standard rat chow 24 hours prior to trauma. In all gro ups, ana est he si a was in du ced with 25 mg/kg -1 thi o pent hal so di um (Pen tal, İE Ula gay, Tur key) be fo re the tra u ma. Gro up C re ce - i ved only ana est he si a wit ho ut any tra u ma. Gro up TT was ex po sed to TT with a for ce of 2.7 J using the mec ha nism pub lis hed by Rag ha ven dran et al fol lo wed by ana est he si a. 3 In the HT gro up, se qu - en ti al tho ra cic and he ad tra u mas we re cre a ted in Göğüs Cerrahisi the sa me man ner as men ti o ned abo ve in gro up HTT (Fi gu re 1). 12 Twenty-fo ur ho urs af ter the tra u ma, the rats we re ana est he ti zed, and the chest ca vi ti es we re ope ned. The ani mals we re eut ha ni zed by car di ac blo od as pi ra ti on. Blo od samp les (1 ml each) we re in cu ba ted ae ro bi cally for 48 ho urs at 37 0 C in 5 ml of triptych soy broth and were pla ted on triptych soy agar with 5% blo od. Li ver, sple en, me sen te ric lymph no des and lung we re ex trac ted, were we ig - hed se pa ra tely and were pla ced in a ste ri le grin ding tu be. The samp les we re ho mo ge ni zed with 1 ml of triptych soy broth using ste ri le gro und glass stoppers. Af ter grin ding (Pot te re S, Bi o lab, Mel cun - gen-ger many), 500 µl of ho mo ge na te was trans fer red in to a tu be con ta i ning 4.5 ml of 0.9% NaCl and was used to per form fo ur se ri al di lu ti ons; the fi nal di lu ti on was From this di lu ti on, 100- µl ali qu ots we re inoculated on to two dif fe rent pla - tes, tyrip tic soy agar with 5% blo od and EMB agar. Qu an ti ta ti ve cul tu re re sults we re de ter mi ned by the num ber of co lony-for ming units (CFU) per FI GU RE 1: Sche ma tic rep re sen ta ti on of the iso la ted bi la te ral pul mo nary contu si on mo del: The pre cor di al wo od shi eld al lo wed the in duc ti on of bi la te ral pul mo nary con tu si on but spa red the me di as ti num and as so ci a ted struc tu res. 860 Turkiye Klinikleri J Med Sci 2009;29(4)

3 Thoracic Surgery Ayan et al gram cal cu la ted from the di lu ti ons of tis su e ho mo - ge na te cul tu res with the following for mu la; [(number of CFU x re cip ro cal of di lu ti on x10) / we ight of tis su e]. 13 Fi nally, the ter mi nal ile al lo op was ex ci sed to de ter mi ne in di ge no us bac te ri a and was pla ced in a tu be of thi ogl ycol la te broth. To pre vent con ta mi - na ti on from the en vi ron ment, the cul tu res we re pre pa red as the last step of the pro ce du re. All agar pla tes and thigl ycol la te broth tu bes we re in cu ba - ted ae ro bi cally in 5% CO 2 for 24 ho urs at 37 0 C. We did not study ob li ga te ana e ro bes be ca u se they are ra re ca u ses of trans lo ca ti on. 13 The Gram ne ga ti ve en te ric or ga nisms we re iden ti fi ed by their bi oc he - mi cal pro fi les; Staph ylo coc cus was iden ti fi ed by the ca ta la se test and the tu be co a gu la se test, and En te - ro coc cus was iden ti fi ed by es cu lin hydroly sis in the pre sen ce of bi le and grown in broth con ta i ning 6.5% NaCl. Chi-squ a re analy sis in SPSS 11.5 was used to eva lu a te the dif fe ren ce bet we en the gro ups. RE SULTS Bi la te ral ven tral and dor sal mar ked he morr ha ge and pul mo nary con tu si on was ob ser ved in all rats ex po sed to TT (Fi gu re 2). Wit hin the first 30 mi n- u tes fol lo wing tra u ma 3 rats in the HT gro up and anot her 3 rats in the TT gro up di ed and we re exc - lu ded from the study. Of the 3 rats which di ed in the HT gro up, 2 had epis ta xis, whi le the remaining one had no mar ked mac ros co pic signs. An eva lu a - ti on of the 3 rats which di ed in the TT gro up re ve - a led mas si ve he mot ho rax. The re fo re, 3 rats we re ad ded to each of the se gro ups and cor res pon ding tra u mas we re re pe a ted to ma in ta in the stan dard n num ber of 12. All rats, which we re sub jec ted to tra - u ma, de ve lo ped se ri o us dyspne a and re ma i ned moti on less for an ho ur fol lo wing the tra u ma. Dyspne a reg res sed af ter the first six ho urs, whi le mo tor mo - ve ments re ma i ned mostly unc han ged. At 12 ho urs, the rats we re ob ser ved to be mo ti le in the ir ca ges, and at 24 ho urs they sho wed a mar ked in cre a se in mo ti lity and dec re a se in dyspne a. No tre at ment or oxy gen sup port was gi ven to the rats in this ob ser - va ti on pro cess. All rats that we re ex po sed to TT we re fo und to ha ve mac ros co pic con tu si on. When ab do mens of the rats we re ope ned to ob ta in tis su e FIGURE 2: The ap pe a ran ce of the lungs af ter the tra u ma. Bilateral upper lobes of the lungs have to be seen contused. samp les, no se con dary signs to tra u ma we re fo und in the ab do mi nal or gans of tra u ma ti zed rats. Any bac te ri al growth in so lid or gans (li ver, sple en, lymph no des) wit ho ut any growth in lung was considered a po si ti ve sign of BT which oc cur - red in 9 rats of the HTT gro up (75%), 5 rats of the TT gro up (41.6%) and 2 rats each in the C and the HT gro ups (17% each). Blood cultures re ma i ned ste ri le in all rats. In only one rat in the HT gro up, bac te ri al growth in lung tis su e was ob ser ved. The dis tri bu ti on of bac te ri al growth among gro ups and har ves ted tis su es were de mons tra ted in Tab le 1. The bac te ri a iso la ted we re E. co li (90%), en te - ro coc ci (7%) and staph ylo coc ci (3%). As the in di - ge no us flo ra of the in tes ti nes al so inc lu des en te ro coc ci and staph ylo coc ci be si des E. co li, the - ir growth in har ves ted tis su e cul tu res was considered a sign for BT, as well. When com pa red to ot her gro ups, the in ci den - ce of BT in the HTT gro up was sig ni fi cantly hig her Turkiye Klinikleri J Int Med Med Sci 2009;29(4) Sci 2008, 4 861

4 Ayan ve ark. Göğüs Cerrahisi TABLE 1: The distribution of bacterial growth among groups. Groups Lymph Node Liver Spleen Lung Group BT / Total BT* BT in Multiple Organs HTT (n= 12) 5 /12 (42%) 7/12 (58%) 4/12 (33%) - 16/27 (59%) 5/12 (42%) TT (n= 12) 5/12 (42%) - 1/12 (8%) - 6/27 (22%) 1/12 (8%) HT (n= 12) 2/12 (17%) - - 1/12 (8%) 3/27 (11%) 1/12 (8%) C (n= 12) 2/12 (17%) /27 (8%) * (Group BT / Total BT): Group BT; the number of BTs in each group, Total BT; the sum of number of BTs in all groups. HTT; Head +Thoracic trauma, TT; Thoracic trauma, HT; Head trauma, C; Control, BT; Bacterial translocation. (p= 0.003). Alt ho ugh the ra te of BT in the TT gro - up seemed than the rate in the C and the HT gro - ups, the difference was not significant (Figure 1). DIS CUS SI ON BT is the spre ad of bac te ri a from the in tes ti nal tract to ot her syste mic or gans thro ugh lympha tic channels se con dary to im mu ne fa i lu re, pro li fe ra ti on of bac te ri a in the small in tes ti nes, in jury to in tes ti nal mu co sa and in cre a se in vas cu lar per me a bi lity. It is be li e ved that sep sis re sul ting from bac te ri al lo ca ti - on plays an im por tant ro le in MOF, which is among the most sig ni fi cant post-tra u ma tic comp - li ca ti ons. 9,14 It is na tu ral that as the num ber of tissu es and or gans in vol ved in the tra u ma and/or the deg re e of in vol ve ment in cre a ses, the re sul ting comp li ca ti ons in cre a se as well. 15 In this study, we de mons tra ted that BT de ve lo ped in the rats in which TT and HT we re in du ced to get her as a multip le tra u ma. Although the rate of bacterial translocation in the mesenteric lymph nodes of rats with only TT was 41.6%, this was not significant when compared to the control group. Blunt tho ra cic tra u mas ra te high among problems experienced in traumatic patients presenting in the emergency units. A study in vol ving pa ti ents with a ma jor tra u ma fo und a high ra te of ma jor tra - u mas as so ci a ted with tho rax, inc lu ding TT at a ra - te of 68% and pul mo nary con tu si on at a ra te of 55%. 15 Of all tra u ma pa ti ents, 30% de ve lop syste - mic inf lam ma tory res pon se syndro me (SIRS) and MOF trig ge red by tra u ma and al most 20% of the pa ti ents are lost du e to post-tra u ma tic MOF. 14 Although the mortality rate associated with MOF has decreased from 80% to 25-36% in the last decade GRAPHIC 1: The distribution of bacterial growth among groups. (C; Control, HT; Head Trauma, TT; Thoracic Trauma, HTT; Head + Thoracic Trauma). due to the changes in the treatment protocols based on results of studies aiming to clarify this pathologic process, MOF remains an important issue in traumas. 16,17 Syste mic dif fu si on of inf lam ma tory me di a tors af ter tra u ma was reported to have a ro le in the on - set of MOF. Pat ho lo gi es that most likely developed af ter pul mo nary con tu si ons li ke ALI and ARDS had a cen tral ro le in the de ve lop ment of MOF. 14 Pre vi - o us stu di es de mons tra ted that ef forts to pre vent post-tra u ma tic pul mo nary pat ho lo gi es re du ced the in ci den ce of MOF Pul mo nary con tu si on that de ve lops af ter blunt tho ra cic tra u ma is a risk factor for pne u mo ni a, ALI and ARDS, and re sults in de ath in 10 to 25% of adults. The fun da men tal pat - hoph ysi o logy of con tu si on was de fi ned as ven ti la - ti on/per fu si on mis match, in cre a sed in tra- 862 Turkiye Klinikleri J Med Sci 2009;29(4)

5 Thoracic Surgery pul mo nary shunt, en han ced pul mo nary flu id, segmen tal pul mo nary in jury and re du ced comp li an - ce. 3 Pre vi o us stu di es reported that the res pi ra tory system was the first or gan that un der went fa i lu re in MOF. Lungs co uld be the pa ce ma ker of MOF; ARDS pla yed a ma jor ro le in MOF and pre ven ti on of ARDS co uld de pend on dec re a sing the MOF inci den ce Lung-pre ser ving tre at ment ap pro ac - hes, par ti cu larly in pa ti ents with mec ha ni cal ven ti la ti on, brings abo ut a dec li ne in MOF in ci - den ce. 22,23 The se stu di es we re car ri ed out on pa ti - ents with MOF; the facus infection co uld be iden ti fi ed in only 1/3 of pa ti ents gro ups who we re cli ni cally considered sep tic. Bacterial translocation was reported to be a potential sig ni fi cant so ur ce of in fec ti on. 24 Ra pid im pa ir ment of the mu co sal barri er func ti on du e to in tes ti nal hypo per fu si on, and the as so ci a ted spre ad of bac te ri a in the in tes ti nal flo ra thro ugh trans lo ca ti on had a sig ni fi cant role in the de ve lop ment of SIRS and MOF. The ma in fo - un da ti on of this hypot he sis is the de ve lop ment of pne u mo ni a and ot her in fec ti ons in pa ti ents due to bacteremia of the trans lo ca ted in tes ti nal bac te ri a. 25 Un der nor mal con di ti ons, the in tes ti nal wall ser ves as a bar ri er pro tec ting aga inst bac te ri a. In te - rest in BT has in cre a sed because bac te ri a in the intes ti nal flo ra in cre a se mor ta lity and mor bi dity by ca u sing pne u mo ni a, bac te re mi a, uri nary in fec ti on and sep sis thro ugh BT, which was shown to de ve - lop in SIRS and MOF. 25 Li te ra tu re stu di es de mons - tra ted that BT oc cur red in va ri o us types of tra u ma, par ti cu larly in ab do mi nal tra u ma, burns and he m- orr ha gic shock. 26,27 The or gans pri ma rily af fec ted by the pas sa ge of or ga nisms or the ir pro ducts are the me sen te ric lymph no des fol lo wed by the li ver, the sple en and the ge ne ral cir cu la ti on. In the HTT mo - del that we in du ced, BT oc cur red prin ci pally in me - sen te ric lymph no des and li ver, whi le sep ti ce mi a or BT in to the pul mo nary tis su e did not de ve lop. Ad di ti o nally, as pre vi o us stu di es sho wed that the first 24 ho urs fol lo wing tra u ma was the most mar ked pe ri od for BT, we looked for BT at 24 ho - urs in our study. 25 One report de mons tra ted the de ve lop ment of BT in rats in with lo wer ex tre mity Ayan et al frac tu res and HT. In the same study, BT did not oc cur in ca se of mul tip le frac tu res in the iso la ted lo wer ex tre mity. In re la ti on to the res pi ra tory system, the li te ra tu re sho wed de ve lop ment of BT only in ri gid bronc hos copy and ARDS. 28,29 Pre vi o us cli ni cal stu di es re por ted that 35-40% of tra u ma ti zed pa ti ents de ve lo ped an in fec ti on. The most com mon in fec ti on fo ci we re shown to be the res pi ra tory tract (23-28%) and the uri nary tract (17-24%). The most com mon mic ro or ga nisms were Staphylococcus aureus, E. co li, en te ro coc ci and Pse u do mo nas, which, in te res tingly, are mic ro or ga - nisms de tec ted in the BT. It was al so no ted that mo re than half of the pa ti ents who had in fec ti ons de ve lo ped SIRS, and had a high ra te of mor ta lity. The ra te of ALI in such pa ti ents was 20%. Ra te of in fec ti on in pa ti ents who had ALI and who re qu i - red ven ti la tor sup port was re por ted to be sig ni fi - cantly hig her and sep sis and ARDS de ve lo ped mo re fre qu ently in tho se pa ti ents. Sep sis was cla i med to be res pon sib le for mor ta lity in 44% of pa ti ents with blunt tra u ma. Bac te ri a in the in tes ti nal tract rank first among the ca u ses of in fec ti ons that de ve lop in tra u ma pa ti ents and sep sis is the ma jor ca u se of mor ta lity in pa ti ents with blunt tra u ma. 16,17 Ac cor - ding to pre vi o us stu di es, fac tors that in cre a se the risk of in fec ti on in tra u ma ca ses inc lu de spi nal cord in jury, re qu i re ment for in tu ba ti on and ven ti la ti on, cen tral cat he te ri za ti ons, mul tip le trans fu si ons and mul tip le sur gi cal pro ce du res. Sa lim et al emp ha si - zed in the ir study that comp li ca ti on ra tes and morbi dity in cre a sed in ca ses with HT and concurrent ARDS or lung in jury. 30 In our study, we si mi larly fo und that BT was less com mon in rats with iso la - ted he ad tra u ma or iso la ted TT, whe re as BT was mo re com mon in the HTT gro up, whe re HTT we - re concurrent. In or der to re du ce comp li ca ti ons and in fec ti - ons, patients should undergo sur gi cal in ter ven ti on, if ne ces sary, in the early pe ri od. Early sur gi cal inter ven ti on in ca ses that re qu i re elec ti ve sur gery af - ter tra u ma was reported to have a pro tec ti ve ef fect aga inst de ve lop ment of in fec ti ons. In an ex pe ri - men tal study, Öz tu na et al sta ted that use of early in ter nal fi xa ti on in rats which de ve lo ped bo ne fractu re pre ven ted BT. 31 In addition, avoidance of un- Turkiye Klinikleri J Int Med Med Sci 2009;29(4) Sci 2008, 4 863

6 Ayan ve ark. necessary catheterizations is recommended, and development of sepsis and MOF can be significantly reduced by selection of pulmonary functionpreserving ventilator strategies to refrain from ventilator-induced lung injury (VILI) in patients who require mechanical ventilation Our study was designed to include blunt thoracic trauma and head and thoracic trauma, since there is no study to our knowledge on BT in such a model. We eva lu a ted the coexistence of pul mo - nary con tu si on and BT, which we re re por ted to play an ac ti ve ro le in the de ve lop ment of post-tra - u ma tic MOF. 28,29 Whi le BT do es not oc cur in iso la - ted blunt tho ra cic tra u ma or iso la ted HT, it de ve lops in HTT, in vol ving the he ad and tho rax. Res pi ra tory system is the ma in system that af fects mor bi dity and mor ta lity in pa ti ents who had a ma - jor tra u ma. Göğüs Cerrahisi The results of our study suggest that the pre s- en ce of TT in multiple trauma ma kes a sig ni fi cant dif fe ren ce in the de ve lop ment of BT. We think that calrifying de mons tra ting the re la ti on bet we en BT and TT, which is con si de red to ser ve as a pa ce ma - ker in the de ve lop ment of ARDS, sep sis and MOF can help pre vent de aths re sul ting from post-tra u - ma tic comp li ca ti ons, which are the most com mon ca u ses of mor ta lity among the yo ung. The cor re la - ti on bet we en inf lam ma tory res pon se and BT that de ve lops af ter HTT sho uld be eva lu a ted in furt her stu di es should be extensively investigated to prevent the se pro ces ses, which ha ve high mor ta lity ra - tes. Ack now led ge ment The aut hors thank Se ma Er den for sta tis ti cal analy sis and Nec met tin Yıl maz for grap hic rep re sen ta ti on. REFERENCES 1. Rag ha ven dran K, Da vid son BA, Woy tash JA, He lins ki JD, Marsc hke CJ, Man ders che id PA, et al. 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