ࡱ>    q`@?bjbjqPqPZ-::&XXXXYYY$YPb\Y @ <hzYXXXxxxiX8YRxxxN]X`Y" &?Tef!LET)n0Q8t`YxdYYJ]8?YYJ]YYYXXXXXX SVEU ILI`TE U ZAGREBU MEDICINSKI FAKULTET Mirjana Balen Topi Bolni ke infekcije krvotoka u mehani ki ventiliranih infektoloakih bolesnika starije ~ivotne dobi DISERTACIJA Zagreb, 2011. Disertacija je izraena u Klinici za infektivne bolesti  Dr. Fran Mihaljevi Medicinskog fakulteta Sveu iliata u Zagrebu Voditelj rada: prof. dr. sc. Bruno Barai ZAHVALA Najljepae zahvaljujem mentoru prof. dr. sc. Bruni Baraiu, pro elniku Zavoda za neuroinfektologiju sa centrom za intenzivno lije enje infektoloakih bolesnika, koji me je potaknuo na izradu ovog rada te mi je pritom svesrdno pomogao svojim znanjem i iskustvom. Zahvaljujem se kolegici mr. sc. Mariji Santini, dr. med. koja je sudjelovala u ureivanju baze podataka te prof. dr. sc. Arijani Tambi - Andraaevi, pro elnici Zavoda za klini ku mikrobiologiju i viaoj medicinskoj sestri Mariji ulo zbog strpljenja i pomoi pri nadopunjavanju bakterioloakih podataka za provedbu ovog istra~ivanja. Posebno se zahvaljujem mojoj obitelji na razumijevanju i podraci. SADR}AJ  TOC \o "1-4" \h \z \u  HYPERLINK \l "_Toc311049247" 1. UVOD  PAGEREF _Toc311049247 \h 1  HYPERLINK \l "_Toc311049248" 1.1. DOSADA`NJE SPOZNAJE O BOLNI KIM INFEKCIJAMA KRVOTOKA U BOLESNIKA STARIJE }IVOTNE DOBI  PAGEREF _Toc311049248 \h 2  HYPERLINK \l "_Toc311049249" 2. HIPOTEZA  PAGEREF _Toc311049249 \h 4  HYPERLINK \l "_Toc311049250" 3. CILJEVI ISTRA}IVANJA  PAGEREF _Toc311049250 \h 4  HYPERLINK \l "_Toc311049251" 3.1. OPI CILJ  PAGEREF _Toc311049251 \h 4  HYPERLINK \l "_Toc311049252" 3.2. SPECIFI NI CILJEVI  PAGEREF _Toc311049252 \h 4  HYPERLINK \l "_Toc311049253" 4. ISPITANICI I METODE  PAGEREF _Toc311049253 \h 5  HYPERLINK \l "_Toc311049254" 4.1. USTROJ ISTRA}IVANJA  PAGEREF _Toc311049254 \h 5  HYPERLINK \l "_Toc311049255" 4.2. MJESTO I VRIJEME  PAGEREF _Toc311049255 \h 5  HYPERLINK \l "_Toc311049256" 4.3. ISPITANICI  PAGEREF _Toc311049256 \h 5  HYPERLINK \l "_Toc311049257" 4.4. ISTRA}IVANI IMBENICI  PAGEREF _Toc311049257 \h 6  HYPERLINK \l "_Toc311049258" 4.4.1. ISTRA}IVANE DEMOGRAFSKE I KLINI KE ZNA AJKE  PAGEREF _Toc311049258 \h 6  HYPERLINK \l "_Toc311049259" 4.4.2. IMBENICI ISHODA  PAGEREF _Toc311049259 \h 7  HYPERLINK \l "_Toc311049260" 4.5. KLINI KI KRITERIJI  PAGEREF _Toc311049260 \h 7  HYPERLINK \l "_Toc311049261" 4.6. STATISTI KA ANALIZA  PAGEREF _Toc311049261 \h 8  HYPERLINK \l "_Toc311049262" 5. REZULTATI  PAGEREF _Toc311049262 \h 10  HYPERLINK \l "_Toc311049263" 5.1. UKLJU IVANJE BOLESNIKA U ISTRA}IVANJE  PAGEREF _Toc311049263 \h 10  HYPERLINK \l "_Toc311049264" 5.2. KRETANJE BROJA BOLESNIKA PO GODINAMA PRAENJA PREMA DOBNIM SKUPINAMA  PAGEREF _Toc311049264 \h 12  HYPERLINK \l "_Toc311049265" 5.3. OSNOVNE DEMOGRAFSKE I KLINI KE ZNA AJKE BOLESNIKA  PAGEREF _Toc311049265 \h 14  HYPERLINK \l "_Toc311049266" 5.4. U ESTALOST BOLNI KIH INFEKCIJA KRVOTOKA  PAGEREF _Toc311049266 \h 18  HYPERLINK \l "_Toc311049267" 5.5. IMBENICI POVEZANI S NASTANKOM BOLNI KIH INFEKCIJA KRVOTOKA  PAGEREF _Toc311049267 \h 23  HYPERLINK \l "_Toc311049268" 5.5.1. UTVRIVANJE IMBENIKA POVEZANIH S NASTANKOM BOLNI KIH INFEKCIJA KRVOTOKA  BIVARIJANTNA ANALIZA  PAGEREF _Toc311049268 \h 23  HYPERLINK \l "_Toc311049269" 5.5.2. UTVRIVANJE IMBENIKA POVEZANIH S NASTANKOM BOLNI KIH INFEKCIJA KRVOTOKA - MULTIVARIJANTNA ANALIZA  PAGEREF _Toc311049269 \h 30  HYPERLINK \l "_Toc311049270" 5.6. UTJECAJ POJAVE BOLNI KIH INFEKCIJA KRVOTOKA NA ISHOD LIJE ENJA  PAGEREF _Toc311049270 \h 32  HYPERLINK \l "_Toc311049271" 5.6.1. ANALIZA 28-DNEVNOG PRE}IVLJAVANJA  PAGEREF _Toc311049271 \h 32  HYPERLINK \l "_Toc311049272" 5.6.2. ANALIZE ISHODA LIJE ENJA NA PSEUDORANDOMIZIRANOM UZORKU  PAGEREF _Toc311049272 \h 35  HYPERLINK \l "_Toc311049273" 5.6.2.1. ANALIZA PRE}IVLJAVANJA NA PSEUDORANDOMIZIRANOM UZORKU  PAGEREF _Toc311049273 \h 38  HYPERLINK \l "_Toc311049274" 5.6.2.2. ANALIZA 28-DNEVNOG PRE}IVLJAVANJA NA PSEUDORANDOMIZIRANOM UZORKU  PAGEREF _Toc311049274 \h 40  HYPERLINK \l "_Toc311049275" 5.6.2.3. ANALIZA TRAJANJA LIJE ENJA NA PSEUDORANDOMIZIRANOM UZORKU  PAGEREF _Toc311049275 \h 42  HYPERLINK \l "_Toc311049276" 5.7. ETIOLOGIJA BOLNI KIH INFEKCIJA KRVOTOKA  PAGEREF _Toc311049276 \h 44  HYPERLINK \l "_Toc311049277" 6. RASPRAVA  PAGEREF _Toc311049277 \h 50  HYPERLINK \l "_Toc311049278" 7. ZAKLJU AK  PAGEREF _Toc311049278 \h 67  HYPERLINK \l "_Toc311049279" 8. SA}ETAK  PAGEREF _Toc311049279 \h 68  HYPERLINK \l "_Toc311049280" 9. SUMMARY  PAGEREF _Toc311049280 \h 69  HYPERLINK \l "_Toc311049281" 10. LITERATURA  PAGEREF _Toc311049281 \h 70  HYPERLINK \l "_Toc311049282" 11. }IVOTOPIS  PAGEREF _Toc311049282 \h 81  POPIS KRATICA (abecednim redom) APACHE II score -  Acute Physiology And Chronic Health II score - skor akutne fiziologije i kroni nog zdravlja II ARE - Ampicillin Resistant Enterococci  enterokoki neosjetljivi na ampicilin BIK - bolni ka infekcija krvotoka BSI -  Blood stream infection  infekcija krvotoka CDC -  Centers for Disease Control  Centri za kontrolu bolesti CEF 3 R  neosjetljivi na cefalosporine tree generacije CI - Confidence Interval granice pouzdanosti CVK - centralni venski kateter ESBL - Extended Spectrum Beta-Lactamase beta-laktamaze proirenog spektra GCS - Glasgow Coma Score glasgovski skor kome HR - Hazard Ratio omjer rizika JIM - jedinica intenzivne medicine KNS - koagulaza negativni stafilokoki MDR - Multidrug Resistant neosjetljiv na vie antibiotika MRSA meticilin rezistentni Staphylococcus aureus MSSA meticilin osjetljivi Staphylococcus aureus OR - Odds Ratio omjer aansi SAD - Sjedinjene ameri ke dr~ave SD - standardna devijacija SS - stupnjevi slobode SV - srednja vrijednost S}S - sredianji ~iv ani sustav UVOD S poveanjem trajanja ~ivota u posljednjih 50 godina za 12 godina u muakaraca i za 15 godina u ~ena, Republika Hrvatska se svrstava u red razvijenih europskih zemalja koje bilje~e gotovo progresivno demografsko starenje.1 U skladu s tim demografskim promjenama u druatvu mijenja se i dobna struktura bolesnika koji se hospitalno lije e, a proporcionalno tome i bolesnika koji se lije e u jedinicama intenzivne medicine (JIM), u smislu porasta udjela bolesnika starije ~ivotne dobi.2,3 Prema podatcima iz studija iz razli itih dijelova svijeta u danaanje vrijeme bolesnici starije ~ivotne dobi ine 12-58% bolesnika koji se lije e u JIM.4-8 U prospektivnoj studiji iz Francuske koja obuhvaa razdoblje od 1993.-1998. godine 36% od 1888 bolesnika koji su bili hospitalizirani u JIM dulje od 30 dana je bilo starije od 70 godina.4 Openito gledano, bolni ki ste ene infekcije predstavljaju znatan problem suvremene medicine zbog njihovog negativnog utjecaja na morbiditet i mortalitet bolni ki lije enih osoba, a samim tim i zbog znatnog poveanja ukupnih troakova lije enja. Bolni ki ste ene infekcije se javljaju u 5-10% hospitaliziranih bolesnika u Europi i sjevernoj Americi te u viae od 40% hospitaliziranih bolesnika u nekim dijelovima Azije, ju~ne Amerike i sub-saharske Afrike.9,10 Meu najviaim objavljenim stopama prevalencije bolni ki ste enih infekcija u Europi je ona s Kosova, koja iznosi 17.4%.11 Posljednjih desetljea, zbog sve eaeg koriatenja invazivnih dijagnosti kih i terapijskih postupaka te sve eae primjene imunosupresivnih lijekova u JIM, rizik za nastanak bolni ki ste ene infekcije u JIM je za 2-5 puta vei od rizika meu bolesnicima hospitaliziranim na obi nim odjelima.12,13 Stope prevalencije bolni kih infekcija ste enih u JIM se meu 14 promatranih europskih zemalja kreu od 9.7% u `vicarskoj do 31.6% u Italiji.14 Bolni ke infekcije krvotoka (BIK) smatraju se naj eaim, najsmrtonosnijim i najskupljim bolni kim infekcijama meu bolesnicima lije enim u JIM.14-16 Procjenjuje se da se BIK mogu pripisati stope mortaliteta od 12-80%, ato najviae ovisi o vrsti uzro nika, izvoru infekcije, prikladnost empirijski zapo etog lije enja, vrsti i te~ini predle~eih bolesti te prateem zakazivanju organa i organskih sustava.17-28 Istra~ivanja pojavnosti BIK u bolesnika lije enih u JIM s obzirom na dob i istra~ivanja utjecaja dobi na ishod BIK ste enih u JIM su vrlo oskudna te je namjera ovog rada daljnje rasvjetljavanje problema BIK u bolesnika starije ~ivotne dobi. DOSADA`NJE SPOZNAJE O BOLNI KIM INFEKCIJAMA KRVOTOKA U BOLESNIKA STARIJE }IVOTNE DOBI Bolni ki ste ene bakterijske infekcije su sve eae u bolesnika starije ~ivotne dobi, ne samo zato ato oni ine sve vei udio meu bolni ki lije enim osobama, ve i stoga ato je u njih vei rizik nastanka bolni ke infekcije po danu provedenom na bolni kom lije enju.29 Razlozi za to su viaestruki, a svode se na poviaenu prijem ljivost za infekcije opa~enu u starijoj ~ivotnoj dobi. Jedan od uzroka tome je slabljenje imunoloakog sustava zamijeeno sa starenjem. Iako su mnoga istra~ivanja pokazala da sa starenjem ne dolazi do pada broja stanica uroenog i ste enog imuniteta, izgleda da s dobi dolazi do funkcionalnih promjena u barem nekim od tih stanica.30-32 Za sada postoje dvije teorije koje to nastoje objasniti; prva je teorija  oateenja starenjem koja smatra da je slabljenje imunoloakog sustava posljedica postupnog slabljenja svih sastavnih dijelova obrambenog sustava domaina30,31 a druga je teorija koja smatra da je slabljenje imunoloakog sustava uzrokovano slabljenjem odreenih specifi nih dijelova imunoloakog sustava, i smatra da je skraenje telomera u imunoloakim stanicama koje se brzo dijele klju ni mehanizam slabljenja funkcije, ato budi nadu u mogunost utjecaja na to zbivanje telomeraza-temeljenim terapijama.33 Iako to an mehanizam slabljenja imunoloakog sustava s dobi joa nije poznat, nema dvojbe oko postojanja te pojave, koja se u svakidaanjici dade najbolje potkrijepiti slu ajevima reaktivacije tuberkuloze, ili pak smanjene u inkovitosti cijepljenja protiv gripe u osoba starije ~ivotne dobi. 34-36 Meu ostale imbenike koji dovode do porasta prijem ljivosti osoba starije ~ivotne dobi za infekciju spadaju pothranjenost (koja se bilje~i u 10-25, pa ak i u do 50% osoba starije ~ivotne dobi koje se primaju na bolni ko lije enje u razvijenim zemljama)37-40 zatim anatomske i fizioloake promjene koje nastaju starenjem i koje povisuju sklonost infekcijama (promjene epitela ko~e i aupljih organa, promjene mukocilijarnih aparata, valvularnih mehanizama i normalnog protoka tekuina, slabljenje refleksa gutanja i kaaljanja, smanjeno lu enje ~elu ane kiseline, promjene crijevne flore, promjene kapaciteta mokranog mjehura i nepotpuno pra~njenje itd.). Takoer, prisutne popratne bolesti, ija prevalencija raste s dobi, mogu povisiti sklonost infekcijama (diabetes mellitus, reumatske bolesti, kroni na opstruktivna bolest plua, neuroloaka oateenja nakon mo~danog udara itd.).41,42 `to se ti e ishoda lije enja, postoje izvjeataji koji govore da su teake vanbolni ki ste ene infekcije, kao ato su upale plua i infekcije krvotoka, u estalije, povezane s viae komplikacija i imaju loaiji ishod u osoba starije ~ivotne dobi nego u mlaih odraslih osoba.42 Jedna je studija japanskih autora pokazala da bolesnici starije ~ivotne dobi iz ope populacije s vanbolni ki ste enom infekcijom krvotoka imaju statisti ki zna ajno veu 90-dnevnu stopu smrtnosti nego mlai odrasli bolesnici; ona je iznosila 26.2% u dobnoj skupini e"85 godina, zatim 20.2% u dobnoj skupini od 65-84 godina i 15.4% u dobnoj skupini 18-64 godine.43 Jedna retrospektivna studija koja je obuhvatila 1740 bolesnika s podru ja jugoisto ne Francuske s infekcijom krvotoka koja je nastala u vanbolni kim ili u bolni kim uvjetima je zaklju ila da nema statisti ki zna ajne razlike u 7-dnevnoj stopi smrtnosti meu bolesnicima kada su usporeivane dobne skupine od 65-75 g, 76-85 g. i >85 g.18 Iako je davno uo eno da teako bolesne osobe starije ~ivotne dobi openito imaju ni~e stope pre~ivljavanja44 vrlo je oskudna literatura koja opisuje epidemiologiju i klini ki utjecaj bolni kih infekcija krvotoka na ishod lije enja teako bolesnih osoba starije ~ivotne dobi u JIM. Istra~ivanje belgijskih autora izvraeno na 984 bolesnika starije ~ivotne dobi lije enih u JIM koja zbrinjava nekirurake, opekirurake, kardiokirurake i bolesnike s teakim opekotinama je pokazalo da je u promatanom 15-godianjem razdoblju (1992. -2006. g.) rastao udio bolesnika e"65 godina lije enih u JIM i da je incidencija BIK bila statisti ki zna ajno ni~a u najstarijoj promatranoj dobnoj skupini e"75 godina, ali je istovremeno u toj dobnoj skupini zabilje~en najvei negativan utjecaj tih infekcija na ishod bolesti, u smislu vee stope smrtnosti.45 Analiza je pokazala da se dob e"75 godina pojavljuje kao nezavisni pokazatelj stope smrtnosti, nakon prilagoavanja kovarijanti.45 Za sada nema objavljenih istra~ivanja koja se bave utvrivanjem rizika za nastanak BIK u bolesnika starije ~ivotne dobi lije enih u JIM, kao niti istra~ivanja epidemioloakih obilje~ja i klini kog utjecaja BIK u primarno infektoloakih bolesnika starije ~ivotne dobi. Takva istra~ivanja mogla bi ukazati na mogunost preventivnog djelovanja s ciljem sprije avanja nastanka BIK u bolesnika starije ~ivotne dobi, koji su primarno lije eni od teakih infekcija te doprinjeti razvoju smjernica njihovog lije enja. HIPOTEZA Starija ~ivotna dob (e"65 g.) je povezana s veom vjerojatnoau nastanka bolni kih infekcija krvotoka u mehani ki ventiliranih infektoloakih bolesnika te u navedenih bolesnika starije ~ivotne dobi bolni ke infekcije krvotoka imaju ja e izra~en negativni utjecaj na ishod lije enja CILJEVI ISTRA}IVANJA OPI CILJ Ustanoviti rizik nastanka BIK u mehani ki ventiliranih infektoloakih bolesnika starije ~ivotne dobi SPECIFI NI CILJEVI Utvrditi utjecaj dobi i utjecaj prisutnosti BIK na ishod lije enja mehani ki ventiliranih infektoloakih bolesnika starije ~ivotne dobi u JIM Opisati epidemiologiju BIK u mehani ki ventiliranih infektoloakih bolesnika starije ~ivotne dobi ISPITANICI I METODE USTROJ ISTRA}IVANJA Radi se o retrospektivnoj analizi prospektivno sakupljanih podataka pohranjenih u jedinstvenu bazu podataka. Podatci su unoaeni u bazu u okviru prospektivnih opservacijskih istra~ivanja u sklopu projekata Ministarstva znanosti, obrazovanja i aporta Republike Hrvatske pod nazivom  Na ela primjene antimikrobnih lijekova u jedinicama intenzivnog lije enja i  Procjena potrebe i u inkovitosti lije enja teakih infekcija u jedinicama intenzivne medicine . Izvor podataka su bile povijesti bolesti lije enih bolesnika, a podatke su u elektroni ku bazu upisivali lije nici Zavoda za neuroinfektologiju s centrom za intenzivno lije enje infektoloakih bolesnika, pridr~avajui se standardnih mjera za zaatitu osobnih podataka ispitanika. MJESTO I VRIJEME Baza podataka je formirana u Zavodu za neuroinfektologiju s centrom za intenzivno lije enje infektoloakih bolesnika Klinike za infektivne bolesti  Dr. Fran Mihaljevi u Zagrebu. Ovim istra~ivanjem obraeni su podatci uneaeni u bazu u 15-godianjem razdoblju od 1. sije nja 1994. godine do 31. prosinca 2008. godine. ISPITANICI U istra~ivanje su uklju eni bolesnici oba spola oboljeli od teakih infekcija, dobi e"18 godina, lije eni u JIM e"48h, koji su bili mehani ki ventilirani. Iz istra~ivanja su isklju eni bolesnici lije eni zbog neinfektivnih bolesti, mlai od 18 godina, lije eni u JIM <48h i oni koji nisu bili mehani ki ventilirani. ISTRA}IVANI IMBENICI ISTRA}IVANE DEMOGRAFSKE I KLINI KE ZNA AJKE Dob (izra~ena u godinama) Spol Prethodni zdravstveni status (prema Knaus-ovoj klasifikaciji)46 Poremeenost svijesti - Glasgow comma score (GCS) 47 kod primitka Stanje akutne fiziologije i kroni nog zdravlja - APACHE II46 kod primitka Prilagoeni APACHE II (APACHE II kod primitka umanjen za bodove koje donosi dob)7,46 Vrsta infekcije; 1- zahvaen sredianji ~iv ani sustav (S}S) (uklju uje i sepsu sa zahvaenim S}S i tetanus), 2- ostale infekcije bez zahvaenosti S}S-a Primjena centralnog venskog katetera (CVK)  da/ne Trajanje primjene CVK (u danima) Trajanje mehani ke ventilacije (u danima) Pojava BIK za vrijeme lije enja u JIM (numeri ki  broj epizoda) Dan boravka u JIM kada je nastupila prva BIK Prisustvo ostalih bolni ki ste enih infekcija (infekcija mokranog sustava, upala plua) Etiologija BIK (pojedina ni uzro nici navedeni u skupine: gram-pozitivne bakterije, enterobakterije, nefermentirajue gram-negativne bakterije, Candida spp, ostali uzro nici, polimikrobne infekcije krvotoka) Antimikrobna osjetljivost uzro nika BIK: uz dobro osjetljive bakterije izdvojene su skupine: MRSA  meticilin rezistentni Staphylococcus aureus,48 enterokoki neosjetljivi na ampicilin, enterobakterije neosjetljive na cefalosporine 3. generacije (za izolate do godine 1999.),49 ESBL (extended spectrum beta -lactamases) enterobakterije enterobakterije koje proizvode betalaktamaze proirenog spektra (za izolate od godine 1999, kada je uvedeno testiranje na ESBL),50 MDR (multidrug resistant) bakterije  sojevi nefermentirajuih gram-negativnih bakterija koji su neosjetljivi na po jedan antibiotik iz tri ili viae razli itih grupa antibiotika51 Prikladnost primjenjenog empirijskog antibiotskog lije enja BIK (odgovarajue, neodgovarajue ili djelomi no odgovarajue)52 Dokazano ishodiate BIK (CVK, diani sustav, mokrano-spolni sustav, ko~a) Trajanje lije enja u JIM (u danima) Pre~ivljenje u JIM (da/ne) IMBENICI ISHODA Primarni imbenik ishoda: nastanak BIK Sekundarni imbenici ishoda: pre~ivljavanje u JIM, 28-dnevno pre~ivljavanje u JIM, trajanje lije enja u JIM (u danima) KLINI KI KRITERIJI Bolni kom infekcijom krvotoka ste enom u JIM je smatana ona infekcija krvotoka koja je bila praena klini kim i laboratorijskim obilje~ima sepse (prema konsensusu konferencije Ameri kog koled~a pulmologa i Druatva za intenzivnu medicinu),53 izolacijom uzro nika iz periferne venske krvi bolesnika i koja je nastupila nakon e"48h od primitka bolesnika u JIM.54 Koagulaza negativni stafilokok je smatran uzro nikom sepse ako je uz postojanje klini kih simptoma uzro nik izoliran iz dvije razli ite hemokulture uzete u razli ito vrijeme.55 BIK je smatrana polimikrobnom ako su u bolesnika izolirane hemokulturom dvije ili viae vrsta uzro nika unutar 48h od vaenja prve hemokulture.56 Empirijski zapo eto lije enje je smatrano odgovarajuim ako je zapo eto d"24h od pojave simptoma infekcije lijekom na koji je izolirani soj bio dobro osjetljiv.7,52 Empirijsko lije enje je smatrano neodgovarajuim ako je izolirani soj bio neosjetljiv na empirijski primjenjeni antibiotik ili je antibiotik primijenjen >24h od po etka simptoma a empirijsko lije enje je smatrano djelomi no odgovarajuim u slu aju intermedijarne osjetljivosti izoliranog soja te u slu ajevima polimikrobnih infekcija krvotoka ukoliko je empirijski zapo eto lije enje bilo odgovarajue za jedan izolirani soj, a neodgovarajue za drugi/e izolirane sojeve, a lije enje je zapo eto d"24h od po etka simptoma. Za utvrivanje ishodiata BIK koriateni su standardni klini ko-bakterioloaki kriteriji. CVK je smatran ishodiatem BIK ukoliko je isti uzro nik izoliran iz periferne venske krvi bolesnika i nakon kvantitativne i semikvantitativne kultivacije vrha CVK metodom po Makiju.57 Diani sustav je smatran ishodiatem ukoliko je isti uzro nik izoliran iz periferne venske krvi bolesnika i iz aspirata bronha u bolesnika s bolni ki ste enom, radioloaki potvrenom upalom plua prema kriterijima ameri kog nacionalnog sustava za kontrolu nozokomijalnih infekcija,58 ili ukoliko je isti uzro nik izoliran iz periferne venske krvi bolesnika i iz aspirata bronha u bolesnika s klini ki prisutnim purulentnim traheobronhitisom. Mokrani sustav je smatran ishodiatem ukoliko je isti uzro nik izoliran iz periferne venske krvi i iz urina bolesnika s uvedenim urinarnim kateterom u broju e"105 CFU/ml urina, pri emu je bolesnik mogao ali nije morao imati klini ke simptome urinarne infekcije.54 Ko~a je smatrana ishodiatem ako je isti uzro nik izoliran iz krvi bolesnika i iz brisa bilo koje ko~ne promjene ili ko~nog upalnog procesa.59 Ukoliko je u bolesnika sa sepsom izoliran uzro nik iz periferne venske krvi, bez znakova infekcije drugih lokalizacija u tijelu, BIK je smatrana primarnom.54 Molekularna subtipizacija uzro nika radi egzaktnog utvrivanja ishodiata BIK nije raena. STATISTI KA ANALIZA U statisti koj analizi podataka su koriatene standardne metode obrade podataka za opservacijske studije. Univarijatna analiza za kontinuirane varijable je prikazana kao prosje na vrijednost, standardna devijacija i medijan, a za kategorijske varijable kao frekvencija i postotak pojedinih vrijednosti. Grupe su, s obzirom na broj bolesnika, usporeivane primjenom parametarskih testova. Razlika izmeu grupa bolesnika je za kontinuirane varijable testirana primjenom T-testa ili analizom varijance, a za kategorijske varijable hi-kvadrat testom ili Fisherovim exact testom. Mjere asocijacije su iskazane omjerom aansi ( odds ratio - OR) izmeu dviju grupa. Kretanje trendova je testirano Cochran-Armitage testom. Utjecaj nastanka BIK na ishod lije enja je ispitan ovisno o zavisnoj varijabli; za kontinuirane zavisne varijable generaliziranim linearnim mijeaanim modelom (glimmix), a za kategorijske zavisne varijable logisti kom regresijskom metodom, nakon prilagodbe za ostale imbenike koji utje u na ishod lije enja. Raena je analiza 28-dnevne smrtnosti. Razina statisti ke zna ajnosti je postavljena na p<0.05. Kako bi se u analizi ishoda lije enja izbjeglo optereenje koje proizlazi iz opservacijskog dizajna studije zbog nejednakosti promatranih dobnih skupina bolesnika prema njihovim demografskim i klini kim obilje~jima i kako bi se dobio kvazi-randomizirani uzorak, za svakog bolesnika uklju enog u studiju izra unata je vjerojatnost nastanka BIK ("propensity score") logisti kom regresijskom analizom prekomjerno parametriziranog modela u koji su uklju eni svi promatrani imbenici koji bi mogli doprinjeti u estalosti pojave BIK: dob, spol, vrsta primarne infekcije s obzirom na zahvaenost S}S-a, te~ina predle~eih kroni nih bolesti (referentna vrijednost = odsustvo kroni nih bolesti), APACHE II, APACHE II umanjen za bodove dobi i GCS te njihove interakcije. Prije daljnjih analiza provjerena je eksplanatorna vrijednost modela i uravnote~enost grupa ispitivanjem standardizirane razlike za svaku varijablu. Kao pokazatelji neravnote~e uzete su vrijednosti standardizirane razlike vee od 0.1. Na temelju dobivenih skorova su nakon poravnanja za sve utjecajne imbenike formirani parovi bolesnika s i bez BIK, ukoliko im se logit vjerojatnosti nastanka BIK podudarao unutar dviju desetina standardne devijacije logit-a nastanka BIK, koji su uklju eni u analize ishoda lije enja. Za obradu podataka koriaten je SAS 9.2 statisti ki paket. REZULTATI UKLJU IVANJE BOLESNIKA U ISTRA}IVANJE U razdoblju od 01.01.1994.  31.12.2008. je u JIM Klinike za infektivne bolesti  Dr. Fran Mihaljevi lije en 2171 infektoloaki bolesnik e"18 g. Od ukupnog broja bolesnika njih 1078 je isklju eno iz istra~ivanja; 922 bolesnika koji nisu bili mehani ki ventilirana i 156 bolesnika koji su boravili u JIM krae od 48 h. Stablo uklju ivanja bolesnika u istra~ivanje prikazano je na Slici 1. Od 1093 preostala bolesnika koji su zadovoljili uvjete uklju ivanja u istra~ivanje njih 584/1093 (53.4%) je bilo dobi 18-64 godina, a 509/1093 (46.6%) bolesnika je bilo dobi e"65 godina. Kako bi se u analizi ishoda lije enja izbjeglo optereenje nejednakoau promatranih dobnih skupina bolesnika prema njihovim demografskim i klini kim obilje~jima i kako bi se dobio kvazi-randomizirani uzorak, za svakog bolesnika uklju enog u studiju izra unata je vjerojatnost nastanka BIK logisti kom regresijskom metodom ("propensity score"), na temelju koje je nakon poravnanja za ostale utjecajne imbenike izdvojeno 212 parova bolesnika (s i bez BIK), koji su uklju eni u analize ishoda lije enja.  * JIM  jedinica intenzivne medicine ** BIK  bolni ka infekcija krvotoka Slika  SEQ "Figure" \*Arabic 1: Uklju ivanje bolesnika u istra~ivanje KRETANJE BROJA BOLESNIKA PO GODINAMA PRAENJA PREMA DOBNIM SKUPINAMA U promatranom razdoblju po godinama je postupno rastao apsolutni broj promatranih bolesnika lije enih u JIM, a u okviru toga i apsolutni broj bolesnika iz starije promatrane dobne skupine. Tijekom promatranih godina zna ajno se mijenjao omjer promatranih dobnih skupina (p=0.037), pri emu se udio bolesnika starije ~ivotne dobi kretao od najmanjeg 36.2% godine 1996. do najveeg 56.5% godine 2007. (Slika 2).  p=0.037, Cochran-Mantel-Haenszel test Slika  SEQ "Figure" \*Arabic 2: Raspodjela odraslih mehani ki ventiliranih bolesnika lije enih zbog teakih infekcija u jedinici intenzivne medicine u razdoblju od 1994-2008. g, prema dobnim skupinama U promatranom razdoblju nije utvren trend porasta udjela bolesnika starije ~ivotne dobi meu promatranim bolesnicima (p=0.161) (Slika 3).  p=0.161, Cochran-Armitage test Slika  SEQ "Figure" \*Arabic 3: Kretanje udjela bolesnika e"65 godina u razdoblju od 1994-2008. g. OSNOVNE DEMOGRAFSKE I KLINI KE ZNA AJKE BOLESNIKA Da bismo utvrdili usporedivost dviju promatranih dobnih skupina usporedili smo ih s obzirom na demografske i klini ke zna ajke bolesnika. Usporedba promatranih dobnih skupina bolesnika prema njihovim osnovnim demografskim i klini kim zna ajkama pri prijemu u JIM je prikazana u Tablici 1. Promatrane dobne skupine su se zna ajno razlikovale prema veini promatranih demografskih i klini kih obilje~ja. U skupini bolesnika 18-64 godine su sa 63.9% udjela prevladavali muakarci, dok su u skupini bolesnika e"65 godina sa 50.9% udjela prevladavale ~ene (p<0.0001). Dobne skupine su se zna ajno razlikovale i prema te~ini predle~eih bolesti i stanja (p=0.0050). Promatrane dobne skupine su se zna ajno razlikovale prema vrsti infekcije zbog koje su zaprimljeni u JIM; bolesnici 18-64 godine su imali eae infekcije sa zahvaanjem S}S-a, uklju ujui i sepse sa zahvaenim S}S-om i tetanus (55.0% vs. 42.6%) dok su bolesnici e"65 godina eae imali infekcije ostalih sijela, bez zahvaenosti S}S-a (57.4% vs. 45.0%) (p<0.0001). Bolesnici starije dobne skupine su imali zna ajno vei prosje ni APACHE II skor kod primitka u JIM (22.3 vs. 19.1) (p<0.0001), ali kada se izvraila prilagodba APACHE II skora, tj njegovo umanjenje za bodove koje donosi dob, razlika izmeu promatranih dobnih skupina nije bila statisti ki zna ajna (17.5 vs. 16.9) (p=0.1056), ato upuuje na to da su bolesnici iz obje promatrane dobne skupine bili podjednako teako bolesni kod primitka u JIM. Prosijek GCS je bio zna ajno ni~i u dobnoj skupini 18-64 godine (10.1 vs 10.9) (p=0.0009) (u toj dobnoj skupini su zabilje~ene i eae infekcije S}S-a). Tablica  SEQ "Table" \*Arabic 1: Osnovne demografske i klini ke zna ajke bolesnika pri prijemu u jedinicu intenzivne medicine, prema dobnim skupinama 18- 64 godine (N=584)e"65 godina (N=509)Ukupno (N=1093)p Dob (godine)Srednja vrijednost47.674.960.3Standardna devijacija12.86.517.1SpolN (%)N (%)N (%)<.0001*}enski211 ( 36.1%)259 ( 50.9%)470 ( 43.0%)Muaki373 ( 63.9%)250 ( 49.1%)623 ( 57.0%)Predle~ee kroni ne bolesti/stanja (po Knausu)0.0050*Zdrav213 ( 36.5%)141 ( 27.7%)354 ( 32.4%)Bla~a kroni na bolest215 ( 36.8%)224 ( 44.0%)439 ( 40.2%)Teaka kroni na bolest126 ( 21.6%)105 ( 20.6%)231 ( 21.1%)Terminalno stanje30 ( 5.1%)39 ( 7.7%)69 ( 6.3%)Vrsta infekcije<.0001*Infekcija S}S-a1321 ( 55.0%)217 ( 42.6%)538 ( 49.2%)Ostale teake infekcije263 ( 45.0%)292 ( 57.4%)555 ( 50.8%)APACHE II<.0001**Srednja vrijednost19.122.320.6Standardna devijacija8.18.88.5APACHE II prilagoen za dob0.1056**Srednja vrijednost17.516.917.2Standardna devijacija7.98.78.3Glasgow Coma Score0.0009**Srednja vrijednost10.110.910.5Standardna devijacija4.34.14.2 1 S}S  sredianji ~iv ani sustav; uklju uje i sepsu sa zahvaenim S}S-om te tetanus * Hi-kvadrat test ** Wilcoxon rank-sum test Usporedba promatranih dobnih skupina prema pojedinim klini kim obilje~jima i u injenim zahvatima je prikazana u Tablici 2. U obje promatrane dobne skupine je estoa primjene CVK bila podjednaka, CVK je primjenjen u 94.0% bolesnika iz mlae i u 95.1% bolesnika iz starije promatrane dobne skupine (p=0.437), ali je u bolesnika starije dobne skupine CVK bio primjenjivan zna ajno du~e, za prosje no 2.7 dana (15.8 vs. 13.1 dan) (p=0.005). Takoer, u starijoj promatranoj dobnoj skupini je zabilje~eno zna ajno du~e trajanje mehani ke ventilacije, za prosje no 3.5 dana (srednja vrijednost: 16.2 vs. 12.7 dana) i zna ajno du~e trajanje lije enja u JIM, za prosje no 4.4 dana (srednja vrijednost: 22.9 vs. 18.5 dana) (p=0.0052 i p=0.0049). U starijoj promatranoj dobnoj skupini zabilje~en je zna ajno vei broj bolni kih infekcija mokranog sustava  ukupno 141 epizoda u 114/509 (22.4%) bolesnika u odnosu na 94 epizode u 84/584 (14.4%) bolesnika u mlaoj promatranoj dobnoj skupini (p=0.0052). Promatrane dobne skupine se nisu zna ajno razlikovale po broju bolni ki ste enih upala plua  zabilje~ene su 72 epizode u 67/509 (13.2%) bolesnika u starijoj vs. 90 epizoda u 81/584 (13.9%) bolesnika u mlaoj promatranoj dobnoj skupini. (p=0.9168). Pripadnici starije promatrane dobne skupine su imali zna ajno ni~u stopu pre~ivljavanja u JIM u odnosu na mlau promatranu dobnu skupinu, 47.2 vs. 57.2% (p=0.0010) te su imali 49.2% vei ukupni rizik smrtnog ishoda u odnosu na bolesnike iz mlae promatrane dobne skupine; HR: 1.492 (95% CI: 1.175-1.845). Navedeni podatci su pokazali da su se promatrane dobne skupine zna ajno razlikovale kako u nizu zna ajki prilikom prijema u JIM tako i u svim klini kim zna ajkama va~nim za ocjenu ishoda lije enja u JIM. Bolesnici iz starije promatrane dobne skupine su imali znatno du~e uveden CVK, bili su znatno du~e mehani ki ventilirani i du~e lije eni u JIM te je njihova stopa pre~ivljavanja u JIM bila zna ajno ni~a u odnosu na bolesnike iz mlae promatrane dobne skupine. To pokazuje da se prilikom ispitivanja utjecaja dobi na u estalost nastanka BIK kao i utjecaja dobi na ishod lije enja moraju uzeti u obzir navedene razlike i da se mora izvraiti  poravnanje usporeivanih skupina u odnosu na imbenike koji utje u na promatrani ishod. Tablica  SEQ "Table" \*Arabic 2: Pojedina klini ka obilje~ja i u injeni zahvati u promatranih bolesnika tijekom lije enja u jedinici intenzivne medicine (JIM), prema dobnim skupinama 18- 64 godine (N=584)e"65 godina (N=509)p N (%)N (%)Bolesnici s primjenjenim CVK1 549 (94.0)484 (95.1)0.437*SV2 (SD3)SV (SD)Primjena CVK (dani) 13.1 (12.2)15.8 (14.6)0.0069**Mehani ka ventilacija (dani) 12.7 (14.1)16.2 (20.4)0.0052**Lije enje u JIM (dani) 18.5 (18.1)22.9 (26.4)0.0049**Broj epizoda bolni kih infekcija mokranog sustava N (%)N (%)0.0052*0500 (85.6)395 (77.6)175 (12.8)92 (18.1)28 (1.4)19 (3.7)31 (0.2)2 (0.4)501 (0.2)Broj epizoda bolni kih upala plua 0.9168*0503 (86.1)442 (86.8)174 (12.7)63 (12.4)25 (0.9)3 (0.6)32 (0.3)1 (0.2)Ishod lije enja u JIM 0.0010*Pre~ivio 334 (57.2)240 (47.2)Umro250 (42.8)268 (52.7) 1 centralni venski kateter 2 srednja vrijednost 3 standardna devijacija * Hi-kvadrat test ** Wilcoxon rank-sum test U ESTALOST BOLNI KIH INFEKCIJA KRVOTOKA Od promatranih 1093 bolesnika BIK je zabilje~ena u njih 256/1093 (23.4%). Kod 256 bolesnika s BIK su zabilje~ene ukupno 353 epizode BIK; 186/256 (72.7%) bolesnika je imalo po jednu epizodu, a preostalih 70/256 (27.3%) bolesnika je imalo 2-5 epizoda BIK tijekom lije enja u JIM. Podatci o u estalosti BIK u odnosu na promatrane dobne skupine prikazani su u Tablici 3. U starijoj promatranoj dobnoj skupini zabilje~en je grani no statisti ki zna ajno vei udio bolesnika koji su tijekom boravka u JIM imali BIK - 133/509 (26.1%) vs. 123/584 (21.1%) (p=0.0484). Bolesnici iz starije promatrane dobne skupine su imali za 32.6% vei rizik nastanka BIK u odnosu na bolesnike iz mlae promatrane dobne skupine; HR: 1.326 (95% CI: 1.001-1.795). Promatrane dobne skupine se nisu zna ajno razlikovale po raspodjeli broja epizoda BIK (p=0.0914). Poato se primjena CVK kod bolesnika lije enih u JIM smatra najzna ajnijim rizi nim imbenikom za nastanak BIK, u estalost pojave BIK prikazali smo i u odnosu na du~inu primjene CVK. U starijoj promatranoj dobnoj skupini utvren je grani no zna ajno vei prosje ni broj epizoda BIK na 1000 dana primjene CVK (17.7 vs. 16.4 epizoda BIK) (p=0.0464), dok se prosje an broj epizoda BIK na 1000 dana lije enja u JIM nije zna ajno razlikovao meu promatranim dobnim skupinama (12.4 vs. 12.3 epizoda BIK) (p=0.0966). Tablica  SEQ "Table" \*Arabic 3: Pojava bolni kih infekcija krvotoka (BIK) u promatranih bolesnika, s obzirom na dobne skupine 18-64 godine (N=584)e"65 godina (N=509)Ukupno (N=1093)pBolni ka infekcija krvotoka (BIK)N (%)N (%)N (%)0.0484*Ne461 ( 78.9%)376 ( 73.9%)837 ( 76.6%)Da123 ( 21.1%)133 ( 26.1%)256 ( 23.4%)Broj epizoda BIK 0.0914**0461 ( 78.9%)376 ( 73.9%)837 ( 76.6%)196 ( 16.4%)90 ( 17.7%)186 ( 17.0%)220 ( 3.4%)31 ( 6.1%)51 ( 4.7%)36 ( 1.0%)7 ( 1.4%)13 ( 1.2%)41 ( 0.2%)3 ( 0.6%)4 ( 0.4%)5-2 ( 0.4%)2 ( 0.2%)Broj epizoda BIK na 1000 dana CVK10.0464***Srednja vrijednost16.417.717.0Standardna devijacija43.836.340.4Broj epizoda BIK na 1000 dana lije enja u JIM20.0966***Srednja vrijednost12.312.412.4Standardna devijacija32.626.930.1 1 CVK  centralni venski kateter 2 JIM  jedinica intenzivne medicine *Hi-kvadrat test **Fisher-ov exact test ***Wilcoxon rank-sum test S ciljem dobivanja uvida u kretanje udjela bolesnika s BIK po godinama praenja, u injena je analiza iji rezultati pokazuju da u promatranim godinama nije bilo trenda promjene udjela bolesnika s BIK u ukupnom promatranom uzorku bolesnika (p=0.0626). Nakon stratifikacije po dobi utvreno je da se u promatranom razdoblju udio bolesnika s BIK u mlaoj promatranoj dobnoj skupini kretao od najveeg 32.5% godine 2007. do najmanjeg 10.2% godine 2003. U mlaoj promatranoj dobnoj skupini nije primjeen trend promjene udjela bolesnika s BIK (p=0.1207) (Slika 4).  p=0.1207, Cochran-Armitage test Slika  SEQ "Figure" \*Arabic 4: Udio bolesnika s bolni kim infekcijama krvotoka (BIK) u dobnoj skupini 18-64 g. u promatranom razdoblju Udio bolesnika s BIK se u starijoj promatranoj dobnoj skupini kretao od najveeg 48.3% godine 1999. do najmanjeg 8.3% godine 2008. i zabilje~en je trend zna ajnog pada udjela bolesnika s BIK meu bolesnicima starije promatrane dobne skupine u promatranom razdoblju (p=0.0002) (Slika 5).  p=0.0002, Cochran-Armitage test Slika  SEQ "Figure" \*Arabic 5: Udio bolesnika s bolni kim infekcijama krvotoka (BIK) u dobnoj skupini e"65 g. u promatranom razdoblju Kretanje udjela bolesnika s BIK u dvije promatrane dobne skupine u promatranom razdoblju je prikazano na Slici 6.  p=0.1207, Cochran-Armitage test (18-64 g.) p=0.0002, Cochran-Armitage test (e"65 g.) Slika  SEQ "Figure" \*Arabic 6: Udio bolesnika s bolni kom infekcijom krvotoka (BIK) u dobnoj skupini 18-64 g. i dobnoj skupini e"65 g. u promatranom razdoblju Podatci su pokazali da je u starijoj promatranoj dobnoj skupini zabilje~en grani no zna ajno vei udio bolesnika s BIK te da su oni imali za 32.6% vei rizik nastanka BIK i grani no zna ajno vei prosje an broj BIK na 1000 dana primjene CVK, no kroz promatrane godine je utvren trend zna ajnog pada udjela bolesnika s BIK meu bolesnicima starije ~ivotne dobi, ato nije zamjeeno u mlaoj promatranoj dobnoj skupini. IMBENICI POVEZANI S NASTANKOM BOLNI KIH INFEKCIJA KRVOTOKA UTVRIVANJE IMBENIKA POVEZANIH S NASTANKOM BOLNI KIH INFEKCIJA KRVOTOKA  BIVARIJANTNA ANALIZA Da bismo analizirali imbenike koji utje u na nastanak BIK i prema njima u inili poravnanje u multivarijantnoj analizi, usporedili smo grupe bolesnika s i bez BIK bivarijantnom analizom. Odnos pojedinih demografskih i klini kih zna ajki bolesnika pri prijemu u JIM s pojavom BIK prikazan je u Tablici 4. Bolesnici s BIK bili su zna ajno stariji u odnosu na bolesnike bez BIK; prosje na dob u grupi bolesnika s BIK iznosila je 62.9 godina vs. 59.5 godina u grupi bolesnika bez BIK (p=0.0169). Bolesnici s BIK su bili zna ajno eae ~enskog spola (53.1%), dok su u skupini bolesnika bez BIK prevaladavali muakarci (60.1%) (p=0.0002). Skupine bolesnika bez i s BIK nisu se statisti ki zna ajno razlikovale prema predle~eim bolestima i stanjima (po Knausu) pri primitku u JIM (p=0.0827). S obzirom na sijelo primarne infekcije zbog koje su bolesnici bili zaprimljeni u JIM utvrena je zna ajna razlika izmeu skupine s i skupine bez BIK; u skupini bolesnika bez BIK prevladavali su bolesnici s primarnim infekcijama bez zahvaenosti S}S-a (53.9%), dok su u skupini bolesnika s BIK prevladavali bolesnici koji su primarno zaprimljeni u JIM zbog teake infekcije sa zahvaenim S}S-om, uklju ujui i sepse sa zahvaenim S}S-om i tetanus (59.4%) (p=0.0002). Statisti ki zna ajna razlika je utvrena meu skupinama s i bez BIK u odnosu na APACHE II skor kod primitka; srednja vrijednost skora je bila vea u skupini bolesnika bez BIK i iznosila je 21.1 vs. 19.9 u grupi bolesnika s BIK (p=0.0004). Nakon prilagodbe APACHE II skora za dob takoer je razlika izmeu skupina bez i s BIK bila statisti ki zna ajna; srednja vrijednost prilagoenog skora je bila vea u skupini bolesnika bez BIK i iznosila je 17.7 vs. 15.3 u grupi bolesnika s BIK (p<.0001). Promatrane skupine bez i s BIK su se zna ajno razlikovale i prema GCS pri primitku u JIM, s ni~im prosje nim vrijednostima GCS u skupini bolesnika bez BIK; 10.2 vs. 11.2 (p=0.0005). Tablica  SEQ "Table" \*Arabic 4: Odnos pojedinih demografskih i klini kih zna ajki bolesnika pri prijemu u jedinicu intenzivne medicine s pojavom bolni kih infekcija krvotoka (BIK) Bolni ka infekcija krvotoka Ukupno (N=1093) pNE (N bolesnika=837)DA (N bolesnika=256)Dob (godine)0.0169*Srednja vrijednost59.562.960.3Standardna devijacija17.615.117.1Dobna skupinaN (%)N (%)N (%)0.0484**18-64 godine461 ( 55.1%)123 ( 48.0%)584 ( 53.4%)e"65 godina376 ( 44.9%)133 ( 52.0%)509 ( 46.6%)Spol0.0002**}enski334 ( 39.9%)136 ( 53.1%)470 ( 43.0%)Muaki503 ( 60.1%)120 ( 46.9%)623 ( 57.0%)Kroni ne bolesti/stanja (po Knausu)0.0827**Zdrav276 ( 33.0%)78 ( 30.5%)354 ( 32.4%)Bla~a kroni na bolest320 ( 38.2%)119 ( 46.5%)439 ( 40.2%)Teaka kroni na bolest188 ( 22.5%)43 ( 16.8%)231 ( 21.1%)Terminalno stanje53 ( 6.3%)16 ( 6.3%)69 ( 6.3%)Vrsta infekcije0.0002**Infekcija S}S-a1386 ( 46.1%)152 ( 59.4%)538 ( 49.2%)Ostale teake infekcije451 ( 53.9%)104 ( 40.6%)555 ( 50.8%)APACHE II0.0004*Srednja vrijednost21.119.020.6Standardna devijacija8.68.18.5APACHE II prilagoen za dob<.0001*Srednja vrijednost17.715.317.2Standardna devijacija8.38.18.3Glasgow Coma Score0.0005*Srednja vrijednost10.211.210.5Standardna devijacija4.24.24.21 S}S  sredianji ~iv ani sustav; uklju uje i sepse sa zahvaenim S}S-om, kao i tetanus, * Wilcoxon rank-sum test ** Hi-kvadrat test Navedeni rezultati su pokazali da su bolesnici koji su tijekom lije enja u JIM imali BIK bili prosje no zna ajno stariji od onih koji nisu imali BIK, da su zna ajno eae bili ~enskog spola, eae su primarno bolovali od infekcijske bolesti sa zahvaenoau S}S-a, a usporedba APACHE II skorova i GCS pokazuje da su oni pri prijemu u JIM bili klini ki bla~e bolesni od bolesnika koji tijekom lije enja u JIM nisu oboljeli od BIK. Odnos pojedinih klini kih zna ajki bolesnika tijekom lije enja u JIM s pojavom BIK je prikazan u Tablici 5. Bolesnici s BIK su imali zna ajno du~e prosje no trajanje primjene CVK (25.6 vs. 10.9 dana) (p=<.0001) te su bili prosje no zna ajno du~e mehani ki ventilirani nego bolesnici bez BIK (28.3 vs. 10.1 dan) (p<.0001) a takoer su bili prosje no zna ajno du~e lije eni u JIM (38.4 vs. 15.1 dan) (p<.0001). Promatrane skupine su se zna ajno razlikovale prema broju epizoda bolni kih infekcija mokranog sustava (p<.0001); meu bolesnicima s BIK zabilje~eno je ukupno 116 epizoda bolni kih infekcija mokranog sustava u 93/256 (36.3%) bolesnika, dok je u 106/837 (12.7%) bolesnika bez BIK zabilje~eno 119 epizoda bolni kih infekcija mokranog sustava. Promatrane skupine su se zna ajno razlikovale prema broju epizoda bolni kih upala plua (p<.0001); meu bolesnicima s BIK zabilje~ene su ukupno 94 epizode bolni ke upale plua u 80/256 (31.3%) bolesnika sa BIK, dok je u bolesnika bez BIK zabilje~eno ukupno 68 epizoda bolni kih upala plua u 68/837 (8.1%) bolesnika bez BIK. Meu bolesnicima s BIK bio je zna ajno veu udio bolesnika koji su pre~ivjeli lije enje u JIM (59.8% vs. 50.3%) (p=0.0079). Navedeni rezultati pokazuju da su bolesnici koji su tijekom lije enja u JIM oboljeli od BIK imali zna ajno du~e primjenjen CVK, da su bili zna ajno du~e mehani ki ventilirani i du~e lije eni u JIM, da su zna ajno eae imali bolni ku infekciju mokranog sustava i bolni ku upalu plua, no usprkos tome, bivarijantna analiza je pokazala da su bolesnici s BIK imali ni~u stopu smrtnosti u odnosu na bolesnike koji tijekom lije enja u JIM nisu imali BIK. Tablica  SEQ "Table" \*Arabic 5: Odnos pojedinih klini kih zna ajki bolesnika tijekom lije enja u jedinici intenzivne medicine s pojavom bolni kih infekcija krvotoka (BIK) Bolni ka infekcija krvotoka Ukupno (N=1093) pNE (N bolesn.=837)DA (N bolesn.=256)Trajanje primjene CVK1 (dani)<.0001*N835XX2561091XXSrednja vrijednost10.925.614.3Standardna devijacija9.617.413.4Trajanje mehani ke ventilacije (dani)<.0001*N836 X255 X1091XXSrednja vrijednost10.128.3Standardna devijacija10.326.4Trajanje lije enja u JIM2 (dani)<.0001*Srednja vrijednost15.138.420.5Standardna devijacija14.332.822.5Broj epizoda bolni kih infekcija mokranog sustavaN (%)N (%)N (%)<.0001**0731 (87.3)164 (64.1)895 (81.9)194 (11.2)73 (28.5)167 (15.3)211 (1.3)16 (6.2)27 (2.5)31 (0.1)2 (0.8)3 (0.3)501 (0.4)1 (0.1)Broj epizoda bolni kih upala plua<.0001**0769 (91.9)176 (68.8)945 (86.5)168 (8.1)69 (26.9)137 (12.5)208(3.1)8 (0.7)303 (1.2)3 (0.3)Ishod lije enja u JIM0.0079***Pre~ivio421 (50.3)153 (59.8)574 (52.5)Umro416 (49.7)103 (40.2)519 (47.5) 1 CVK  centralni venski kateter, 2 JIM  jedinica intenzivne medicine X za jednog bolesnika nedostaje podatak, XX za dva bolesnika nedostaju podatci * Wilcoxon rank-sum test, **Cochran-Mantel-Haenszel test, ***Hi-kvadrat test Takoer, predhodno navedeni podatci su upuivali na inhomogenost grupa s obziroma na rizi ne imbenike koji mogu utjecati na u estalost BIK. Zbog toga nije bilo mogue provesti zaklju ivanje o utjecaju dobi na u estalost BIK bez prethodne prilagodbe ostalih rizi nih imbenika, ato je provedeno multivarijatnom logisti kom regresijskom analizom, iji su rezultati navedeni u poglavlju 7.5.2. S ciljem utvrivanja razlika pojavnosti BIK u odnosu na promatrane dobne skupine, u injena je bivarijantna usporedba pojedinih klini kih imbenika u bolesnika s BIK, s obzirom na dobnu skupinu. Rezultati te usporedbe su prikazani u Tablici 6. Prva epizoda BIK se u mlaoj promatranoj dobnoj skupini javljala prosje no 20.5 dana nakon prijema bolesnika u JIM, a u starijoj promatranoj dobnoj skupini se javljala prosje no 23.3 dana nakon prijema (medijani: 15.5 vs. 19.0 dana), no ta se razlika nije pokazala statisti ki zna ajnom (p=0.2044) (Tablica 6). U najveem broju slu ajeva su u obje promatrane dobne skupine BIK bile primarne, bez bakterioloakog dokaza ishodiata  u 63.2% slu ajeva u mlaoj i u 59.0% slu ajeva u starijoj promatranoj dobnoj skupini. Naj eae definirano ishodiate BIK je u obje promatrane dobne skupine bio diani sustav  u 15.2% u mlaoj i u 20.0% u starijoj dobnoj skupini. Na drugom mjestu po u estalosti je ishodiate BIK bio CVK  u 14.6% u mlaoj i u 19.2% u starijoj promatranoj dobnoj skupini. Na treem mjestu po u estalosti je ishodiate BIK bio mokrani sustav  u 7.0% u mlaoj i u 9.2% u starijoj promatranoj dobnoj skupini, dok je ko~a kao ishodiate BIK bila definirana u svega 2.6% bolesnika starije dobne skupine. Prema ishodiatu BIK promatrane dobne skupine se nisu statisti ki zna ajno razlikovale (p=0.1384) (Tablica 6). U veini epizoda BIK (61.2%) je primjenjeno empirijsko antibiotsko lije enje bilo neodgovarajue; u mlaoj promatranoj dobnoj skupini u 62.7%, i u starijoj promatranoj dobnoj skupini u 60.0% epizoda. Odgovarajue empirijsko lije enje je primjenjeno u 34.0% epizoda; u mlaoj dobnoj skupini u 34.2% a u starijoj dobnoj skupini u 33.8% epizoda BIK. Empirijsko antibiotsko lije enje je bilo djelomi no odgovarajue u 4.8% epizoda; u mlaoj dobnoj skupini u 3.2% a u starijoj dobnoj skupini u 6.2% epizoda BIK. Razlika u prikladnosti upotrijebljenog empirijskog antibiotskog lije enja BIK meu promatranim dobnim skupinama nije bila statisti ki zna ajna (p=0.422) (Tablica 6). Tablica  SEQ "Table" \*Arabic 6: Epidemiologija i prikladnost empirijskog lije enje bolni kih infekcija krvotoka (BIK) u promatranih bolesnika, s obzirom na dobne skupine 18-64 godine (N bolesnika=123) N BIK=158e"65 godina (N bolesnika=133) N BIK=195Ukupno (N bolesnika=256) N BIK=353 pDan boravka u JIM1 kod nastanka prve BIK0.2044*Srednja vrijednost20.523.322.1Standardna devijacija16.122.419.8Medijan15.519.017.0Ishodiate BIKN (%)N (%)N (%)0.1384**Diani sustav24 (15.2)39 (20.0)63 (17.8)CVK223 (14.6)18 (19.2)41 (11.6)Mokrani sustav11 (7.0)18 (9.2)29 (8.2)Ko~a05 (2.6)5 (1.4)Primarne BIK100 (63.2)115 (59.0)215 (61.0)Prikladnost empirijskog lije enja BIK0.422**Odgovarajue54 (34.2)66 (33.8)120 (34.0)Neodgovarajue99 (62.7)117 (60.0)216 (61.2)Djelomi no odgovarajue5 (3.2)12 (6.2)17 (4.8) 1 JIM  jedinica intenzivne medicine 2 CVK  centralni venski kateter *Wilcoxon rank-sum test **Hi-kvadrat Dodatna analiza razloga neadekvatnosti empirijskog antibiotskog lije enja u injena je na ukupno 108 epizoda BIK iz obje usporeivane dobne skupine za koje su postojali detaljniji podatci. Rezultati su pokazali da je razlog neadekvatnosti empirijskog antibiotskog lije enja bila neosjetljivost izoliranog soja na primjenjeni antibiotik u 54/108 (50%) epizoda BIK, dok je u 54/108 (50%) epizoda uzrok neadekvatnosti empirijskog lije enja bila primjena odgovarajueg antibiotika nakon viae od 24 h od po etka simptoma BIK. Navedeni rezultati su pokazali da se u obje dobne skupine prva BIK prosje no pojavljivala nakon oko 3 tjedna lije enja u JIM, u obje dobne skupine se u visokom udjelu (neato manje od 2/3) bolesnika ishodiate BIK nije uspjelo utvrditi a meu utvrenim ishodiatima je u obje promatrane dobne skupine diani sustav minimalno prednja io ispred CVK te je u obje dobne skupine empirijski zapo eto antibiotsko lije enje bilo neadekvatno u gotovo 2/3 bolesnika. UTVRIVANJE IMBENIKA POVEZANIH S NASTANKOM BOLNI KIH INFEKCIJA KRVOTOKA - MULTIVARIJANTNA ANALIZA Prije provoenja multivarijatne analize su bivarijantnom analizom ispitani imbenici koji mogu utjecati na nastanak BIK, koji su zatim uklju eni u model zajedno s promatranim dobnim skupinama (Tablice 4 i 5). Zavisna varijabla uklju ena u model je bio nastanak BIK u promatranih bolesnika lije enih u JIM, a nezavisne varijable uklju ene u model su bile spol, dobna skupina, vrsta infekcije s obzirom na zahvaenost S}S-a, APACHE II skor umanjen za bodove dobi, GCS te trajanje primjene CVK. Trajanje primjene CVK uklju eno je u model iako se mo~e pretpostaviti da nastanak BIK mo~e utjecati i na produljenje koriatenja CVK. Meutim, poato se prva BIK u promatranih bolesnika u prosjeku javljala nakon tri tjedna boravka u JIM, smatramo da je duljina primjene CVK opravdano uklju ena u model, tim viae ato se nakon postavljanja dijagnoze BIK u promatranoj ustanovi CVK vadi. Zbog interakcije s trajanjem primjene CVK, trajanje primjene mehani ke ventilacije je isklju eno iz analize logisti kom regresijom. Rezultati analize povezanosti pojedinih imbenika s nastankom BIK logisti kom regresijom su prikazani u Tablici 7. Rezultati analize su pokazali da starija ~ivotna dob u promatranih bolesnika nije bila povezana s eaom pojavom BIK. Takoer, pojava BIK nije ovisila o spolu niti o vrsti primarne infekcije (infekcije sa zahvaenim S}S-om u odnosu na infekcije ostalih sijela). Najzna ajniji imbenik povezan s nastankom BIK bilo je trajanje primjene CVK. Rezultati pokazuju da sa svakim danom primjene CVK raste vjerojatnost nastanka BIK za 9%. Zanimljivo, analizom je utvrena negativna povezanost APACHE II skora umanjenog za bodove koje donosi dob i nastanka BIK. To upuuje da bolesnici s ni~im za dob prilagoenim APACHE II skorom vjerojatno zbog du~eg pre~ivljavanja u JIM imaju veu vjerojatnost nastanka BIK, dok oni s viaim APACHE II skorom ranije umiru. To smo potvrdili ponavljanjem analize kod bolesnika koji su pre~ivjeli boravak u JIM, ato je prikazano u Tablici 8. U grupi bolesnika koji su pre~ivjeli lije enje u JIM APACHE II skor prilagoen za bodove dobi viae nije bio povezan s vjerojatnoau nastanka BIK (OR: 0.978, 95% CI: 0.950-1.006) (Tablica 8). Tablica  SEQ "Table" \*Arabic 7: Rezultati analize povezanosti pojedinih imbenika s nastankom bolni kih infekcija krvotoka logisti kom regresijom Vjerojatnost nastanka bolni ke infekcije krvotokaOmjer aansi95% granice pouzdanosti prema WalduDob 18-64 g. / e"65 g. 0.9920.7121.381}ene / muakarci1.2940.9341.795Infekcije S}S1 / ostale infekcije 1.1660.8331.633APACHE II umanjen za bodove dobi0.9720.9510.992Trajanje primjene CVK2 (dani) 1.0901.0751.105 1 S}S  sredianji ~iv ani sustav (uklju ujui i sepse sa zahvaenim S}S i tetanus) 2 CVK  centralni venski kateter Tablica  SEQ Table \* ARABIC 8: Rezultati analize povezanosti pojedinih imbenika s nastankom bolni ke infekcije krvotoka logisti kom regresijom, u bolesnika koji su pre~ivjeli lije enje u jedinici intenzivne medicine Vjerojatnost nastanka bolni ke infekcije krvotokaOmjer aansi95% granice pouzdanosti prema WalduDob 18-64 g. / e"65 g. 1.4590.9442.256}ene / muakarci0.8300.5381.281Infekcije S}S1 / ostale infekcije 0.7340.4661.155APACHE II umanjen za bodove dobi0.9780.9501.006Trajanje primjene CVK2 (dani) 1.0881.0671.110 1 S}S  sredianji ~iv ani sustav (uklju ujui i sepse sa zahvaenim S}S i tetanus) 2 CVK  centralni venski kateter UTJECAJ POJAVE BOLNI KIH INFEKCIJA KRVOTOKA NA ISHOD LIJE ENJA ANALIZA 28-DNEVNOG PRE}IVLJAVANJA Kao ato je predhodno navedeno (Tablica 5) stopa pre~ivljavanja je bila zna ajno viaa u grupi bolesnika s BIK (59.8 vs. 50.3%) (p=0.0079). Sukladno tome izra unavanje 28-dnevnog pre~ivljavanja je pokazalo da je vjerojatnost 28-dnevnog pre~ivljavanja bila zna ajno viaa meu bolesnicima koji su tijekom lije enja u JIM imali BIK te je u bolesnika s BIK vjerojatnost 28-dnevnog pre~ivljavanja iznosila 77%, dok je kod bolesnika bez BIK ona iznosila 43% (p<0.001) (Slika 7).  p<0.001, log-rank test Slika  SEQ "Figure" \*Arabic 7: 28-dnevno pre~ivljavanje u bolesnika lije enih u jedinici intenzivne medicine (JIM), s obzirom na prisutnost bolni ke infekcije krvotoka (BIK, BSI) Zbog neo ekivanog rezultata raena je i Cox regresijska analiza kako bi se uklonilo optereenje rezultata uvjetovano ostalim klini kim razlikama izmeu bolesnika s i bez BIK, no i nakon poravnanja za ostale promatrane imbenike ostala je prisutna zna ajna razlika u 28-dnevnom pre~ivljavanju izmeu grupa bolesnika s i bez BIK (p<.0001) (Tablica 9). Tablica  SEQ "Table" \*Arabic 9: Odnos 28-dnevne smrtnosti i promatranih rizi nih imbenika na ukupnom uzorku Cox regresijskom analizom Promatrani imbeniciSS4P>Hi kvadratOmjer rizikaDob 18-64 g. / e"65 g. 10.14101.004Kroni ne bolesti/stanja (po Knausu)10.91831.005APACHE II umanjen za bodove dobi1<.00011.047GCS110.24301.016Infekcije S}S2 / ostale infekcije10.00101.395BIK3 da/ne1<.00010.381 1 GCS - Glasgow coma socre 2 S}S - sredianji ~iv ani sustav (uklju ujui i sepse sa zahvaenim S}S i tetanus) 3 BIK - bolni ka infekcija krvotoka 4 SS  stupnjevi slobode Na Slici 8 je prikazana vjerojatnost 28-dnevnog pre~ivljavanja u JIM nakon stratifikacije bolesnika prema dobnim skupinama i prema prisutnosti BIK. Rezultati pokazuju da su najveu vjerojatnost pre~ivljavanja imale osobe starije ~ivotne dobi koje su tijekom boravka u JIM imale BIK. Sve je to upuivalo na optereenje naaih rezultata selekcijom bolesnika pa je bilo potrebno provesti proces pseudorandomizacije na temelju vjerojatnosti nastanka BIK. Usporedbom bolesnika dobi 18-64 i onih e"65 godina koji su tijekom lije enja u JIM imali BIK nije utvrena zna ajna razlika u 28-dnevnoj smrtnosti; vjerojatnost pre~ivljavanja je u starijoj promatranoj skupini iznosila 82.5%, a u mlaoj 70% (p=0.389) (Slika 8).  p=0.389, log-rank test Slika  SEQ "Figure" \*Arabic 8: 28-dnevno pre~ivljavanje u jedinici intenzivne medicine (JIM) nakon stratifikacije bolesnika prema dobnim skupinama i prema prisutnosti bolni ke infekcije krvotoka (BIK, BSI) ANALIZE ISHODA LIJE ENJA NA PSEUDORANDOMIZIRANOM UZORKU Rezultati predhodno navedene bivarijatne i multivarijantne analize su pokazali da na ishod lije enja uz pojavu BIK mogu djelovati i drugi imbenici koji remete statisti ko zaklju ivanje o utjecaju pojave BIK na smrtnost i trajanje lije enja u JIM. ak i nakon multivarijatne analize ostala je neravnote~a izmeu usporeivanih grupa s obzirom na imbenike koji utje u na u estalost pojave BIK. Da bismo smanjili optereenje koje proizlazi iz opservacijskog ustroja studije, proveli smo proces  pseudorandomizacije izra unavanjem vjerojatnosti nastanka BIK za svakog bolesnika te stvaranjem parova bolesnika s i bez BIK prema vrijednosti logit-a vjerojatnosti nastanka BIK. Vjerojatnost nastanka BIK ( propensity score ) izra unata je logisti kom regresijskom analizom prekomjerno parametriziranog modela u koji su uklju eni svi promatrani imbenici koji bi mogli doprinjeti u estalosti pojave BIK: dob, spol, vrsta primarne infekcije s obzirom na zahvaenost S}S-a, te~ina predle~eih kroni nih bolesti (referentna vrijednost = odsustvo kroni nih bolesti), APACHE II, APACHE II umanjen za bodove dobi i GCS te njihove interakcije. Dobiveni model imao je visoku eksplanatornu vrijednost (c=0.801), ato zna i da je objaanjavao preko 80% nastanka BIK. Svakom bolesniku koji je tijekom lije enja u JIM imao BIK pridodan je jedan bolesnik koji tijekom lije enja nije imao BIK, ukoliko im se logit vjerojatnosti nastanka BIK podudarao unutar dviju desetina standardne devijacije logit-a nastanka BIK. Na taj na in smo dobili 212 parova bolesnika, sa injenih od po jednog bolesnika s i jednog bolesnika bez BIK. Prije daljnjeg zaklju ivanja ispitana je uravnote~enost grupa ispitivanjem standardizirane razlike za svaku varijablu. Kao pokazatelji neravnote~e uzete su vrijednosti vee od 0.1. Test je pokazao da su grupe bilo dobro uravnote~ene (rezultati nisu prikazani). U Tablici 10 su prikazane osnovne demografske i klini ke zna ajke usklaenih parova bolesnika bez i s BIK. Tablica  SEQ "Table" \*Arabic 10: Osnovne demografske i klini ke zna ajke usklaenih parova bolesnika bez i s bolni kom infekcijom krvotoka Bolni ka infekcija krvotoka Ukupno (N=424) pNE (N=212)DA (N=212)Dob (godine)0.8812*Medijan63.065.064.025 percentila52.052.552.075 percentila74.073.574.0Dobna skupinaN (%)N (%)N (%)0.5600**18-64 g.111 (52.4%)105 (49.5%)216 (50.9%)e"65 g. 101 (47.6%)107 (50.5%)208 (49.1%)Spol0.8459**}enski 102 (48.1%)104 (49.1%)206 (48.6%)Muaki110 (51.9%)108 (50.9%)218 (51.4%)Predle~ee kron. bolesti/stanja0.9900**Zdrav71 (33.5%)68 (32.1%)139 (32.8%)Bla~a kron. bolest89 (42.0%)92 (43.4%)181 (42.7%)Te~a kron. bolest 38 (17.9%)38 (17.9%)76 (17.9%)Terminalno stanje14 (6.6%)14 (6.6%)28 (6.6%)Primarna infekcija (S}S1 da/ne)0.6955**Sa zahvaenim S}S121 (57.1%)117 (55.2%)238 (56.1%)Bez zahvaenog S}S91 (42.9%)95 (44.8%)186 (43.9%)APACHE II0.7969*Medijan19.018.019.025 percentila13.013.513.075 percentila24.024.024.0APACHE II minus bodovi dobi0.8036*Medijan16.015.016.025 percentila10.09.09.075 percentila20.021.020.0Glasgow coma score0.4061*Medijan12.013.013.025 percentila7.08.07.075 percentila15.015.015.0Primjena CVK2 (dani)0.8534*Medijan20.020.520.025 percentila11.011.011.075 percentila28.028.528.0 * Wilcoxon rank-sum test ** Hi kvadrat test 1 S}S - sredianji ~iv ani sustav (uklju ujui i sepse sa zahvaenim S}S i tetanus) 2 CVK  centralni venski kateter Iz podataka u Tablici 10 je vidljivo da su parovi bolesnika bili potpuno usklaeni glede promatranih rizi nih imbenika za nastanak BIK (za sve promatrane imbenike p>0.05, standardizirana razlika <0.1). Zbog toga je njihovom analizom bilo mogue pouzdanije zaklju ivati koliko BIK utje u na tijek hospitalizacije i ishod lije enja. U Tablici 11 je prikazana usporedba usklaenih parova bolesnika bez i s BIK prema imbenicima koji su va~ni za procjenu ishoda lije enja u JIM. Podatci u Tablici 11 pokazuju da meu usklaenim parovima bolesnika nije bilo zna ajne razlike u pre~ivljavanju bolesnika s i bez BIK (p=0.5513), ali su bolesnici s BIK bili zna ajno du~e mehani ki ventilirani i du~e lije eni u JIM (p=0.0013 i p=0.0024). Tablica  SEQ "Table" \*Arabic 11: Klini ke zna ajke usklaenih parova bolesnika bez i s bolni kom infekcijom krvotoka, va~ne za procjenu ishoda lije enja Bolni ka infekcija krvotoka Ukupno (N=424) pNE (N=212)DA (N=212)Trajanje MV1 (dani)0.0013*Medijan15.020.017.025 percentila8.010.09.075 percentila25.029.027.0Trajanje lije enja u JIM2 (dani)0.0024*Medijan23.028.025.025 percentila11.517.014.075 percentila35.041.037.5Ishod lije enja u JIMN (%)N (%)N (%)0.5513**}iv125 (59.0%)131 (61.8%)256 (60.4%)Umro87 (41.0%)81 (38.2%)168 (39.6%)* Wilcoxon rank-sum test ** Hi kvadrat test 1 MV  mehani ka ventilacija 2 JIM  jedinica intenzivne medicine ANALIZA PRE}IVLJAVANJA NA PSEUDORANDOMIZIRANOM UZORKU Pre~ivljavanje bolesnika dobi 18-64 g. unutar usklaenih parova bolesnika prema prisutnosti BIK je prikazano na Slici 9. Rezultati analize usklaenih parova s obzirom na dobnu skupinu i pre~ivljenje pokazuju da kod mlaih bolesnika pojava BIK nije imala zna ajnog u inka na smrtnost (p=0.3256); u mlaoj dobnoj skupini je stopa smrtnosti bila neato vea meu bolesnicima s BIK - umrlo je 42/105 (40.0%) bolesnika s BIK i 37/111 (33.3%) bolesnika bez BIK.  p=0.3256, Cochran-Mantel-Haenszel test Slika  SEQ "Figure" \*Arabic 9: Pre~ivljavanje bolesnika dobi 18-64 g. unutar usklaenih parova bolesnika, prema prisutnosti bolni ke infekcije krvotoka (BIK) Pre~ivljavanje bolesnika dobi e"65 g. unutar usklaenih parova bolesnika prema prisutnosti BIK je prikazano na Slici 10. Kod bolesnika iz starije promatrane dobne skupine je zabilje~eno suprotno  kod njih je bila izra~ena tendencija viae smrtnosti kod bolesnika koji tijekom lije enaj u JIM nisu imali BIK (p=0.0686); u starijoj dobnoj skupini je umrlo 50/101 (49.5%) bolesnika bez BIK i 39/107 (36.4%) bolesnika s BIK. Bolesnici iz starije promatrane dobne skupine koji su tijekom lije enja u JIM imali BIK su imali 42% manji rizik smrtnog ishoda (HR: 0.5850, 95% CI: 0.3361-1.0182), ali statisti ka zna ajnost nije postignuta.  p=0.0686, Cochran-Mantel-Haenszel test Slika  SEQ "Figure" \*Arabic 10: Pre~ivljavanje bolesnika dobi e"65 g. unutar usklaenih parova bolesnika, prema prisutnosti bolni ke infekcije krvotoka (BIK) ANALIZA 28-DNEVNOG PRE}IVLJAVANJA NA PSEUDORANDOMIZIRANOM UZORKU Na Slici 11 je prikazana vjerojatnost 28-dnevnog pre~ivljavanja unutar usklaenih parova bolesnika, s obzirom na prisutnost BIK. Vjerojatnost pre~ivljavanja unutar 28 dana lije enja u JIM je bila vea kod bolesnika koji su imali BIK (71.2%) u odnosu na one koji nisu imali BIK (63.9%) no ta razlika nije bila statisti ki zna ajna (p=0.070). Cox proporcijski hazardni model pokazao je da nakon stratifikacije usklaenih parova bolesnika prema vjerojatnosti nastanka BIK nije bilo statisti ki zna ajne razlike u riziku smrti unutar 28 dana meu bolesnicima s i bez BIK (p=0.1001).  p=0.070, log-rank test Slika  SEQ "Figure" \*Arabic 11: 28-dnevno pre~ivljavanje usklaenih parova bolesnika lije enih u jedinici intenzivne medicine (JIM), s obzirom na prisutnost bolni ke infekcije krvotoka (BIK, BSI) Na Slici 12 je prikazana vjerojatnost 28-dnevnog pre~ivljavanja usklaenih parova bolesnika u JIM nakon stratifikacije bolesnika prema dobnim skupinama i prema prisutnosti BIK. Na slici se vidi da je vjerojatnost 28-dnevnog pre~ivljavanja bila najvea u grupi bolesnika starije ~ivotne dobi koji su tijekom lije enja u JIM imali BIK, a najmanja u grupi mlaih bolesnika koji tijekom lije enja u JIM nisu imali BIK. Razlike u vjerojatnosti 28-dnevnog pre~ivljavanja izmeu prikazanih grupa bolesnika su bile grani no statisti ki zna ajne (p=0.047).  p=0.047, log-rank test Slika  SEQ "Figure" \*Arabic 12: 28-dnevno pre~ivljavanje usklaenih parova bolesnika lije enih u jedinici intenzivne medicine (JIM), nakon stratifikacije bolesnika prema dobnim skupinama i prema prisutnosti bolni ke infekcije krvotoka (BIK, BSI) ANALIZA TRAJANJA LIJE ENJA NA PSEUDORANDOMIZIRANOM UZORKU Nakon ato smo analizirajui usklaene parove bolesnika ustanovili veu (negativnu) povezanost prisutnosti BIK i 28-dnevne smrtnosti kod bolesnika starije dobi, postavili smo pitanje da li postoje razlike izmeu mlaih i starijih bolesnika s i bez BIK u odnosu na trajanje lije enja u JIM. Rezultati usporedbe usklaenih parova bolesnika prema trajanju lije enja u JIM, s obzirom na prisutnost BIK i s obzirom na pripadnost dobnoj skupini su prikazani na Slici 13. Usporedbom mlaih i starijih bolesnika s BIK utvreno je zna ajno du~e prosje no trajanje lije enja u JIM kod starijih bolesnika s BIK: 27.5 vs. 36.3 dana (p=0.0054). Usporedbom mlaih i starijih bolesnika bez BIK nije naena zna ajna razlika u prosje nom trajanju lije enja u JIM: 25.0 vs. 27.6 dana (p=0.3379). Dakle, zna ajan utjecaj dobi na trajanje lije enja u JIM zamjeen je samo u grupi bolesnika s BIK, u smislu du~eg lije enja bolesnika iz starije promatrane dobne skupine. Usporedbom mlaih bolesnika bez i s BIK nije naena zna ajna razlika u trajanju lije enja u JIM: 25.0 vs. 27.5 dana (p=0.3710). Usporedbom starijih bolesnika bez i s BIK utvreno je zna ajno du~e prosje no trajanje lije enja u JIM u starijih bolesnika s BIK: 36.3 vs. 27.6 dana (p=0.0042). Dakle, u inak prisutnosti BIK na produljenje boravka u JIM je uo en kod bolesnika starije dobi, ali ne i kod bolesnika iz mlae promatrane dobne skupine.  1 JIM  jedinica intenzivne medicine 2 SV- srednja vrijednost 3 SD  standardna devijacija Slika  SEQ "Figure" \*Arabic 13: Rezultati usporedbe usklaenih parova bolesnika t-testom prema trajanju lije enja u jedinici intenzivne medicine (JIM), s obzirom na prisutnost bolni ke infekcije krvotoka i s obzirom na pripadnost dobnoj skupini ETIOLOGIJA BOLNI KIH INFEKCIJA KRVOTOKA Udjeli pojedinih uzro nika koji su uzrokovali BIK u promatranim dobnim skupinama prikazani su na Slici 14. Razlika u raspodjeli pojedinih uzro nika prema dobnim skupinama nije se pokazala statisti ki zna ajnom (p=0.4940). Najzastupljenija grupa uzro nika BIK su bile nefermentirajue gram-negativne bakterije koje su uzrokovale 47/158 (29.7%) BIK u dobnoj skupini 18-64 g. i 66/196 (33.9%) BIK u dobnoj skupini e"65g. Iza njih su po u estalosti bile enterobakterije koje su uzrokovale 44/158 (27.9%) BIK u mlaoj promatranoj dobnoj skupini i 41/195 (21.0%) BIK u starijoj promatranoj dobnoj skupini. Na treem mjestu su po u estalosti bile gram-pozitivne bakterije koje su uzrokovale 29/158 (18.3%) BIK u mlaoj i 35/195 (18.0%) BIK u starijoj promatranoj dobnoj skupini. Takoer je utvren visok udio polimikrobnih BIK; 23/158 (14.6%) u mlaoj i 39/195 (20.0%) u starijoj promatranoj dobnoj skupini. Kandida se kao uzro nik BIK u mlaoj promatranoj dobnoj skupini pojavljivala u 14/158 (8.9%) a u starijoj u 11/195 (5.6%) slu ajeva. Navedeni podatci prikazani su u Tablici 12. Meu  Ostale uzro nike ubrojen je u mlaoj promatranoj dobnoj skupini jedan soj Trichosporon beigelii, a u starijoj dobnoj skupini ubrojeni su po jedan Aerococcus viridans, Bacteroides i Flavobacterium meningosepticum soj. Meu 10  Ostalih enterobakterija u mlaoj promatranoj dobnoj skupini ubrojena su: etiri Escherichia coli, etiri Enterobacter aerogenes, jedan Enterobacter cloacae i jedan Salmonella enteritidis soj, a meu 15  Ostalih enterobakterija u starijoj promatranoj dobnoj skupini ubrojena su tri E. coli, etiri Proteus mirabilis, dva Enterobacter aerogenes, tri Enterobacter cloacae, jedan Citrobacter diversus i dva Morganella morganii soja.  *KNS  koagulaza-negativni stafilokoki p=0.4940, Hi-kvadrat test Slika  SEQ "Figure" \*Arabic 14: Raspodjela pojedinih uzro nika bolni kih infekcija krvotoka (BIK) s obzirom na dobne skupine Udjeli pojedinih uzro nika BIK i njihova antimikrobna osjetljivost prema promatranim dobnim skupinama su prikazani u Tablici 12. U ukupnom uzorku udio MRSA meu S. aureus sojevima iznosio je 33/40 (82.5%). Udio MRSA je u obje promatrane dobne skupine bio podjednak; u mlaoj promatranoj dobnoj skupini je taj udio iznosio 14/17 (82.4%), a u starijoj promatranoj skupini 19/23 (82.6%). Nije zabilje~en niti jedan soj S. aureusa rezistentan na vankomicin. Neosjetljivost na ampicilin zabilje~ena je u 4/14 (28.6%) sojeva enterokoka u ukupnom uzorku; po dva su soja neosjetljiva na ampicilin zabilje~ena u obje promatrane dobne skupine. Nije zabilje~en niti jedan soj enterokoka neosjetljiv na vankomicin. Unutar grupe enterobakterija ukupno je udio sojeva neosjetljivih na cefalosporine 3. generacije + sojeva koji stvaraju ESBL (sojevi do 1999. i sojevi nakon 1999. godine) iznosio 50/85 (58.8%). U mlaoj promatranoj dobnoj skupini je taj udio iznosio 30/44 (68.2%), a u starijoj promatranoj dobnoj skupini 20/41 (48.8%). Tablica  SEQ "Table" \*Arabic 12: Uzro nici bolni kih infekcija krvotoka (BIK) i njihova antimikrobna osjetljivost, s obzirom na dobne skupine 18-64 godine (N bolesnika=123) (N BIK=158)e"65 godina (N bolesnika=133) (N BIK=195)Ukupno (N bolesnika=256) (N BIK=353)Uzro niciN (%BIK)N (%BIK)N (%BIK)Gram-pozitivni29 (18.3)35 (18.0)64 (18.1)Staphylococcus aureus17 (10.8)23 (11.8)40 (11.3) MRSA114 (8.9)19 (9.7)33 (9.3)KNS25 (3.2)5 (2.6)10 (2.8)Enterococcus sp.7 (4.4)7 (3.6)14 (4.0) ARE32 (1.3)2 (1.0)4 (1.1)Enterobakterije44 (27.9)41 (21.0)85 (24.1)Klebsiella pneumoniae26 (16.5)18 (9.2)44 (12.5)Serratia marscescens8 (5.1)8 (4.1)16 (4.5)Ostale enterobakterije10 (6.3)15 (7.7)25 (7.1) CEF 3 neosjetljivi414 (8.9)6 (3.1)20 (5.7) ESBL516 (10.1)14 (7.2)30 (8.5)Nefermentirajue gram-negativne bakterije47 (29.7)66 (33.9)113 (32.0)Acinetobacter sp.30 (19.0)44 (22.6)74 (20.9)Pseudomonas aeruginosa16 (10.1)20 (10.3)36 (10.2)Stenotrophomonas maltophilia1 (0.6)2 (1.0)3 (0.8) MDR65 (3.2)11 (5.6)16 (4.5)Candida sp. 14 (8.9)11 (5.6)25 (7.1)Ostali uzro nici 1 (0.6)3 (1.5)4 (1.1)Polimikrobne sepse23 (14.6)39 (20.0)62 (17.6) 1 MRSA  meticilin rezistentni Staphylococcus aureus, 2 KNS  koagulaza negativni stafilokoki, 3 ARE enterokoki rezistentni na ampicilin,4 CEF 3 neosjetljivi sojevi neosjetljivi na cefalosporine 3. generacije (za sojeve do 1999. godine), 5 ESBL Extended-spectrum beta-lactamase sojevi koji proizvode beta-laktemaze proirenog spektra (za sojeve od 1999. godine), 6 MDR Multidrug resistant neosjetljiv na po jedan antibiotik iz tri ili vie razli itih grupa antimikrobnih lijekova Udjeli sojeva neosjetljivih na antibiotike prema pojedinim uzro nicima ili grupama uzro nika u ukupnom uzorku bolesnika s BIK su prikazani u Tablici 13. Unutar grupe nefermentirajuih gram-negativnih bakterija ukupno je udio MDR sojeva iznosio 16/113 (14.2%). Navedeni udio je u mlaoj promatranoj dobnoj skupini iznosio 5/47 (10.6%), a u starijoj promatranoj dobnoj skupini 11/66 (16.7%). Prema udjelu MRSA, ESBL+CEF 3 neosjetljivih i MDR sojeva meu odgovarajuim grupama uzro nika BIK se promatrane dobne skupine bolesnika nisu zna ajno razlikovale. Za udio MRSA je omjer rizika bio 1.003 (95% CI: 0.395-2.549), za udio ESBL+CEF 3 neosjetljivih je omjer rizika bio 0.444 (95% CI: 0.184-1.073), za udio MDR je omjer rizika bio 1.680 (95% CI: 0.542-5.205). Navedeni rezultati pokazuju da se usporeivane dobne skupine nisu zna ajno razlikovale prema uzro nicima BIK, niti su se uzro nici BIK u promatranim dobnim skupinama zna ajno razlikovali prema antimikrobnoj osjetljivosti. Vodei uzro nici BIK-a su u obje promatrane dobne skupine bile nefermentirajue gram-negativne bakterije (32.0% BIK), koje po u estalosti slijede enterobakterije (24.1% BIK) pa gram-pozitivni uzro nici (18.1% BIK). U ukupnom uzorku je udio MRSA meu sojevima S. aureusa iznosio 82.5%, ukupno je 28.6% enterokoka bilo neosjetljivo na ampicilin, meu enterobakterijama je udio CEF 3 neosjetljivih + ESBL sojeva iznosio 58.8%, a unutar grupe nefermentirajuih gram-negativnih bakterija je udio MDR sojeva iznosio 14.2%. Tablica  SEQ "Table" \*Arabic 13: Udjeli sojeva neosjetljivih na antibiotike meu pojedinim uzro nicima, u ukupnom uzorku bolesnika s bolni kim infekcijama krvotoka (BIK) Uzro nik BIK NSojevi uzro nika neosjetljivi na antibiotike N (%)Staphylococcus aureus 40 MRSA1 33 (82.5)Enterococcus spp. 14 ARE2 4 (28.6)Enterobacteriaceae 85CEF 3 R3 + ESBL4 50 (58.8)Nefermentirajui gram-negativni uzro nici 113MDR5 16 (14.2) 1 MRSA  meticilin rezistentni Staphylococcus aureus 2 ARE enterokoki neosjetljivi na ampicilin 3 CEF 3 R sojevi neosjetljivi na cefalosporine 3. generacije (za sojeve do 1999. godine) 4 ESBL Extended-spectrum beta-lactamase sojevi koji proizvode beta-laktemaze proirenog spektra (za sojeve od 1999. godine) 5 MDR Multidrug resistant sojevi neosjetljivi na po jedan antibiotik iz tri ili vie razli itih grupa antimikrobnih lijekova RASPRAVA Rezultati ovog istra~ivanja su pokazali da starija ~ivotna dob nije bila povezana s veom vjerojatnoau nastanka BIK u promatranih teakih, mehani ki ventiliranih infektoloakih bolesnRT\^bd f h ԸiVCV-+hc hc 5CJOJQJ^JaJmHsH%h`.5CJOJQJ^JaJmHsH%hc 5CJOJQJ^JaJmHsH+hc h`.5CJOJQJ^JaJmHsHhc hc 5CJaJmHsHhc 5CJaJmHsHh`.5CJaJmHsHh`.56CJaJmHsHhc h`.5CJaJmHsHhc CJaJmHsHh`.CJaJmHsHhc h`.mHsH(hc h`.CJOJQJ^JaJmHsH,TVXZ\^`b: f h j l $^a$$a$^ $^a$gdc >4?8?>?l n p r t v x f $7^7`a$$7`7a$$$a$$a$$a$$^a$h n p t v x f  . 4 z精{n^S^@$jhh?0J7UmHnHuh+5hW\f5;\jh+5hW\f5;U\hW\f5CJaJmHsHhnh`.6mHsHhnh`.mHsHhnh`.mHsHhnhc mHsHh`.mHsH#hc h`.5OJQJ^JmHsH hc hc OJQJ^JmHsHhc OJQJ^JmHsHh`.OJQJ^JmHsH hc h`.OJQJ^JmHsH   " $ & ( * , . 0 2 4 6 8 H J L 7dh`77`7gdc ^$a$$7^7a$$7`7a$ $7^7`a$L T V xzP&|0HDN*D8woq $7d`7gdW\f $7dh`7a$ DFHJLNPRTFHJ~λ񞏞~dU񞏞h?:mHnHsHtHu2jh?h?>*B*UmHnHphu j}h?UmHnHujh?UmHnHuh?mHnHu"h?5;\mHnHsHtHu$jhh?0J7UmHnHu2jh?h?>*B*UmHnHphuh?mHnHuhh?0J7mHnHu~ "$&(*bd³¥¥p_p¥ jqh?UmHnHu"h?5;\mHnHsHtHu2jh?h?>*B*UmHnHphuh?mHnHuhh?0J7mHnHuh?:mHnHsHtHu$jhh?0J7UmHnHuh?mHnHujh?UmHnHu jwh?UmHnHudfhln$&8:<pųŨӳeVŨh?:mHnHsHtHu2jh?h?>*B*UmHnHphuh?mHnHu jkh?UmHnHujh?UmHnHuh?mHnHu"h?5;\mHnHsHtHuhh?0J7mHnHu$jhh?0J7UmHnHu2jh?h?>*B*UmHnHphuprtvxz|~$&(*,.024lnprv³¥¥q³¥W¥2jh?h?>*B*UmHnHphu j_h?UmHnHu2jh?h?>*B*UmHnHphuh?mHnHuhh?0J7mHnHuh?:mHnHsHtHu$jhh?0J7UmHnHuh?mHnHujh?UmHnHu jeh?UmHnHuvx "$,.TVXյƢp_Ƣp jSh?UmHnHuh?:mHnHsHtHu2jh?h?>*B*UmHnHphuh?mHnHu$jhh?0J7UmHnHu jYh?UmHnHujh?UmHnHuh?mHnHuhh?0J7mHnHu"h?5;\mHnHsHtHu!<>@BDFHJLŶūӶłhŶūWӶ jG h?UmHnHu2jh?h?>*B*UmHnHphuh?mHnHu jMh?UmHnHujh?UmHnHuh?mHnHuh?:mHnHsHtHuhh?0J7mHnHu$jhh?0J7UmHnHu2jh?h?>*B*UmHnHphu"(*,.68bdfLNPλ衒gZ衒h?mHnHsHtHu2j h?h?>*B*UmHnHphu jA h?UmHnHujh?UmHnHuh?mHnHuh?:mHnHsHtHu$jhh?0J7UmHnHu2j h?h?>*B*UmHnHphuhh?0J7mHnHuh?mHnHu8:<>@BDFHµ§§sµ§Y§2j h?h?>*B*UmHnHphu j5 h?UmHnHu2j h?h?>*B*UmHnHphuh?mHnHuhh?0J7mHnHuh?mHnHsHtHu$jhh?0J7UmHnHuh?mHnHujh?UmHnHu j; 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(2005.) predpostavljaju da bolesnici starije ~ivotne dobi imaju vei rizik za nastanak domicilne sepse, zbog niza rizi nih imbenika prisutnih u bolesnika starije ~ivotne dobi (predle~ee kroni ne bolesti, eai agresivni zahvati, boravak u ustanovama za skrb, slabljenje imunoloakog sustava, malnutricija, smanjena pokretnost), no oni ne izra unavaju taj rizik.62 Navedene imbenike rizika za nastanak infekcija prisutne u starijoj ~ivotnoj dobi detaljno opisuju Gavazzi i Krause 2002. koji zaklju uju da su zbog njihove prisutnosti osobe starije ~ivotne dobi prijem ljivije za infekcije i da u njih infekcije imaju loaiji ishod.41 Viae se dosadaanjih istra~ivanja bavilo procjenom odnosa dobi i nastanka bolni ki ste enih infekcija razli itih sijela, no one su dale opre ne rezultate. U studiji turskih autora (Erbay et al, 2003.) kao i u studiji avedskih autora (Appelgren et al, 2001.) starija ~ivotna dob se nije pokazala kao imbenik rizika za nastanak bolni kih infekcija, kao niti u studiji ameri kih autora (Stephan et al. 2001.) koja je raena na uzorku u JIM lije enih kirurakih bolesnika i koja je ocjenjivala rizik nastanka bolni kih infekcija u bolesnika >75 g.8,17,63 Studija prevalencije bolni ki ste enih infekcija u 1417 JIM iz 17 europskih zemalja (Vincent et al, 1995.) i studija prevalencije nozokomijalnih infekcija u etiri JIM u `vicarskoj (Pittet et al, 1999.) nisu utvrdile stariju ~ivotnu dob kao nezavisni imbenik rizika za nastanak bolni kih infekcija.14, 64 Suprotno tome, nekoliko je europskih i ameri kih studija utvrdilo da je dob >60 g. bila zna ajan imbenik rizika za razvoj bolni ki ste enih infekcija (Craven et al. 1988, Smith PW. 1989, Gross et al, 1997. i Legras et al, 1998.).65-68 Takoer, u jednoj starijoj studiji (Saviteer et al. 1988.) je utvreno da incidencija nozokomijalnih infekcija progresivno raste s dobi bolesnika te da bolesnici starije ~ivotne dobi imaju vei rizik za nastanak bolni kih infekcija po danu provedenom na bolni kom lije enju nego mlai bolesnici.69 Velika retrospektivna studija (Emori et al, 1991.) na 101 479 prijavljenih bolni ki ste enih infekcija zabilje~enih u 75 398 bolesnika starih e"15 godina s bolni kim infekcijama, hospitalno lije enih u SAD od godine 1986.-1990. je zaklju ila da je 54% bolni ki ste enih infekcija bilo zabilje~eno meu bolesnicima starim e"65 g. te su meu njima u toj dobnoj skupini BIK inile 8% od svih bolni ki ste enih infekcija.29 Ista je studija takoer zaklju ila da su bolesnici e"65 g. imali vei rizik za nastanak bolni ki ste ene infekcije po danu boravka na bolni kom lije enju. 29 Zaklju no mo~emo rei da anatomski, fizioloaki i epidemioloaki rizi ni imbenici za nastanak infekcija prisutni u bolesnika starije ~ivotne dobi vjerojatno utje u na poveanje njihove sklonosti za nastanak domicilnih infekcija, no njihov utjecaj na vjerojatnost razvoja bolni ki ste enih infekcija je prema rezultatima dosadaanjih istra~ivanja dvojben. Rezultati malobrojnih dosadaanjih istra~ivanja koja su se bavila odnosom starije ~ivotne dobi i nastanka BIK, kao i rezultati naae studije, upuuju na zaklju ak da ti imbenici rizika koji optereuju bolesnike starije ~ivotne dobi vjerojatno imaju znatno manju ulogu kod nastanka BIK, i da su zbog razlika u epidemiologiji i patogenezi infekcija ste enih tijekom boravka u JIM, za nastanak BIK vjerojatno klju ni imbenici od strane okoline i postupaka lije enja u JIM, o kojima ovisi izlo~enost bolesnika bolni koj infekciji, bez obzira na njihovu dob (otvorena ulazna mjesta infekcije, horizontalni prijenos, vrsta i antimikrobna osjetljivost prisutnih uzro nika itd.). Kao jedini imbenik koji je bio pozitivno povezan s vjerojatnosti nastanka BIK se u ovom istra~ivanju pokazalo trajanje primjene CVK (OR: 1.090, 95% CI: 1.075-1.105); rezultati su pokazali da sa svakim danom primjene CVK u bolesnika raste vjerojatnost nastanka BIK za 9%, bez obzira na njihovu dob. CVK je bio prosje no zna ajno du~e primjenjivan u bolesnika starije ~ivotne dobi u odnosu na mlae promatrane bolesnike (15.8 vs. 13.1 dan) (p=0.0069) te su bolesnici starije ~ivotne dobi imali zna ajno vei prosje an broj BIK na 1000 dana primjene CVK (17.7 vs. 16.4 epizoda) (p=0.0464). Veliki broj predhodnih studija se bavio odnosom primjene CVK i nastupa primarnih BIK i s CVK povezenih BIK, pri emu se za  s CVK povezanu BIK koristila definicija CDC-a, koja zahtjeva bakterioloaki dokaz uzro nika na CVK. 70 Kako je zaklju io Maki u studiji iz 1981. g, i 2/3 primarnih BIK su uzrokovane infekcijom CVK.71 Primjena CVK je jasno prepoznata kao najva~niji imbenik rizika za nastanak primarnih BIK (Richet et al, 1999, Rojo et al, 1999.).72,73 U SAD se s CVK povezene BIK javljaju u 3-7% bolesnika kod kojih je CVK koriaten, ato zna i da se te infekcije javljaju u oko 200 000 ljudi u SAD godianje (Raad I, 1998.), dok prema procjenama CDC-a ta brojka u SAD iznosi 80 000 ljudi godianje .70,74 Sli ne podatke je objavila prospektivna studija koja se odnosi na jednu suburbanu kiruraku i internisti ku JIM u SAD (Warren et al, 2001.); tamo je 4% bolesnika kod kojih je CVK bio primijenjen razvilo primarnu BIK, odnosno incidencija primarne BIK je bila 3.4/1000 CVK dana.5 Studija raena na bolesnicima iz 15 bolnica Novog Ju~nog Wales-a (McLaws i Taylor, 2003.) je zaklju ila da je incidencija s CVK povezanih BIK 5/1000 CVK dana.75 Novija prospektivna studija iz Nizozemske (van der Kooi et al, 2007.) provedena u JIM iz 19 bolnica, s uklju enih 2 644 bolesnika je objavila da se s CVK povezana BIK javljala u 3% bolesnika s primjenjenim CVK, odnosno da je incidencija BIK bila 4/1000 CVK dana te da je trajanje koriatenja CVK bilo glavni imbenik rizika za nastanak s CVK povezane BIK; bolesnici koji su imali CVK e"10 dana su imali 8.4 puta vei rizik nastanka BIK u odnosu na bolesnike koji su CVK imali uveden do 4 dana.76 U ovoj studiji smo na 1000 CVK dana izrazili incidenciju BIK svih ishodiata, a ne samo BIK povezenih s CVK, i ona je za ukupni uzorak iznosila 17.0/1000 CVK dana. Ako uzmemo u obzir da je CVK bio dokazan kao ishodiate u 41/353;11.6% epizoda BIK, mo~e se izra unati da je u naaih bolesnika incidencija s CVK povezenih BIK bila 1.97/1000 CVK dana, ato je ni~a incidencija od onih u predhodno navedenim studijama. Moguim razlogom za to smatramo dosljedno pridr~avanje mjera preporu enih za smanjenje rizika nastanka s CVK povezenih BIK (dosljedno i propisno pranje ruku, koriatenje svih propisanih fizi kih barijera prilikom uvoenja CVK, dezinfekcija ko~e klorheksidinom, izbjegavanje femoralnog pristupa, ato skorije vaenje nepotrebnih CVK), koje su se u velikoj prospektivnoj studiji ameri kih autora koja je obuhvatila 103 JIM i ukupno 375 757 CVK dana (Pronovost et al, 2006.) pokazale kao vrlo u inkovite u smanjenju incidencije s CVK povezanih BIK; nakon samo 3 mjeseca praenja je medijan incidencije s CVK povezanih BIK pao s 2.7/1000 na 0/1000 CVK dana (p<0.002), a nakon 16-18 mjeseci praenja je prosijek incidencije s CVK povezanih BIK pao s po etnih 7.7/1000 na 1.4/1000 CVK dana.77 Drugi razlog niske incidencije s CVK povezanih BIK kod naaih, primarno infektoloakih bolesnika bi mogla biti esta predhodna primjena antimikrobnih lijekova zbog osnovne bolesti, koja je mogla utjecati na smanjenje stope bakterioloakog dokaza uzro nika iz vrha CVK. Navedeno bi moglo biti i razlogom visokog udjela bolesnika s primarnom BIK koji je meu naaim bolesnicima iznosio 215/353;61%, dok se u drugim dosadaanjim studijama taj udio kretao od 20-30% (Banerjee at al, 1991, Brun-Buisson et al, 1996, Renaud et al, 2001.). 78-80 Sama te~ina bolesti pri prijemu u JIM, izra~ena kroz APACHE II skor korigiran za bodove koje donosi dob, prvotno se u naaoj studiji u analizi logisti kom regresijom pokazala zna ajno negativno povezana s vjerojatnoau nastanka BIK (OR: 0.972, 95% CI: 0.951-0.992), ato bi zna ilo da su pri prijemu bla~e bolesni bolesnici imali veu vjerojatnost nastanka BIK tijekom lije enja u JIM. Uzevai u obzir podatak da se u naaih promatranih bolesnika prva epizoda BIK javljala prosje no nakon oko tri tjedna boravka u JIM, naaa je pretpostavka bila da je takav rezultat posljedica toga ato su inicijalno klini ki te~e bolesni bolesnici ranije umirali, pa tijekom boravka u JIM nisu stigli razviti BIK. Tu su pretpostavku potvrdili rezultati dodatne multivarijantne analize u podskupini bolesnika koji su pre~ivjeli lije enje u JIM, u kojoj APACHE II skor umanjen za bodove dobi viae nije imao zna ajan utjecaj na vjerojatnost nastanka BIK (OR: 0.978, 95% CI: 0.950-1.006). Navedeni podatci odudaraju od rezultata drugih studija, koje su utvrdile da je te~ina bolesti pri prijemu, izra~ena kroz APACHE II skor, predstavljala imbenik rizika za nastanak BIK (Laupland et al, 2004, Magnason et al, 2008, Pratikaki et al, 2009.).81-83 Retrospektivna studija australskih autora (Prowle et al, 2011.) je utvrdila da je APACHE III skor pri prijemu imbenik koji je bio zna ajno pozitivno povezan s rizikom nastanka BIK.60 Suprotno tome, jedna starija velika multicentri na europska studija (Vincent et al, 1995.) nije naala povezanost izmeu te~ine bolesti pri prijemu u JIM iskazane APACHE II skorom i rizika za nastanak infekcija u JIM; kao imbenike rizika navedena studija je definirala dijagnozu traume pri prijemu, prisutnost odreenih kroni nih bolesti, upotrebu CVK i urinarnog katetera, prisutnost pneumonije nastale u JIM, prisutnost neuroloakog oateenja, produ~eni boravak u JIM, primjenu mehani ke ventilacije i visoki intenzitet skrbi.14 Kao imbenik najja e povezan s nastankom BIK u JIM navedena studija je utvrdila primjenu CVK (OR: 4.6, 95% CI: 3.12-6.81).14 Meu bolesnicima promatranim u ovom istra~ivanju je BIK zabilje~ena u njih 253/1093;23.4%, odnosno 12.4/1000 dana lije enja u JIM. Europska studija prevalencije nozokomijalnih infekcija u JIM koja je uklju ila podatke iz 1417 JIM iz 17 europskih zemalja (Vincent et al, 1995.), u kojima je na dan studije lije eno 10 038 bolesnika starijih od 10 g, je zaklju ila da je u JIM ste ena infekcija bila prisutna u 2064 bolesnika, ato ini prevalenciju od 20.6%, a meu tim infekcijama su BIK inile 12% i nalazile su se po u estalosti na teem mjestu, iza bolni ki ste enih infekcija dianog i mokranog sustava.14 Iz niza studija (Pittet et al, 1994, Valls et al, 1997, Fagon et al, 1996, Rello et al, 1994, Pittet et al, 1996.) se doznaje da se incidencija BIK ste enih u JIM kree od 2.7-7.4 na 100 prijema u JIM.15,84-88 U novoobjavljenoj retrospektivnoj studiji australskih autora (Prowle et al, 2011.) se incidencija BIK u promatranim godinama (1998.-2009.) kretala u rasponu od 4.4-8.1%.60 U Izraelu je zabilje~ena pojava 2.43 epizode BIK na 100 dana provedenih u JIM (Mnatzaganian et al, 2005.), pri emu su BIK bile zna ajno eae meu bolesnicima koji su bili lije eni u JIM u odnosu na bolesnike koji su zadovoljavali kriterije za lije enje u JIM ali su bili lije eni na obi nim odjelima (2.43 vs. 0.76 epizoda BIK na 100 bolesni kih dana, p<0.001) te su bolesnici lije eni u JIM imali 3.1 puta veu vjerojatnost nastanka BIK.13 U multicentri noj studiji koja je obuhvatila 24 francuske bolnice je incidencija BIK na obi nim odjelima bila 0.44/100 prijema, dok je u JIM bila deseterostruko vea: 4.1/100 prijema u JIM (Brun-Buisson et al, 1996.).79 U jednoj avicarskoj JIM je u desetogodianjem periodu zabilje~en trostruki porast incidencije BIK: sa 6.7/1000 na 18.4/1000 otpusta (Pittet i Wenzel, 1995.).89 Vrlo visoku incidenciju BIK  44/1000 dana lije enja u JIM javljaju autori iz Egipta (Ahmed et al, 2009.).90 Smatramo da je relativno visok udio bolesnika s BIK meu naaim bolesnicima (23.4%) posljedica izmeu ostalog i kriterija uklju ivanja bolesnika u studiju; naaa je studija naime analizirala samo subpopulaciju teakih, mehani ki ventiliranih bolesnika, a prema rezultatima velike multicentri ne europske studije prevalencije nozokomijalnih infekcija, koja je uklju ila podatke iz 1417 JIM iz 17 europskih zemalja (Vincent et al, 1995.), mehani ka ventilacija je univarijantnom analizom utvrena kao jedan od 14 utvrenih imbenika povezanih s rizikom za nastanak nozokomijalnih infekcija, kao i u prospektivnoj ameri koj studiji iz jedne ustanove (Warren et al, 2001) te u novoobjavljenoj studiji australskih autora (Prowle et al, 2011.).14,5,60 Uz to, naai su bolesnici imali primjenjem CVK, ija je du~ina primjene nedvojbeno zna ajan imbenik rizika za nastanak BIK, u gotovo 95% slu ajeva, dok je u drugim studijama primjena CVK (iako podatci o u estalosti primjene znatno variraju) bila znatno rjea nego kod naaih bolesnika: 29.1% (Warren et al, 2001), 61% (van der Kooi et al, 2007.).5,76 Takoer, iako je ponekad teako odrediti smjer uzro no-posljedi ne veze izmeu nastanka BIK i du~ine lije enja u JIM, treba napomenuti da je prosje no trajanje lije enja u JIM u naaih promatranih bolesnika bilo dugo, prosje no oko 21 dan. Dosadaanje su studije utvrdile povezanost du~ine lije enja u JIM i nastanka infekcija ste enih u JIM; velika multicentri na europska studija (Wincent et al, 1995) je utvrdila da vjerojatnost nastanka infekcija ste enih u JIM zna ajno raste s danom boravka u JIM te da bolesnici koji se lije e u JIM 21 dan i du~e imaju 33 puta vei rizik za nastanak u JIM ste enih infekcija nego bolesnici koji se u JIM lije e 1-2 dana.14 Jedna manja retrospektivna brazilska studija (Marra et al, 2006.), koja se odnosila samo na BIK uzrokovane s Pseudomonas aeruginosa, je zaklju ila da nakon 21 dana boravka u JIM polovina bolesnika dobije BIK.91 Stoga, ako se pojava BIK izrazi na broj dana lije enja u JIM, u naaih su se bolesnika javljale 12.4 epizode BIK na 1000 dana lije enja u JIM, ime se naai rezultati uklapaju u rezultate drugih studija u kojima se pojava BIK kree u rasponu od 5-19/1000 dana lije enja u JIM (Pittet et al, 1994, Rello et al, 1994. i Laupland et al, 2002.).84,87,92 U naaih promatranih bolesnika se prva epizoda BIK javljala relativno kasno, prosje no 22.1 dan nakon prijema u JIM. Jedna prospektivna studija ameri kih autora (Warren et al, 2001.) je zaklju ila da se u njihovoj JIM, u kojoj su lije eni internisti ki i kiruraki bolesnici, prva epizoda BIK ( ija je incidencija bila 4/1000 CVK dana) prosje no pojavljivala nakon 15 dana boravka u JIM, no polovina ih se javila unutar prvih 8 dana boravka u JIM.5 Sli an podatak je objavila studija brazilskih autora koja je promatrala 127 bolesnika s BIK uzrokovanom s P. aeruginosa ili enterokokom (Marra et al, 2006.), koja je ustanovila da se BIK pojavljivala prosje no nakon 15 dana boravka u JIM kod bolesnika <65 g, i prosje no nakon 16.5 dana kod bolesnika e"65 godina, i ta razlika u vremenu pojavljivanja izmeu mlaih i starijih bolesnika nije bila statisti ki zna ajna (p=0.66).7 Sli an podatak je objavila i retrospektivna studija belgijskih autora (Blot et al, 2002.) koja je prou avala utjecaj kandidemije na ishod lije enja u 73 bolesnika, i koja je zaklju ila da je medijan pojave kandidemije u njihovih bolesnika bio 15 dana boravka u JIM, iako se u drugom radu (Flanagan i Barnes, 1998.) navodi da se kandidemija openito via relativno kasno, nakon 14-30 dana boravka u JIM, ato se pripisuje injenici da se kandidemija kao oportunisti ka infekcija, javlja obi no u teako bolesnih, imunosuprimiranih i bolesnika s dugotrajnom antibiotskom terapijom te dugotrajnim boravkom u JIM.93,94 Australski su autori (Prowle et al, 2011.) objavili da je u njihovih bolesnika medijan pojavljivanja prve epizode BIK bio nakon 7 dana boravka u JIM, pri emu su, za razliku od naaeg istra~ivanja, oni promatrali bolesnike koji su lije eni u JIM du~e od 72 sata.60 Takoer, oni su zaklju ili da ako se BIK javila rano tijekom boravka u JIM, kada je openito stopa smrtnosti u JIM najvea, onda je i negativni u inak prisutnosti BIK na pre~ivljavanje bio ja e izra~en.60 Sli an je bio i zaklju ak retrospektivne francuske studije raene nakon sparivanja izlo~enih i neizlo~enih bolesnika prema du~ini boravka u JIM prije nastupa BIK i prema te~ini bolesti mjerene TRIO skorom (Garrouste-Orgeas et al, 2006.); u navedenom istra~ivanju je rizik smrti povezan s BIK bio najvei kod bolesnika s rano nastalom BIK (nastalom izmeu 4.-6. dana boravka u JIM) (OR: 2.75, 95% CI: 1.35-4.88, p=0.0034).15 Kasno pojavljivanje prve epizode BIK u naaih primarno teakih, infektoloakih bolesnika bi moglo biti posljedica este predhodne primjene antibiotika zbog osnovne bolesti, ime se mo~e dijelom prevenirati i/ili u odreenoj mjeri odgoditi nastup BIK. Rezultati ispitivanja ishoda lije enja na pseudorandomiziranom uzorku su u naaem istra~ivanju pokazali da prisutnost BIK u bolesnika starije ~ivotne dobi nije imala negativan utjecaj na stopu smrtnosti niti na 28-dnevno pre~ivljavanje, ime je odba ena hipoteza o negativnom utjecaju BIK na pre~ivljavanje bolesnika starije ~ivotne dobi. U bolesnika starije ~ivotne dobi s BIK je primjeena tendencija ni~e smrtnosti te su oni imali 42% manju aansu smrtnog ishoda u usporedbi s bolesnicima starije ~ivotne dobi bez BIK, no statisti ka zna ajnost nije postignuta. Veina dosadaanjih studija je utvrdila negativan utjecaj prisutnosti BIK na pre~ivljavanje u JIM (Garrouste-Orgeas et al, 2006, Prowle et al, 2011, Brun-Buisson et al, 1996, Renaud et al, 2001, Pittet et al, 1994, Valls et al, 1997, Rello et al, 1994, Girou et al, 1998, Higuera et al, 2007. i Thompson DS, 2008.).15,60,79,80,84,85,87,95-97 U studiji australskih autora (Prowle et al, 2011.) je prisutnost BIK bila nezavisno povezana s rizikom smrti (HR: 2.89, 95% CI: 2.41-3.46, p<0.001), dok su druge dvije studije (Garrouste-Orgeas et al, 2006. i Renaud et al, 2001.) utvrdile da prisutnost BIK povisuje rizik smrti za tri odnosno viae od etiri puta.60,15,80 Prowle et al. (2011.) zaklju uju da iako prisutnost BIK znatno negativno utje e na pre~ivljavanje bolesnika koji dobiju BIK, zbog niske incidencije BIK (5%) njihova pojava ima atributivnu smrtnost u ukupnoj populaciji u JIM od tek 1%.60 Blot et al, 2009. zaklju uju da iako je incidencija BIK bila najni~a u bolesnika e"75 g, u toj dobnoj skupini je prisutnost BIK imala najja e izra~eni negativan utjecaj na pre~ivljavanje.45 Takoer, rezultati dosadaanjih studija su pokazali da je ishod lije enja ovisio i o ishodiatu BIK; primarne i s CVK povezane BIK su imale mnogo manji negativni u inak na pre~ivljavnaje nego sekundarne BIK. Retrospektivna studija sparenih izlo~enih i neizlo~enih bolesnika belgijskih autora (Blot et al, 2005.) koja je obuhvatila 10-godianji period i 176 bolesnika sa s CVK povezanom BIK je zaklju ila da su s CVK povezane BIK imale vrlo malu atributivnu stopu smrtnosti (1.8%).16 Takoer retrospektivna studija francuskih autora koja je obuhvatila 96 parova bolesnika (Renaud et al, 2001.) je objavila da je atributivna stopa smrti za s CVK povezane BIK bila 11.5%, za primarne BIK zajedno sa s CVK povezanim BIK 20.4%, a za sekundarne BIK 55%.80 Neke su dosadaanje studije utvrdile da odnos BIK i pre~ivljavanja ovisi i o vrsti uzro nika i osjetljivosti uzro nika na antibiotike. Studija australskih autora (Prowle et al, 2011.) je zaklju ila da su Candida, Staphylococcus aureus i gram-negativne bakterije bile nezavisno povezane s poviaenim rizikom smrti.60 Zna ajan negativan utjecaj na pre~ivljavanje kod BIK uzrokovanih s MRSA je utvrdila i studija belgijskih autora (Blot et al, 2002.), koji su objavili da su BIK uzrokovane s MRSA imale atributivnu stopu smrti 23.4%, dok je s druge strane atributivna stopa smrti kod MSSA BIK iznosila svega 1.3%.24 Meta-analiza ameri kih autora (Cosgrove et al, 2002.) je utvrdila da bolesnici s MRSA bakterijemijom imaju veu vjerojatnost za smrtni ishod nego bolesnici s MSSA bakterijemijom, omjer aansi je bio 1.93, dok je neato kasnija retrospektivna kohortna analiza iste grupe autora (Cosgrove et al, 2005.) raena na 348 bolesnika sa S. aureus bakterijemijom zaklju ila da rezistencija na meticilin S. aureusa nije bila povezana s veom stopom smrtnosti, ali je bila povezana sa zna ajno du~im trajanjem i veim troakovima lije enja.98,99 Jedna je studija (Tacconelli et al, 2006.) zaklju ila da je negativan utjecaj MRSA BIK bio ja e izra~en u bolesnika starije ~ivotne dobi, koji su imali 3.7 puta vei rizik smrtnog ishoda tijekom MRSA BIK nego mlai promatarani bolesnici.100 S druge strane, itav niz retrospektivnih studija belgijskih autora provedenih na istoj kohorti bolesnika (Blot et al, 2002.-2003.) nije naaao zna ajnu atributivnu stopu smrti kod s CVK povezanih BIK uzrokovanih s gram-negativnim bakterijama (Acinetobacter baumanii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella i Enterobacter) te su isti autori u jednom radu zaklju ili da nije bilo zna ajne razlike u smrtnosti kod s CVK povezanih BIK izazvanim dobro osjetljivim u odnosu na one uzrokovane rezistentnim sojevima gram-negativnih bakterija (41.8% vs. 45.0%); bez obzira na antimikrobnu osjetljivost, njihova smrtnost je bila u okvirima na temelju APACHE II skora predviene smrtnosti pri prijemu.20-23,101,102 Studija brazilskih autora koja je istra~ivala 127 bolesnika s BIK uzrokovanom s P. aeruginosa i enterokokom (Marra et al, 2006.) je takoer zaklju ila da BIK uzrokovane navedenim uzro nicima nisu imale negativan utjecaj na pre~ivljavanje.7 Smatramo da su bolje pre~ivljavanje i bolje 28-dnevno pre~ivljavanje naaih bolesnika koji su tijekom lije enja u JIM imali BIK posljedica toga ato je glavnina smrtnosti promatrane skupine bolesnika vjerojatno otpadala na raniju smrtnost uzrokovanu osnovnom boleau i njenim komplikacijama. Smatramo da postoje imbenici koji su utjecali na pre~ivljavanje a koji nisu bili obuhvaeni ovim istra~ivanjem. Predpostavljamo da su ti imbenici, vezani uz osnovnu infektoloaku bolest, bili naro ito utjecajni u bolesnika starije ~ivotne dobi, jer je meu njima zabilje~ena zna ajno viaa ukupna stopa smrtnosti u odnosu na promatranu mlau skupinu odraslih bolesnika (52.7% vs. 42.8%, p=0.001), dok u analizi pre~ivljavanja na pseudorandomiziranom uzorku nije utvren negativan utjecaj prisutnosti BIK na pre~ivljavanje bolesnika starije ~ivotne dobi. Naaa razmialjanja su u skladu sa zaklju cima francuske studije iji autori (Pequignot et al, 1999.) navode da stopa mortaliteta od vanbolni ki ste enih infektivnih bolesti eksponencijalno raste s dobi za bolesnike e"65 g.103 Takoer, studija francuskih autora (Gavazzi et al, 2002.) zaklju uje da je dob bila nezavisni faktor rizika za smrtni ishod samo kod bolesnika >85 g. s domicilnom sepsom, dok takav utjecaj nije imala u bolesnika s BIK, a gr ki su autori (Vosylius et al, 2005.) svojom prospektivnom kohortnom studijom zaklju ili da je dijagnoza infektivne bolesti pri prijemu bila (uz dijagnozu kome, te~inu bolesti pri prijemu i infekciju ste enu tijekom lije enja u JIM) nezavisni imbenik rizika za bolni ku smrtnost.18,104 Stoga zaklju ujemo da su naai bolesnici koji su pre~ivjeli rane, zbog osnovne bolesti najkriti nije dane, kasnije tijekom boravka u JIM dobijali BIK, no ona nije imala znatnijeg utjecaja na njihovo pre~ivljavanje. Razlog tome mo~e biti taj ato je velika veina naaih bolesnika imala primarnu i s CVK povezanu BIK (ukupno 72.6% epizoda BIK) za koje je veina predhodno navedenih studija zaklju ila da ili nemaju utjecaja na pre~ivljavanje, ili je njihov negativni utjecaj malen. Takoer, udio MRSA kao mogueg rizi nog uzro nika je u naaem uzorku bio relativno malen; MRSA je meu naaim bolesnicima uzrokovao 9.3% svih epizoda BIK. Usporedbe radi, u studiji ameri kih autora (Cosgrove et al, 2005.) od 348 bolesnika s domicilnom ili bolni kom S. aureus bakterijemijom, njih 28% je imalo MRSA infekciju te prema nacionalnim rezultatima nadzora bolni kih infekcija (NNISS, 2001.), MRSA je sa svojim 29%-tnim porastom incidencije u etverogodianjem razdoblju, i s udjelom od 55% meu svim nozokomijalnim infekcijama u JIM, predstavljao rastui problem u SAD.99,105 Iako retrospektivnim istra~ivanjem nije mogue utvrditi smjer uzro no-posljedi nog odnosa prisutnosti BIK i du~ine lije enja u JIM, mnoge su studije, pa tako i naaa, istra~ivale du~inu lije enja u JIM kao jednu od varijabli ishoda. Analiza naaih podataka donjela je zanimljive rezultate; zna ajno du~e lije enje u JIM je utvreno samo u bolesnika starije ~ivotne dobi s BIK, kada smo ih usporedili sa mlaim promatranim bolesnicima koji su takoer tijekom lije enja u JIM imali BIK (36.3 vs. 27.5 dana, p=0.0056) i kada smo ih usporedili sa bolesnicima starije ~ivotne dobi koji tijekom boravka u JIM nisu imali BIK (36.3 vs. 27.6 dana, p=0.0042). itav niz dosadaanjih studija je utvrdio zna ajno du~e trajanje lije enja u JIM i lije enja u bolnici u bolesnika s BIK (Warren et al, 2001, Pittet et al, 1994, Valles et al, 1997. i Girou et al, 1998.); u prvonavedenoj prospektivnoj studiji to produ~enje boravka u JIM je iznosilo prosje no ak 25 dana.5,84,85,95 Renaud et al, 2001. su promatrajui 111 bolesnika s BIK iz 15 fancuskih JIM zaklju ili da u pre~ivjelih bolesnika navedene infekcije produ~uju lije enje u JIM za 9.5 dana, bez obzira na ishodiate BIK (primarna, s CVK povezana ili sekundarna BIK).80 Nalaz zna ajno produ~enog lije enja u JIM samo kod bolesnika starije ~ivotne dobi s BIK u naaem istra~ivanju mo~e biti znak sporijeg oporavka bolesnika s BIK koji su starije ~ivotne dobi, ali poato je analiza du~ine lije enja raena i na bolesnicima koji su pre~ivjeli i na bolesnicima koji su umrli, mogue je da smo dobili prividno krae trajanje lije enja u bolesnika starije ~ivotne dobi bez BIK, zbog njihovog ranijeg umiranja od komplikacija osnovne bolesti, ato ih je onemoguilo da kasnije tijekom boravka u JIM dobiju BIK i ato je skratilo prosje no trajanje njihovog lije enja. Iako prema podatcima Dr~avnog zavoda za statistiku Republike Hrvatske naae druatvo progresivno stari,1 meu naaim bolesnicima lije enim u JIM nismo utvrdili porast udjela bolesnika starije ~ivotne dobi u promatranom 15-godianjem razdoblju, no oni su inili znatnih 46.6% od promatranih bolesnika. Navedeni podatci nisu u skladu s demografskim podatcima iz europske (Jakob i Rothen, 1997.) i ameri ke studije (Groeger et al, 1993.) koje su navele da je prosje na dob bolesnika lije enih u JIM rasla sa starenjem njihove ope populacije.2,3 Udio bolesnika starije ~ivotne dobi meu naaim promatranim bolesnicima je bio u skladu s podatcima iz drugih dosad objavljenih studija; njihov se udio u JIM kretao u rasponu od 12.5% do 58% (Castillo-Lorente et al, 1997, Groeger et al, 1993.).3,106 Prema studiji ameri kih autora (Angus et al, 2000.) bolesnici e"65 g. su koristili gotovo 2/3 dana lije enja u JIM, a isti su autori u studiji iz 2001. g. objavili podatak da su bolesnici >70 g. inili 36% bolesnika lije enih u JIM u aestogodianjem razdoblju do 1998. g. te je 10% njih bilo lije eno u JIM du~e od 30 dana.61,107 Belgijski autori (Blot et al, 2009.) su zaklju ili da je u promatranom 15-godianjem razdoblju do 2006. g. padao apsolutni broj bolesnika e"45 g. lije enih u JIM za oko 10%, ali je meu njima rastao broj bolesnika e"75 g. za 33%, dok su francuski autori (Somme et al, 2003.) iznjeli podatak da je u njihovoj JIM 24.2% bolesnika koji su bili lije eni od godine 1991.-1996. bilo e"75 g. te su oni koristili 21.8% od svih dana lije enja u JIM.45,108 Meu naaim bolesnicima je u promatranom razdoblju zabilje~en trend zna ajnog pada udjela bolesnika s BIK meu bolesnicima starije ~ivotne dobi (p=0.0002), no predpostavljamo da je takav trend posljedica znatno veeg udjela bolesnika s BIK meu bolesnicima starije ~ivotne dobi u odnosu na mlae promatrane bolesnike u prvom dijelu promatranog razdoblja, do godine 2001, dok nakon navedene godine ti udjeli kod mlaih i starijih promatranih bolesnika postaju sve sli niji. Od godine 2002. dolazi i do jasnog poveanja apsolutnog broja promatranih bolesnika lije enih u JIM; do tada je godianje lije eno veinom do 60, a od 2002. g. je u JIM lije eno uglavnom viae od 80 promatranih bolesnika godianje, iako nije doalo do poveanja kapaciteta promatrane JIM. Navedeni podatci ukazuju na promjene poslovanja promatrane JIM od godine 2002, koje su uklju ile vei protok bolesnika i dosljedno provoenje mjera prevencije bolni kih infekcija, ato bi moglo biti uzrokom smanjenja udjela bolesnika s BIK meu bolesnicima starije ~ivotne dobi, s posljedi nim izjedna avanjem tog udjela meu bolesnicima iz obje promatrane dobne skupine. Rezultati naaeg istra~ivanja su takoer pokazali da izmeu promatranih dobnih skupina bolesnika nije bilo zna ajne razlike u raspodjeli uzro nika BIK, niti u njihovim profilima osjetljivosti na antibiotike. Navedeni rezultati odudaraju od rezultata predhodnih studija koje su promatrale i bolni ki i vanbolni ki ste ene infekcije krvotoka te su zaklju ile da se u starijoj dobi uzro nici infekcija krvotoka razlikuju u odnosu na one u mlaih bolesnika (Yoshikawa TT, 2000, Leibovici et al, 1993.) i da u starijih bolesnika openito nalazimo airi spektar uzro nika infekcija (Gavazzi i Krause, 2002.).41,42,109 Promatrajui tri dobne podskupine bolesnika starijih od 65 g. (65-75 g, 76-85 g. i e"85 g.) autori retrospektivne studije koja je obuhvatila podatke o bolni ki i vanbolni ki ste enim infekcijama krvotoka iz 46 francuskih bolnica tijekom 1998. g. (Gavazzi et al, 2002.) su zaklju ili da je u najstarijoj promatranoj dobnoj skupini (e"85 g.) zna ajno vei udio bolesnika s gram-negativnim uzro nicima infekcija krvotoka nego u mlaim promatranim dobnim podskupinama.18 Meu naaim bolesnicima su kao uzro nici BIK jasno prednja ile gram-negativne bakterije; one su uzrokovale 56.1% svih epizoda BIK ato je neato vei udio gram-negativnih bakterija nego u studiji francuskih autora (Gavazzi et al, 2002.) koji su promatrali i bolni ki i vanbolni ki ste ene infekcije krvotoka u bolesnika e"65 g. i koji su utvrdili gram-negativne uzro nike u 50% bolesnika.18 Gram-negativni uzro nici su prednja ili u uzrokovanju BIK i u Brazilu, gdje su prema jednoj studiji (Sander et al, 2001.) uzrokovale neato manje od 60% epizoda BIK.110 Joa vei udio gram-negativnih uzro nika BIK su utvrdili indijski autori (Taneja et al, 2010.) kod kojih je od 253 epizoda BIK ste enih u JIM njih oko 82% bilo uzrokovano gram-negativnim bakterijama.111 Suprotno tome, postoji veliki broj studija koje su istra~ivale etiologiju BIK u kojima su kao uzro nici prevladavale gram-pozitivne bakterije, s razli itim udjelima; njihov je udio iznosio 52.5% (Garrouste-Orgeas et al, 2006.) zatim 56% (Erbay et al, 2003.), 61% (Smith et al, 1991.), 62% (Richards et al, 2000.), 69% (Ahmed et al, 2009.) pa sve do 76% (Warren et al, 2001.).5,8,15,26,90,112 Zanimljiv je zaklju ak nizozemskih autora (van der Kooi et al, 2007.) koji su utvrdili da Staphylococcus aureus uzrokuje 60% s CVK povezanih BIK u prva dva tjedna primjene CVK, a nakon tog vremena mu udio meu uzro nicima pada na 41%, a raste udio enterobakterija, ato ukazuje na mogunost da se etiologija BIK mijenja s trajanjem primjene CVK.76 U naaoj populaciji bolesnika su gram-pozitivni uzro nici uzrokovali svega 18.1% epizoda BIK. Smatramo da su razlike u zastupljenosti gram-pozitivnih uzro nika BIK izmeu naaih bolesnika i bolesnika u predhodno navedenim studijama uzrokovani razlikama u uzorku bolesnika; u naau su studiju uklju eni samo teaki primarno infektoloaki bolesnici, dok su u predhodno navedene studije bili osim internisti kih uklju eni i kiruraki, traumatoloaki i bolesnici s opekotinama, koji zbog oateenja cjelovitosti ko~e imaju veu vjerojatnost nastanka BIK uzrokovane gram-pozitivnim uzronicima koji ulaze u krvotok s ko~e. Drugi razlog malog udjela gram-pozitivnih bakterija u naaih bolesnika mo~e biti relativno kasni nastup prve epizode BIK (prosje no nakon tri tjedna boravak u JIM) i dugo koriatenje CVK (prosje no 2 tjedna), jer kako je u predhodno navedenoj studiji nizozemskih autora zaklju eno, s vremenom i du~inom primjene CVK se udio BIK uzrokovanih sa S. aureus smanjuje, a raste udio epizoda BIK uzrokovanih enterobakterijama. Naj eae izolirani uzro nici BIK su meu naaim bolesnicima bili Acinetobacter baumanii (20.9% epizoda BIK) i Klebsiella pneumoniae (12.5% epizoda BIK). Sli ne, ali neato manje udjele navedenih bakterija izvjeatavaju izraelski autori (Mnatzaganian et al, 2005.) koji su istra~ivali sve vrste bolni ki ste enih infekcija; udio navednih uzro nika u JIM ste enih infekcija je bio 16.6% za A. baumanii i 10.9% za K. pneumoniae, dok znatno viae udjele navedenih gram-negativnih bakterija javljaju indijski autori (Taneja et al, 2010.); u njihovom uzorku bolesnika s 253 epizode BIK ste ene u JIM njih 26.2% je bilo uzrokovano s K. pneumoniae, a 25.8% s A. baumanii.13,111 Sa svega 7 uzrokovanih epizoda BIK, E. coli je kao uzro nik u naaih bolesnika bila od minornog zna aja, ime se naai rezultati uklapaju u rezultate prijaanjih studija koje su zaklju ile da E. coli nije uobi ajeni uzro nik BIK u odraslih bolesnika te se rijetko izolira iz kultura vrha CVK (Maki et al, 1973, Duggan et al, 1985.), dok je za razliku od nalaza naae studije u uzorku indijskih autora (Taneja et al, 2010.) E. coli uzrokovala 10.6% od 253 epizode, a u uzorku brazilskih autora (Sander et al, 2001.) ak 11.3% od 2008 epizoda BIK.110,111,113,114 Iako su se BIK u naaih bolesnika javljale relativno kasno, prosje no nakon tri tjedna boravka u JIM, sa 7.1% uzrokovanih epizoda BIK je incidencija kandidemije u naaih bolesnika bila ni~a nego u drugim do sada objavljenim studijama. U studiji ameri kih autora (Smith et al, 1991.) je 15% primarnih BIK bilo uzrokovano s C. albicans.26 Mo~emo zaklju iti da meu naaim promatranim bolesnicima za sada ne primjeujemo porast udjela infekcija uzrokovanih kandidom, kao ato je to slu aj u nizu zemalja: u studiji iz Izraela kandida je uzrokovala 21.5% svih infekcija ste enih u JIM (Mnatzaganian et al, 2005.), u multicentri noj studiji iz 17 europskih zemalja kandida je uzrokovala 17% svih bolni ki ste enih infekcija (Vincent et al, 1995.), dok je u SAD od godine 1980.-1990. udio gljivi nih infekcija meu svim bolni ki ste enim infekcijama porastao s 6% na 10.4% (Beck-Sagu et al, 1993.).13,14,115 Iako je S. aureus sa 40/353;11.3% izolata bio po u estalosti tek trei pojedina ni uzro nik BIK u naaih bolesnika, udio MRSA je meu S. aureus izolatima iznosio 82.5%, ato spada meu najviae postotke zabilje~ene u Europi. U multicentri noj studiji iz 17 europskih zemalja (Vincent et al, 1995.) je udio MRSA meu S. aureus izolatima BIK iznosio 72.4%, a najviai udjeli MRSA su u toj studiji zabilje~eni u Italiji (81%) i u Francuskoj (78.4%),14 dok je u studiji belgijskih autora (Blot et al, 2002.) udio MRSA iznosio 55.3%, a u studiji egipatskih autora (Ahmed et al, 2009.) je udio MRSA meu S. aureus izolatima BIK iznosio 65%.24,90 U SAD je prema nacionalnim podatcima nadzora (NNIS 2001.) MRSA bio uzro nik 55% od svih bolni kih infekcija, uz porast incidencije od 29% u etverogodianjem razdoblju.105 Od kada je godine 1986. zabilje~en prvi soj enterokoka neosjetljiv na vankomicin te od kada je godine 1996. g. zabilje~en prvi S. aureus soj intermedijarno osjetljiv na vankomicin, neosjetljivost navedenih uzro nika na vankomicin postaje postupno rastui problem u mnogim dijelovima svijeta, uz znatne geografske varijacije. U jednoj studiji iz SAD (Bar et al, 2006.) je u 17/50;34% izolata enterokoka koji su bili uzro nici BIK zabilje~ena neosjetljivost na vankomicin (60% izolata je bilo E. faecalis a 34% E. faecium).116 Prema rezultatima naae studije neosjetljivost gram-pozitivnih uzro nika na vankomicin joa nije zabilje~ena u populaciji naaih promatranih bolesnika. Enterokoki su u naaih bolesnika uzrokovali 4% BIK, ato je vei udio od onog naenog u Brazilu  2.7% (Sander et al, 2001.), a manji od njihovog udjela u populaciji bolesnika u SAD, gdje su enterokoki uzrokovali gotovo 10% BIK (Jones et al, 1998.).110,117 Meutim, udio ARE je meu naaim izolatima enterokoka bio visok - 28.6%, dok je u studiji avedskih autora taj udio iznosio 8.1% meu svim bolni kim izolatima enterokoka godine 1995. (Torell et al, 2001.).118 Udio ESBL i sojeva neosjetljivih na cefalosporine III generacije je meu enterobakterijama u naaih bolesnika iznosio 58.8%, ato je ni~i udio nego u drugim objavljenim studijama; udio ESBL meu gram-negativnim uzro nicima BIK od 64.7% (Ahmed et al, 2009.), udio ESBL meu K. pneumoniae izolatima BIK od 70.7% (Taneja et al, 2010.) dok je studija brazilskih autora (Sander et al, 2001.) utvrdila udio ESBL sojeva meu izolatima K. pneumoniae koji su uzrokovali bolni ke infekcije openito, od 50.3%.90,110,111 Udio MDR sojeva je meu nefermentirajuim gram negativnim bakterijama u naaih bolesnika iznosio 14.2% tj. 4.5% od svih epizoda BIK, ato odgovara podatku iz novije studije belgijskih autora (Blot et al, 2009.) gdje je njihov udio u epizodama BIK iznosio 5.7%.45 U studiji takoer belgijskih autora (Depuydt et al, 2006.) je u 129 epizoda sekundarnih BIK s ishodiatem u bolni ki ste enim upalama plua udio MDR nefermentirajuih gram-negativnih bakterija bio znatno vei i iznosio je 13.2%.119 Zaklju no mo~emo rei da prema uzro nicima naaa JIM spada meu JIM u kojima kao uzro nici BIK prevladavaju gram-negativne bakterije, i da prema profilu neosjetljivosti na antibiotike naai gram negativni sojevi koji uzrokuju BIK ne odudaraju od onih opisanih u drugim studijama, dok je udio neosjetljivih meu gram-pozitivnim uzro nicima vei nego u drugim studijama, osim ato u promatranom razdoblju nismo imali zabilje~ene neosjetljivosti na vankomicin. U obje promatrane dobne skupine naaih bolesnika je zabilje~en visok postotak primjenjene neodgovarajueg empirijskog antibiotskog lije enja (ukupno 61.2%). Viae je dosadaanjih studija utvrdilo da je antimikrobna neosjetljivost imbenik rizika za odgoenu primjenu odgovarajueg antimikrobnog lije enja (Depuydt et al, 2006, Dupont et al, 2003, Kollef et al, 1999.).27,120,121 Meu bolesnicima sa sekundarnim BIK, ije je ishodiate bilo u bolni ki ste enim upalama plua, koje su vrlo esto uzrokovane neosjetljivim sojevima, je takoer zabilje~en visok udio primjene neodgovarajueg antimikrobnog lije enja od 62% (Depuydt et al, 2006.).27 U nizu studija belgijskih autora, koji su istra~ivali BIK izazvane nizom gram-negativnih uzro nika (Blot et al, 2002.-2003.), je udio primjenjene odgovarajueg antimikrobnog lije enja bio visok, iznad 90%.20-23 U inak odgoene primjene odgovarajueg antimikrobnog lije enja na pre~ivljavanje bolesnika s BIK je dvojben; neke studije su zaklju ile da rana primjena odgovarajueg antimikrobnog lije enja nije bila povezana s boljim pre~ivljavanjem (Depydt et al, 2006.), ili nisu naale da kaanjenje s odgovarajuom terapijom umanjuje stopu pre~ivljavanja (Blot et al, 2002), dok su neke studije zaklju ile da je rano odgovarajue antimikrobno lije enja bilo klju no za pre~ivljavanje kod nekih ja e virulentnih uzro nika, npr. kod bakterijemija uzrokovanih s P. aeruginosa (Bodey et al, 1985, Vidal et al, 1996.).27,101,122,123 Zaklju no mo~emo rei da iako je udio primjene neodgovarajueg antimikrobnog lije enja u naaih bolesnika bio visok, nije primjeen negativan utjecaj prisutnosti BIK na njihovo pre~ivljavanje. Najvei nedostatak ovog istra~ivanja je njegov opservacijski ustroj koji iako je pogodan za opisivanje epidemiologije BIK, zbog mogunosti meusobnog utjecaja niza razli itih imbenika nije pogodan za ocjenu ishoda lije enja, ato smo pokuaali premostiti stvaranjem pseudorandomiziranog uzorka, koji nam je omoguio pouzdanije zaklju ivanje o odnosu prisutnosti BIK i ishoda lije enja. Nedostatak ovog istra~ivanja je i manjak detaljnijih podataka o vrsti primarne infekcije zbog koje su bolesnici bili lije eni u JIM, o njenom klini kom tijeku, primjenjenim mjerama intenzivnog lije enja, i primjenjenom antimikrobnom lije enju osnovne bolesti, ime bi se moglo pokuaati objasniti veu smrtnost meu bolesnicima koji tijekom boravka u JIM nisu imali BIK. Takoer, nedostatak ovog istra~ivanje je i izostanak praenja bolesnika nakon otpusta iz JIM, ato onemoguava uvid u njihovu kasnu smrtnost, kao i uvid u kvalitetu njihovog ~ivota nakon pre~ivljavanja lije enja u JIM. ZAKLJU AK Rezultati ovog rada pokazuju da starija ~ivotna dob nije bila povezana s veom vjerojatnoau nastanka BIK te da prisutnost BIK nije imala negativan utjecaj na pre~ivljavanje bolesnika starije ~ivotne dobi u JIM, ime predhodno postavljena hipoteza o veoj u estalosti i loaijem ishodu BIK u bolesnika starije ~ivotne dobi nije potvrena. U promatranom razdoblju nije uo en trend porasta udjela bolesnika starije ~ivotne dobi meu promatranim bolesnicima lije enim u JIM te nije bilo razlike u epidemiologiji niti u antimikrobnoj osjetljivosti uzro nika BIK izmeu usporeivanih dobnih skupina bolesnika. SA}ETAK Uvod: Infekcije nastale tijekom lije enja u jedinici intenzivne medicine (JIM) predstavljaju rastui problem suvremene medicine i malo se zna o odnosu starije ~ivotne dobi i u JIM nastalih infekcija. Cilj: Utvrditi odnos starije ~ivotne dobi i rizika nastanaka bolni kih infekcija krvotoka (BIK) u JIM, utvrditi njihov ishod i epidemiologiju. Ustroj: Retrospektivno kohortno istra~ivanje. Ustanova: JIM Klinike za infektivne bolesti, Zagreb. Bolesnici: Mehani ki ventilirani infektoloaki bolesnici oba spola e"18 g, lije eni u JIM e"48h od 1994-2008. Metode: Uni i bivarijantne analize, multivarijantna analiza, izra unavanje  propensity skorova. Rezultati: Od 1093 bolesnika 46.6% je bilo e"65 g, a 23.4% je imalo BIK. Dob bolesnika nije bila povezana s vjerojatnoau nastanka BIK (OR:0.992, 95%CI: 0.712-1.381). Iako su bili zna ajno du~e lije eni u JIM, utvrena je tendencija boljeg pre~ivljavanja i 28-dnevnog pre~ivljavanja u bolesnika e"65 g. s BIK (p=0.0686 i p=0.047). Etiologija 353 BIK je bila podjednaka u promatranim dobnim skupinama (p=0.4940); nefermentirajue gram-negativne bakterije: 32.0% (MDR 4.5%), enterobakterije: 24.1% (ESBL+CEF3 R 14.2%), gram-pozitivne bakterije: 18.1% (MRSA 9.3%, enterokoki rezistentni na ampicilin 1.1%), polimikrobne: 17.6%, kandida: 7.1%, ostalo: 1.1%. Zaklju ak: Starija ~ivotna dob nije bila povezana s vjerojatnoau nastanka BIK. Bolesnici e"65 g. s BIK su bili zna ajno du~e lije eni u JIM, ali su imali bolje ukupno i 28-dnevno pre~ivljavanje. Nije utvrena razlika u etiologiji niti u antimikrobnoj osjetljivosti uzro nika BIK izmeu promatranih dobnih skupina. SUMMARY TITLE: Intensive care unit acquired bloodstream infections  impact of the patient`s age Author: Mirjana Balen Topic Year: 2011 Introduction: The intensive care units (ICU) aquired infections are the rising problem of the modern medicine and the little is known about the relationship between older age and ICU acquired infections. Objective: To assess the relationship between the older age and risk for acquisition of ICU aquired bloodstream infections (BSI), determine their outcome and epidemiology. Design: Retrospective cohort study. Setting: ICU of the University Hospital for Infectious Diseases, Zagreb. Patients: Mechanically ventilated infectious disease patients of both sexes e"18 yrs, treated in ICU e"48h from 1994-2008. Methods: Uni-, bi- and multi-variate analysis,  propensity score calculation. Results: Of 1093 patients 46.6% were e"65 yrs. and 23.4% had BSI. The corelation between age and BSI aquisition was not found (OR:0.992, 95%CI: 0.712-1.381). Although showing significantly longer ICU stay, tendency of better survival and 28-days survival was found among patients e"65 yrs. with BSI (p=0.0686, p=0.047). Etiology of 353 episodes of BSI was similar in both age-groups (p=0.4940); nonfermenting gram-negative bacteria: 32.0% (MDR 4.5%), enterobacteria: 24.1% (ESBL+CEF3 R 14.2%), gram-positive bacteria 18.1% (MRSA 9.3%, ARE 1.1%), polymicrobial: 17.6%, Candida sp: 7.1%, other: 1.1%. Conclusions: No correlation between older age and BSI acquisition was found. Analyses showed significantly longer ICU stay, but better overall and 28-day survival among patients e"65 yrs. with BSI. 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Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999;115:462-74. Bodey G, Jadeja L, Elting L. Pseudomonas bacteremia: retrospective analysis of 410 episodes. Arch Intern Med 1985;145:1621-9. Vidal F, Mensa J, Almela M, et al. Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphasis on the influence of antibiotic treatment. Arch Intern Med 1996;156:2121-6. }IVOTOPIS Mirjana Balen Topi je roena 18.10.1966. godine u Zagrebu, udata je i majka je dvoje djece. Na Medicinskom fakultetu Sveu iliata u Zagrebu je diplomirala godine 1991. Stru ni lije ni ki ispit je polo~ila godine 1992. Godine 1995. je nostrificirala diplomu na Univerzitetu Karl-Franzens u Grazu, Austrija. U razdoblju od godine 1993.  96. je radila kao predava  stru nih medicinskih predmeta pri Srednjoj akoli za medicinske sestre, primalje i fizioterapeute u Vinogradskoj ulici u Zagrebu, zatim u Ambulanti turisti ke medicine u Pore u te kao sekundarac na kirurgiji Ope bolnice Naaice. Godine 1996. je radila kao lije nik - gost u Klinici za traumatologiju u Grazu, Austrija. Od godine 1997. je radila kao sekundarac, a od 1998. kao specijalizant infektologije u Klinici za infektivne bolesti  Dr. Fran Mihaljevi u Zagrebu. Specijalisti ki ispit iz infektologije je polo~ila godine 2003. Znanstveni magistarski rad s temom  Epidemioloake i klini ke osobitosti kampilobakterioza u hospitaliziranih bolesnika je obranila godine 2007. Trenutno radi kao specijalist infektolog u Klinici za infektivne bolesti  Dr. Fran Mihaljevi u Zagrebu, pri Zavodu za gastrointestinalne infekcije, a od rujna godine 2008. je izabrana u suradni ko zvanje asistenta pri Katedri za infektologiju Medicinskog fakulteta Sveu iliata u Zagrebu.      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