Division of Infectious Diseases, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 2

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1 PUBLIC HEALTH ORIGINAL RESEARCH ARTICLE published: 15 November 2013 doi: /fpubh Short- nd long-term mortlity in severe sepsis/septic shock in setting with low ntibiotic resistnce: prospective observtionl study in Swedish University Hospitl Ann Linnér 1, Jons Sundén-Cullberg 1, Lind Johnsson 1, Hns Hjelmqvist 2, Ann Norrby-Teglund 1 * nd Crl John Treutiger 1 1 Division of Infectious Diseses, Center for Infectious Medicine, Krolinsk Institutet, Krolinsk University Hospitl, Stockholm, Sweden 2 Deprtment of Anesthesiology, Krolinsk Institutet, Krolinsk University Hospitl, Stockholm, Sweden Edited by: Evngelos Gimrellos-Bourboulis, University of Athens, Greece Reviewed by: Christin Ionnis Routsi, University of Athens, Greece Efthymi Ginnitsioti, Attikon University Generl Hospitl, Greece *Correspondence: Ann Norrby-Teglund, Division of Infectious Diseses, Center for Infectious Medicine, Krolinsk Institutet, Krolinsk University Hospitl, Huddinge F59, Stockholm SE , Sweden e-mil: nn.norrby-teglund@ki.se Bckground:There is little epidemiologic dt on sepsis, prticulrly in res of low ntibiotic resistnce. Here we report prospective observtionl study of severe sepsis nd septic shock in ptients dmitted to the Intensive Cre Unit (ICU) t Krolinsk University Hospitl, Sweden. We imed to evlute short- nd long-term mortlity, nd risk fctors for sepsis-relted deth. A second im ws to investigte ptient cre in reltion to gender. Methods: One hundred nd one ptients with severe sepsis nd septic shock, dmitted to the ICU between 2005 nd 2009, were prospectively enrolled in the study. Defined primry endpoints were dy 28, hospitl, nd 1-yer mortlity. Risk fctors for sepsis-relted deth ws evluted with multivrite nlysis in pooled nlysis with two previous sepsis cohorts. In the subset of ptient dmitted to the ICU through the emergency deprtment (ED), time to clinicin evlution nd time to ntibiotics were ssessed in reltion to gender. Results: In the septic cohort, the dy 28, hospitl, nd 1-yer mortlity rtes were 19, 29, nd 34%, respectively. Ninety-three percent of the ptients received dequte ntibiotics from the beginning. Multi-resistnt bcteri were only found in three cses. Among the 43 ptients dmitted to the ICU through the ED, the medin time to ntibiotics ws 86 min (interqurtile rnge ), nd overll 77% received pproprite ntibiotics within 2 h. Femle ptients received ntibiotics significntly lter compred to mle ptients (p = 0.047). Conclusion: The results demonstrte reltively low mortlity rtes mong ICU ptients with severe sepsis/septic shock, s compred to reports from outside Scndinvi. Erly dequte ntibiotic tretment nd the low incidence of resistnt isoltes my prtly explin these findings. Importntly, gender difference in time to ntibiotic therpy ws seen. Keywords: severe sepsis, septic shock, mortlity, gender, ntibiotics INTRODUCTION Despite better understnding of the pthophysiology nd improved mngement of sepsis, severe sepsis, nd septic shock, the incidence continues to increse (1 5). The mortlity rtes still remin uncceptbly high, rnging from 31 to 61% in multicentre trils of septic shock (6 10). Efforts hve been mde during the pst decde to develop protocols for mngement, in nlogy with the previous evolution of stndrdized cre of other cute medicl conditions like myocrdil infrction nd multitrum (11 14). An outcome benefit is ssocited with erly dignosis nd structured resuscittion of ptients with severe sepsis nd septic shock, i.e., Erly- Gol-Directed-Therpy (EGDT) (12, 15, 16). Elpsed time from trige nd qulifiction for EGDT to dministrtion of pproprite ntimicrobils re primry determinnts of mortlity in ptients with severe sepsis nd septic shock (17). Kumr et l. (18) reported tht correct nd rpid dministrtion of dequte ntibiotics significntly reduces mortlity rtes, with ech hour of dely in ntimicrobil dministrtion over the ensuing 6 h being ssocited with n verge decresed survivl of 7.6%. However, it ws recently emphsized tht in ptients who received ntibiotics fter shock recognition, there is no increse in mortlity ssocited with dely in ntibiotics dministrtion (19). Levy et l. (20) recently reported significnt difference between the USA nd Europe in undjusted mortlity in severe sepsis/septic shock ptients. Importntly, this difference disppered when djusting for severity of illness, emphsizing the complexity in interpreting results from different sites. Severl fctors including mong others regionl helth cre pproches s well s ccess to cre, ge, nd comorbid disese burden will November 2013 Volume 1 Article 51 1

2 ll influence outcome. In Scndinvin countries lower mortlity rtes re commonly reported, for instnce in the Finnsepsis study the Intensive Cre Unit (ICU), hospitl, nd 1-yer mortlity rtes in severe sepsis were 15.5, 28.3, nd 40.9%, respectively (21). The Finnsepsis study group lso reported low mortlity rtes in community-cquired septic shock with ICU nd hospitl mortlities of 22 nd 35%, respectively (22). In Norwy, hospitl mortlity in severe sepsis nd septic shock were 27 nd 29%, respectively (23). Likewise, we hve in our previous studies on biomrkers in sepsis observed reltively low dy 28 mortlity rte of 15.6 nd 26% in severe sepsis nd septic chock (24, 25). The Scndinvin countries shre beneficil ntibiotic susceptibility setting tht llows for studies of clinicl outcome in severe infections not complicted by ntibiotic resistnce. The im of this pper ws to investigte dy 28, hospitl, nd 1- yer mortlity in prospective study of hospitl nd communitycquired severe sepsis nd septic shock ptients treted in n ICU in Swedish University Hospitl, nd to evlute risk fctors for sepsis-relted deth. A second im ws to investigte ptient cre in the emergency deprtment (ED), in prticulr time to ntibiotics nd time to clinicin evlution in reltion to gender. MATERIALS AND METHODS STUDY SETTING AND PATIENT COHORTS In this prospective observtionl cohort study, totl of 101 ptients were included in the septic cohort during the study period from October 2005 to June Inclusion criteri were dignosis of severe sepsis or septic shock within the lst 24 h in ptients dmitted to the mixed medicl nd surgicl ICU (12 beds) of Krolinsk University Hospitl Huddinge, tertiry cre fcility. Becuse of hospitl sub-speciliztion in Stockholm County, the Krolinsk University hospitl in Huddinge does not dmit multi-trum ptients nd ptients with elective lower GI, thorcic, or brin surgery re operted elsewhere. In the septic cohort, 43 ptients were dmitted to the ICU through the ED, llowing for evlution of immedite ptient cre. Identifiction nd enrollment of ptients ws performed by reserch nurse during dy-time, Mondy to Fridy recruitment, which explins the inclusion of ptients over n extended period of time. Severe sepsis nd septic shock, including the clinicl vribles were defined ccording to the criteri proposed by the Americn College of Chest Physicins/Society of Criticl Cre Medicine (26). The dignosis of sepsis required clinicl ssessment of infection together with systemic inflmmtory rection. Systemic inflmmtory rection ws defined by t lest two of the following criteri: fever or hypothermi (temperture >38.0 or <36.0 C, respectively), tchycrdi (hert rte >90 bets/min), tchypne (respirtory rte >20 breths/min, or PCO2 <32 torr (4.3 kp) or the requirement of mechnicl ventiltion), nd white blood cell count > /L (or >10% immture white blood cells). Severe sepsis ws defined s sepsis in ddition to signs of cute reduction of orgn perfusion (not relted to primry septic focus or underlying chronic disese) s mnifested by t lest one of the following: () cute deteriortion of mentl sttus; (b) rteril hypoxemi [PO2 <75 torr (10 kp) without evidence of primry lung disese]; (c) oliguri (urine production <0.5 ml/kg/h for >2 h); (d) cute deteriortion of liver function (S-bilirubin >43 µmol/l, or S-lnine trnsminse more thn twice elevted bove reference vlue; (e) metbolic cidosis (plsm lctte elevted bove norml levels or bse excess 5 meq/l); or (f) recent cogultion bnormlity (prothrombin time or ctivted prtil thromboplstin time 1.2 times the upper limit plus D-dimer 0.5 mg/l or pltelets /L or 50% reduction in 24 h). Septic shock ws defined s severe sepsis in ddition to hypotension requiring vsopressor support, or men rteril pressure <70 mmhg for 30 min despite dequte fluid resuscittion. In ddition to the prospective cohort bove, we lso included sepsis ptients enrolled in two previous prospective studies s confirmtory cohort for comprison of mortlity rtes. These studies hd similr or identicl inclusion criteri nd were conducted t the sme study site between 1998 nd 2001 (n = 54; 22 severe sepsis nd 32 septic shock) nd 2003 nd 2005 (n = 50; 9 severe sepsis nd 41 septic shock) (24, 25). The study ws conducted in ccordnce with the declrtion of Helsinki nd ws pproved by the locl ethics committee of Krolinsk University Hospitl. Written informed consent ws obtined from the ptients or their close reltives, nd re rchived by the uthors. DATA COLLECTION AND OUTCOMES Blood smples were collected from ll ptients nd controls t inclusion (0 h). Tubes were immeditely centrifuged t 3000 rpm for 10 min nd liquots of plsm were stored t 70 C until nlysis. Stndrd lbortory nlyses were performed t the Clinicl chemistry lbortory, Huddinge, ccording to the mnufcturer s instructions. Clinicl dt, including vribles specified in Tble 1, were registered ccording to predesigned Cse Record Form dily for ll ptients until dy 7. Severity of disese ws mesured by Acute Physiology nd Chronic Helth Evlution (APACHE) II (27) t dmittnce nd lso by dily Sepsis-relted Orgn Filure Assessment (SOFA) scores until dy 7 (28). These scores nd finl dignoses were determined retrospectively, on the bsis of complete ptient chrts nd lbortory tests. The results of blood nd microbiologicl cultures were recorded. The primry outcomes studied were dy 28 mortlity, inhospitl mortlity (deth during hospitl sty), nd 1-yer mortlity. The outcomes were further compred with the bove described independent cohorts. The multivrite regression nlysis for risk fctors of deth in severe sepsis nd septic shock ws performed nd the survivl rte ws further nlyzed in groups strtified by ge. We lso retrospectively registered dequte ntibiotic tretment (determined bsed on comprison between dministered ntibiotics nd blood culture findings nd/or dignosis) nd the presence of multi-resistnt bcteri defined s Extended Spectrum Bet Lctmse (ESBL) or other multi-resistnt Grm-negtives, Vncomycin Resistnt Enterococci (VRE), or Meticillin Resistnt Stphylococcus ureus (MRSA). We retrospectively studied the timing of ntibiotic dministrtion nd clinicin evlution in those ptients tht were dmitted to the ICU through the ED (n = 43) nd performed comprison bsed on gender. At Krolinsk University Hospitl the exct time (hours:minutes) of the bove specified fctors s well s time of dmission is recorded in the electronic ptient chrt. Frontiers in Public Helth Infectious Diseses November 2013 Volume 1 Article 51 2

3 Tble 1 Bseline ptient chrcteristics nd lbortory findings in totl cohort, nd survivors vs. non-survivors. Vrible Septic cohort*, n = 101 Survivors, n = 82 Non-survivors, n = 19 p-vlue GENDER, AGE Mle, n (%) 55 (55) 43 (52) 12 (63) Age, medin (rnge) 64 (23 89) 64 (23 89) 64 (45 86) SEVERITY OF DISEASE, MEAN ± SD SOFA 0 h 10 ± ± ± SOFA 24 h 8.9 ± ± ± SOFA 96 h 5.2 ± ± ± APACHE II 22.7 ± ± ± ACQUISITION OF INFECTION, n (%) Community 62 (61) 51 (62) 11 (58) Hospitl 39 (39) 31 (38) 8 (42) UNDERLYING CONDITIONS, n (%) Previously helthy, n (%) 11 (11) 9 (11) 2 (11) 1.0 Dibetes 16 (16) 13 (16) 3 (16) 1.0 Smoking 15 (15) 10 (12) 5 (42) Alcohol buse 11 (11) 7 (9) 4 (21) History of cncer 31 (31) 22 (27) 9 (47) Immunosuppression 27 (27) 19 (23) 8 (42) Hypertension 24 (24) 23 (28) 1 (5) Hert disese b 21 (21) 17 (21) 4 (21) 1.0 Pulmonry c 3 (3) 3 (4) 0 (0) Liver disese d 8 (4) 4 (5) 4 (21) Neurologic disese e 5 (5) 3 (4) 2 (11) Renl filure 4 (4) 3 (4) 1 (5) Other diseses f 15 (15) 12 (15) 3 (16) 1.0 Blood cultures (n = 92) Confirmed positive (%) 50 (54) 40 (53) 10 (63) CLINICAL MANIFESTATIONS, n (%) Pneumoni 25 (28) 17 (21) 8 (80) Urinry trct infection 16 (16) 14 (17) 2 (10) Intr-bdominl infection 42 (42) 36 (44) 6 (60) Skin/soft tissue infection 9 (9) 7 (9) 2 (10) Neutropeni 4 (4) 3 (4) 1 (5) Bcteril meningitis 3 (3) 3 (4) 0 (0) 1.0 Undefined origin 2 (2) 2 (2) 0 (0) 1.0 LABORATORY FINDINGS, MEDIAN (IQR) C-rective protein (mg/l) 226 ( ) 227 ( ) 210 (89 276) WBC (10 9 /L) 14.3 ( ) 14.3 ( ) 13.6 ( ) Hemoglobin (g/l) 105 ( ) ( ) 106 (99 113) Pltelet count (10 9 ) 165 (82 265) (83 266) 126 (66 213) P-glucose (mmol/l) 7.0 ( ) 7.1 ( ) 6.4 ( ) PTT (s) 46 ( ) 45.5 ( ) 52 (44 62) Cretinine (µmol/l) 155 ( ) 153 (86 250) 163 ( ) Bilirubin (µmol/l) 18 (9 30.5) 16 (8 30) 23 (15 54) INR 1.4 ( ) 1.4 ( ) 1.6 ( ) D-dimer (mg/l) 1.9 ( ) 1.5 ( ) 3.3 ( ) Lctte (mmol/l) 3.2 ( ) 3 ( ) 7.6 ( ) *Septic cohort consisted of 86 ptients with septic shock nd 15 ptients with severe sepsis. According to APACHE II criteri. b A history of hert disese contins of coronry rtery disese nd congestive hert filure. c Chronic obstructive pulmonry disese or emphysem or sthm. d Liver disese contins of heptitis with or without cirrhosis nd primry biliry cirrhosis. e Neurologic diseses: previous stroke nd multiple sclerosis. f Inflmmtory bowel disese, rheumtoid rthritis, psychitric disese, ventriculr ulcer, or hypothyreos. November 2013 Volume 1 Article 51 3

4 STATISTICAL ANALYSIS Descriptive dt re presented s men (SD) for continuous dt, nd medins with interqurtile rnges (IQRs) for numerous dt tht did not follow Gussin distribution. To test for normlity, we used recommended D Agostino nd Person omnibus normlity test. Comprisons between groups were mde by the non-prmetric Mnn Whitney U test, or for ctegoricl vlues, Fisher s exct test. A two-tiled p-vlue <0.05 ws considered sttisticlly significnt. The survivl nlysis ws mde by using Kpln Meier survivl curve. The nlysis of risk fctors for deth in the septic cohort ws performed using multivrite cox regression nlysis performed in two steps. In the first step, univrite nlyses were performed for demogrphic nd clinicl fctors listed in Tble 3. All fctors with univrite p-vlue of <0.1 were entered into stepwise Cox regression model where the model selection ws bsed on the Akike Informtion Criteri (AIC) pproch. The GrphPd Prism 5 (GrphPd Softwre, L Joll) ws used for ll sttisticl nlyses except the multivrite nlysis where the R version ws used. RESULTS PATIENTS: CLINICAL AND MICROBIOLOGICAL CHARACTERISTICS After finl clssifiction, 86 ptients with septic shock nd 15 ptients with severe sepsis were included in the study, i.e., totl number of 101 ptients referred to s the septic cohort. Clinicl chrcteristics nd lbortory findings re presented in Tble 1. In ech group of ptients, the mjority (>89%) hd underlying medicl conditions, such s history of cncer, crdic disese, nd dibetes. In ddition to crdiovsculr shock, 49% of septic shock ptients hd kidney filure, 84% hd respirtory filure, nd 15% hd cogultion bnormlities. All septic shock ptients were put on vsopressor support, 93% were on insulin therpy t study inclusion, nd four ptients were treted with intrvenous immunoglobulin djunctive therpy. Thirtyeight ptients were immunosuppressed ccording to APACHE II criteri. High-dose cortisone (i.e., exceeding dose of 1000 mg of hydrocortisone dily) ws given to only one ptient with septic shock, wheres 73% of septic shock nd 60% of severe sepsis ptients received low dose cortisone ( mg of hydrocortisone three to four times dily). The medin ICU nd hospitl length of stys were 5 nd 26 dys, respectively, in the septic cohort. The most prevlent underlying cuses of severe sepsis nd septic shock were bdominl infections, pneumoni, nd urosepsis (Tble 1), which together represented 82% of the septic cohort. Five ptients hd infections of undefined origin. In ll ptients with severe sepsis nd septic shock, blood cultures were tken in 92 out of the 101 ptients nd 49% of these were culture-positive. The highest frequency of blood cultures were obtined in ptients with urinry trct infections (88% positive cultures), skin/soft tissue infections (77% positive cultures), nd intr-bdominl infections (36% positive cultures). There ws n overrepresenttion of Grm-negtive bcteri (59%) s compred to Grm-positive bcteri (41%), consistent with bdominl origin being the most prevlent source of infection. Escherichi coli ws the pthogen most commonly isolted (Tble 2), predominntly from ptients with urinry trct or intrbdominl infections. Etiology ws estblished in nother 38 cses Tble 2 Microbiologicl findings of blood cultures. Orgnism No. isoltes (n = 49) Escherichi coli 18 Stphylococcus ureus (MSSA ) 5 Klebsiell pneumoni 3 Pseudomons 3 Streptococcus pneumoni 3 Serrti mrcescens 2 Enterococcus feclis 7 Proteus mirbilis 1 Cndid 1 Corynebcterium 1 Clostridium septicum 1 Peptostreptococci 1 Neisseri meningitides 1 Stphylococcus epidermidis 1 G+ cocci b 1 MSSA, meticillin-susceptible S. ureus. b Not possible to identify further. through lterntive microbiologicl cultures nd serology. Fourteen ptients in the septic cohort lcked conclusive microbiologicl dignosis. In reltion to microbiologicl findings or dignosis, 93% of ptients with severe sepsis or septic shock received dequte ntibiotic tretment. Seven ptients received suboptiml ntibiotic tretment in reltion to subsequent culture findings, but none of these hd multi-resistnt bcteri (i.e., ESBL, other multi-resistnt Grm-negtives, VRE, or MRSA). Of the 101 ptients in our septic cohort, only 2 hd positive blood cultures of ESBL producing bcteri (E. coli), 1 hd VRE, nd 2 hd Serrti mrcescens resistnt to Cefuroxim. The most common initil empiric ntibiotic tretment ws crbpenems (60%), followed by cephlosporins (20%), nd pipercillin-tzobctm (13%). Twenty-three percent received concurrent tretment with minoglycosides. Adequte ntimicrobil therpy refers to empiricl tretment on dmittnce, t which time most ptients did not hve microbiologicl dignosis. Mny ptients hd postsurgicl or hospitl cquired infections, for which crbpenems re recommended in Swedish guidelines. SHORT- AND LONG-TERM MORTALITY, AND RISK FACTORS FOR DEATH The overll dy 28 mortlity rte ws 19% in the septic cohort nd the hospitl mortlity ws 29%. There were five dditionl deths fter dischrge in the septic cohort, yielding 1-yer mortlity rte of 34%. Ptients were strtified by ge with cut off t 70 yers. As expected, the elderly ptients (n = 33 vs. 68 in the younger group), hd higher dy 28, hospitl, nd 1-yer mortlity compred with the younger group (21, 33, nd 48 vs. 18, 26, nd 26%) (Figure 1). The dy 28 non-survivors ll died of septic shock with multiple orgn filure. The most common cuse of deth between dys 28 nd 365 ws lso sustined septic shock with multiple orgn filure followed by crdic hert filure, pneumoni, crdic rrest, cute myocrdil infrct, nd liver filure. Frontiers in Public Helth Infectious Diseses November 2013 Volume 1 Article 51 4

5 Tble 3 Risk fctors for negtive outcome in severe sepsis nd septic chock*, univrite nlysis with cox proportionl hzrds regression. Hzrd rtio Lower limit Upper limit p-vlue FIGURE 1 Kpln Meier estimted survivl in the septic cohort by ge (<70, or 70 yers nd older). (p-vlue = 0.021, log-rnk test, χ 2 = 5.36). Two previous studies with independent cohorts of 54 nd 50 ptients with severe sepsis nd septic shock, enrolled t the sme site s the current study, reported low dy 28 mortlity rtes (24, 25). Here, we retrospectively clculted the hospitl nd 1- yer mortlity of these previous cohorts. The hospitl mortlity rte ws 33% nd the 1-yer mortlity rte ws 41%, consistent with our current study. Mortlity rtes in pooled dt with ll three cohorts were 22% t dy 28 (n = 45/205) nd 38% t dy 365 (n = 77/205). The hospitl mortlity rte ws 31% (n = 62/205). A multivrite regression nlysis for risk fctors of deth in severe sepsis nd septic shock ws performed using ll ptients in the three sepsis cohorts (n = 205, septic shock n = 159, severe sepsis n = 46). All independent fctors with p-vlue of <0.1 in the univrite nlysis listed in Tble 3 were included in the multivrite nlyses in which ge, crdic hert filure, immunosuppression, nd SOFA score were shown to be independent risk fctors for deth (Tble 4). PATIENTS WITH COMMUNITY-ACQUIRED SEVERE SEPSIS/SEPTIC SHOCK ADMITTED TO THE ICU THROUGH THE ED The septic cohort included 43 ptients with community-cquired severe sepsis nd septic shock rriving to the ICU directly from the ED (Tble 5). This cohort ws used to specificlly ssess time to see clinicin nd to ntibiotic dministrtion. In the totl cohort, the immedicy of fluid tretment ws lso registered. Nine ptients received pre-hospitl (mbulnce) fluid tretment. The remining 34 received fluid fter men 46 min (rnge min), whereof 21% within 15 min, 47% within 30 min, nd 71% of the ptients within 60 min. Pre-ICU fluids consisted only of crystlloids, colloids were only given in the ICU. Sixty-three percent of the ptients were ssessed by physicin within 30 min, 98% within 60 min. The medin time to first dose of ntibiotic tretment ws 86 min (IQR ). Seventy-three percent of the ptients received ntibiotic tretment within 2 h. Mortlity rtes within ech hour of ntibiotic dely is shown in Figure 2. The nlyses were lso mde ccording to gender, nd s shown in Tble 5, the femle ptients were younger thn the mle ptients (p = 0.013) but were similr with respect to severity Gender Age Pneumoni Abdominl infection Urinry trct infection Smoking Alcohol Dibetes Coronry rtery disese Crdic hert filure Liver disese Chronic obstructive lung disese Immunosuppression Lctte level SOFA score (dy 1) <0.001 *Ptients from the current study nd the two pooled comprtive cohorts of severe sepsis nd septic chock. According to APACHE II criteri. Tble 4 Risk fctors for negtive outcome in severe sepsis nd septic shock*, multivrite stepwise cox regression nlysis. Hzrd rtio Lower limit Upper limit p-vlue Age Smoking Crdic hert filure Liver disese Immunosuppression <0.001 Lctte SOFA score (dy 1) *Ptients from the current study nd the two pooled comprtive cohorts of severe sepsis nd septic shock. According to APACHE II criteri. of disese, dignosis, nd comorbidities. In ddition, no significnt difference in bseline cytokine levels were found, lthough femle showed slightly higher levels of ll three cytokines. Femle ptients wited for physicin evlution for medin time of 32 min (IQR 8 39 min) s compred to 12 min (IQR 4 35 min) fter dmission to the ED for mle ptients (p = 0.22). In ddition, femle ptients hd significntly delyed time to ntibiotic tretment s compred to men, medin of 144 min (IQR ) compred to 67 min (IQR min; p = ) (Figure 3A). Mesuring time from physicin ssessment to first dose of ntibiotics, we found similr gender differences. Women received the first dose t 101 min (IQR min) s compred to 52 min (IQR min) for mles (p = ) (Figure 3B). November 2013 Volume 1 Article 51 5

6 Tble 5 Sepsis ptients dmitted to ICU through emergency deprtment (ED): bseline ptient chrcteristics in totl cohort nd in femle vs. mle ptients. Vrible Septic ED cohort*, n = 43 Femle, n = 17 (40%) Mle, n = 26 (60%) p-vlue AGE Age, medin (rnge) 64 (23 89) 61 (26 76) 71 (23 89) MORTALITY, n (%) 28-dy mortlity 8 (19) 4 (24) 4 (15) yer mortlity 13 (30) 5 (29) 8 (31) 1.0 SEVERITY OF DISEASE, MEAN ± SD SOFA 0 h 10 ± ± ± APACHE II 24.1 ± ± ± UNDERLYING CONDITIONS, n (%) Previously helthy, n (%) 11 (26) 3 (18) 8 (31) Dibetes 7 (16) 2 (12) 5 (19) Smoking 1 (2) 0 (0) 1 (4) 1.0 Alcohol buse 7 (16) 2 (12) 1 (4) History of cncer 10 (23) 5 (29) 5 (19) Immunosuppression 10 (23) 5 (29) 5 (19) Hypertension 14 (33) 5 (29) 9 (35) 1.0 Coronry rtery disese 6 (14) 4 (24) 2 (8) Chronic hert filure 3 (7) 1 (6) 2 (8) 1.0 CLINICAL MANIFESTATION, n (%) Pneumoni 17 (40) 7 (41) 10 (38) 1.0 Urinry trct infection 11 (26) 6 (35) 5 (19) Intr-bdominl infection 4 (9) 0 (0) 4 (15) Skin/soft tissue infection 6 (14) 2 (12) 4 (15) 1.0 Neutropeni 1 (2) 1 (6) 0 (0) Bcteril meningitis 1 (2) 1 (6) 0 (0) Undefined origin 3 (7) 0 (0) 3 (12) Time to see physicin, medin (IQR) (min) 20 (5 35) 32 (8 39) 12 (4 35) Time to dequte ntibiotics from trige, medin (IQR) (min) 86 (52 165) 144 (70 185) 67 (36 135) CYTOKINES, MEDIAN (IQR) IL-6 (pg/ml) 560 ( ) 1902 ( ) 477 ( ) IL-8 (pg/ml) 79 ( ) 200 ( ) 43 (23 890) IL-10 (pg/ml) 23 (9 67) 32 (9 248) 18 (9 53) *Septic cohort of 43 ptients with 34 ptients with septic shock nd 9 ptients with severe sepsis coming to the ICU through the ED. According to APACHE II criteri. DISCUSSION This prospective observtionl study of severe sepsis nd septic shock in mixed medicl nd surgicl ICU in Swedish University Hospitl is bsed on septic cohort, which is comprble with cohorts of previously reported interntionl studies in respect to severity of sepsis, defined by severity scores, ge, nd underlying conditions (10, 18, 21). We report mortlity rtes of 19% (dy 28), 29% (hospitl), nd 34% (1 yer). Both short- nd long-term mortlity ws due to septic shock with multiple orgn filure which in the lte mortlity cses were followed by crdic hert filure, pneumoni, crdic rrest, cute myocrdil infrct, nd liver filure. Risk fctors for deth were ge, crdic hert filure, immunosuppression, nd SOFA score. The noted mortlity rtes re lower thn tht reported in the study by Kumr et l. (18), in which the hospitl mortlity rte mounted to 56% in septic shock ptients, s well s in the study by Rnieri et l. (29) with reported dy 28 mortlity rte of 25.3%. Similrly, in n Europen multicentre study of septic shock ptients (10), in which ges nd SOFA scores mtched those of our study, the 28-dy mortlity rte ws 33% nd the hospitl mortlity rte ws 43%. It is importnt to highlight tht our septic cohort includes 15% severe sepsis ptients wheres the others only hd septic shock. However, inclusion of only septic shock ptients from our cohort resulted in even lower mortlity rtes; dy 28 mortlity of 17% nd hospitl mortlity of 29%. Our mortlity rtes re in line with those reported from Scndinvi such s in the Finnsepsis study (21). As highlighted in the recent report by Levy et l. (20) mny fctors influence mortlity rtes in different settings, not the lest different helth cre systems nd pproches to criticl cre. In the Stockholm re, clinicl subspecilties re lrgely dministrtively centrlized to different hospitls, such s upper gstrointestinl surgery for which Krolinsk University Hospitl Huddinge is the Frontiers in Public Helth Infectious Diseses November 2013 Volume 1 Article 51 6

7 FIGURE 2 Time to dequte ntibiotics in hours, nd reltion to mortlity rte. The figure includes severe sepsis nd septic shock ptients (n = 43) dmitted to the ICU directly from the emergency deprtment. FIGURE 3 Gender differences in (A) time from trige to ntibiotics (p = 0.047) nd (B) time from seeing the physicin to dequte ntibiotics (p = 0.022). Sttisticlly significnt differences between the groups were determined by the non-prmetric Mnn Whitney U test. A two-tiled p-vlue <0.05 ws considered sttisticlly significnt nd the p-vlues re indicted. Horizontl lines denote medin vlues. min center; explining the dominnce of bdominl infections in our study, with E. coli being the most prevlent pthogen. There re few dt relted to the effects of different sources of infection on outcome. It hs previously been suggested tht bdominl infections my be more severe (30, 31) thn respirtory infections. A recent study showed no differences in ge, sex, severity score, or mortlity rtes between the two groups, but the development of septic shock, erly cogultion, nd cute renl filure ws more common in ptients with bdominl infections (32). The fct tht bdominl infections dominte should, if nything, influence our mortlity rtes negtively. Mny studies hve shown tht the prognosis of severe sepsis nd septic shock cn be improved by using interntionlly recommended guidelines (33). The efficcy nd speed of erly mngement nd dequte tretment in the initil hours fter onset of illness re likely to influence outcome, in nlogy with the tretment of cute myocrdil infrction or cute trum. Erly Gol-Directed Therpy in severe sepsis nd septic shock ptients hs been shown to improve 1-yer mortlity rte compred to stndrd tretment (34). Our 1-yer mortlity rte mtches this outcome lthough there ws no explicit dherence to n EGDT protocol. Importntly, the severity of disese in our septic shock ptients ws higher (SOFA score 10.4 ± 3.4 vs. 7 ± 4) suggesting tht our ptients were more severely ill compred to the ptients in the study of Puskrich et l. (34). Ntionl guidelines in Sweden, t the time of the study recommended the use of low dose corticosteroids for septic shock ptients in the need of inotropic support, but is currently restricted to those with persisting hypotension despite inotropic therpy. Seventy-three percent of our septic shock ptients received hydrocortisone, indicting underprescription by guidelines t the time, but overprescription by current stndrds. Overprescription likely hd no effect on mortlity (10). Time to receive dequte ntibiotics is criticl survivl fctor (18), in prticulr prior to shock recognition (19). In this study, we report tht the mjority of ptients received pproprite ntibiotics within 2 h, which is shorter thn in mny other studies reporting 3 h or longer (19, 22). This, nd the fct tht 93% of the ptients in our cohort were given dequte ntibiotics from the onset could prtly explin the low mortlity rte. So fr, Sweden hs mnged to contin ntibiotic resistnce (35, 36). It is mong the countries with the lowest rtes of MRSA (<1%) nd E. coli-producing ESBL (<5%). First-line ntibiotics still work for exmple, S. pneumonie is routinely treted with penicillin G or V. A troubling finding ws the noted gender difference in time to seeing clinicin nd receiving dequte ntibiotics, which could not be explined by severity of disese, clinicl presenttion, dignoses, or inflmmtion (i.e., plsm cytokine levels t inclusions). Previous studies hve reported potentil impct of gender on mortlity in sepsis, but the results re inconsistent: some found higher risk in men (37), some in women (38), nd some found no difference (39). Here we report, for the first time, tht gender influences time to ntibiotic tretment. Considering the strong link between time to ntibiotics nd outcome of severe sepsis nd septic shock, this is cliniclly importnt finding. In n ttempt to seek the underlying reson for this dely in tretment, the femle nd mle cohorts were compred with respect to dignosis, etiology, nd severity of infection but no differences were identified expect the fct tht the femles were younger. However it should be noted tht this subgroup nlyses is bsed on smll ptient cohort nd the results need to be verified in lrger studies. November 2013 Volume 1 Article 51 7

8 In summry, the results demonstrte low mortlity rtes, both short- nd long-term, in this ptient cohort despite high APACHE II scores nd presence of multiple comorbidities. A multivrite nlysis reveled tht risk fctors for ftl outcome in sepsis ws ge, crdic hert filure, immunosuppression, nd SOFA score. Our low mortlity rtes my be explined by the combintion of well-functioning trige system tht directs the ptient to the right priority group, the presence of n Infectious Disese specilist both in the ER nd the ICU, the lck of resistnt isoltes nd short-time to dequte ntibiotics together with erly ggressive fluid resuscittion. Although the mjority of the ptients received dequte ntibiotics from the beginning, the dt suggested tht women with community-cquired severe sepsis nd septic shock hd dely in ntibiotic tretment s compred to men; concerning observtion tht wrrnts further studies. ACKNOWLEDGMENTS We thnk the ptients nd their fmilies for prticipting, Lilin Wlther-Jllow for ssistnce in cytokine nlysis, nd reserch nurse Gunill Hermn. Sttisticl dvise nd nlyses were performed by Ph.D. Mrcus Thuresson. The study ws supported, in prt, by grnts from the Swedish Reserch Council, the Swedish Society of Medicine, the Europen society of Clinicl Microbiology nd Infectious diseses, ALF project funding, nd the Krolinsk University Hospitl Huddinge Reserch Foundtion. REFERENCES 1. Annne D, Aegerter P, Jrs-Guincestre MC, Guidet B. Current epidemiology of septic shock: the CUB-Re Network. Am J Respir Crit Cre Med (2003) 168: doi: /rccm Mrtin GS, Mnnino DM, Eton S, Moss M. The epidemiology of sepsis in the United Sttes from 1979 through N Engl J Med (2003) 348: doi: /nejmo Dombrovskiy VY, Mrtin AA, Sunderrm J, Pz HL. Rpid increse in hospitliztion nd mortlity rtes for severe sepsis in the United Sttes: trend nlysis from 1993 to Crit Cre Med (2007) 35: doi: /01.ccm E9 4. 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9 30. Vlles J, Rello J, Ochgvi A, Grncho J, Alcl MA. Community-cquired bloodstrem infection in criticlly ill dult ptients: impct of shock nd inpproprite ntibiotic therpy on survivl. Chest (2003) 123: doi: / chest Guidet B, Aegerter P, Guzit R, Meshk P, Dreyfuss D. Incidence nd impct of orgn dysfunctions ssocited with sepsis. Chest (2005) 127: doi: /chest Volkli E, Spies C, Michlopoulos A, Groeneveld AB, Skr Y, Vincent JL. Infections of respirtory or bdominl origin in ICU ptients: wht re the differences? Crit Cre (2010) 14:R32. doi: /cc Cstellnos-Orteg A, Suberviol B, Grci-Astudillo LA, Holnd MS, Ortiz F, Llorc J, et l. Impct of the surviving sepsis cmpign protocols on hospitl length of sty nd mortlity in septic shock ptients: results of threeyer follow-up qusi-experimentl study. Crit Cre Med (2010) 38: doi: /ccm.0b013e3181d455b6 34. Puskrich MA, Mrchick MR, Kline JA, Steuerwld MT, Jones AE. One yer mortlity of ptients treted with n emergency deprtment bsed erly gol directed therpy protocol for severe sepsis nd septic shock: before nd fter study. Crit Cre (2009) 13:R167. doi: /cc Hnberger H, Erlndsson M, Burmn LG, Crs O, Gill H, Lindgren S, et l. High ntibiotic susceptibility mong bcteril pthogens in Swedish ICUs. Report from ntion-wide surveillnce progrm using TA90 s novel index of susceptibility. Scnd J Infect Dis (2004) 36: doi: / Molstd S, Crs O, Struwe J. Strm Swedish working model for continment of ntibiotic resistnce. Euro Surveill (2008) 13:ii: Adrie C, Azouly E, Frncis A, Clec h C, Drques L, Schwebel C, et l. Influence of gender on the outcome of severe sepsis: repprisl. Chest (2007) 132: doi: /chest Pietropoli AP, Glnce LG, Okes D, Fisher SG. Gender differences in mortlity in ptients with severe sepsis or septic shock. Gend Med (2010) 7: doi: /j.genm 39. Esper AM, Moss M, Lewis CA, Nisbet R, Mnnino DM, Mrtin GS. The role of infection nd comorbidity: fctors tht influence disprities in sepsis. Crit Cre Med (2006) 34: doi: /01.ccm E Conflict of Interest Sttement: The uthors declre tht the reserch ws conducted in the bsence of ny commercil or finncil reltionships tht could be construed s potentil conflict of interest. Received: 22 Februry 2013; ccepted: 10 June 2013; published online: 15 November Cittion: Linnér A, Sundén-Cullberg J, Johnsson L, Hjelmqvist H, Norrby-Teglund A nd Treutiger CJ (2013) Short- nd long-term mortlity in severe sepsis/septic shock in setting with low ntibiotic resistnce: prospective observtionl study in Swedish University Hospitl. Front. Public Helth 1:51. doi: /fpubh This rticle ws submitted to Infectious Diseses, section of the journl Frontiers in Public Helth. Copyright 2013 Linnér, Sundén-Cullberg, Johnsson, Hjelmqvist, Norrby-Teglund nd Treutiger. This is n open-ccess rticle distributed under the terms of the Cretive Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the originl uthor(s) or licensor re credited nd tht the originl publiction in this journl is cited, in ccordnce with ccepted cdemic prctice. No use, distribution or reproduction is permitted which does not comply with these terms. November 2013 Volume 1 Article 51 9