Effects of statins on the development of sepsis and organ dysfunction in hospitalized older patients in China

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w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Effects

of

statins

on

the

development

of

sepsis

and

organ

dysfunction

in

hospitalized

older

patients

in

China

Qifeng

Gui,

Yunmei

Yang

∗

,

Jiajia

Zhang

ZhejiangUniversity,FirstAfﬁliatedHospitalSchoolofMedicine,DepartmentofGeriatrics,Hangzhou,China

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received9August2016 Accepted16December2016 Availableonline7March2017

Keywords: Mortality Organdysfunction Olderadults Sepsis Statins

a

b

s

t

r

a

c

t

Thisstudyaimedtoevaluatetheprotectiveroleofstatinsonthedevelopmentofsepsis andinfection-relatedorgandysfunctionandmortalityinahospitalizedolderChinese pop-ulationwithbacterialinfections.Inthisretrospectivecohortstudy,257olderpatientswith bacterialinfectionweredividedintotwogroups:astatingroup,thosewhohadreceived statintherapyfor≥1monthbeforeadmissionandcontinuedreceivingstatinduring hos-pitalization;andanon-statingroup,thosewhohadneverreceivedstatinorusedstatinfor <1monthpriortoadmission.Amultivariatelogisticregressionanalysiswasperformedto identifyriskandprotectivefactorsforseveresepsis.Asignificantlylowerincidenceoforgan dysfunctionwasfoundinthestatingroup,ascomparedwiththenon-statingroup(13.3%vs 31.1%,respectively;p=0.002),correspondingtoadjustedratesratioof0.32(95%confidence interval[CI],0.13–0.75;p=0.009).Nosignificantdifferencewasfoundbetweenstatinand non-statingroupsin30-daysepsis-relatedmortality(4.4%vs10.2%,respectively;p=0.109), incidenceofintensivecareunitadmission(13.3%vs16.8%,respectively;p=0.469),orlength ofhospitalstay(20.5vs25.9days,respectively;p=0.61).Statinssignificantlyreducedthe developmentofsepsisandinfection-relatedorgandysfunctioninhospitalizedolder Chi-nesepatientsbutdidnotreduce30-daymortality,ICUadmissionincidence,orlengthof hospitalstay.

Introduction

Sepsis occurs in approximately 2% of generalhospitalized populations in developed countries, including 6%–30% of allpatients admittedtointensivecareunits(ICU).1,2 _About

∗ _{Corresponding}_author.

E-mailaddress:yangyunmei2008@sina.com(Y.Yang).

one-halftothree-quartersofpatientswithsepsisexperience organ failure.3 _In _the _United_States, _{approximately} _751,000

patients developedsevere sepsis in1995; currently,among themorethan1,000,000hospitalizedpatientsintheUnited Statesdiagnosedwithsepsisannually,theincidenceis pro-jected toincrease by1.5% annually,with only50%–70% of

http://dx.doi.org/10.1016/j.bjid.2016.12.008

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patientssurviving.1,4 _However,_a_20-year_study_showed_that

sepsisisincreasingatarateof8.7%peryear,whichisgreater thanthepopulationgrowthrate.5_The_incidence_of_sepsis_is

alsohighinChina;olderpatientswithcomorbiditieswhoare admittedwithbacterialinfectionshaveahigherrisk.6

Although the pathophysiology of sepsis has not been fully elucidated, general consensus indicates that sepsis arisesfromimmunodysregulationanduncontrolledsystemic inﬂammatoryresponses.7_The_{inﬂammatory}_cascade_is

mul-tilevel and involves the production of pro-inﬂammatory cytokines,adhesionmolecules,andreactiveoxygenspecies.8

Giventhispathophysiology, clinicaltrials haveinvestigated adjuvantmediatortherapytoidentifydrugsthatblock spe-ciﬁc inﬂammatory mediators.9–11 _Toward _that _end, _statins

are well known as lipid-lowering agents and have also demonstrated anti-inﬂammatory and immunomodulatory properties.12 _Almog _et _al.13 _demonstrated _that _prior _statin

therapymightreduceratesofseveresepsisandICU admis-sions. This ﬁndings have prompted researchers worldwide tostudy the pleiotrophic effects ofstatins on sepsis, with largelyunconﬁrmedresults.12,14–16Arecentmeta-analysisof randomized controlled trials (RCTs) suggested that statins shouldnotberecommendedtomanageseveresepsisin crit-icallyill patients.17 _In_addition, _a_recent _systematic_review

reportedthatstatinsdonotdecreasetheincidenceofsepsis, progressiontoseveresepsis,orassociatedmortalityrates.18

Nevertheless, patients receiving statins prior to hospital admissionduetoinfection,bacteremia,sepsis,and infection-relatedorgandysfunctioncontinuetodemonstratereduced risksofsepsisprogression/severity,ratesofhospital-acquired bacteremia,andhospitalmortality.13,16_Most_previous_studies

wereconductedinWesternpopulationsexceptfora retrospec-tivestudyconductedbyYangetal.19 _who_studied_an_Asian

populationinTaiwan,indicatingthatstatinsneitherbeneﬁted Asianpatientswithsepsisnorimprovedshort-termsurvival. Although RCTs have examined the potential value of statins in sepsis through meta-analysis and systematic review,17,18 _to_our _knowledge_Asian _patients _or _exclusively

olderpatientswithbacterialinfections havenotbeen stud-ied,andconclusionshavenotshownabeneﬁcialroleofstatins inbacterialinfections.Therefore,thepresentstudyaimedto investigatetheprotectiveroleofstatinsonthedevelopment ofbacterialinfectionsandinfection-relatedorgandysfunction andmortalityinolderChinesepatientshospitalizeddueto bacterialinfections.

Material

and

methods

Studydesignandpatients

AretrospectivecohortstudyenrollingolderChinesepatients hospitalizedduetobacterialinfectionwasconductedbetween March2011andMarch2012intheGeriatricMedicine Depart-ment at First Affiliated Hospital, School of Medicine of Zhejiang University, Zhejiang Province, China. This study wasapprovedbytheClinicalResearchEthics Committeeof FirstAffiliated Hospital. As patient datawere de-identified andpatientsremainedanonymousduringtheretrospective review,signedinformedconsentwaswaived.

Fordatacollectionpurposes,onlytheﬁrstadmissionfrom aseriesofmultipleadmissionsinvolvingthesamepatients duringthestudyperiodwasincluded.Forthisstudy,inclusion criteriawere:patientsaged≥65yearsoldwithsepsiswhose recordsincludedcompleteclinicalandlaboratorydata.

Patientsweredividedintotwogroupsbasedonthosewho hadpriorstatinuseandnostatinuse.Thestatingroupwere thosewhohadusedastatinforatleastonemonthpriortothe ﬁrsthospitaladmissionandcontinuedstatintreatment dur-inghospitalization.Basedonapriorstudythatindicatedthat thetherapeuticeffectsofstatinsaredemonstratedafterone monthofcontinuoususe,thenon-statingroupwas charac-terizedbypatientswhoeitherhadnevertakenstatinsorhad taken astatinfor<1monthpriortoadmission.13_Although

othercharacteristicsbetweenthetwogroupsweredifferent, allpatientsreceivedtreatmentforbacterialinfection,andthe study endpoint was developmentofsepsis. Patientsin the statingroupweretreatedwithseveraldifferentstatindrugs anddosagesincludingatorvastatin,20mgdaily;simvastatin, 40mgdaily;ﬂuvastatin,40mgdaily;pravastatin,20mgdaily; and rosuvastatin,10mgdaily.Data from bothgroups were reviewed30daysafteradmission.

Sepsisandseveresepsiswithorganfailureweredeﬁnedby themostrecentcriteriafromtheThirdInternational Consen-susDeﬁnitionsforSepsisandSepticShock(Sepsis-3)written bySingeretal.20_Patients_were_assessed_using_Acute

Physiol-ogyandChronicHealthEvaluationII(APACHEII)criteria,and theirAPACHEIIscoresweredetermineduponadmission. Sep-sismanagementwasbasedonSCCMpracticeparametersfor thehemodynamicsupportofsepsisinadultpatients.

Datawereobtainedfromelectronicmedicalrecordsfrom time ofadmission and in the following 30 days, with the exception ofthose withnosocomial infections whose data were collected atthe time theirsepsis diagnosis was con-ﬁrmed. Patient characteristics were collected from data on a single admission, including demographics, pre-existing medical conditions, concurrentmedications,infection type and site, APACHE II scores, laboratory data, microbiologi-cal culture results, ICU admission, lengthof hospital stay, andsepsis-relatedmortality.Laboratoryvalues(e.g.,albumin, triglycerides, C-reactive protein[CRP]) selected foranalysis were a singlemeasurein any24-h periodthat most accu-ratelyrepresentedpatientstatus(i.e.,highestorlowestvalue dependingonspeciﬁctest).Theprimaryendpointswerethe developmentofsepsisasindicatedbytheincidenceof multi-pleorgandysfunctionsyndrome(ICDCode995.92)and30-day sepsis-relatedmortality.Secondaryoutcomes included inci-denceofICUadmissionandlengthofhospitalstay.

Statisticalanalysis

Continuous data are presented as median and interquar-tile range and were compared between groups using the Mann–WhitneyUtest.Categoricaldataarepresentedas num-ber and percentage (%) and were assessed using 2 _test

or Fisher’s exacttest. Logisticregression analysiswas con-ductedtoscreenforvariablesindependentlyassociatedwith severesepsis(deﬁnedassepsiswithorgandysfunction).Age, gender, andvariableswithapof<0.05inunivariate analy-siswere included inamodel forthemultivariate analysis.

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Table1–Baselinedemographicandclinicalcharacteristicsof257olderpatientswithbacterialinfections.

Non-statingroup(n=167) Statingroup(n=90) p-Value

Age,y 81(77,85) 83(78,86) 0.228 Male 109(65.3) 52(57.8) 0.236 APACHEIIscore 12.0(8.0,15.0) 10.5(7.0,15.0) 0.238 Siteofinfection Pulmonary 115(68.9) 66(73.3) 0.454 Urinarytract 10(6.0) 8(8.9) 0.385 Softtissue/skin 8(4.8) 6(6.7) 0.570 Biliary/gastrointestinaltract 24(14.4) 4(4.4) 0.015 Catheter-relatedinfection 6(3.6) 2(2.2) 0.717 Others 4(2.4) 4(4.4) 0.456 Smoking 16(9.6) 11(12.2) 0.510 Drinking 8(4.8) 4(4.4) 0.999

Steroidtreatmentformoreadvancedsepticemia 40(24) 21(23.3) 0.911

Bloodculture(+) 27(16.2) 10(11.1) 0.271

Nosocomialinfection 46(25.7) 38(42.2) 0.007

Bodytemperature 37.2(36.8,38.2) 38.0(36.9,38.7) 0.001

Heartrate 84(76,95) 83.5(76,96) 0.670

Respiratoryrate 19.7(18,20.4) 19(18,20) 0.393

Systolicbloodpressure,mmHg 133(118,148) 130(119,140) 0.177

Diastolicbloodpressure,mmHg 71(64,80) 72(67,78) 0.310

Laboratorytests

WBCcount,109_/L _8.7_(5.8,_12.9) _10.1_(7.5,_12.2) _0.178

Albumin,g/dL 36.0(32.7,38.8) 36.7(34.2,39.4) 0.185

Alanineaminotransferase,U/L 22.0(13.0,41.0) 25.5(17.0,38.0) 0.153

TBil,␮mol/L 11.4(8.4,17) 12(7.8,16) 0.687 TG,mmol/L 1.0(0.8,1.4) 1.0(0.8,1.4) 0.490 TC,mmol/L 4.0(3.2,4.5) 3.6(3.2,4.5) 0.604 HDL-C,mmol/L 1.0(0.8,1.3) 1.1(0.9,1.4) 0.133 LDL-C,mmol/L 2.0(1.5,2.5) 1.8(1.5,2.5) 0.487 Glucose,mmol/L 5.2(4.6,6.3) 5.2(4.7,6.0) 0.933 INR 1.1(1.0,1.2) 1.0(1.0,1.2) 0.696 Fibrinogen,g/L 3.9(3,5) 3.5(2.9,4.7) 0.349 APTT,g/L 29.8(25.6,34.2) 28.1(24.5,33.0) 0.042 Thrombintime,s 18.2(17.1,19.6) 18.2(17.1,19.5) 0.895 Prothrombintime,s 12.3(11.3,13.3) 12.3(11.3,13.3) 0.900 D-dimer,␮g/L 244.0(132.0,455.0) 237.5(129.0,452.0) 0.957 CRP,mg/L 43.5(17.0,80.2) 34.0(13.2,60.6) 0.138

Abbreviations:APACHE,AcutePhysiologyandChronicHealthEvaluation;TBil,totalbilirubin;TG,triglyceride;TC,totalcholesterol;HDL-C,

highdensitylipoproteincholesterol;LDL-C,lowdensitylipoproteincholesterol;INR,internationalnormalizedratio;APTT,activatedpartial thromboplastintime;CRP,C-reactiveprotein.

Continuousvariablesarepresentedasmedian(interquartilerange),andcategoricalvariablesareexpressedasn(%). Boldvaluesindicatesigniﬁcancebetweenthetwogroups,p<0.05.

Associationsbetweenthedependentoutcomevariables

(mul-tipleorgandysfunction, ICUadmissionincidence,lengthof

hospitalstay,30-daymortality)andthevariablesincludedin

theﬁnalmodelareexpressedbyoddsratios(OR)andtheir

respective 95% conﬁdence intervals (CIs). The signiﬁcance

levelwassetat0.05.Allstatisticsweretwo-sidedandanalyzed

usingSPSS22.0(IBMCorp.,Armonk,NY).

Results

Atotalof257eligiblepatientswereincluded,amongwhom

90 (35%) used statins. Baseline patient characteristics are

summarized in Table 1. Comparing the statin and

non-statingroups, nosigniﬁcant differencesweredemonstrated inage,genderdistribution, APACHEIIscores,smoking and drinking habits, steroid treatment, heart rate, respiratory

rate, blood culture results, blood pressure, and most bio-chemical andhematologicalparameters. However,ahigher percentage of patients not treated with statins had bac-terial infections in the biliary/gastrointestinal tract (14.4% vs 4.4%,respectively; p=0.015)and higheractivatedpartial thromboplastintime(APTT)levels(p=0.042)thanstatinusers (Table1).Body temperaturewas higherinthe statingroup thanthenon-statingroup(p=0.001).Patientsofthenon-statin groupwerelesslikelytohavenosocomialinfections,as com-paredwithstatin-grouppatients(25.7%vs42.2%,respectively; p=0.007).

Bloodsampleswereobtainedfromallpatientsforculture, but conﬁrmatory culturesusing other biologicalspecimens includingurineorsputumwerenotcollectedfromallpatients. Asforpatientswithapositiveblood culture,threepatients had apositivesputumculture(Acinetobacterspp,Aeromonas spp.,andStaphylococcusspp.).Twopatientshadapositiveurine

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Table2–Medicationsandcomorbiditiesofthepatientsbygroup(n=257).

Non-statingroup(n=167) Statingroup(n=90) p-Value Comorbidities

COPD 46(27.5) 28(31.1) 0.547

Hypertension 110(65.8) 70(77.7) 0.047

Diabetes 49(29.3) 37(41.1) 0.056

Malignancy 33(19.7) 15(16.6) 0.544

Coronaryarterydisease 37(22.1) 47(52.2) <0.001

Cerebrovasculardisease 32(19.1) 23(25.5) 0.233

Chronicrenalfailure 12(7.1) 7(7.7) 0.863

Chronicheartfailure 21(12.5) 17(18.8) 0.174

Chronicliverdisease 10(5.9) 1(1.1) 0.065

Peripheralvasculardisease 6(3.5) 6(6.6) 0.265

Preadmissionmedication

ACEIorangiotensinIIantagonists 28(16.7) 24(26.6) 0.059

Aspirin 30(17.9) 30(33.3) 0.005

Betablockers 17(10.1) 22(24.4) 0.002

Calciumantagonists 43(25.7) 34(37.7) 0.045

Antiplateletagents(other) 19(11.3) 31(34.4) <0.001

Spironolactone 20(11.9) 9(10.0) 0.633 Furosemide 17(10.1) 9(10.0) 0.964 Nitrateesters 23(13.7) 22(24.4) 0.032 Oralhypoglycemics 22(13.1) 27(30.0) 0.001 Digoxin 14(8.3) 9(10.0) 0.665 Trimetazidine 14(8.3) 28(31.1) <0.001 Antiarrhythmicagents 5(2.9) 8(8.8) 0.040 Insulin 9(5.3) 8(8.8) 0.282 Warfarin 5(2.9) 2(2.2) 0.717 Donepezilhydrochloride 8(4.7) 4(4.4) 0.900 Memantine 6(3.5) 2(2.2) 0.546

Steroiduseforchronicdiseases 3(1.7) 3(3.3) 0.436

Abbreviations:COPD,chronicobstructivepulmonarydisease;ACEI,angiotensin-convertingenzymeinhibitors.

Dataareshownasn(%).

culture(KlebsiellapneumoniaandCorynebacteriumspp.),andone

patienthadapositivethroatswabculture(Aeromonasspp.).

Asforpatientswithnegativebloodcultures,11patients

had positive sputum culture results (all positive, but the

specieswerenotreported).Somepatientshadpositiveurine

cultureresults(KlebsiellapneumoniaandEscherichiacoli).One

patienthadapositivebilecultureresult(Moraxellaosloensis,

Candidaalbicans, Klebsiellapneumonia,Enterococcushirae);one

patienthadpositivestoolculture(Candidaalbicans)andthroat

swabcultureresults(Aeromonasspp.).

Table 2 shows differences in medications and comor-biditiesbetweenstatinusersand non-users.Proportionsof hypertension(77.7%vs65.8%,respectively;p=0.047)and coro-nary artery disease (52.2% vs 22.1%, respectively; p<0.001) were higherinthe statingroupthan thenon-statingroup. Patientsinthestatingroupweremorelikelytotakeaspirin (33.3% vs 17.9%, respectively; p=0.005), ␤-blockers (24.4% vs10.1%,respectively;p=0.002),calciumantagonists(37.7% vs 25.7%, respectively; p=0.045), other antiplatelet agents (34.4%vs11.3%,respectively;p<0.001),nitrateesters(24.4% vs13.7%,respectively;p=0.032),oralhypoglycemics(30.0%vs 13.1%,respectively; p=0.001), trimetazidine(31.1% vs 8.3%, respectively; p<0.001), and antiarrythmics (8.8% vs 2.9%, respectively;p=0.040)thanthenon-statingroup.

Fig.1illustrates30-daysepsis-relatedmortality, develop-mentofseveresepsischaracterizedbyorgandysfunction,ICU admission, and length of hospitalstay between the statin

andnon-statingroups.Sepsis-relatedmortalitywasdefined as cause ofdeathdirectly orindirectly relatedto infection ordefinedascauseofdeathnotrelatedtoinfectionbutthe patienthadanuncontrollableinfectionatthetimeofdeath. Non-statinusershadhigherratesofseveresepsis character-izedbyorgandysfunctionthanstatinusers(31.1%vs13.3%, respectively;p=0.002).Nodifferencewasfoundbetweenthe two groups in 30-day sepsis-related mortality, ICU admis-sion, or lengthof hospitalstay. However,more patientsin thenon-statingroup(10.2%)diedsecondarytosepsis-related causes within 30 days of admission for a bacterial infec-tionthanthoseinthestatingroup(4.4%).Theproportionof patients admittedto the ICUwas 13.3% forthe non-statin group and 16.8% forthe statin group, but notsignificantly different. Regardless of statin use, one-halfof all enrolled patients were hospitalizedforsepsistreatmentforatleast 15days.

Variables associated with severe sepsis are reported in Table 3. A univariateanalysis showedthat 10 factors were associatedwithseveresepsis,butonlysixremained signiﬁ-cantintheﬁnalmultivariatemodel.Statinuseandalbumin were showntobeprotectivefactors forseveresepsis,with ORs of 0.28 (95% CI, 0.13–0.62; p=0.002) and 0.91 (95% CI, 0.85–0.98; p=0.013), respectively. Triglycerides (TG), throm-bintime,chronicobstructivepulmonarydisease(COPD),and chronicheartfailurewereallassociatedwithseveresepsisand mayindicaterisk.

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100.0%

No statin Statin No statin

Hospital sta y (da ys) Statin Statin 80.0% 60.0% 40.0% 20.0% 0.0% 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% Survival

A

B

C

D

30-day sepsis-related death

No ICU admission

P = 0.610

No Sepsis with organ dysfunction

P = 0.109 P = 0.469 P = 0.002 300 200 100 0

Fig.1–Barchartsof30-daysepsis-relatedmortality:(A),sepsiswithorgandysfunction(B),ICUadmission(C),andaboxplot oflengthofhospitalstay(D)(n=257).Theboxplotcomprisesthe75thpercentile(topofbox),median(boldlineinbox),and 25thpercentile.Circlesandasterisksintheboxplotindicateoutliersgreaterthan1.5and3timestheinterquartilerange (IQR).Chi-squaretestwasusedtocomparedifferencesamong30-dayinfection-relatedmortality,bacterialinfectionwith organdysfunction,andICUadmissionbetweenthetwogroups.Mann–WhitneyUtestwasimplementedforhospitalstays.

Discussion

Toour knowledge, this retrospective cohort study was the ﬁrst to evaluate the effects of statins in older Chinese patients hospitalized due tobacterial infection. Signiﬁcant decreases were demonstrated in the development of sep-sisandinfection-relatedorgandysfunctioninolderpatients treatedwithstatinsfor>1monthpriortohospitalizationand whocontinuedstatintreatmentduringhospitalization infec-tion.Althoughnodifferenceswerefoundbetweenstatinusers andnon-usersin30-daysepsis-relatedmortality,ICU admis-sion,orlengthofhospitalstay,thepercentageofpatientswho diedbecauseofsepsis-relatedcauseswithin30daysof admis-sionduetobacterialinfectionwaslowerinthestatingroup (4.4%)thanthenon-statingroup(10.2%).

Basedon a literature review, the results of the present study arecongruent withthose ofpreviousstudies.Almog etal.13_concluded_that_prior_statin_treatment_might_be

asso-ciatedwithreducedratesofseveresepsisandICUadmission inpatientswithacutebacterialinfections.Similarly,Martin etal.21_reported_that_statins_appear_to_curtail_the_progression

ofsepsisbypreventingsepsis-inducedhypotension.Further, patientswithsepsis-associatedacuterespiratorydistress syn-drome(ARDS) alsoexperiencedgreater beneﬁcial effectsof priorand continuous statin therapy in moresevere ARDS,

underscoringthepotentialtherapeuticbeneﬁtsofstatinsin ahigh-riskARDScohort.22_The_present_study _demonstrated

that statinshad aprotective effectbyreducing the rateof sepsisdevelopment,asnon-statinusershadhigherratesof severesepsischaracterizedbyorgandysfunctionthanstatin users(31.1%vs13.3%,respectively;p=0.002).

Prospective studies have also demonstrated the beneﬁ-cial effectsofstatins. Acute administration ofatorvastatin (40mg/day)reducedsepsisseverityinhospitalizedpatients, suggesting that statins may act acutely to prevent organ dysfunction.9_When_atorvastatin_was_administered_to_about

half(n=123)ofacohortof250criticallyillpatients,IL-6 lev-elswere notreducedduringtreatment,butpriorstatinuse wasassociatedwithlowerbaselineIL-6levelsandimproved survival.10 _We_found_that_statin_use_and_albumin_were

pro-tective factors forsevere sepsis, with ORs of0.28 (95% CI, 0.13–0.62; p=0.002) and 0.91 (95% CI, 0.85–0.98; p=0.013), respectively.Further,inthisstudy,thestatin-grouppatients had receivedstatin treatmentpriortotheiradmission and alsocontinuedto receivestatins afteradmission.Therefore, we believe continuing statin treatment during hospitaliza-tionmaypositivelyinﬂuencetheprotectiveeffectsofstatins on the progression to sepsis, as evidenced by the higher rates of severe sepsis among non-statin users compared withstatinusers.Nevertheless,ourresultscannotspeciﬁcally

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Table3–Variablesassociatedwithseveresepsis.

Univariateanalysisa _Multivariate_analysis

OR(95%CI) p-Value OR(95%CI) p-Value

Age,years 1.02(0.98,1.07) 0.382

Male 1.08(0.60,1.95) 0.787

Statins 0.34(0.17,0.68) 0.002 0.28(0.13,0.62) 0.002

Infectionatothersites 5.37(1.25,23.13) 0.024

SBP,mmHg 0.99(0.97,1.01) 0.090 DBP,mmHg 0.98(0.95,1.01) 0.089 Laboratorytests Albumin,g/dL 0.88(0.82,0.94) <0.001 0.91(0.85,0.98) 0.013 TBil,␮mol/L 1.02(1.00,1.03) 0.039 TG,mmol/L 2.13(1.41,3.22) <0.001 2.29(1.48,3.55) <0.001 TC,mmol/L 1.07(0.82,1.4) 0.612 Thrombintime,s 1.12(1.01,1.24) 0.033 1.16(1.02,1.30) 0.018 CRP,mg/L 1.01(1.00,1.01) 0.017 1.01(0.99,1.01) 0.096 Comorbidities COPD 1.88(1.04,3.42) 0.038 2.23(1.12,4.45) 0.022

Chronicheartfailure 2.59(1.26,5.32) 0.009 3.07(1.31,7.20) 0.010

Preadmissionmedication

Aspirin 0.46(0.21,0.99) 0.047

Spironolactone 2.82(1.27,6.25) 0.011

Digoxin 2.56(1.06,6.17) 0.036

Abbreviations:OR,oddsratio;CI,conﬁdenceinterval;TBil,totalbilirubin;TG,tryglycerides;CRP,C-reactiveprotein;COPD,chronicobstructive pulmonarydisease;SBP,systolicbloodpressure;DBPdiastolicbloodpressure;TC,totalcholesterol.

a _Logistic_regression_was_implemented,_and_a_backward_procedure_was_applied_to_a_multivariate_analysis_model_(R2₌_0.315).

demonstratewhetherprioruseoronlyin-hospitalusemaybe responsibleforbetterclinicaloutcomes.InseveralRCTs,10,11,13

priorstatinuse,ratherthandenovouse,wasassociatedwith thebiomarkersofsepsisprogression.

Incontrasttotheresultsoftheabovementionedstudies, someotherstudiesdidnotdemonstrateanysigniﬁcant ben-eﬁts ofstatin use on sepsis outcomes.23,24 _Goodin _et _al.23

foundthat priorstatinusersweretypicallyolder andmore obese and had a higher prevalence of smoking, diabetes, andischemicheart diseasethannon-statinusers and ben-eﬁtsof statins were not demonstrated intheir primary or secondaryoutcomes.Leungetal.24_found_no_signiﬁcant

asso-ciationsbetweenstatintherapyandsurvivalinpatientswith bloodstreaminfections.Althoughthepresentstudyfoundno signiﬁcant relationship between statin therapy and 30-day mortalityinourcohortofonlyolderChinesepatients,fewer patientsreceivingstatinsdiedofsepsis-relatedcauseswithin 30daysofabacterialinfectionthanpatientswhowere non-statinusers(4.4%vs10.2%,respectively).

Older patients are characteristically at agreater risk of infection and sepsis and have been shown to have an increasedincidenceofsepsis,progressiontoorgan dysfunc-tion, and sepsis-related mortality.6 _In _a _{population-based}

cohortanalysisof69,168olderpatientswithcardiovascular disease,25 _statin_use _was_associated_with_a_reduced _rate_of

subsequent sepsis. Mortensenet al.26 also foundthat cur-rentstatin use wassigniﬁcantlyassociatedwithdecreased 30-daymortalityinpatientsaged≥65yearshospitalizedfor community-acquired pneumonia. Similarly, reinsure statin usewasassociatedwithsigniﬁcantlydecreasedmortalityin olderburnpatients,althoughtherateofsepsisdevelopment

was unaffected.27 _These_studies_demonstrate_the _beneﬁcial

effectsofstatinuseforboththepreventionandtreatmentof sepsisinolderpatients.Althoughasignificantdecreasewas notedregardingtheprogressionofsepsistoorgandysfunction amongstatinuserscomparedwithnon-usersinthisstudy,the lackofsignificantdifferencesbetweenstatinusersand non-usersin30-daysepsis-relatedmortality,ICUadmission,and lengthofhospitalstaycanpossiblybeexplainedbythegreater incidenceofcomorbiditiesinstatinusersandtheassociated weakphysicalconditionofourolderpatientpopulationthat wasunaffectedbystatinuse.Whilewedidnotfocuson comor-bidities,thepresentstudyresultsdosuggestthatthepresence ofcomorbiditiessuchasCOPDandchronicheartfailuremay contributetothedevelopmentofsepsisandinfection-related organdysfunctioninolderpatientswithbacterialinfections. Theexactmechanismastohowstatinsprovideabeneficial effectinpatientswithbacterialinfectionsremainsunclear, but several mechanisms might explain the reported bene-ficial results. Inseveral animal models, pretreatment with statinsor treatmentafterthe onsetofsepsisimprovedthe survivalofsepticanimals.28–32 _Statin_treatment_also_altered

biodistributionofTc-99m-sestamibiinratswithabdominal sepsis, interpreted asa protectiveeffectbecause of statin-mediatedincreasedtissueperfusion.33 _The_protective_effect

ofstatinsisattributedtotheireffectsoninsulinsensitivity, improving insulin signaling in peripheraltissues,28

preser-vingcardiacfunctionandhemodynamicstatus,29,31_reversing

inﬂammatorycytokineslevels,15–17 _and_enhancing_bacterial

clearance.17 Additionally, statins appear to decrease nitric oxideproductionand restoreimpairedvascular responsive-nessinsepsis.30,31,34

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A direct antibacterial effect has been reported with decreasedbacterialburdenofseveralorganisms.35_In_clinical

studies,statinsexertedantioxidantpropertiesin experimen-tal models on sepsis.36 _Statins _also _blunted _expression _of

toll-likereceptors4and2onmonocytesinahumanmodel ofendotoxemiathatdecreasedtheproductionof inﬂamma-torycytokines.37_Similarly,_an_association_was_shown_between

statintherapyanddecreasedTNF-␣andIL-6levelsinpatients with acute bacterial infections.9 _Another _study _reported _a

10-foldgreaterplasma-freecortisollevelsversusplasmatotal cortisollevels insevere sepsis.38 _Results_of_the

abovemen-tionedstudiessuggest thatthe protectiveeffectsofstatins may bemore relatedto their expansive anti-inflammatory andimmunomodulatoryeffects,ratherthantargeting individ-ualinflammatorymediators.Anationwidepopulation-based study in Taiwan also showed associations between statin potencyandbeneficialeffects,indicatingthattheriskof sep-sisprogressiontoorgandysfunctionandmortalityarelower among high-potency statin users than low-potency statin users.39

Thepresentstudyhadseverallimitations.First,thisstudy was retrospective and neither randomized nor controlled. Second,potentially uncontrolledconfoundersincluding dif-ferencesbetweenthetwostudiedgroupsmayinﬂuencethe interpretationofresults,andresidualconfoundingcannotbe fullyruledout.Third,thesamplesizewassmallbecauseof therestrictiveinclusion criteriainvolvingolder adultswith bacterialinfectionsfromasinglecenter.Consequently,a sam-plesizecalculationwasnotperformed priortoconducting thisresearch,butapowerof0.916wascomputedusingthe groupdifferenceresultsregardingtheproportionofpatients withmultipleorgandysfunction(s).Fourth,becausethestudy objectivewastodetermineeffectsofstatinsonthe progres-sionofbacterialinfectionstosepsis,regardlessofthespeciﬁc statinusedbythestatingroup,itwasassumedthatallstatins hadthesame effect.Other studies10,39 _have_also_suggested

thatstatinpotencyisassociatedwithbetteroutcomes,with improvedoutcomesobtainedwithhigh-potencycomparedto low-potencystatins.Fifth,wedidnotaccountforthepossible inﬂuenceofglucocorticoidusebysomepatients. Moreover, examinationofmanyvariablesmayhaveintroducedatypeII error.Certainothervariablesassociatedwithsepsisseverity werenotmeasured,includingconsciousnesslevel,lactate lev-els,vasoactivedruguse,andventilatoruse.APACHEIIscores andCRPvalueswererelativelylowgivenasepsisdiagnosis inthe study population. Although the mostrepresentative APACHEIIand CRPvaluesduring a24-hperiod wereused foranalysis,thesevaluesdonottypicallychangeimmediately inconjunctionwithdiseaseprogression.Therefore,alonger studyperiodisrequiredtoobtainvaluesconsistentwith pro-gressivesepsis.Lastly,therelativelylownumberofpositive microbiologicalﬁndingsmayhavebeenbecauseofcollection ofasinglebloodsampleforcultureinsteadofmultiple sam-plesatdifferenttimes.

Toourknowledge,this istheﬁrst studytoevaluatethe effectsofstatinsinolderAsianpatientswithbacterial infec-tions.Statintreatmentdecreasedthedevelopmentofsepsis inolderhospitalized Chinesepatients withbacterial infec-tionsbutdidnotreducethe30-daymortality,ICUadmission incidence, or length ofhospital stay. Based on the results

of this study, continuing preadmission statin therapy dur-inghospitalizationmaybeassociatedwithareducedrateof sepsisdevelopmentandperhapsoverallin-hospitalmortality inelderlypatientswithbacterialinfections giventhelower rateofsepsisdevelopmentseeninstatinusersinthisstudy. Giventhesafetyproﬁleofandinfrequentadverseeffectsfrom statinsinolderpatients,additionalprospectivecontrolled tri-alsareneededtoelucidatethepotentialforstatinuseasa therapeuticstrategy inarigorouslyselected groupofolder Asianpatientswithbacterialinfections.

Funding

Thisstudy wassupportedbytheZhejiang Provincial Medi-calandHealthResearchProgram(2012KYB084)andNational ClinicalKeySpecialtyConstructionProjectofGeriatrics.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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