Mongardonetal.CriticalCare2013,17:R18 http://ccforum.com/content/17/1/R18 RESEARCH Open Access Plasma thioredoxin levels during post-cardiac arrest syndrome: relationship with severity and outcome Nicolas Mongardon1,2*, Virginie Lemiale1,2, Didier Borderie2,3, Anne Burke-Gaffney4, Sébastien Perbet5, Nathalie Marin1,2, Julien Charpentier1,2, Frédéric Pène1,2,6, Jean-Daniel Chiche1,2,6, Jean-Paul Mira1,2,6 and Alain Cariou1,2,7 Abstract Introduction: Despite experimental evidence, clinical demonstration of acute state of oxidative stress and inflammation during post-cardiac arrest syndrome is lacking. Plasma level of thioredoxin (TRX), a redox-active protein induced under conditions of oxidative stress and inflammation, is increased in various critical care conditions. We determined plasma TRX concentrations after cardiac arrest and assessed relationships with severity and outcome. Methods: Retrospective study of consecutive patients admitted to a single academic intensive care unit (ICU) for out-of-hospital cardiac arrest (between July 2006 and March 2008). Plasma levels of TRX were measured at admission, day (D) 1, 2 and 3. Results: Of176patientsincluded,medianTRXvaluesmeasuredinICUsurvivorsandnon-survivorswere,respectively: 22ng/mL(7.8to77)vs.72.4(21.9to117.9)atadmission(P<0.001);5.9(3.5to25.5)vs.23.2(5.8to81.4)atD1(P= 0.003);10.8(3.6to50.8)vs.11.7(4.5to66.4)atD2(P=0.22);and16.7(5.3to68.3)vs.17(4.3to62.9)atD3(P=0.96). Patientsdyingwithin24hourshadsignificantly(P<0.001)higherTRXlevels(118.6ng/mL(94.8to280))thanthose whodiedafter24hoursorsurvived(50.8(13.9to95.7)and22(7.8to77)).TheareaundertheROCcurvetopredict earlydeathwas0.84(0.76to0.91). TRXlevelsonadmissionweresignificantlycorrelatedwith‘low-flow’duration(P=0.003),sequentialorganfailure assessment(SOFA)score(P<0.001),andbloodlactateconcentration(P<0.001),butnotwith‘no-flow’durationor simplifiedacutephysiologyscore(SAPS)IIscore.TRXlevelsandadmissionarterialpO2correlatednegatively(r=-0.17, P=0.03).Finally,cardiacarrestwithcardiacetiologyexhibitedlowerlevelsofTRXthanincasesofextra-cardiaccause (46ng/mL(11to104)vs.68(42to137),P=0.01). Conclusions: OurdatashowforthefirsttimethatTRXlevelswereelevatedearlyfollowingcardiacarrest,suggestiveof oxidativestressandinflammationoccurringwiththiscondition.Highestvalueswerefoundinthemostseverepatients. TRXcouldbeausefultoolforfurtherexplorationandcomprehensionofpost-cardiacarrestsyndrome. Introduction the pathophysiology of post-cardiac arrest syndrome is Shock and intractable multi-organ failure are the main complexandremainsonlypartiallyunderstood[2].Ische- causes of death after successfully resuscitated cardiac mia/reperfusion and non-specific acute activation of the arrest (CA) [1]. Whilst cessation and reduction of blood inflammatoryresponsearethoughttocontributetotissular flow are the patent mechanisms of organ dysfunction, andcellularabnormalities[3].Uncontrolledinflammation andoxidativestresscouldplayacentralandcrucialrolein *Correspondence:nicolas.mongardon@cch.aphp.fr the onset of post-cardiac arrest syndrome. Even though 1MedicalIntensiveCareUnit,CochinHospital,HôpitauxUniversitairesParis supportedbyalargeamountofexperimentaldata,clinical Centre,AssistancePubliquedesHôpitauxdeParis,27rueduFaubourg Saint-Jacques,75014Paris,France investigation of these phenomena after CA is lacking. Fulllistofauthorinformationisavailableattheendofthearticle ©2013Mongardonetal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited. Mongardonetal.CriticalCare2013,17:R18 Page2of10 http://ccforum.com/content/17/1/R18 Limitations of in vivo analytical indexes may explain, to than6hoursdespiteadequatefluidloading.Patientman- some extent, this knowledge gap, withissues to translate agement was strictly standardized [2]. When employed, markers from bench (experimental studies) to bedside hypothermia was started immediately at ICU admission (clinicalscenario). using external cooling by forced cold air cooling during While markers of inflammation (C-reactive protein thefirst24hoursinorderto obtainatargettemperature (CRP),procalcitonin(PCT))haveassumedimportanceas between32°Cand34°C.Sedationusingadjusteddosesof biomarkersincriticalcare,theirinterpretationshavebeen midazolamandmorphineorfentanyl,andneuromuscular questioned after CA [4]. Moreover, markers of oxidative blockingagent infusionduringtherapeutic hypothermia, stress investigated in acute illness suggest disappointing were applied. In the absence of shock or complications, results[5,6]. sedation was interrupted at the end of the hypothermia Meanwhile, translational research has highlighted the period.Normothermiabetween37°Cand37.5°Cwasthen major role of thioredoxin (TRX) in physiological and achieved using passive rewarming at the targeted rate of pathologicalconditions.Thisubiquitous,12kDaintracel- 0.3°C/hour and maintained during the next 24 hours. lular redox-active thiol protein is increased and released Patients with neither admission nor day 1serum sample during inflammation and oxidative stress. Indeed, TRX, were excluded.Part ofthe cohort was previously studied withitsredox-activedisulfide/dithiolsiteactingasapro- to investigate PCT levels for the diagnosis of early onset tein disulfide-reducing system, is a major intracellular pneumonia after CA; however, patients who died within redoxregulatorymoleculescavengingreactiveoxygenspe- the first 24 hours, with aninfectionprior to CA, or with cies. TRX also regulates inflammation, cell signaling, anextra-pulmonaryinfectiondevelopingwithin5daysfol- growth, andapoptosis[7,8].IntracellularTRXisreleased lowing admission had been excluded [4]. The study was fromcellsonoxidativestress,leadingtohighextracellular approvedbyourlocalCochinUniversityHospitalinstitu- levels in numerous situations relevant to critical care, tional review board. Written consentwaswaived for this including: severe burn injury [9], acute lung injury [10], studysinceTRXdosagesdidnotrequirespecificoraddi- and in particular, ischemia-reperfusion injury, heart dis- tionalblood drawing.Informedassessment wasobtained easeandsepsis[11-14]. fromallpatientsornextofkin. To date, neither animal nor human studies have mea- suredplasmaconcentrationsofTRXafterCA.Thus,this Blood sampling study was designed to further explore the biological AllTRXmeasurementswereperformedinApril2010by stormoccurring after CA.We hypothesizedthatTRXis the same investigator (DB) by using blood samples increased after CA, and that the magnitude of the collected at admission, day 1 (D1), day 2 (D2) and day increaseislinkedwithclinicalcourse.Thus,wefirstmea- 3(D3).Thesesampleswereinitiallycentrifugedandstored sured TRX levels following CA and second, determined at-80°Cwithin 4hours,asapprovedbyourlocalinstitu- associationsbetweenTRXlevelsand markersof severity tional review board, as part of a serum collection. ofpost-cardiacarrestsyndromeandclinicaloutcomes. MeasurementsofTRXwereperformedinduplicatesam- pleswithacommerciallyavailablesensitiveenzyme-linked Materials and methods immunosorbent assay(RedoxBiosciences, Kyoto,Japan). Study setting and population Patients exhibiting hemolysis were excluded due to the All consecutive patients over 18 admitted to our 24-bed high intracellular concentration of TRX, which will bias medical ICU between July 2006 and March 2008 after a assessment[7].PlasmalevelsofTRXwerealsodetermined successfullyresuscitatedCAwereeligible. Weretrospec- in 30 healthy volunteers in stable condition at rest tivelyreviewedallmedicalrecordsanddatafromourpro- (checked for the absence of chronic or acute illness by spectively acquired ICU database, in which all CA questionnaireandmedicalexamination).AnalysesofCRP survivors’ characteristics are registered according to the were performed with a fully automated immunoturbidi- Utsteinstyle[15].Thefollowingdatawereextractedpro- metricassay(CRPLX, ModularPP™,RocheDiagnostics, spectively for each patient: demographic data, clinical Mannheim, Germany).PCTconcentrationswerequanti- parameters,causeofCA,“no-flow”and“low-flow”period fied with an immunofluorimetric assay (PCT sensitive, (respectively,timefromcollapsetobasiclifesupportand Kryptor™,Brahms,Berlin,Germany). timefrombasiclifesupporttoreturnofspontaneouscir- Thioldeterminations(expressedasμmol/L)werebased culation), initial rhythm, Simplified Acute Physiology onthethiol/disulfidereactionofthiolandEllman’sreagent Score II (SAPS II) and Sequential Organ Failure Assess- (5,5’-dithiobis(2-nitrobenzoicacid) DTNB).Fifty microli- ment(SOFA)scores,hypothermiamanagement,biological ters of the sample mixed with 1 ml 0.1 M Tris, 10 mM parameters and ICU mortality. Post-resuscitation shock EDTApH8.2,constitutingtheblankreaction,wasassessed was defined as the need for vasoconstrictive drug at412nm(UVIKON,KontronInstruments,Milan,Italy). (epinephrine or norepinephrine) infusion lasting more Theadditionof40μl10mMDTNBinmethanoltriggered Mongardonetal.CriticalCare2013,17:R18 Page3of10 http://ccforum.com/content/17/1/R18 thereactionandabsorptionat412nmwasmeasuredafter PerformanceCategory1or2(n=64).Table1reportsthe stablecolourformation(1to3min).Theconcentrationsof maincharacteristicsofICUsurvivorsandnon-survivors. thiolgroupswerecalculatedusingamolarextinctioncoef- TRX concentration was 10.7 ng/mL (9.1 to 20.9) in ficientof13,600M-1cm-1. healthy volunteers (14 male, age 49 (39 to 54)). In our Advanced oxidation protein products (AOPP) were patientcohort,medianserumTRXvaluesinICUsurvivors quantifiedasfollows:200μlofserumdiluted1:5inphos- andnon-survivorswererespectively(Figure1):22ng/mL phate-buffered saline was placed into each well of a (7.8to77)vs.72.4(21.9to117.9)atadmission(P<0.001), 96-wellmicrotiterplate andadded20 μlofaceticacidto 5.9 (3.5 to 25.5) vs. 23.2 (5.8 to 81.4) at D1 (P = 0.003), each well. For the standards, we added 10 μl of 1.16 M 10.8(3.6to50.8)vs.11.7(4.5to66.4)atD2(P=0.22),and potassiumiodide(Sigma-Aldrich,StLouis,MO,USA)to 16.7(5.3to68.3)vs.17(4.3to62.9)atD3(P=0.96).The 200μlofchloramine-Tsolution(0to100μmol/l)(Sigma- areasundertheROCcurvesofTRXthatdiscriminatessur- Aldrich,StLouis,MO,USA)inawellandthenadded20 vivorsandnon-survivorswere:0.66(0.57to0.74)atadmis- μl of aceticacid. The absorbance ofthe reactionmixture sion,0.65(0.55to0.74)atD1,0.56(0.45to0.67)atD2and wasimmediatelyreadat340nmagainstablankconsisting 0.5(0.38to0.62)atD3(Figure2). of 200 μl of phosphate-buffered saline, 10 μl of 1.16 M When timing of death was considered, patients dying potassiumiodide,and20μlofaceticacid.AOPPconcen- within24hours(n=17)hadhigheradmissionTRXlevels trationsareexpressedasmicromoles/literofchloramine-T (118.6 ng/mL (94.8 to 280)) compared with cases of late equivalents. deathorsurvival (respectively, 50.8(13.9to 95.7) and22 (7.8 to 77), P < 0.001); area under ROC curve to predict Statistical analysis early death was 0.84 (0.76 to 0.91) (Figure 3). Refractory Continuous variables were expressed as medians (with shockwasthecauseof88%oftheseearlydeaths. interquartilerange)andqualitativevariableswerereported AdmissionTRXcorrelated significantly with ‘low-flow’ ascountandproportions,unlessspecifiedotherwise.Sta- duration (r = 0.24, P = 0.003), SOFA score (r =0.27, P < tisticalanalysiscomparedICUsurvivorsandnon-survivor 0.001), and admission arterial lactate concentration (r = patientswithnonparametrictests,asappropriate:continu- 0.38, P < 0.001), but was not associated with ‘no-flow’ ousvariableswiththeWilcoxonranksumtest;categorical duration (r = 0.07, P = 0.39) or SAPS II score (r = 0.04, variables with the c2 test. Statistical significance was P=0.6).TRXlevelsandadmissionarterialpO2correlated, defined as P < 0.05. Correlation was performed with the negatively(r=-0.17,P=0.03). Spearman test. Receiver-operated characteristic (ROC) Finally,patientsexperiencingCAduetoacardiacetiol- curves were performed to assess the ability of TRX con- ogy exhibited lower levels of TRX at admission than in centrationstopredict ICUdeath.Resultswere expressed casesofextra-cardiaccause(46ng/mL(11to104)vs.68 with area under the curve (AUC) and 95% confidence (42 to 137), P = 0.01); similarly, patients with shockable interval.AnalyseswereperformedwithStata7.0software rhythm had lower admission TRX concentrations (16.5 (StataCorp.,CollegeStation,TX,USA). (6.5 to 73.7) vs. 74 (27 to 132) than in cases of non- shockablerhythm). Results Routinely available inflammationbiomarkers, CRPand During the 20-month study period, 245 patients were PCT,werealso measured andthiol group formationand admitted for a successfully resuscitated CA. After AOPP quantified. Non-survivors exhibited higher CRP excluding 59 patients with neither sample at admission levelsatadmissionandatD1,whereastheirPCTconcen- nor D1 and 10 patients with hemolytic blood samples, trations were higher from admission to D3. Conversely, we enrolled 176 consecutive patients in the final AOPPandthiolconcentrationsdidnotdifferirrespective analysis. ofoutcome(Table2). Cohorthadamedianageof60years(48to73)and116 patients were men. Characteristics of CA were: ‘no-flow’ Discussion duration 5(0to10) min, ‘low-flow’duration15(8to25) InalargecohortofCApatients,weassessedthelevelsof min, initial shockable rhythm n = 71 (41%), and cardiac plasmaTRXandfoundthatveryhighlevelsoccurredafter etiologyn=93(53%).Non-cardiaccauseswererespiratory CA, with an early peak and subsequent decrease over (n=39),neurological(n=9)andmiscellaneous(n=35). 3days;highestlevelswereassociatedwithworstoutcome. Severity of the population was highlighted by SAPS II To our knowledge, this is the first study evaluating the score of 68 (60 to 81) and admission SOFA score of 9 potentialusefulnessofTRXdeterminationforassessment (6to12).Post-resuscitationshockoccurredin131patients ofbothpathophysiologyandseverityafterCA. (74%); 152 patients (89%) were treated with therapeutic Thepathophysiologyofpost-cardiacarrestsyndromeis hypothermia. ICU mortality rate reached 61% (107 dominatedbyaglobalischemia-reperfusionphenomenon patients), whereas most of the survivors were Cerebral andnon-specificactivationofthesystemicinflammatory Mongardonetal.CriticalCare2013,17:R18 Page4of10 http://ccforum.com/content/17/1/R18 Table 1Baseline admissioncharacteristics andoutcome ofICUsurvivors and non-survivors. Allpatients Survivors Non-survivors P (n=176) (n=69) (n=107) Age(year) 60(48-73) 57(46-68) 60(49-74) 0.18 No-flowduration(min) 5(0-10) 2(0-5) 5(1-10) 0.004 Low-flowduration(min) 15(8-25) 10(5-16) 20(10-26) <0.001 Shockablerhythm 71(41) 47(68) 24(22) <0.001 Cardiacetiology 93(53) 44(68) 47(44) 0.02 SAPSIIscore 68(60-81) 68(61-82) 67(58-81) 0.55 AdmissionSOFAscore 9(6-12) 7(5-10) 11(8-13) <0.001 Admissiontemperature(°C) 35.4(34.7-36.6) 35.8(34.8-36.5) 35.3(34.7-36.9) 0.65 Therapeutichypothermia 152(89) 65(94) 87(81) 0.02 Post-resuscitationshock 131(74) 49(71) 82(76) 0.4 Dataareexpressedasmedian(withinterquartilerange)orabsolutevalue(%).Statisticalanalysisisperformedbetweensurvivorsandnon-survivors.SAPSII, SimplifiedAcutePhysiologyScoreII;SOFA,SequentialOrganFailureAssessment. response [2]. During the ‘no-flow’ phase ofCA, reduced duringearlyreperfusionandsubsidedrapidly,suggesting oxygensupplyleadsquicklytocellulardamage.Reperfu- that oxidant injury contributes widely to the lesions sion(’low-flow’phaseofCA),generatesaburstofradical observedafterCA[21,22].Inparticular,theoxidativestress oxygenspeciesproduction[3,16-18].Anumberofanimal statusduringCAmayinactivatemyocardialenzymesand studies have explored the role of radical oxygen species therebycauseischemicderangementsofmyocardialmeta- inorgandamageafterCA[19,20].Otherstudiesrevealed bolism. Similar features in humans were only recently that oxidative stress increased quickly after CA, peaked shown in a study in which plasma of out-of-hospital CA Figure1Serumthioredoxin(TRX)levelsonadmission,then1,2and3daysaftercardiacarrest,accordingtotheICUsurvival.White boxesrepresentICUsurvivors,greyboxesrepresentnon-survivorpatients.Themedianisshownbythehorizontallinewithinthebox.The valuesbetweenthelowerandupperquartiles(25thto75thcentiles)arewithinthebox. Mongardonetal.CriticalCare2013,17:R18 Page5of10 http://ccforum.com/content/17/1/R18 Figure2Receiver-operatedcharacteristic(ROC)curvescomparingtheabilityofthioredoxin(TRX)concentrationstopredictICUdeath atadmission,day1,day2andday3. Figure3Receiver-operatedcharacteristic(ROC)curvedeterminingtheabilityofthioredoxin(TRX)concentrationtopredictdeath within24hours. Mongardonetal.CriticalCare2013,17:R18 Page6of10 http://ccforum.com/content/17/1/R18 Table 2Plasmaconcentrations ofthiol, advancedoxidation proteinproduct (AOPP),C-reactive protein (CRP)and procalcitonin (PCT)according to the outcome. Survival Earlydeath Latedeath P n=69 (<24h) (>24h) n=17 n=90 Thiols(μmol/L) Admission 275(223-316) 251(193-358) 247(193-299) 0.31 Day1 310(239-358) 299(219-360) 0.97 Day2 272(221-319) 267(228-331) 0.64 Day3 240(191-273) 244(210-292) 0.23 AOPP(μmol/L) Admission 36.8(22.2-64.7) 42(25.3-78.6) 40.4(21.7-59.5) 0.87 Day1 27.9(14.7-54.1) 37(23.4-60.4) 0.11 Day2 32.4(19.9-65.8) 36.5(25.8-62.1) 0.43 Day3 28.4(22.3-48) 28.9(28.9-58.6) 0.98 CRP(mg/mL) Admission 2.15(1-6.5) 4.6(1-28.9) 3.95(1.3-32.7) 0.05 Day1 42.1(18-1-79.6) 66.2(19.9-135.8) 0.02 Day2 137.4(94.9-180) 158(84-198) 0.34 Day3 176(102-199) 170(79.9-217) 0.94 PCT(ng/mL) Admission 0.18(0.1-0.67) 0.55(0.23-2.2) 0.66(0.18-3.74) 0.0004 Day1 1(0.25-6.04) 6.38(1.18-29.7) 0.0001 Day2 0.82(0.22-4.83) 4.54(1.28-29.2) 0.0001 Day3 0.96(0.28-3.45) 5.8(1.08-19.6) 0.0002 Dataareexpressedasmedian,withinterquartilerange.Statisticalanalysisisperformedbetweensurvivorsandnon-survivors. survivors induced acute and major endothelial toxicity, in patients with acute lung injury [10] and up to 161.6 attributabletoanacutepro-oxidantstateoccurringwithin ng/mLinpatientswithsepsis[14]aresimilartothelevels the cells, as shown by a significant decrease of the main andmagnitudeofincreasewefoundinpatientsfollowing antioxidant defences. Another striking finding was that CA. TRX was also found to be elevated after cardiopul- plasmatoxicitylastingformorethan3daysafterCA[23]. monary bypass or heart failure, two clinical situations With respect to the inflammatory response associated thatcombine greatinflammationandcirculatory distur- withCA,awidepanelofproteinsandbiomarkersinvesti- bances [27,28]. Moreover, as has been previously gated in several animal models and human cohorts sug- reported for patients with sepsis [14] or meningococcal gests that a major inflammatory syndrome occurs after septicshock[11],wefoundthatTRXlevelsweresignifi- CA[2,24,25].Consequently,post-cardiacarrestsyndrome cantly higher in non-survivors than in survivors, even if wasdefinedasa‘sepsis-likesyndrome’,withclinical,bio- ability to predict ICU deathwas not robust. Inaddition, chemicalandhematologicalfeaturesthatareverysimilar patients dying within 24 hours exhibited the highest to those observed during severe sepsis, and increased levels of TRX, with admission concentration carrying a levelsofpro-andanti-inflammatorycytokinescomparable verygoodabilitytopredictearlydeath. to the variations described during septic shock [24,26]. Ourfindingssuggestthatpatientssufferfrommajoroxi- Moreover,disseminatedvascularendothelial damagealso dativestressandinflammationduringpost-cardiacarrest suggests that ischemia-reperfusion associated with CA syndrome, which cannot be counteracted by increased evolves toward systemic inflammation with overproduc- TRX production. Others have suggested that prolonged tionofcytokines,complementactivation,synthesisofara- oxidative stress in patients with coronary risk factors chidonic acid metabolites, expression of leukocyte wastestheserumantioxidantpoolsuchasvitaminCand adhesion molecules and activation and chemotaxis of thatserumTRXisrecruitedtocompensate[29].Thatour polymorphonuclear neutrophils contributing to the data show highest levels associated with worse outcome inflammatoryresponse[2]. followingCAisperhapssuggestiveoftheseverityofoxi- TRXconcentrationsinhealthyvolunteersweresimilar dativestressassociatedwiththecondition.Thesefindings inourstudytothosepreviouslyreportedbyothers(15to confirmandbroadenthe data ofpost-cardiac arrest syn- 25 ng/mL). Also, increased levels of TRX of 36.1 ng/mL drome pathophysiology, supporting the hypothesis that Mongardonetal.CriticalCare2013,17:R18 Page7of10 http://ccforum.com/content/17/1/R18 oxidativestressandinflammatoryinsultsaremuchmore biologicaldisordersoccurringafterCAandpost-cardiac markedinthemostseverepatientsandcontributelargely arrestsyndrome.TRXiselevatedonadmission, whereas to the high initial mortality. Likewise, when focusing on vasoplegia and myocardial dysfunction typically begin a thecauseofCA,cardiacetiologieshadlowerTRXlevels. fewhoursafterCA.Inthefuture,utilizingbiomarkersof This is in line with the overall better prognosis of CA of inflammation and oxidative stress might allow tailoring coronaryorigin[30]. therapeuticinterventionsthatmodulateinflammationor Whenfocusingondiseaseseverity,TRXconcentrations oxidative stress suchashighvolume hemofiltration[41] werecorrelatedtoadmissionarteriallactatelevels,abiolo- orsteroidsadministration[42]. gicalparameterthatisconstantlyassociatedwithunfavor- Besides its role of biomarker, TRX could be a future able outcome [31]. We also found a strong association therapeutic target. Hofer et al. demonstrated, in an betweenlow-flow duration and TRXlevels, whereas this experimental model of cecal ligature and puncture, that was not observed with the no-flow duration. This illus- neutralization of endogenous TRX was deleterious for trates the pathophysiology of the ischemia reperfusion septicmicesurvival,whereastreatmentwithrecombinant injury, with a major reactive oxygen species production TRX markedly enhanced theirsurvival [14]. To date, no duringthereperfusionphase[16,17,32].Thisisalsocon- humandataofsuchprotectiveeffectsofTRXisavailable. sistent with the well-knownobservationthat theseverity However, major hope arose in the field of resuscitation ofthepost-cardiacarrestsyndromeismuchmoredriven after the use of coenzyme Q10, a mitochondrial enzyme bythelow-flowduration[33].Finally,theabsenceofcor- playing a key role in antioxidant defense. In 49 patients relation with SAPS II, by contrast with association with experiencingCA,exogenousadministrationofthisanti- SOFA score, could be explained by the fact that SOFA oxidant improved both survival and neurological out- score describes strictly organ failures [34]. Conversely, come [43]. Further investigations are required to SAPSIIscoretakesintoaccountnotonlymedicalcondi- determinetheplaceofTRXmodulationinthearmamen- tion,butalsounderlyingcomorbidities[35]. tariumofcriticalcaretherapeutics. Perhaps, surprisingly, we observed that TRX levels Although these data suggest that TRX could reflect a decreasedwithinofshortrangeoftime.Asinflammatory responsetoinflammation and oxidative stress, the func- andpro-oxidantstatesareknowntopersistafterCA,this tional consequences of high levels of TRX are not com- findingmightsuggestthatTRXhalf-lifeisrelativelyshort, pletely understood. The potential biological significance orthatreleaseisminimizedaftertheinitialinsult,orthat of TRX upregulation can be inferred from experimental otherserumantioxidantshavebeenreplenished.Thiscon- studies,whichsupporta roleasanantioxidantandanti- trasts with sustained levels of other biomarkers such as inflammatoryprotein,throughmodulationofbothheme PCT,whichremainelevated3daysafterCA[4].Thedif- oxygenase-1 and NADPH oxidase-mediated generation ferenceinkineticprofileisintriguingandwarrantsfurther ofsuperoxideanion.ExtracellularTRXhasbeenreported investigation. to reduce interleukin 1-beta expression by monocyte- The negative correlation between plasma TRX levels macrophagesininflammatoryconditions[7].Inaddition, andarterialpO2atadmissionthatwefoundinourstudy circulating TRX suppresses neutrophil chemotaxis [44]. advocatesagainstaroleofhyperoxiaintheonset ofoxi- Morerecently,ithasbeensuggestedthattheanti-inflam- dative stress. There is a great controversy surrounding matory mechanisms of TRX could be mediated, at least hyperoxiaafterCAresuscitation,withsomeexperimental inpart,bymigrationinhibitoryfactor(MIF)downregula- data suggesting that hyperoxia might increase oxidative tion [45]. However, in septic conditions, TRX and MIF stress. While animal models were inconclusive [36], a plasma levels showed a strong correlation, suggesting humanstudysuggestedthathyperoxiawasindependently that pro- and anti-inflammatory agents are balanced to associated with in-hospital mortality, as compared with maintainhomeostasis[46]. hypoxemiaornormoxia[37].However,thelatterfinding Inthepresentstudy,weconfirmthelimitedinterestof wasrefutedbybothastudy,inwhichthisassociationdid AOPP measurement and thiol content determination in notappearinalargecohort,withadjustmentonseverity acute setting, at least after CA, despite their place in scores [36] and also our findings in the current work. experimentalconditions[5,6].Onthecontrary,highCRP Nevertheless, further studies are required to elucidate andPCTlevelsareconsistentwithpreviousfindingssug- thishottopic[38,39]. gestingthe overwhelming impactof systemic inflamma- TRX reflects both inflammation and oxidative stress, tion[4].Overall,theseresultsenhance thevalueofTRX two major determinants of severity of post-cardiac arrest afterCA. syndrome and could be considered as a potential marker Despitethelargenumberofpost-CApatientsenrolled, of the global insult. However, the clinical utility of TRX some limitations of this study need consideration. First, has to be further established [40], as does the mechanis- we considered a retrospective single-institution cohort. tic explanation linking increased TRX levels with the However, all analyzeddata were prospectively collected, Mongardonetal.CriticalCare2013,17:R18 Page8of10 http://ccforum.com/content/17/1/R18 and medical management was homogeneous. Second, (cid:129) Cardiac arrest with cardiac etiology exhibited lower this is a merely observational study, allowing only asso- levels of TRX than in cases of extra-cardiac cause. ciationratherthancausationconclusions.Third,theuti- (cid:129) Admission TRX levels were significantly correlated lity of TRX to predict death was evaluated as a single with other pertinent severity markers, like ‘low-flow’ parameter,without combination ofTRXlevel to clinical duration, SOFA score, and arterial lactate concen- or biological data that may have improved the overall tration. prognosisvalue. Fourth,measurementofotheroxidative (cid:129) No correlation was found between TRX levels and stressparameters,likeMIFormanganesesuperoxidedis- admission arterial pO2, arguing against a potential mutase (MnSOD), or main inflammatory cytokines role of hyperoxia after cardiac arrest. would have provided further mechanistic tracks. Simi- larly, determination of the TRX interacting protein Abbreviations (TXNIP) could give valuable data to help explain the AOPP:advancedoxidationproteinproducts;AUC:areaunderthecurve;CA: TRXkineticsafterCA.However,TXNIPisanintracellu- cardiacarrest;CRP:C-reactiveprotein;ICU:intensivecareunit;kDa: lar protein that cannot be routinely measured in serum kiloDaltons;MIF:migrationinhibitoryfactor;MnSOD:manganesesuperoxide dismutase;PCT:procalcitonin;ROC:receiver-operatedcharacteristic;SAPSII: samples.Fifth,CAhastheparticularityofexhibitingtwo SimplifiedAcutePhysiologyScoreII;SOFA:SequentialOrganFailure maincausesofICUdeath,thatis,shockandneurological Assessment;TRX:thioredoxin;TXNIP:TRXinteractingprotein. damage withsubsequent care withdrawal. As inflamma- Authors’contributions tion and oxidative stress are expected to be greater in NMo,DBandACdesignedthestudy.NMo,VLandSPextractedthedata. case of shock, subanalysis focused on this last group. DBperformedthebiochemicalanalysis.VLperformedthestatisticalanalysis. Finally,thevastmajorityofpatientsunderwenttherapeu- ABG,SP,NMa,JC,FP,JDCandJPMcontributedtotheconductofstudyand dataanalysis.NMoandACwrotethemanuscript.Alltheauthorsreadand tic hypothermia. If the relationship between inflamma- approvedthefinalversionofthemanuscript. tory cytokines or biomarkers and effect of therapeutic hypothermia is controversial [4,25], the influence of Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. hypothermia on TRX is as yet, unknown. As the vast majorityofourpatientsweretreatedbyhypothermia,we Acknowledgements couldnotperformameaningfulanalysisoftheimpactof WeareindebtedtoTimothyWEvans,MDFRCP,forcriticalreadingofthe manuscript. temperature on TRX levels. Similarly, there is no data about clearance of TRX during renal replacement ther- Authordetails apy,whichiswidely appliedinpost-cardiac arrestsurvi- 1MedicalIntensiveCareUnit,CochinHospital,HôpitauxUniversitairesParis Centre,AssistancePubliquedesHôpitauxdeParis,27rueduFaubourg vors. To note, we report a high proportion of patients Saint-Jacques,75014Paris,France.2UniversitéParisDescartes,SorbonneParis experiencing post-resuscitation shock. This is related to Cité,FacultédeMédecine,15ruedel’EcoledeMédecine,75006Paris, the study design, including all consecutive patients and France.3DepartmentofBiochemistry,CochinHospital,Hôpitaux UniversitairesParisCentre,AssistancePubliquedesHôpitauxdeParis,27rue in particular those dying within 24 hours. These most duFaubourgSaint-Jacques,75014Paris,France.4UnitofCriticalCare, severe patients are generally excluded from clinical stu- RespiratoryScience,NationalHeartandLungInstituteDivision,Facultyof dies. Nonetheless, it is likely to be the group of patients Medicine,ImperialCollegeLondon,DovehouseStreet,LondonSW36LY,UK. 5GeneralIntensiveCareUnit,EstaingHospital,1placeLucieAubrac,63000 ofthemostsignificantclinicalinterest. Clermont-Ferrand,France.6InstitutCochin,INSERMU1016,CNRSUMR8104, 22rueMéchain,75014Paris,France.7INSERMU970,ParisCardiovascular ResearchCenter(PARCC),EuropeanGeorgesPompidouHospital,56rue Conclusions Leblanc,75015Paris,France. InpatientssuccessfullyresuscitatedfromCA,serumTRX Received:25September2012 Revised:30November2012 levelsmeasuredduringthefirst3dayswerehigherinICU Accepted:24January2013 Published:29January2013 non-survivors, and were dramatically greater in patients dying early from circulatory failure. Besides assessing References severityandoutcome,suchabiomarkeroffersinteresting 1. LaverS,FarrowC,TurnerD,NolanJ:Modeofdeathafteradmissiontoan intensivecareunitfollowingcardiacarrest.IntensiveCareMed2004, perspectives in the comprehension and management of 30:2126-2128. post-cardiacarrestsyndrome. 2. MongardonN,DumasF,RicomeS,GrimaldiD,HissemT,PeneF,CariouA: Postcardiacarrestsyndrome:fromimmediateresuscitationtolong-term outcome.AnnIntensiveCare2011,1:45. Key messages 3. EltzschigHK,EckleT:Ischemiaandreperfusion-frommechanismto (cid:129) Thioredoxin (TRX), a surrogate global marker of translation.NatMed2011,17:1391-1401. 4. MongardonN,LemialeV,PerbetS,DumasF,LegrielS,GuerinS, inflammation and oxidative stress, was largely CharpentierJ,ChicheJD,MiraJP,CariouA:Valueofprocalcitoninfor increasedduringpost-cardiacarrestsyndrome. diagnosisofearlyonsetpneumoniainhypothermia-treatedcardiac (cid:129) The highest values were found in the most severe arrestpatients.IntensiveCareMed2010,36:92-99. 5. LentiniP,deCalM,CruzD,ChronopoulosA,SoniS,NalessoF,ZanellaM, patients. GarzottoF,BrendolanA,PiccinniP,RoncoC:Theroleofadvanced Mongardonetal.CriticalCare2013,17:R18 Page9of10 http://ccforum.com/content/17/1/R18 oxidationproteinproductsinintensivecareunitpatientswithacute Successfulcardiopulmonaryresuscitationaftercardiacarrestasa kidneyinjury.JCritCare2010,25:605-609. “sepsis-like”syndrome.Circulation2002,106:562-568. 6. WinterbournCC,BussIH,ChanTP,PlankLD,ClarkMA,WindsorJA:Protein 25. CallawayCW,RittenbergerJC,LogueES,McMichaelMJ:Hypothermiaafter carbonylmeasurementsshowevidenceofearlyoxidativestressin cardiacarrestdoesnotalterseruminflammatorymarkers.CritCareMed criticallyillpatients.CritCareMed2000,28:143-149. 2008,36:2607-2612. 7. Burke-GaffneyA,CallisterME,NakamuraH:Thioredoxin:friendorfoein 26. AndradesME,MorinaA,SpasicS,SpasojevicI:Bench-to-bedsidereview: humandisease?TrendsPharmacolSci2005,26:398-404. sepsis-fromtheredoxpointofview.CritCare2011,15:230. 8. Burke-GaffneyA,EvansTW,QuinlanGJ:Thioredoxininsepsis:Justanother 27. KishimotoC,ShiojiK,NakamuraH,NakayamaY,YodoiJ,SasayamaS: biomarkeroraplausibletherapeutictarget?CritCareMed2009, Serumthioredoxin(TRX)levelsinpatientswithheartfailure.JpnCircJ 37:2304-2305. 2001,65:491-494. 9. AbdiuA,NakamuraH,SahafB,YodoiJ,HolmgrenA,RosenA:Thioredoxin 28. NakamuraH,VaageJ,ValenG,PadillaCA,BjornstedtM,HolmgrenA: bloodlevelincreasesaftersevereburninjury.AntioxidRedoxSignal2000, Measurementsofplasmaglutaredoxinandthioredoxininhealthy 2:707-716. volunteersandduringopen-heartsurgery.FreeRadicBiolMed1998, 10. CallisterME,Burke-GaffneyA,QuinlanGJ,NicholsonAG,FlorioR, 24:1176-1186. NakamuraH,YodoiJ,EvansTW:Extracellularthioredoxinlevelsare 29. HoshinoY,ShiojiK,NakamuraH,MasutaniH,YodoiJ:Fromoxygen increasedinpatientswithacutelunginjury.Thorax2006,61:521-527. sensingtoheartfailure:roleofthioredoxin.AntioxidRedoxSignal2007, 11. CallisterME,Burke-GaffneyA,QuinlanGJ,BettsH,NadelS,EvansTW: 9:689-699. Persistentlylowplasmathioredoxinisassociatedwithmeningococcal 30. DumasF,CariouA,Manzo-SilbermanS,GrimaldiD,VivienB,RosencherJ, septicshockinchildren.IntensiveCareMed2007,33:364-367. EmpanaJP,CarliP,MiraJP,JouvenX,SpauldingC:Immediate 12. JekellA,HossainA,AlehagenU,DahlstromU,RosenA:Elevated percutaneouscoronaryinterventionisassociatedwithbettersurvival circulatinglevelsofthioredoxinandstressinchronicheartfailure.Eur afterout-of-hospitalcardiacarrest:insightsfromthePROCAT(Parisian JHeartFail2004,6:883-890. RegionOutofhospitalCardiacArresT)registry.CircCardiovascInterv 13. LeaverSK,MacCallumNS,PingleV,HackingMB,QuinlanGJ,EvansTW, 2010,3:200-207. Burke-GaffneyA:Increasedplasmathioredoxinlevelsinpatientswith 31. DumasF,GrimaldiD,ZuberB,FichetJ,CharpentierJ,PeneF,VivienB, sepsis:positiveassociationwithmacrophagemigrationinhibitoryfactor. VarenneO,CarliP,JouvenX,EmpanaJP,CariouA:Ishypothermiaafter IntensiveCareMed2010,36:336-341. cardiacarresteffectiveinbothshockableandnonshockablepatients?: 14. HoferS,RosenhagenC,NakamuraH,YodoiJ,BoppC,ZimmermannJB, insightsfromalargeregistry.Circulation2011,123:877-886. GoebelM,SchemmerP,HoffmannK,Schulze-OsthoffK,BreitkreutzR, 32. BeckerLB:Newconceptsinreactiveoxygenspeciesandcardiovascular WeigandMA:Thioredoxininhumanandexperimentalsepsis.CritCare reperfusionphysiology.CardiovascRes2004,61:461-470. Med2009,37:2155-2159. 33. LaurentI,MonchiM,ChicheJD,JolyLM,SpauldingC,BourgeoisB, 15. JacobsI,NadkarniV,BahrJ,BergRA,BilliJE,BossaertL,CassanP, CariouA,RozenbergA,CarliP,WeberS,DhainautJF:Reversible CoovadiaA,D’EsteK,FinnJ,HalperinH,HandleyA,HerlitzJ,HickeyR, myocardialdysfunctioninsurvivorsofout-of-hospitalcardiacarrest. IdrisA,KloeckW,LarkinGL,ManciniME,MasonP,MearsG,MonsieursK, JAmCollCardiol2002,40:2110-2116. MontgomeryW,MorleyP,NicholG,NolanJ,OkadaK,PerlmanJ,ShusterM, 34. VincentJL,MorenoR,TakalaJ,WillattsS,DeMendoncaA,BruiningH, SteenPA,SterzF,TibballsJ,TimermanS,TruittT,ZidemanD:Cardiac ReinhartCK,SuterPM,ThijsLG:TheSOFA(Sepsis-relatedOrganFailure arrestandcardiopulmonaryresuscitationoutcomereports:updateand Assessment)scoretodescribeorgandysfunction/failure.Onbehalfof simplificationoftheUtsteintemplatesforresuscitationregistries.A theWorkingGrouponSepsis-RelatedProblemsoftheEuropeanSociety statementforhealthcareprofessionalsfromataskforceofthe ofIntensiveCareMedicine.IntensiveCareMed1996,22:707-710. internationalliaisoncommitteeonresuscitation(AmericanHeart 35. LeGallJR,LemeshowS,SaulnierF:AnewSimplifiedAcutePhysiology Association,EuropeanResuscitationCouncil,AustralianResuscitation Score(SAPSII)basedonaEuropean/NorthAmericanmulticenterstudy. Council,NewZealandResuscitationCouncil,HeartandStroke JAMA1993,270:2957-2963. FoundationofCanada,InterAmericanHeartFoundation,Resuscitation 36. BellomoR,BaileyM,EastwoodGM,NicholA,PilcherD,HartGK,ReadeMC, CouncilofSouthernAfrica).Resuscitation2004,63:233-249. EgiM,CooperDJ:Arterialhyperoxiaandin-hospitalmortalityafter 16. AmbrosioG,TrittoI:Reperfusioninjury:experimentalevidenceand resuscitationfromcardiacarrest.CritCare2011,15:R90. clinicalimplications.AmHeartJ1999,138:S69-75. 37. KilgannonJH,JonesAE,ShapiroNI,AngelosMG,MilcarekB,HunterK, 17. HessML,MansonNH:Molecularoxygen:friendandfoe.Theroleofthe ParrilloJE,TrzeciakS:Associationbetweenarterialhyperoxiafollowing oxygenfreeradicalsysteminthecalciumparadox,theoxygenparadox resuscitationfromcardiacarrestandin-hospitalmortality.JAMA2010, andischemia/reperfusioninjury.JMolCellCardiol1984,16:969-985. 303:2165-2171. 18. VandenHoekTL,ShaoZ,LiC,ZakR,SchumackerPT,BeckerLB: 38. HoedemaekersCW,vanderHoevenJG:Hyperoxiaaftercardiacarrest Reperfusioninjuryoncardiacmyocytesaftersimulatedischemia.Am maynotincreaseischemia-reperfusioninjury.CritCare2011,15:166. JPhysiol1996,270:H1334-1341. 39. IscoeS,BeasleyR,FisherJA:Supplementaryoxygenfornonhypoxemic 19. CerchiariEL,SclabassiRJ,SafarP,HoelTM:Effectsofcombinedsuperoxide patients:O2muchofagoodthing?CritCare2011,15:305. dismutaseanddeferoxamineonrecoveryofbrainstemauditoryevoked 40. ZhangH,DamasP,PreiserJC:Thelongwayofbiomarkers:frombench potentialsandEEGafterasphyxialcardiacarrestindogs.Resuscitation tobedside.IntensiveCareMed2010,36:565-566. 1990,19:25-40. 41. LaurentI,AdrieC,VinsonneauC,CariouA,ChicheJD,OhanessianA, 20. KompalaSD,BabbsCF,BlahoKE:Effectofdeferoxamineonlatedeaths SpauldingC,CarliP,DhainautJF,MonchiM:High-volumehemofiltration followingCPRinrats.AnnEmergMed1986,15:405-407. afterout-of-hospitalcardiacarrest:arandomizedstudy.JAmCollCardiol 21. BasuS,NozariA,LiuXL,RubertssonS,WiklundL:Developmentofanovel 2005,46:432-437. biomarkeroffreeradicaldamageinreperfusioninjuryaftercardiac 42. MentzelopoulosSD,ZakynthinosSG,TzoufiM,KatsiosN,PapastylianouA, arrest.FEBSLett2000,470:1-6. GkisiotiS,StathopoulosA,KollintzaA,StamatakiE,RoussosC:Vasopressin, 22. IdrisAH,RobertsLJ,CarusoL,ShowstarkM,LayonAJ,BeckerLB,Vanden epinephrine,andcorticosteroidsforin-hospitalcardiacarrest.ArchIntern HoekT,GabrielliA:Oxidantinjuryoccursrapidlyaftercardiacarrest, Med2009,169:15-24. cardiopulmonaryresuscitation,andreperfusion.CritCareMed2005, 43. DamianMS,EllenbergD,GildemeisterR,LauermannJ,SimonisG,SauterW, 33:2043-2048. GeorgiC:CoenzymeQ10combinedwithmildhypothermiaaftercardiac 23. HuetO,DupicL,BatteuxF,MatarC,ContiM,ChereauC,LemialeV, arrest:apreliminarystudy.Circulation2004,110:3011-3016. HarroisA,MiraJP,VicautE,CariouA,DuranteauJ:Postresuscitation 44. NakamuraH,HerzenbergLA,BaiJ,ArayaS,KondoN,NishinakaY,YodoiJ: syndrome:potentialroleofhydroxylradical-inducedendothelialcell Circulatingthioredoxinsuppresseslipopolysaccharide-induced damage.CritCareMed2011,39:1712-1720. neutrophilchemotaxis.ProcNatlAcadSciUSA2001,98:15143-15148. 24. AdrieC,Adib-ConquyM,LaurentI,MonchiM,VinsonneauC,FittingC, 45. TamakiH,NakamuraH,NishioA,NakaseH,UenoS,UzaN,KidoM,InoueS, FraisseF,Dinh-XuanAT,CarliP,SpauldingC,DhainautJF,CavaillonJM: MikamiS,AsadaM,KiriyaK,KitamuraH,OhashiS,FukuiT,KawasakiK, Mongardonetal.CriticalCare2013,17:R18 Page10of10 http://ccforum.com/content/17/1/R18 MatsuuraM,IshiiY,OkazakiK,YodoiJ,ChibaT:Humanthioredoxin-1 amelioratesexperimentalmurinecolitisinassociationwithsuppressed macrophageinhibitoryfactorproduction.Gastroenterology2006, 131:1110-1121. 46. BrennerT,RosenhagenC,SteppanJ,LichtensternC,WeitzJ,BrucknerT, MartinEO,HoffmannU,WeigandMA,HoferS:Redoxresponsesin patientswithsepsis:highcorrelationofthioredoxin-1andmacrophage migrationinhibitoryfactorplasmalevels.MediatorsInflamm2011, 2010:985614. doi:10.1186/cc12492 Citethisarticleas:Mongardonetal.:Plasmathioredoxinlevelsduring post-cardiacarrestsyndrome:relationshipwithseverityandoutcome. CriticalCare201317:R18. 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Plasma thioredoxin levels during post-cardiac arrest syndrome: relationship with severity and outcome.

Similar Plasma thioredoxin levels during post-cardiac arrest syndrome: relationship with severity and outcome.