以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件1以病程分期為依據(jù)之兒童腸病毒重癥治療

TheStageBasedTherapyof

CriticallyIllChildrenwithEV71Infection

林口長庚兒童醫(yī)院兒童加護科 夏紹軒吳昌騰兒童心臟科 黃茂盛鍾宏濤兒童神經(jīng)科 林光麟王傳育兒童呼吸胸腔科 黃健燊兒童感染科 張鑾英黃玉成邱政洵林奏延以病程分期為依據(jù)之兒童腸病毒重癥治療

TheSta2ACardiopulmonarydisasterrequiringmultidisciplinarytreatmentACardiopulmonarydisasterre3I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks4Outbreaks(1)民國八十七年五月初

一個一歲兩個月大的小女孩被帶到門診，主訴是feverwithoralulcersandvesiclesonhands,feetandknees.母親對於小朋友的高燒不退、躁動不安、食慾減退、入睡困難、無力站立非常擔(dān)心。Outbreaks(1)民國八十七年五月初5Outbreaks(2)醫(yī)生說：這是典型手足口病癥狀，只要吃一些退燒藥，多休息、多喝水就好了。第二天，小女孩被帶回急診，已經(jīng)發(fā)生意識不清、發(fā)紺等癥狀，當(dāng)時，急診醫(yī)師為她插上氣管內(nèi)管，大量粉紅色泡沫狀液體從氣管內(nèi)冒出。Outbreaks(2)醫(yī)生說：這是典型手足口病癥狀，只要6Outbreaks(3)小女孩被送到PICU.發(fā)生心肺衰竭，CPR無效後，被宣布死亡。此後一個月，共有七名兒童因同一癥狀死在本院，醫(yī)師立即通報疾病管制局，並發(fā)現(xiàn)幾乎全臺灣各大醫(yī)學(xué)中心都有類似案例。Outbreaks(3)小女孩被送到PICU.發(fā)生心肺7Enetrovirustype71

腸病毒七十一型分別在糞便、咽喉、及腦脊髓液檢體中被培養(yǎng)出來。

Enetrovirustype71腸病毒七十一型分別8EV71OutbreaksEnterovirustype71wasfirstlyisolatedfromthestoolofaninfantwithencephalitisinUSin19691975,44/705werekilledinBulgaria1997,30werekilledinMalaysia1998,78werekilledinTaiwan1999,8werekilledinHong-KongEV71OutbreaksEnterovirustyp91998腸病毒流行之統(tǒng)計估計約一百萬至兩百萬人口被感染？！查有實據(jù)者129106人為EV71感染405人為重癥78人死亡80%死於肺水腫與肺出血1998腸病毒流行之統(tǒng)計估計約一百萬至兩百萬人口被感染？！10腸病毒的傳染途徑飛沫傳染唾液與呼吸道分泌物在痊癒之後2-3weeks仍可分離出EV71病毒糞口傳染糞便在痊癒之後6-8weeks仍可分離出EV71病毒病毒離開人體可存活8小時左右腸病毒的傳染途徑飛沫傳染11I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks12

EV71(174) non71EV(241)UncomlicatedcasesHFMD/herpanginaViralexanthemFebrileillnessOthersComlicatedcasesMeningitisEncephalitis/myelitisPolio-likesyndromePulmonaryOedemaFatalcasesSurvivorswithsevereneurologicalsequela119(68%)108(63%)2(1.1%)7(4%)2(1.1%)55(32%)13(7.5%)26(14.5%)#4(2.3%)12(6.9%)#14(8.0%)#5(2.8%)#187(78%)105(43%)5(2%)18(7.4%)59(24%)54(22%)44(18%)5(2.1%)0(0%)0(0%)0(0%)0(0%)#:p<0.001,Changetal. EV71(174) non71EV(241)Unc13Table1:Demographicandclinicalcharacteristicsof154patients

GroupPulmonaryCNScasesUncomplicated oedema(N=11)(N=38)cases(N=105)Sex(M/F) 5/6 24/14 56/49Age(months) 20(21) 29(21) 30(33)Fever 11(100%) 38(100%)* 93(89%)PeakBT(°C) 39.8(0.6)# 39.3(0.7) 39.1(0.8)WBC(109/L) 27.1(8.9)@

14.2(5.8) 13.4(4.5)Glucose 22.4(12.7)?

7.0(3.5)# 5.6(1.0)(mmol/L)CRP(mg/L) 13.9(14.3) 15.1(24.8) 16.6(27.6)Comparedcasesofpulmonaryedema/CNSinvolvementwithuncomplicatedcases,*:p=0.03;#:p=0.01;@:p=0.004;?:p=0.001.Changetal.Lancet354(9191):1682,1999Table1:Demographicandclinic14Table4:Riskfactorsassociatedwithpulmonaryoedema

Pulmonary CNScases OR PRiskFactors oedema(N=11) (N=38)

(95%CI)Glu>150 9(82%) 4(11%) 38(6-211) 0.001*Leukocytosis 9(82%) 12(32%) 9.7(2.9-34) 0.003#Upperlimb 4(36%) 4(11%) 4.9(2.6-9.2) 0.04weaknessLowerlimb 7(64%) 11(29%) 4.3(2.0-9.2) 0.04weaknessChangetal.Lancet354(9191):1682,1999Table4:Riskfactorsassociat15SkinandMucosaLesionsOralulcersdistributednotonsoftpalateonlyastypicalhand-footmouthdiseaseVesiclesonhandandfootweresmaller(pin-point)thantypicalHFMdiseaseSometimestheskinlesionconsistedofpetechiae-likeclustersSkinandMucosaLesionsOralul16以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件17以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件18以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件19以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件20PhasesBasedTherapyofCriticalEV-71Infection

腸病毒重癥之臨床分期第一期：上呼吸道感染─手足口病第二期：神經(jīng)癥狀─腦膜腦脊髓炎第三A期：高血壓—肺水腫出血─自主神經(jīng)失調(diào)第三B期：低血壓─心臟衰竭？心肌炎？SIRS?第四期：逐漸恢復(fù)─神經(jīng)後遺癥PhasesBasedTherapyofCritic21分期標(biāo)的Stage1:Oralulcer,skinrash,feverStage2:Neurologicalsymptoms myoclonicjerk,limbweakness,seizure,consciousnessdisturbanceStage3A:ElevatedBPStage3B:DecreasedBP,useofcatecholaminesStage4:Cessationofcatecholamines.分期標(biāo)的Stage1:Oralulcer,skin22ResultsWeobservedamajorityofpatients(58%14/24)presenteddifferentfiveclinicalphases.Twopatients

developedPE

withoutaHFMprodromeOne

patientdevelopedPEwithout

previous

CNS

involvementsignsIn

sixpatients,

hypertensionphases

werenotobservedThreepatients

didnotdevelop

hypotension

phenomenonResultsWeobservedamajority23TableASevereHypertensionCriteriabyAgeAgeGroupSystolic(mmHg)Diastolic(mmHg)NB＜7days106

8-20days110

Infants＜2yo11882Children3-5yo118846-9yo1308610-12yo1349013-15yo1449216-18yo15096ModifiedfromHycanetal..TaskForceonBloodPressurecontrolinChildren.Pediatrics79:1,1987.TableASevereHypertensionCr24TableB.NormalBloodPressurebyAgeAgeSystolic(mmHg)Diastolic(mmHg)Neonate60-9020-60Infant(6mo)87-10553-66Toddler(2yr)95-10553-662-7yo97-11257-717-15yo112-12866-80HazinskiMF:NursingCareoftheCriticallyIllChild,2nded.St.Louis,Mo:MosbyYearBook;1992TableB.NormalBloodPressure25第一期：手足口病持續(xù)約數(shù)天可能發(fā)高燒類手足口病Hand-Foot-Mouthdisease類皰疹性咽峽炎Herpangina大多數(shù)病人可自然痊癒，無後遺癥手足水泡較典型手足口病小〈約針尖大小〉高危險群可能向後期發(fā)展第一期：手足口病持續(xù)約數(shù)天26重癥病例之前趨癥狀及危險因子I重癥病例前趨癥狀四肢反射性抖動 (myoclonicjerk)

嘔吐嗜睡中樞神經(jīng)受侵犯之危險因子年齡小於三歲高燒超過39度燒超過3天嗜睡、抽筋、頭痛嘔吐高血糖(>150mg/dl)重癥病例之前趨癥狀及危險因子I重癥病例前趨癥狀中樞神經(jīng)受侵27重癥病例之前趨癥狀及危險因子II重癥病例中肺水腫之危險因子年齡小於三歲高血糖(>150mg/dl)

肢體無力白血球升高 重癥包含中樞神經(jīng)受侵犯及肺水腫重癥病例之前趨癥狀及危險因子II重癥病例中肺水腫之危險因子28第二期：腦膜腦炎持續(xù)數(shù)天包括睡眠易驚醒startling、手足抖動myoclonicjerk、肢體無力weakness可能嘔吐、嗜睡可能發(fā)生痙攣腦脊髓液可能有發(fā)炎跡象亦可能無到此仍可能自然痊癒，或許有後遺癥第二期：腦膜腦炎持續(xù)數(shù)天29第三A期：高血壓—肺水腫出血─自主神經(jīng)失調(diào)？持續(xù)約數(shù)小時至一天左右，民國八十七年肺水腫出血為最主要死因血壓上升為最早徵兆、高燒、心搏過快200/min以上、呼吸急促、出冷汗。高血糖(>200mg/dl)肺水腫、肺泡出血、血氧含量降低神經(jīng)癥狀持續(xù)惡化，昏迷指數(shù)降低、四肢更無力第三A期：高血壓—肺水腫出血─自主神經(jīng)失調(diào)？持續(xù)約數(shù)小時至一30以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件31以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件32LungsarecongestedRedbloodcellsarefoundinsmallairwaysandalveoli,LungsarecongestedRedbloodc33ParametersSequenceAroundPEParametersSequenceAroundPE34ParametersSequence(2)ParametersSequence(2)35第三B期：低血壓：心臟衰竭持續(xù)約二至七天心搏速率漸降但血壓可能更低肺水腫出血漸好轉(zhuǎn)但仍需呼吸器，自呼能力差血糖正?；窠?jīng)癥狀之變化：垂直眼震顫、斜視、肢體無力、抽筋…等，此期間腦灌流可能變差造成缺氧缺血性腦病變。第三B期：低血壓：心臟衰竭持續(xù)約二至七天36第四期：逐漸恢復(fù)持續(xù)？月？年心臟功能幾乎完全恢復(fù)肺功能可能不好但足堪負(fù)擔(dān)換氣，然而病人自呼、吞嚥功能不好有嚴(yán)重影響，所以仍需呼吸器支持。漸漸甦醒，神經(jīng)可能有嚴(yán)重後遺癥可能發(fā)生反覆性肺炎。第四期：逐漸恢復(fù)持續(xù)？月？年37I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks38PathophysiologyofPulmonaryOedemaStarling’sformulaFlow=K(Pc－Pis)－Π(Oncpl－Oncis)InterstitiumAlveolusLymphaticsPulmonarycapillaryPcPisKOncplOncisO2ΠPathophysiologyofPulmonaryO39HypothesesoftheMechanismofpulmonaryoedemaSIRS/ARDSNeurogenicpulmonaryedemaCardiogenic↑Capillarypermeability↑Systemic/pulmonaryvasculerresistenceLVsystolicdysfunctionLVdiastolicdysfunctionHypothesesoftheMechanismof40EvidenceSupportingSIRSGroupEncephalitiswithPulmonaryOedema(N=8)Encephalitis(N=8)Uncomplicated(N=170)NormalControl(N=21)P-value*WBC(109/L)28.3+7.615.5+6.812.3+4.7--0.0001CRP(mg/L)18.5+16.331.0+35.815.9+29.1--0.49Glucose(mg/dL)501+186165+117103+15--0.0001IL-1(pg/ml)48.4+85.24.9+10.11.6+0.91.8+1.00.006IL-6(pg/ml)947+12394.9+3.12.8+1.91.9+0.50.0001TNF-α(pg/ml))22.4+29.55.3+1.05.6+1.66.8+1.50.004Linetal.EvidenceSupportingSIRSGroupE41EvidencesRelatedtoNeurogenicPulmonaryOedemaCNSinvolvementpreceedspulmonaryoedemaIncreasedcortisollevelandclinicalevidencessuggestedanautonomicnervoussystemdysfunction(increasedsympathetictone)LackofstudyofpulmonarycapillarypermeabilitySystemicvascularresistencedoesnotincreasesignificantly.EvidencesRelatedtoNeurogeni42DiffuseinflammatorycellinfiltrationinCerebrum,midbrainandbrainstemPerivascularcuffingwasalsocommonDiffuseinflammatorycellinfi43以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件44CortisolLevelvs.VitalSignsCortisolLevelvs.VitalSigns45EvidencesRelatedtoCardiogenicIncreasedpulmonaryarterywedgepressure?EchorevealedsystolicanddiastolicdysfunctionHypertensionassociatedInappropriatetachycardiaassociatedIncreasedcardiacenzymesHowever,autopsyfindingsareagainstmyocarditisEvidencesRelatedtoCardioge46InitialSwan-GanzMonitorData#123Age1y5m10m1y6mPAWP(mmHg)262222CVP(mmHg)10813CI(L/min/m2)SI(mL/beat/m2)25.920.219.8SVRI(dyne-s-cm-5)129614391363PVRI(dyne-s-cm-5)7967168InitialSwan-GanzMonitorData47EchocardiographyEvidencesSystolicdysfunction:Theinitialejectionfraction:18-75%(mean±SE=51.5±3.6%)(n=18)Diastolicdysfunction:Mitralflowvelocities:E/A,DT,IVRT,E=peakvelocityoftheearlyfillingwave,A=peakvelocityofthelatefillingwaveduetoatrialcontraction,DT=decelerationtime,IVRT=isovolumicrelaxationtimeMitralannulusvelocities:E/E',E'=earlydiastolicannulusvelocity(therateofchangeinlong-axisdimensionandLVvolume)EchocardiographyEvidencesSyst48DiastolicFunction#12345ClinicalPE+HFPE+HFMildPEHTonlyHTonlyE/A3.20.862.94mergedDT(ms)48.1973.0954.6152.6IVRT(ms)54.2220.0844.860.24E/E'15.1114.769.7577.4CommentRestrictivephysiologyRestrictivephysiologyRelaxationimpairmentAdequatediastoleAdequatediastoleOutcomeDiedSeveresequelaMildsequelaRecovercompletelyRecovercompletelyPE:pulmonaryoedema,HF:heartfailure,HT:hypertensionDiastolicFunction#12345Clinic49CardiacEnzymesCKMB(normal<16U/L):

4-92U/L,mean±SE=31.17±7.73(n=12)TroponinI(normal<2ng/ml): 0.4-50ng/ml,mean±SE=21.92±4.36(n=17)CardiacEnzymesCKMB(normal<1650Grossly,theheartishypertrophicUndermicroscope,thereisnoinflammatorychangeGrossly,theheartishypertro51I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks52WhenPatientBecomesVeryCriticalNeurologicaldeterioratesGCS<9Apnea,chokeUnabletoprotectairwayParadoxicalrespirationPulmonaryoedema/hemorrhagedevelopsCardiovascularsystemmalfunctions:hypertension,tachycardia…WhenPatientBecomesVeryCrit53VirusSIRSCytokinesRVLVNeuromediator?ChangecapillarypermeabilityCatecholaminesDiastolicdysfunctionSystemicvascularresistence?Hypervolemia?SystolicfunctioncongestionVirusSIRSCytokinesRVLVNeuromed54VirusSIRSCytokinesRVLVNeuromediator?ChangedcapillarypermeabilityCatecholaminesDiastolicdysfunctionSystemicvascularresistence?Hypervolemia?SystolicfunctionIVIGdiureticsDobutamine,milrinone?vasodilatorVaccine?PPVcongestionSteroid??clonidineVirusSIRSCytokinesRVLVNeuromed55StageⅠ Hand,foot&mouthdisease

andtreatmentCharacterizedbyfever,oralulcerandskinrashSymptomatictreatmentAwarehighriskfactors: ?age<3y/o ?fever>39℃

?lethargic ?vomiting ?limbweakness,seizureincludingmyoclonicjerk ?hypertension?4. AdmitsuspiciouschildrenStageⅠ Hand,foot&mouthdise56StageⅡ CNSInvolvement

GeneralTreatment1.AdmittoPICUp.r.n.2.MonitorBP,HR,sugar,ABG,e–,comascale3.IntubatepatientandprovidemechanicalventilatorforGCS<9orsignificantIICP4.IVIG:dosage?5.Fluidrestriction:1/2-2/3maintenance,6.FurosemideforpatientswithhighCVP7.Invasivemonitorings:CVPABP?

StageⅡ CNSInvolvement

Genera57StageⅡ CNSInvolvement

SpecificTreatmentforCNSAnticonvulsantstocontrolseizureKeepheadinmidlinepositionwith15-30°tiltAggressivelycontrolbodytemperatureWatchIncreasedICPsignsandgiveMannitolorglycerolasneededSedatives?midazolam,morphineorpropofolConsultneurologistsMonitoring:GCS,

TCD,NIRS,ICP?,SjvO2?StageⅡ CNSInvolvement

Specif58StageⅢA:TreatmentRistrictpreload:Fluidrestriction,diureticsReduceafterloadcautiously?:BP,withnormalcardiaccontractility:vasodilatororβ-blocker: ?XNitroprusside? 0.5-4mcg/kg/min

?XEsmolol? 50-300mcg/kg/min

?Milrinone 0.25-0.75mcg/kg/min Sedatives?midazolam,morphineorpropofolAugmentmyocardiumcontractility

?Milrinone 0.25-0.75mcg/kg/min ?Dobutamine 5-20mcg/kg/minStageⅢA:TreatmentRistrictpr59StageⅢA:TreatmentMechanicallyVentilatedwithPEEP:6-8cmH2OConsiderHFOVwhenhypoxemiaandhemorrhagepersistdespitePEEP>8cmH2OorMAP>15cmH2OChangeIVFtoNSwhenglucose>200mg%,andshifttoD2.5HSwhenglucosedropsto≦200mg%AnticipatethedropofBPwhenhyperglycemiacorrects.Steroids?CentralAntisympathetics?StageⅢA:TreatmentMechanicall600 0.2 0.4 0.6 0.8 1.0 1.2 1.4Seconds302520151086Airwaypressure(cmH2O)oscillatorPPVMeanairwaypressurePIPPEEPΔP0 0.2 0.4 0.6 0.8 1.0 1.2 1.4S61以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件62StageⅢB Hypotension:treatmentMaintainadequatecerebralandvitalorganperfusionduringhypotension,optimizepreload,afterloadandmyocardiumcontractility ?Inotropes

dopamine 5-20mcg/kg/min

epinephrine 0.05-0.4(?)mcg/kg/minDuetointrinsiccatecholaminedepletion,HIGHinfusionrateofinotropesmaybeneededtokeepadequateBP2.ECMOandventricularassistdevice?StageⅢB Hypotension:treatme63StageⅢB Hypotension:treatmentWeanventilatorastolerated,switchbacktoconventionalventilatorwhenMAP≦15cmH2OCNSevaluation:↓cerebralperfusion?AddglucoseinIVFwhensugardropstoaboutunder200mg%StageⅢB Hypotension:treatme64StageⅣConvalescence--TreatmentWeanoffinotropesTracheostomyforventilatordependentpatients

ChestcareismandatorytoavoidaspirationpneumoniaSwallowingdisturbancetubefeeding(gastricorduodenum)RehabilitationRefertorespiratorycarecenterorhomecareStageⅣConvalescence--Trea65以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件66以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件67Outcome(2000-2001)Group1234Patients7737Age(mo)31.712.514.11.92.5ICUstay(days)6.93.1363.35.9Tracheostomy1631CPR6100Outcome**********Reposition6inRCC,1home1home,2inRCCAllhome,1inRCW*diedorvegetatestate,withdrawn,**moderatesequela,ventilatordependent,***mildtomoderatesequela,partialventilatordependent,****minimalsequela,RCC:respiratorycarecenter,RCW:respiratorycareward.Outcome(2000-2001)Group1234Pat68Gr1 2 3 4 p-valueCPReverAge(M)NeutralAbCSFWBCCKMB﹫TroponinI﹫EF%0﹫GCS0﹫IEResuscitateFluid(ml/kg)7/8

1/5 0 0 <0.0136.411.8

15.62.4 12.33.7 9.02.2 <0.058811.7 70.415.7 53.337.3 10217 0.17140.430.3 8432.1 9.33.3 16.26.4<0.0549.7

25.5 34.715.3 155 42.36.8 20.96.0 9.93.3 8.12.8 <0.00144.89.4 40.25.0 641.7 59.25.1<0.059.3±1.3 12.6±0.9 8.6±0.7 10.2±1.280.21

﹫thefirstvaluearoundadmissiontoPICUorER,IE(inotropeequivalent)=infusionrateofdopamine+dobutamine+100xepinephrne+10xmilrinonemcg/kg/min38.9±5.68 56.9±3.8

33.3±5.8 10.3±3.4 <0.00142.1±10.1 53.8±15.6 63.7±6.8 45±19.3 0.74Gr1 2 3 4 p-valueCPRever769Gr1 2 3 4 p-valueBP0﹫3Ahours3BhoursSugar0﹫Sugar>200(h)HR0﹫HR>180hP/F0﹫P/FminP/F<300h2.4±1.2

5.6±2.0 4.3±2.8 76.4±30.7 <0.0593.6±42.3 200.9±34.4 149.1±35.7 35.6±14.3 <0.052.6±0.8 5.1±1.4 2.8±1.5 5.7±2.4 0.521.3±13.6 38.7±8.2 10.1±3.2 10.4±3.1 0.2453.1±20.9 106.35±53.5 27.33±1.5 51.0±30.6 0.593.94.0 11814.2 1189.0 12410.2 <0.05373.158.9 281.647.5 22629.2 233.738.7 <0.05171.516.0 158.820.0 176.721.2 174.315.7 0.913433.2 329.061.9 167.431.3 203.627.9 <0.05﹫thefirstvaluearoundadmissiontoPICUorER,P/F=PaO2÷FiO2,*P=0.05583.7±18.1* 128.6±37.7 99±47.6

203±27.9

<0.05Gr1 2 3 4 p-valueBP0﹫2.70Conclusions(1)MostEV71infectedcriticallyillchildrenpresenteda

clinicalcoursewithclear-cutstages.Differentstagesmayneeddifferenttherapeuticconsiderationsandmonitoring.TheprognosisofEV71infectedchildrenisrelatedwiththe

damagesofrespiratory,cardiovascularandcerebralsystems.An

earlyintensivecare

maybethemajorcauseinthatpatientsof2000-2001hadabetteroutcomethanof1998

Conclusions(1)MostEV71infect71Conclusions(2)AlmostallpatientseverexperiencedCPRdiedeventually.ThemeandurationbeforeCPRoccurredis

7.1±2.4hours

whichistooshorttowaitforallriskfactorspresent.ECMOorLVADshouldbeconsidered

inthebeginning

forpatientswithevidenceofsevereheartinjurysuchas

Troponin>40,significantlycompromisedsystolic/diastolicfunctionandshock.Conclusions(2)Almostallpatie72Conclusion(3)ThefollowingactionsareimportantinmanagingtherespiratoryfailureonchildrenwithEV71infectionHospitalizechildrenwithriskyclinicalsigns.EarlyidentificationofthedevelopmentofpulmonaryoedemaandhemorrhageAnticipationofheartfailureandoptimizetheuseofinotropesPreventrecurrentpneumoniainconvalescentstage.Vaccinationmaybethewayouttoavoidrepeatedtragedieseveryyear.Conclusion(3)Thefollowingact73以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件74以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件75以病程分期為依據(jù)之兒童腸病毒重癥治療

TheStageBasedTherapyof

CriticallyIllChildrenwithEV71Infection

林口長庚兒童醫(yī)院兒童加護科 夏紹軒吳昌騰兒童心臟科 黃茂盛鍾宏濤兒童神經(jīng)科 林光麟王傳育兒童呼吸胸腔科 黃健燊兒童感染科 張鑾英黃玉成邱政洵林奏延以病程分期為依據(jù)之兒童腸病毒重癥治療

TheSta76ACardiopulmonarydisasterrequiringmultidisciplinarytreatmentACardiopulmonarydisasterre77I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks78Outbreaks(1)民國八十七年五月初

一個一歲兩個月大的小女孩被帶到門診，主訴是feverwithoralulcersandvesiclesonhands,feetandknees.母親對於小朋友的高燒不退、躁動不安、食慾減退、入睡困難、無力站立非常擔(dān)心。Outbreaks(1)民國八十七年五月初79Outbreaks(2)醫(yī)生說：這是典型手足口病癥狀，只要吃一些退燒藥，多休息、多喝水就好了。第二天，小女孩被帶回急診，已經(jīng)發(fā)生意識不清、發(fā)紺等癥狀，當(dāng)時，急診醫(yī)師為她插上氣管內(nèi)管，大量粉紅色泡沫狀液體從氣管內(nèi)冒出。Outbreaks(2)醫(yī)生說：這是典型手足口病癥狀，只要80Outbreaks(3)小女孩被送到PICU.發(fā)生心肺衰竭，CPR無效後，被宣布死亡。此後一個月，共有七名兒童因同一癥狀死在本院，醫(yī)師立即通報疾病管制局，並發(fā)現(xiàn)幾乎全臺灣各大醫(yī)學(xué)中心都有類似案例。Outbreaks(3)小女孩被送到PICU.發(fā)生心肺81Enetrovirustype71

腸病毒七十一型分別在糞便、咽喉、及腦脊髓液檢體中被培養(yǎng)出來。

Enetrovirustype71腸病毒七十一型分別82EV71OutbreaksEnterovirustype71wasfirstlyisolatedfromthestoolofaninfantwithencephalitisinUSin19691975,44/705werekilledinBulgaria1997,30werekilledinMalaysia1998,78werekilledinTaiwan1999,8werekilledinHong-KongEV71OutbreaksEnterovirustyp831998腸病毒流行之統(tǒng)計估計約一百萬至兩百萬人口被感染？！查有實據(jù)者129106人為EV71感染405人為重癥78人死亡80%死於肺水腫與肺出血1998腸病毒流行之統(tǒng)計估計約一百萬至兩百萬人口被感染？！84腸病毒的傳染途徑飛沫傳染唾液與呼吸道分泌物在痊癒之後2-3weeks仍可分離出EV71病毒糞口傳染糞便在痊癒之後6-8weeks仍可分離出EV71病毒病毒離開人體可存活8小時左右腸病毒的傳染途徑飛沫傳染85I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks86

EV71(174) non71EV(241)UncomlicatedcasesHFMD/herpanginaViralexanthemFebrileillnessOthersComlicatedcasesMeningitisEncephalitis/myelitisPolio-likesyndromePulmonaryOedemaFatalcasesSurvivorswithsevereneurologicalsequela119(68%)108(63%)2(1.1%)7(4%)2(1.1%)55(32%)13(7.5%)26(14.5%)#4(2.3%)12(6.9%)#14(8.0%)#5(2.8%)#187(78%)105(43%)5(2%)18(7.4%)59(24%)54(22%)44(18%)5(2.1%)0(0%)0(0%)0(0%)0(0%)#:p<0.001,Changetal. EV71(174) non71EV(241)Unc87Table1:Demographicandclinicalcharacteristicsof154patients

GroupPulmonaryCNScasesUncomplicated oedema(N=11)(N=38)cases(N=105)Sex(M/F) 5/6 24/14 56/49Age(months) 20(21) 29(21) 30(33)Fever 11(100%) 38(100%)* 93(89%)PeakBT(°C) 39.8(0.6)# 39.3(0.7) 39.1(0.8)WBC(109/L) 27.1(8.9)@

14.2(5.8) 13.4(4.5)Glucose 22.4(12.7)?

7.0(3.5)# 5.6(1.0)(mmol/L)CRP(mg/L) 13.9(14.3) 15.1(24.8) 16.6(27.6)Comparedcasesofpulmonaryedema/CNSinvolvementwithuncomplicatedcases,*:p=0.03;#:p=0.01;@:p=0.004;?:p=0.001.Changetal.Lancet354(9191):1682,1999Table1:Demographicandclinic88Table4:Riskfactorsassociatedwithpulmonaryoedema

Pulmonary CNScases OR PRiskFactors oedema(N=11) (N=38)

(95%CI)Glu>150 9(82%) 4(11%) 38(6-211) 0.001*Leukocytosis 9(82%) 12(32%) 9.7(2.9-34) 0.003#Upperlimb 4(36%) 4(11%) 4.9(2.6-9.2) 0.04weaknessLowerlimb 7(64%) 11(29%) 4.3(2.0-9.2) 0.04weaknessChangetal.Lancet354(9191):1682,1999Table4:Riskfactorsassociat89SkinandMucosaLesionsOralulcersdistributednotonsoftpalateonlyastypicalhand-footmouthdiseaseVesiclesonhandandfootweresmaller(pin-point)thantypicalHFMdiseaseSometimestheskinlesionconsistedofpetechiae-likeclustersSkinandMucosaLesionsOralul90以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件91以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件92以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件93以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件94PhasesBasedTherapyofCriticalEV-71Infection

腸病毒重癥之臨床分期第一期：上呼吸道感染─手足口病第二期：神經(jīng)癥狀─腦膜腦脊髓炎第三A期：高血壓—肺水腫出血─自主神經(jīng)失調(diào)第三B期：低血壓─心臟衰竭？心肌炎？SIRS?第四期：逐漸恢復(fù)─神經(jīng)後遺癥PhasesBasedTherapyofCritic95分期標(biāo)的Stage1:Oralulcer,skinrash,feverStage2:Neurologicalsymptoms myoclonicjerk,limbweakness,seizure,consciousnessdisturbanceStage3A:ElevatedBPStage3B:DecreasedBP,useofcatecholaminesStage4:Cessationofcatecholamines.分期標(biāo)的Stage1:Oralulcer,skin96ResultsWeobservedamajorityofpatients(58%14/24)presenteddifferentfiveclinicalphases.Twopatients

developedPE

withoutaHFMprodromeOne

patientdevelopedPEwithout

previous

CNS

involvementsignsIn

sixpatients,

hypertensionphases

werenotobservedThreepatients

didnotdevelop

hypotension

phenomenonResultsWeobservedamajority97TableASevereHypertensionCriteriabyAgeAgeGroupSystolic(mmHg)Diastolic(mmHg)NB＜7days106

8-20days110

Infants＜2yo11882Children3-5yo118846-9yo1308610-12yo1349013-15yo1449216-18yo15096ModifiedfromHycanetal..TaskForceonBloodPressurecontrolinChildren.Pediatrics79:1,1987.TableASevereHypertensionCr98TableB.NormalBloodPressurebyAgeAgeSystolic(mmHg)Diastolic(mmHg)Neonate60-9020-60Infant(6mo)87-10553-66Toddler(2yr)95-10553-662-7yo97-11257-717-15yo112-12866-80HazinskiMF:NursingCareoftheCriticallyIllChild,2nded.St.Louis,Mo:MosbyYearBook;1992TableB.NormalBloodPressure99第一期：手足口病持續(xù)約數(shù)天可能發(fā)高燒類手足口病Hand-Foot-Mouthdisease類皰疹性咽峽炎Herpangina大多數(shù)病人可自然痊癒，無後遺癥手足水泡較典型手足口病小〈約針尖大小〉高危險群可能向後期發(fā)展第一期：手足口病持續(xù)約數(shù)天100重癥病例之前趨癥狀及危險因子I重癥病例前趨癥狀四肢反射性抖動 (myoclonicjerk)

嘔吐嗜睡中樞神經(jīng)受侵犯之危險因子年齡小於三歲高燒超過39度燒超過3天嗜睡、抽筋、頭痛嘔吐高血糖(>150mg/dl)重癥病例之前趨癥狀及危險因子I重癥病例前趨癥狀中樞神經(jīng)受侵101重癥病例之前趨癥狀及危險因子II重癥病例中肺水腫之危險因子年齡小於三歲高血糖(>150mg/dl)

肢體無力白血球升高 重癥包含中樞神經(jīng)受侵犯及肺水腫重癥病例之前趨癥狀及危險因子II重癥病例中肺水腫之危險因子102第二期：腦膜腦炎持續(xù)數(shù)天包括睡眠易驚醒startling、手足抖動myoclonicjerk、肢體無力weakness可能嘔吐、嗜睡可能發(fā)生痙攣腦脊髓液可能有發(fā)炎跡象亦可能無到此仍可能自然痊癒，或許有後遺癥第二期：腦膜腦炎持續(xù)數(shù)天103第三A期：高血壓—肺水腫出血─自主神經(jīng)失調(diào)？持續(xù)約數(shù)小時至一天左右，民國八十七年肺水腫出血為最主要死因血壓上升為最早徵兆、高燒、心搏過快200/min以上、呼吸急促、出冷汗。高血糖(>200mg/dl)肺水腫、肺泡出血、血氧含量降低神經(jīng)癥狀持續(xù)惡化，昏迷指數(shù)降低、四肢更無力第三A期：高血壓—肺水腫出血─自主神經(jīng)失調(diào)？持續(xù)約數(shù)小時至一104以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件105以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件106LungsarecongestedRedbloodcellsarefoundinsmallairwaysandalveoli,LungsarecongestedRedbloodc107ParametersSequenceAroundPEParametersSequenceAroundPE108ParametersSequence(2)ParametersSequence(2)109第三B期：低血壓：心臟衰竭持續(xù)約二至七天心搏速率漸降但血壓可能更低肺水腫出血漸好轉(zhuǎn)但仍需呼吸器，自呼能力差血糖正常化神經(jīng)癥狀之變化：垂直眼震顫、斜視、肢體無力、抽筋…等，此期間腦灌流可能變差造成缺氧缺血性腦病變。第三B期：低血壓：心臟衰竭持續(xù)約二至七天110第四期：逐漸恢復(fù)持續(xù)？月？年心臟功能幾乎完全恢復(fù)肺功能可能不好但足堪負(fù)擔(dān)換氣，然而病人自呼、吞嚥功能不好有嚴(yán)重影響，所以仍需呼吸器支持。漸漸甦醒，神經(jīng)可能有嚴(yán)重後遺癥可能發(fā)生反覆性肺炎。第四期：逐漸恢復(fù)持續(xù)？月？年111I.OutbreaksII.臨床分期及其表現(xiàn)III.呼吸衰竭的病生理學(xué)IV.治療的考量V.結(jié)論

I.Outbreaks112PathophysiologyofPulmonaryOedemaStarling’sformulaFlow=K(Pc－Pis)－Π(Oncpl－Oncis)InterstitiumAlveolusLymphaticsPulmonarycapillaryPcPisKOncplOncisO2ΠPathophysiologyofPulmonaryO113HypothesesoftheMechanismofpulmonaryoedemaSIRS/ARDSNeurogenicpulmonaryedemaCardiogenic↑Capillarypermeability↑Systemic/pulmonaryvasculerresistenceLVsystolicdysfunctionLVdiastolicdysfunctionHypothesesoftheMechanismof114EvidenceSupportingSIRSGroupEncephalitiswithPulmonaryOedema(N=8)Encephalitis(N=8)Uncomplicated(N=170)NormalControl(N=21)P-value*WBC(109/L)28.3+7.615.5+6.812.3+4.7--0.0001CRP(mg/L)18.5+16.331.0+35.815.9+29.1--0.49Glucose(mg/dL)501+186165+117103+15--0.0001IL-1(pg/ml)48.4+85.24.9+10.11.6+0.91.8+1.00.006IL-6(pg/ml)947+12394.9+3.12.8+1.91.9+0.50.0001TNF-α(pg/ml))22.4+29.55.3+1.05.6+1.66.8+1.50.004Linetal.EvidenceSupportingSIRSGroupE115EvidencesRelatedtoNeurogenicPulmonaryOedemaCNSinvolvementpreceedspulmonaryoedemaIncreasedcortisollevelandclinicalevidencessuggestedanautonomicnervoussystemdysfunction(increasedsympathetictone)LackofstudyofpulmonarycapillarypermeabilitySystemicvascularresistencedoesnotincreasesignificantly.EvidencesRelatedtoNeurogeni116DiffuseinflammatorycellinfiltrationinCerebrum,midbrainandbrainstemPerivascularcuffingwasalsocommonDiffuseinflammatorycellinfi117以病程分期為依據(jù)之兒童腸病毒重癥治療概要課件118CortisolLevelvs.VitalSignsCortisolLevelvs.VitalSigns119EvidencesRelatedtoCardiogenicIncreasedpulmonaryarterywedgepressure?EchorevealedsystolicanddiastolicdysfunctionHypertensionassociatedInappropriatetachycardiaassociatedIncreasedcardiacenzymesHowever,autopsyfindingsareagainstmyocarditisEvidencesRelatedtoCardioge120InitialSwan-GanzMonitorData#123Age1y5m10m1y6mPAWP(mmHg)262222CVP(mmHg)10813CI(L/min/m2)SI(mL/beat/m2)25.920.219.8SVRI(dyne-s-cm-5)129614391363PVRI(dyne-s-cm-5)7967168InitialSwan-GanzMonitorData121EchocardiographyEvidencesSystolicdysfunction:Theinitialejectionfraction:18-75%(mean±SE=51.5±3.6%)(n=18)Diastolicdysfunction:Mitralflowvelocities:E/A,DT,IVRT,E=peakvelocityoftheearlyfillingwave,A=peakvelocityofthelatefillingwaveduetoatrialcontraction,DT=decelerationtime,IVRT=isovolumicrelaxationtimeMitralannulusvelocities:E/E',E'=earlydiastolicannulusvelocity(therateofchangeinlong-axisdimensionandLVvolume)EchocardiographyEvidencesSyst122DiastolicFunction#12345ClinicalPE+HFPE+HFMildPEHTonlyHTonlyE/A3.20.862.94mergedDT(ms)48.1973.0954.6152.6IVRT(ms)54.2220.0844.860.24E/E'15.1114.769.7577.4CommentRestrictivephysiologyRestrictivephysiologyRelaxationimpairmentAdequatediastoleAdequatediastole