“water under the bridge”: controversies in pediatric ... · 19/03/2019 · of the american...
TRANSCRIPT
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“WaterUndertheBridge”:ControversiesinPediatricSepsis
FluidManagement
DanNguyen,MDAssistantProfessorofEmergencyMedicine&Pediatrics
MCEPCriticalCareConference
March21,2019
DisclosuresandConflictsofInterest
• Ihavenoconflictsofinterestinrelationtothispresentation
• FrancesBalamuth,MD,PhD– PROMTBOLUSStudy– Children’sHospitalofPhiladelphia
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LearningObjectives
• Describecurrentguidelinesforfluidresuscitationinpediatricsepsis
• Compareandcontrastdifferenttypesofcrystalloidfluid
• Appraiseadverseoutcomesofunbalancedfluids• Identifyareasoffutureresearch
“...improvement in the pulse and countenance is almost simultaneous, the cadaverous expression gradually gives place to appearances of returning
animation, the livid hue disappears, the warmth of the body returns.” (Thomas Latta, Letter to Lancet, June 2, 1832)
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IntravenousFluids
• Cornerstoneofmanagementforseptic(another)shockstates
• Mostcommoninterventionincriticalcare(besidesO2)
• Oneoftheleastwell-studiedinterventions,relativetoitsfrequencyofuse
QuestionsinPediatricResuscitation
1. HowmuchIVfluid?2. WhatkindofIVfluid?
– Colloidvs.Crystalloid
3. Balancedcrystalloidfluidbetter?– Balanced(LR,PlasmaLyte)– Unbalanced(Saline)
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FluidVolume?
AmericanCollegeofCriticalCareMedicine2017Guidelines
ClinicalParametersforHemodynamicSupportofPediatricandNeonatalSepticShock
*Infants&Children
Davis,AL.,etal.“AmericanCollegeofCriticalCareMedicineclinicalPracticeParametersforHemodynamicsupportofPediatricandNeonatalSepticShock.”CritCareMed.2017.June;45(6):1061-1093.(PMID:28509730)Davis,AL.,etal.“AmericanCollegeofCriticalCareMedicineclinicalPracticeParametersforHemodynamicsupportofPediatricandNeonatalSepticShock:ExecutiveSummary.”PediatrCritCareMed.2017.Sep;18(9):884-890.(PMID:28723883)
20 mL/kg Isotonic Saline Boluses x 3
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Improvedoutcomeswithhighervolumes
Carcillo,JA.,etal.“Roleofearlyfluidresuscitationinpediatricsepticshock.”JAMA.1991.Sept;266(9):1242-5.(PMID:1870250)Oliveira,CF.,etal.“Time-andfluid-sensitiveresuscitationforhemodynamicsupportofchildreninsepticshock:barrierstotheimplementationoftheAmericanCollegeofCriticalCareMedicine/PediatricAdvancedLifeSupportGuidelinesinapediatricintensivecareunitinadevelopingworld.”PediatricEmergencyCare.2008.Dec;24(12):810-5.(PMID:19050666)
Mor
talit
y
Carcillo et al, JAMA 1991 Oliveira et al, Peds Emerg Care 2008
Fig. The distribution of survivor and non-survivors within fluid resuscitation groups. *Significant difference in survival >40 ml/kg
Fig. Patients with septic shock: mortality vs. first hour resuscitation volume
<20 ml/kg 20-40 ml/kg >40 ml/kg <20 ml/kg 20-40 ml/kg >40 ml/kg
33%
52%
73%
AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay
Paul,R.,etal.“AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay.”Pediatrics.2012.Aug;130(2):273-80.(PMID:22753559)
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AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay
Paul,R.,etal.“AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay.”Pediatrics.2012.Aug;130(2):273-80.(PMID:22753559)
FluidCausesDeath???
Maitland,K.,etal.“MortalityafterfluidbolusinAfricanchildrenwithsepsis.”NEJM.2011.Oct6;365(14):1350-1.(PMID:21991965)
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Maitland,K.,etal.“MortalityafterfluidbolusinAfricanchildrenwithsepsis.”NEJM.2011.Oct6;365(14):1350-1.(PMID:21991965)
Mortality at 48 Hours Mortality Rates Albumin 10.6% Saline 10.5% Control 7.3%
Maitland,K.,etal.“MortalityafterfluidbolusinAfricanchildrenwithsepsis.”NEJM.2011.Oct6;365(14):1350-1.(PMID:21991965)
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Ford,N.,etal.“MortalityafterFluidBolusinChildrenwithShockDuetoSepsisorSevereInfection:ASystematicReviewandMeta-Analysis.”PLOSOne.2012.Aug30;7(8):e43953.
No Bolus Bolus
Study Year Relative Risk (95% CI)
Events Treatment
Events Control
NotjustinAfrica…Increasedmortalitywithcontinuousrenalreplacement
Sutherland,SM.,etal.“Fluidoverloadandmortalityinchildrenreceivingcontinuousrenalreplacementtherapy:theprospectivepediatriccontinuousrenalreplacementtherapy.”AmJKidneyDis.2010.Feb;55(2):316-25.(PMID:20042260)
Sutherland et al, AJKD, 2010
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PALSFluidRecommendations2015
• Initialfluidbolusof20mL/kgtoinfantsandchildrenwithshockisreasonable(ClassIIa,LOEC-LD)
• Whencaringforchildrenwithseverefebrileillnessinsettingswithlimitedaccesstocriticalcareresource,administrationofbolusintravenousfluidsshouldbeundertakenwithextremecaution(ClassIIb,LOEB-R)
DeCaen,AR.,etal.“Part12:PediatricAdvanceLifeSupport:2015AmericanHeartAssociationGuidelinesUpdateforCardiopulmonaryResuscitationandEmergencyCardiovascularCare.”Circulation.2015.Nov3;132(18Suppl2):S526-42.
PALSFluidRecommendations2015
• Fluidnotsafeforallpatientsinallsettings– e.g.shouldn’thave“standingorders”
• Continuedemphasisonfluidresuscitationforshock
• Increasedemphasison– Individualpatientassessmentandreassessment– Considerationofvulnerabilitytofluid
• Nutritionstatus• Diseases(i.e.anemia,malaria)• Criticalcareresources
DeCaen,AR.,etal.“Part12:PediatricAdvanceLifeSupport:2015AmericanHeartAssociationGuidelinesUpdateforCardiopulmonaryResuscitationandEmergencyCardiovascularCare.”Circulation.2015.Nov3;132(18Suppl2):S526-42.
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FluidType?
Finfer,S.,etal.“Acomparisonofalbuminandsalineforfluidresuscitationintheintensivecareunit.”NEngJMed.2004.May27;350(22):2247-56.
Figure 1. Kaplan–Meier Estimates of the Probability of Survival. p = 0.96
RCT 4% Albumin vs. NS N = 6997 Adult ICU patients
The SAFE Study, NEJM 2004
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AlbuminMayBenefitSepsis
Finfer,S.,etal.“Acomparisonofalbuminandsalineforfluidresuscitationintheintensivecareunit.”NEngJMed.2004.May27;350(22):2247-56.
30.7% Mortality 35.3% Mortality
AlbuminMayBenefitSepsis
Annane,D.,etal.“Effectoffluidresuscitationwithcolloidsvscrystalloidsonmortalityincriticallyillpatientspresentingwithhypovolemicshock:theCRISTALrandomizedtrial.”JAMA.2013.Nov6;310(17):1809-17.
CRISTAL Study, JAMA 2013
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2. Werecommendthat,intheresuscitationfromsepsis-inducedhypoperfusion,atleast30mL/kgofIVcrystalloidfluidbegivenwithinthefirst3hours(strongrecommendation,lowqualityofevidence).
Rhodes,A.,etal.“SurvivingSepsisCampaign:Internationalguidelinesfortreatingsepsisandsepticshock:2016.”IntensiveCareMed.2017.Mar;43(3):304-377.
4. Wesuggestusingalbumininadditiontocrystalloidsforinitialresuscitationandsubsequentintravascularvolumereplacementinpatientswithsepsisandsepticshockwhenpatientsrequiresubstantialamountsofcrystalloids(weakrecommendation,lowqualityofevidence).
Finfer,A.,etal.“Resuscitationfluiduseincriticallyadults:aninternationalcross-sectionalstudyin391intensivecareunits.”CritCare.2010;14(5):R185.
391 ICUs, 25 countries… 24 hours, 4,488 resuscitations
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CrystalloidFluidType?
CrystalloidFluids• 0.9%NormalSaline:1880’sHartogJoakobHamburger
– ErythrocytesdidnotlysewhenplacedinNSandconcludedthat“thebloodofmanwasisotonicwithNaClsolutionof0.9%”
– Humanplasmaisactuallycloserto0.6%sodiumchloride
• Ringer’s:1880’sSydneyRinger– Addedcalciumandpotassiumtosalineafterobservingthatinorganic
constituentsofpipewaterbetterpreservedfrogheartmuscleexvivothanjustsaltdissolvedindistilledwater
• Hartmann’ssolution(LR):1932AlexisHartmann– ModifiedRinger’soriginalformulainordertoreducetheacidosisobserved
ininfantswithdiarrheabyaddinglactate
• Plasma-Lyte– DevelopedtoaddresstheslighthypotonicityandpresenceofcalciuminLR
andHartmann’ssolutions– Physiochemicalpropertiessimilartohumanplasma
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CrystalloidFluidComposition
Bartels,K.,etal.“Rationalfluidmanagementintoday’sICUpractice.”CritCare.2013;17Supple1:S6.(5)Epub2013Mar12.Yunos,NM,etal.“Associationbetweenachloride-liberalvschloride-restrictiveintravenousfluidadministrationstrategyandkidneyinjuryincriticallyilladults.”JAMA.2012.Oct17;308(15):1566-72.
Blood NS LR Plasma-Lyte
Na (mEq/L) 140 154 130 140 Cl (mEq/L) 100 154 109 98 K (mEq/L) 4 0 4 5 Ca (mEq/L) 5 0 2-3 0 Lactate (mEq/L) 2 0 28 (Acetate) pH 7.4 4-5 6.5 7.4 SID +40 0 +28 +25 Osmolaltiy 290 308 273 295 Cost (per 500 mL) $1 $1-2 $3-6 SID = Strong Ion Difference
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ClinicalEffectsofCrystalloid
NS LR Hyperchloremia ++++ + Acidosis ++++ Acute Kidney Injury ++ Hyperkalemia Rare Rare-er Coagulation Coagulopathy Hypercoagulability (?)
Lactic Acidosis Only with fulminant liver failure
Fluid Overload ++ + Cerebral Edema ICP é 4 cm H20
Raghunathan,K.,etal.“AssociationbetweenthechoiceofIVcrystalloidandin-hospitalmortalityamongcriticallyilladultswithsepsis.”CritCareMed.2014.Jul;42(7):1585-91.
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“Salineisthefirst-choicecrystalloidfluidandissupportedby150yearsofexperience.Isubmitthatthecurrentlevelofevidencefallsfarbelowthethreshold[practicechange].Ouroptionsaretostickwithwhatistriedandtestedorchangetomoreexpensivefluidsonthebasisofinductivephysiologicreasoningandobservationaldatathataresubjecttobiasandconfounding.”
“Thesimilaravailabilityandcostofeachcrystalloid,establishedsafetyofbalancedcrystalloids,andmountingconcernsaboutacidosis,AKI,andmortalitywithsalinearguethatsalineshouldnotbethefirstchoicefluidforcrystalloidresuscitation.”
Young,P.“Salineisthesolutionforcrystalloidresuscitation.”CritCareMed.2016.Aug;44(8):1538-40.Semler,MW,RiceTW.“Salineisnotthefirstchoiceforcrystalloidresuscitationfluid.”CritCareMed.2016.Aug;44(8):1541-44.
Self,WH.,etal.“Balancedcrystalloidsversussalineinnoncriticallyilladults.”NEnglJMed.2018.Mar1;378(9):819-828.Semler,MW.,etal.“Balancedcrystalloidsversussalineincriticallyilladults.”NEnglJMed.2018.Mar1;378(9):829-839.
SALT-ED SMART N 13,347 15,802 Hospital/ICU-free days 0.98 (0.92, 1.04) 1.00 (0.89, 1.13) MAKE30 0.82 (0.70, 0.95) 0.91 (0.82, 0.99) Hospital Death 0.88 (0.66, 1.16) 0.90 (0.80, 1.01)
aOR, Primary outcome bolded MAKE30: Major adverse kidney events in 30 days
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Semler,MW.,etal.“Balancedcrystalloidsversussalineincriticallyilladults.”NEnglJMed.2018.Mar1;378(9):829-839.
Whatevidenceisthereforuseofspecificcrystalloid
fluidsinpediatrics?
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CrystalloidChoice–CurrentPractice• ICU:10-20%useofLRforcrystalloidfluidresuscitation1,2– DrifttowardincreasedLRuseinICUs3
• ED:Limiteddata– AAP/PERC/Australia:2-3%PEMattendingsusedLRasinitialfluid4,5
– PECARNregistry:4sitesover1year6
Opportunity for a minor shift in clinical practice to substantially alter outcomes if LR superior to NS
1Boulainetal,IntensiveCareMed20152S.Erikson,PersonalCommunicationSAFE-EPIC3Cecconietal,IntensiveCareMed2015
4Longetal,EmergMedAus20155Thompsonetal,JEmergMed20156E.Alpern,PersonalCommunicationPediatricEvidenceforBalancedFluid
Resuscitation
Weiss,SL.,etal.“Crystalloidfluidchoiceandclinicaloutcomesinpediatricsepsis:Amatchedretrospectivecohortstudy.”Pediatrics.2017.Mar;182:304-310.Emrath,ET,etal.“Resuscitationwithbalancedfluidsisassociatedwithimprovedsurvivalinpediatricseveresepsis.”CritCareMed.2017.Jul;45(7):1177-1183.
Premier1 PHIS2
N 4,234 10,724
Design Retrospective Retrospective
Comparison All NS vs. Any LR All NS vs. All LR
Match Integer + fine balance; 1:1
Propensity Score; 1:6
Mortality 7.9% NS vs. 7.2% LR (p = 0.20)
15% NS vs. 13% LR (p = 0.046)
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FutureResearch?
OutcomeforaPediatricTrial?MAKE30• Majoradversekidneyevents30days• Compositeendpoint
– Death– Newrenalreplacementtherapy– Persistentkidneydysfunction
• *Lastcreatintinebeforedischargeor30days>200%baseline(baselinemeasuredorimputed)
• DoesnotrequireserialcreatintineorUOP• AssociatedwithCKDandlongtermmorbidity/mortality(vs.AKI)
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MAKE30inPediatricSepsis
1,685childrenprimarilytreatedinaPHIS+hospital(85%ED)
MAKE30associatedwithhospitalmortality,costs,andCKD
Outcome PHIS+
MAKE30 9.6% (95% CI 8.2, 11.1%)
Mortality 4.5% Renal replacement therapy 1.7% Persistent kidney dysfunction 5.8%
Weiss/Balamuth,submitted
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Planned/OngoingPediatricTrials
Optimal volume? 10 mL/kg vs. 20 mL/kg boluses United Kingdom (Dr. David Inwald)
Optimal duration? Usual care vs. early norepinephrine Canada (Dr. Melissa Parker)
Optimal type? Normal saline vs. lactated ringer’s United States (Dr. F Balamuth, S. Weiss)
References• Davis,AL.,etal.“AmericanCollegeofCriticalCareMedicineclinicalPracticeParametersforHemodynamicsupportofPediatricand
NeonatalSepticShock.”CritCareMed.2017.June;45(6):1061-1093.(PMID:28509730)• Davis,AL.,etal.“AmericanCollegeofCriticalCareMedicineclinicalPracticeParametersforHemodynamicsupportofPediatricand
NeonatalSepticShock:ExecutiveSummary.”PediatrCritCareMed.2017.Sep;18(9):884-890.(PMID:28723883)• Carcillo,JA.,etal.“Roleofearlyfluidresuscitationinpediatricsepticshock.”JAMA.1991.Sept;266(9):1242-5.(PMID:1870250)• Oliveira,CF.,etal.“Time-andfluid-sensitiveresuscitationforhemodynamicsupportofchildreninsepticshock:barrierstothe
implementationoftheAmericanCollegeofCriticalCareMedicine/PediatricAdvancedLifeSupportGuidelinesinapediatricintensivecareunitinadevelopingworld.”PediatricEmergencyCare.2008.Dec;24(12):810-5.(PMID:19050666)
• Paul,R.,etal.“AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay.”Pediatrics.2012.Aug;130(2):273-80.(PMID:22753559)
• Maitland,K.,etal.“MortalityafterfluidbolusinAfricanchildrenwithsepsis.”NEJM.2011.Oct6;365(14):1350-1.(PMID:21991965)• Ford,N.,etal.“MortalityafterFluidBolusinChildrenwithShockDuetoSepsisorSevereInfection:ASystematicReviewandMeta-
Analysis.”PLOSOne.2012.Aug30;7(8):e43953.• Sutherland,SM.,etal.“Fluidoverloadandmortalityinchildrenreceivingcontinuousrenalreplacementtherapy:theprospective
pediatriccontinuousrenalreplacementtherapy.”AmJKidneyDis.2010.Feb;55(2):316-25.(PMID:20042260)• DeCaen,AR.,etal.“Part12:PediatricAdvanceLifeSupport:2015AmericanHeartAssociationGuidelinesUpdateforCardiopulmonary
ResuscitationandEmergencyCardiovascularCare.”Circulation.2015.Nov3;132(18Suppl2):S526-42.• Finfer,S.,etal.“Acomparisonofalbuminandsalineforfluidresuscitationintheintensivecareunit.”NEngJMed.2004.May27;
350(22):2247-56.• Annane,D.,etal.“Effectoffluidresuscitationwithcolloidsvscrystalloidsonmortalityincriticallyillpatientspresentingwith
hypovolemicshock:theCRISTALrandomizedtrial.”JAMA.2013.Nov6;310(17):1809-17.• Rhodes,A.,etal.“SurvivingSepsisCampaign:Internationalguidelinesfortreatingsepsisandsepticshock:2016.”IntensiveCareMed.
2017.Mar;43(3):304-377.• Finfer,A.,etal.“Resuscitationfluiduseincriticallyadults:aninternationalcross-sectionalstudyin391intensivecareunits.”CritCare.
2010;14(5):R185.• Bartels,K.,etal.“Rationalfluidmanagementintoday’sICUpractice.”CritCare.2013;17Supple1:S6.(5)Epub2013Mar12.• Raghunathan,K.,etal.“AssociationbetweenthechoiceofIVcrystalloidandin-hospitalmortalityamongcriticallyilladultswith
sepsis.”CritCareMed.2014.Jul;42(7):1585-91.
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References• Sen,A.,etal.“Chloridecontentoffluidusedforlarge-volumeresuscitationisassociatedwithreducedsurvival.”CritCareMed.2017.
Feb;45(2):e146-e153.• Self,WH.,etal.“Balancedcrystalloidsversussalineinnoncriticallyilladults.”NEnglJMed.2018.Mar1;378(9):819-828.• Semler,MW.,etal.“Balancedcrystalloidsversussalineincriticallyilladults.”NEnglJMed.2018.Mar1;378(9):829-839.• Young,P.“Salineisthesolutionforcrystalloidresuscitation.”CritCareMed.2016.Aug;44(8):1538-40.• Semler,MW,RiceTW.“Salineisnotthefirstchoiceforcrystalloidresuscitationfluid.”CritCareMed.2016.Aug;44(8):1541-44.• Boulain,T.,etal.“Canonesizefitall?Thefinelinebetweenfluidoverloadandhypovolemia.”IntensiveCareMed.2015.Mar;41(3):
544-6.• CecconiM.,etal.“Fluidchallengesinintensivecare:theFENICEstudy:Aglobalinceptioncohortstudy.”IntensiveCareMed.2015.
Sept;41(9):1529-37.• Long,E.,etal.“Fluidresuscitationforpaediatricsepsis:AsurveyofsenioremergencyphysiciansinAustraliaandNewZealand.”Emerg
MedAustralas.2015.Jun;27(3):245-50.• Thompson,GC.,etal.Recognitionandmanagementofsepsisinchildren:Practicepatternsintheemergencydepartment.”JEmerg
Med.2015.Oct;49(4):391-9.• Barhight,MF.,etal.“Increaseinchloridefrombaselineisindependentlyassociatedwithmortalityincriticallyillchildren.”Intensive
CareMedicine.2018.Dec;44(12):2183-2191.• Weiss,SL.,etal.“Crystalloidfluidchoiceandclinicaloutcomesinpediatricsepsis:Amatchedretrospectivecohortstudy.”Pediatrics.
2017.Mar;182:304-310.• Emrath,ET,etal.“Resuscitationwithbalancedfluidsisassociatedwithimprovedsurvivalinpediatricseveresepsis.”CritCareMed.
2017.Jul;45(7):1177-1183.• Inwald,DP.,etalonbehalfofPERUKIandPICSSG.“Restrictedfluidbolusvolumeinearlysepticshock:Resultsofthefluidsinshock
pilottrial.”ArchivesofDiseaseinChildhood.PublishedOnlineFirst:07August2018.