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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

•  Reviewevidenceforcolloidsinhypovolemia•  Comparedifferenttypesofcrystalloidfluid•  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(andother)shockstates

• Mostcommoninterventionincriticalcare(besidesO2)

•  Oneoftheleastwell-studiedinterventions,relativetoitsfrequencyofuse

QuestionsinPediatricResuscitation

1.   HowmuchIVfluid?2.   WhatkindofIVfluid?

–  Hypotonicvs.Isotonic–  Colloidvs.Crystalloid

3.   Balancedcrystalloidfluidbetter?–  Balancedvs.Unbalanced

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FluidVolume?

AmericanCollegeofCriticalCareMedicine2017Guidelines

ClinicalParametersforHemodynamicSupportofPediatricandNeonatalSepticShock

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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ImprovedOutcomeswithHigherFluidVolumesin1stHour

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)

•  19%OverallAdherenceRate–  Recognition,VascularAccess,Fluids,Antibiotics,Inotropes

•  Fluidadherence(60mL/kg)=ShorterLOS

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AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay

Paul,R.,etal.“AdherencetoPALSSepsisGuidelinesandHospitalLengthofStay.”Pediatrics.2012.Aug;130(2):273-80.(PMID:22753559)

79% 67%

37%

70%

35%

FluidCausesDeath???

Maitland,K.,etal.“MortalityafterfluidbolusinAfricanchildrenwithsepsis.”NEJM.2011.Oct6;365(14):1350-1.(PMID:21991965)

FEAST Study: “Fluid Expansion As Supportive Therapy”

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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%

FEASTSubgroupAnalysis

Higherprevalenceofmalariaandanemia

Maitland,K.,etal.“MortalityafterfluidbolusinAfricanchildrenwithsepsis.”NEJM.2011.Oct6;365(14):1350-1.(PMID:21991965)

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NotjustinAfrica…Increasedmortalitywithcontinuousrenalreplacement

Weiss,SL.,etal.“Crystalloidfluidchoiceandclinicaloutcomesinpediatricsepsis:Amatchedretrospectivecohortstudy.”Pediatrics.2017.Mar;182:304-310.(PMID:22753559)Sutherland,SM.,etal.“Fluidoverloadandmortalityinchildrenreceivingcontinuousrenalreplacementtherapy:theprospectivepediatriccontinuousrenalreplacementtherapy.”AmJKidneyDis.2010.Feb;55(2):316-25.(PMID:20042260)

Sutherland et al, AJKD, 2010

PALSFluidsRecommendations2015

•  Initialfluidbolusof20mL/kgtoinfantsandchildrenwithshockisreasonable(ClassIIa,LOEC-LD)

•  Childrenwithseverefebrileillnesswithlimitedaccesstocriticalcareresource,administrationofbolusIVfluidsshouldbeundertakenwithextremecaution(ClassIIb,LOEB-R)

DeCaen,AR.,etal.“Part12:PediatricAdvanceLifeSupport:2015AmericanHeartAssociationGuidelinesUpdateforCardiopulmonaryResuscitationandEmergencyCardiovascularCare.”Circulation.2015.Nov3;132(18Suppl2):S526-42.

Evidenceforrestrictivefluidresuscitationinpediatrics

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PALSFluidsRecommendations2015•  Continuedemphasisonfluidresuscitationforshock–  20mL/kgisotonicsalinebolusx3(Goal15min!)

•  Increasedemphasison–  Individualpatientassessmentandreassessment–  Considerationofvulnerabilitytofluid

• Nutritionstatus• Diseases(i.e.anemia,malaria)• Criticalcareresources

DeCaen,AR.,etal.“Part12:PediatricAdvanceLifeSupport:2015AmericanHeartAssociationGuidelinesUpdateforCardiopulmonaryResuscitationandEmergencyCardiovascularCare.”Circulation.2015.Nov3;132(18Suppl2):S526-42.

FluidType?Hypotonicvs.Isotonic

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Holliday&Segar(1957)

Holliday,M.andSegar,W.“Themaintenanceneedforwaterinparenteralfluidtherapy.”Pediatrics.1957.19(5):823-832.

4-2-1Rule

Holliday&Segar

Holliday,M.andSegar,W.“Themaintenanceneedforwaterinparenteralfluidtherapy.”Pediatrics.1957.19(5):823-832.

•  ElectrolyteRequirements– Na+3mEq/100ml–  Cl-mEq/100ml–  K+mEq/100ml

•  ¼and½normalsalineforyoungerchildren•  Riskofhyponatremia???

– Overstimatedenergy&waterrequirements– ADHstimulation

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RiskofHyponatremia

McNab,S.,etal.“Isotonicversushypotonicsolutionsformaintenanceintravenousfluidsadministrationinchildren.”CochraneDatabaseSystRev.2014.Dec;18(5):CD009457.

Favors Isotonic Favors Hypotonic

AAPGuidelines2018

•  PatientsrequiringmaintenanceIVFsshouldreceiveisotonicsolutionswithappropriatepotassiumchlorideanddextrosebecausetheysignificantlydecreasetheriskofdevelopinghyponatremia(LOE:A;recommendationstrength:strong)

Feld,L.,etal.“ClinicalPracticeGuideline:MaintenanceIntravenousFluidsinChildren.”Pediatrics.2018.Dec;142(6):e20183083.

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FluidType?Colloidsvs.Crystalloid

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

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).

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CrystalloidFluidType?Balancedvs.Unbalanced

LR NS

CrystalloidFluids•  0.9%NormalSaline:1880’sHartogJoakobHamburger

–  ErythrocytesdidnotlysewhenplacedinNSandconcludedthat“thebloodofmanwasisotonicwithNaClsolutionof0.9%”

–  Humanplasmaisactuallycloserto0.6%sodiumchloride

•  Ringer’s:1880’sSydneyRinger–  Addedcalciumandpotassiumtosalineafterobservingthatinorganic

constituentsofpipewaterbetterpreservedfrogheartmuscleexvivothanjustsaltdissolvedindistilledwater

•  Hartmann’ssolution(LR):1932AlexisHartmann(pediatrician)–  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

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

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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.

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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 (Death, Renal Replacement, AKI)

Semler,MW.,etal.“Balancedcrystalloidsversussalineincriticallyilladults.”NEnglJMed.2018.Mar1;378(9):829-839.

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Whatevidenceisthereforuseofspecificcrystalloid

fluidsinpediatrics?

CurrentCrystalloidPractice

•  ICU:10-20%useofLRforcrystalloidfluidresuscitation1–  DrifttowardincreasedLRuseinICUs2

•  ED:Limiteddata–  AAP/PERC/Australia:2-3%PEMattendingsusedLRasinitialfluid3,4

Opportunity for a minor shift in clinical practice to substantially alter outcomes if LR superior to NS

1Boulainetal,IntensiveCareMed20152Cecconietal,IntensiveCareMed2015

3Longetal,EmergMedAus20154Thompsonetal,JEmergMed2015

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PediatricEvidenceforBalancedFluidResuscitation

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)

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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FutureResearch?

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FeasibilityPilotStudyClinicalTrials.gov/NCT03340805

•  CollaborativeeffortwithTrialInnovationNetwork

•  FDAIND(#13698)•  FeasibilityAims:

1.  Estimateproportionofeligiblepatientsenrolled2.  Determineadherencewithstudyfluidadministration3.  DemonstrateacceptabilityofEFIC

Funding:NICHDK12HL109009

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)

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TakeHomePoints1.   HowmuchIVfluid?

-  20cc/kgbolusx3(Goal15minutes!!!)

2.   WhatkindofIVfluid?-  IsotonicSaline>HypotonicSaline

-  Bolus:0.9%NS-  Maintenance:D50.9%NS

-  Nomortalitybenefitforcolloids(sepsis?)

3.   Balancedcrystalloidfluidbetter?–  ñchlorideloadàñMAKE30–  Considerbalancedfluidsinsevereshockstates

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)•  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.•  Holliday,M.andSegar,W.“Themaintenanceneedforwaterinparenteralfluidtherapy.”Pediatrics.1957.19(5):823-832.•  McNab,S.,etal.“Isotonicversushypotonicsolutionsformaintenanceintravenousfluidsadministrationinchildren.”Cochrane

DatabaseSystRev.2014.Dec;18(5):CD009457.•  Feld,L.,etal.“ClinicalPracticeGuideline:MaintenanceIntravenousFluidsinChildren.”Pediatrics.2018.Dec;142(6):e20183083.•  Finfer,S.,etal.“Acomparisonofalbuminandsalineforfluidresuscitationintheintensivecareunit.”NEngJMed.2004.May27;

350(22):2247-56.•  Rhodes,A.,etal.“SurvivingSepsisCampaign:Internationalguidelinesfortreatingsepsisandsepticshock:2016.”IntensiveCareMed.

2017.Mar;43(3):304-377.•  Bartels,K.,etal.“Rationalfluidmanagementintoday’sICUpractice.”CritCare.2013;17Supple1:S6.(5)Epub2013Mar12.•  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.

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References•  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.•  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.

Questions/Evaluation

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