what’s new in pediatric ards nancy g. hoover, md medical director, picu walter reed amc
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What’s New In What’s New In Pediatric ARDSPediatric ARDSNancy G. Hoover, MDNancy G. Hoover, MD
Medical Director, PICUMedical Director, PICU
Walter Reed AMCWalter Reed AMC
New and ImprovedNew and Improved
AcuteAcute Respiratory Distress Respiratory Distress
SyndromeSyndromeAshbaugh, Ashbaugh, LancetLancet, 1967, 1967
AdultAdult Respiratory Distress Respiratory Distress
SyndromeSyndromeTo distinguish from neonatal HMD/RDSTo distinguish from neonatal HMD/RDS
AcuteAcute Respiratory Distress Respiratory Distress
SyndromeSyndromeAmerican-European Consensus conference, 1994American-European Consensus conference, 1994
ARDS: New DefinitionARDS: New Definition
CriteriaCriteriaAcute onsetAcute onsetBilateral CXR infiltratesBilateral CXR infiltratesPA pressure PA pressure << 18 mm Hg 18 mm HgClassificationClassification
Acute lung injury - PAcute lung injury - PaaOO2 2 : F: F11OO22 << 300300
Acute respiratory distress Acute respiratory distress syndrome - Psyndrome - PaaOO2 2 : F: F11OO22 << 200 200 1994 American-European
Consensus Conference
Clinical Disorders Associated Clinical Disorders Associated with ARDSwith ARDS
Direct InjuryDirect Injury Common CausesCommon Causes
PneumoniaPneumonia Gastric aspirationGastric aspiration
Less Common CausesLess Common Causes Pulmonary contusionPulmonary contusion Fat emboliFat emboli Near drowningNear drowning Inhalational injuryInhalational injury
Indirect InjuryIndirect Injury Common CausesCommon Causes
SepsisSepsis Shock after severe Shock after severe traumatrauma
Less Common Less Common CausesCauses Cardiopulm. bypassCardiopulm. bypass Drug overdoseDrug overdose Acute pancreatitisAcute pancreatitis Massive blood Massive blood transfusionstransfusions
The Problem: Lung InjuryThe Problem: Lung Injury
Etiology In Children
Other 4%
Hemorrhage 5%
Trauma 5%
Noninfectious Pneumonia 14%
Cardiac Arrest 12%
Septic Syndrome 32%
Infectious Pneumonia 28%
Davis et al., J Peds 1993;123:35
ARDS - PathogenesisARDS - Pathogenesis
InstigationInstigation
Endothelial injury: increased Endothelial injury: increased
permeability of alveolar - capillary permeability of alveolar - capillary
barrierbarrier
Epithelial injury : alveolar flood, Epithelial injury : alveolar flood,
loss of surfactant, barrier vs. loss of surfactant, barrier vs.
infectioninfection
Proinflammatory mechanismsProinflammatory mechanisms
ARDS PathogenesisARDS Pathogenesis
ResolutionResolution
Equally importantEqually important
Alveolar edema - resolved by Alveolar edema - resolved by
active sodium transportactive sodium transport
Alveolar type II cells - re-Alveolar type II cells - re-
epithelializeepithelialize
Neutrophil clearance neededNeutrophil clearance needed
ARDS - PathophysiologyARDS - Pathophysiology
Decreased complianceDecreased compliance
Alveolar edemaAlveolar edema
HeterogenousHeterogenous
““Baby Lungs”Baby Lungs”
Phases of ARDSPhases of ARDS
Acute - exudative, Acute - exudative, inflammatoryinflammatory
(0 - 3 days)(0 - 3 days)Subacute - proliferative Subacute - proliferative
(4 - 10 days)(4 - 10 days)Chronic - fibrosing Chronic - fibrosing alveolitisalveolitis
( > 10 days)( > 10 days)
ARDS - OutcomesARDS - Outcomes
Most studies - mortality 40% to Most studies - mortality 40% to 60%60%
Majority of deaths sepsis or MOD Majority of deaths sepsis or MOD rather than primary respiratoryrather than primary respiratory
Outcomes similar for adults and Outcomes similar for adults and childrenchildren
Mortality may be decreasingMortality may be decreasing
53/68 % 39/36 %53/68 % 39/36 %
ARDS - Principles of ARDS - Principles of TherapyTherapy
Provide adequate gas Provide adequate gas
exchangeexchange
Avoid secondary Avoid secondary
injuryinjury
It would seem ironic It would seem ironic that the very that the very
existence of humans is existence of humans is fully dependent on a fully dependent on a gas that, in excess gas that, in excess quantities, is toxic quantities, is toxic
and lethaland lethalLynn D. MartinLynn D. Martin
Therapies for ARDSTherapies for ARDS
Innovations:iNOPLVProningSurfactantAnti-Inflammatory
Mechanical Ventilation
Gentle ventilation:
Permissive hypercapnia
Low tidal volume
Open-lung
HFOVARDS
Extrapulmonary Gas Exchange
The Dangers of The Dangers of OverdistentionOverdistention
Repetitive shear stressRepetitive shear stress
inflammatory responseinflammatory response
air trappingair trapping
Phasic volume swings: Phasic volume swings:
volutraumavolutrauma
Injury to normal alveoliInjury to normal alveoli
compliancecompliance
intrapulmonary shuntintrapulmonary shunt
FiOFiO22
WOB WOB
inflammatory responseinflammatory response
The Dangers of The Dangers of AtelectasisAtelectasis
0
10
20
13 33 38
Airway Pressure (cmH 20)
Lung Volume (ml/kg)
AtelectasiAtelectasiss
““Sweet Sweet Spot”Spot”
OverdistentioOverdistentionn
Lung Injury ZonesLung Injury Zones
““Mechanical” Therapies in Mechanical” Therapies in ARDSARDS
Lower tidal volumes but avoidance Lower tidal volumes but avoidance
of atelectasis with higher PEEPof atelectasis with higher PEEP
Permissive hypercapniaPermissive hypercapnia
HFOVHFOV
Prone positioningProne positioning
Lower Tidal Volumes for Lower Tidal Volumes for ARDSARDS
Multi-center trial, 861 adult Multi-center trial, 861 adult ARDSARDS
Randomized:Randomized:Tidal volume 12 cc/kgTidal volume 12 cc/kg
Plateau pressure < 50 cm Plateau pressure < 50 cm H2OH2O
vs.vs. Tidal volume 6 cc/kgTidal volume 6 cc/kg Plateau pressure < 30 cm Plateau pressure < 30 cm H2OH2O
ARDS Network,
NEJM, 342: 2000
Lower Tidal Volumes for Lower Tidal Volumes for ARDSARDS
0
5
10
15
20
25
30
35
40
Percent
Death Vent freedays
Traditional
Lower
*
*
* p < .001
ARDS Network,NEJM, 342: 2000
22% decrease
Ventilator GoalsVentilator Goals
Set the PEEP slightly higher Set the PEEP slightly higher
than the lower inflection pointthan the lower inflection point
Lower tidal volume (generally < Lower tidal volume (generally <
6 mL/kg)6 mL/kg)
Static peak pressure <40 cm HStatic peak pressure <40 cm H2200
Wean oxygen to <60%Wean oxygen to <60%
Permissive HypercapniaPermissive Hypercapnia
Defined: presence of
hypercapnia in the setting of a
mechanically ventilated patient
receiving limited inspiratory
pressures and reduced tidal
volumesHickling, Int Care Med, 1990
Physiologic Effects of Physiologic Effects of HypercapniaHypercapnia
RESP: Net effect is improvement RESP: Net effect is improvement
in oxygenation byin oxygenation byenhancing hypoxic pulmonary enhancing hypoxic pulmonary
vasoconstriction and decreases vasoconstriction and decreases
intrapulmonary shuntingintrapulmonary shunting
Right-shift of oxygen-hemoglobin Right-shift of oxygen-hemoglobin
dissociation curvedissociation curve
Physiologic Effects of Physiologic Effects of HypercapniaHypercapnia
CV: Net effect is often CV: Net effect is often hemodynamic compromisehemodynamic compromise Sympathetic stimulation with increased Sympathetic stimulation with increased C.O.C.O.Increased HR and SV, decreased SVRIncreased HR and SV, decreased SVR
Intracellular acidosis of Intracellular acidosis of cardiomyocyte is reversible when due cardiomyocyte is reversible when due to hypercarbia compared to metabolic to hypercarbia compared to metabolic acidosisacidosis
When combined with high PEEP strategy, When combined with high PEEP strategy, can lead to severely decreased preload can lead to severely decreased preload and cardiovascular compromiseand cardiovascular compromise
Physiologic Effects of Physiologic Effects of HypercapniaHypercapnia
RENAL: RENAL: Compensatory bicarb reabsorptionCompensatory bicarb reabsorption Acidosis leads to direct renal Acidosis leads to direct renal vasoconstrictionvasoconstriction
Sympathetic-meditated release of norepinephrine (NE)
Indirectly, hypercapnia causes a decrease in SVR that in turn releases NE, stimulates the renin-angiotensin-aldosterone system, leading to a further decrease in renal blood flow
Permissive HypercapniaPermissive HypercapniaIs it worth it?Is it worth it?
Early adult ARDS trial showed a Early adult ARDS trial showed a reduction in expected mortality of reduction in expected mortality of 56% to an actual mortality of 26%56% to an actual mortality of 26%
Included in adult trauma patients Included in adult trauma patients protocol for mechanical ventilationprotocol for mechanical ventilation
Several pediatric studies showing Several pediatric studies showing benefit when used in conjunction benefit when used in conjunction with low TV and high PEEPwith low TV and high PEEP
Caution in patients with elevated Caution in patients with elevated ICPICP
Hickling, CCM, 1994
Nathens, J Trauma, 2005
Sheridan, J Trauma, 1995
Paulson, J Pediatr, 1996
High Frequency High Frequency Oscillation:Oscillation:A Whole Lotta A Whole Lotta Shakin’ Goin’ OnShakin’ Goin’ On
Reese ClarkReese Clark
It’s not absolute It’s not absolute pressure, but pressure, but volumevolume or or pressure pressure swings swings that promote lung that promote lung
injury or injury or atelectasis.atelectasis.
Rapid rateRapid rate
Low tidal volumeLow tidal volume
Maintain open lungMaintain open lung
Minimal volume swingsMinimal volume swings
High Frequency High Frequency VentilationVentilation
CMV HFVRate (BPM)Tidal volume (cc/kg)Alveolar pressure swings (cmH20)End exp. lung volume
0-1204-205-50
low
120-12000.1-50.1-5
high
Differences Between Differences Between CMV and HFOVCMV and HFOV
HFOV vs. CMV in Pediatric HFOV vs. CMV in Pediatric
Respiratory Failure: Respiratory Failure: ResultsResultsGreater survival without Greater survival without
severe lung diseasesevere lung diseaseGreater crossover to HFOV Greater crossover to HFOV and improvementand improvement
Failure to respond to HFOV Failure to respond to HFOV strong predictor of deathstrong predictor of death
Arnold et al, CCM, 1994
0
20
40
HFOV CV CV toHFOV
HFOV toCV
Survival with CLD%
--Arnold et al, Arnold et al, CCMCCM, , 19941994
**
HFOV vs. CMV in Pediatric HFOV vs. CMV in Pediatric Respiratory FailureRespiratory Failure
Reduces cost, severity of chronic Reduces cost, severity of chronic lung disease and decreases lung disease and decreases airleak in neonatal RDSairleak in neonatal RDS
Decreases need for ECMO in Decreases need for ECMO in eligible neonateseligible neonates
Improves survival without CLD in Improves survival without CLD in pediatric ARDSpediatric ARDS
HFOV: Outcomes of HFOV: Outcomes of Randomized Controlled Randomized Controlled
TrialsTrials
Severe persistent airleakSevere persistent airleakNeonatal: Neonatal: HMD (*)HMD (*)
PneumoniaPneumonia
Meconium aspirationMeconium aspiration
Lung hypoplasiaLung hypoplasiaAcute respiratory distress Acute respiratory distress syndromesyndrome
Indications for HFOVIndications for HFOV
Prone Positioning in ARDSProne Positioning in ARDS
Theory: let gravity improve Theory: let gravity improve matching perfusion to well-matching perfusion to well-ventilated lungventilated lung
Improvement is immediateImprovement is immediateDecreased shunt: improved Decreased shunt: improved PaOPaO2 2 but variable (75%) but variable (75%)
Uncertain effect on outcomeUncertain effect on outcome
Prone Positioning in Prone Positioning in Adult ARDSAdult ARDS
Randomized trialRandomized trialStandard therapy vs. standard Standard therapy vs. standard + prone positioning+ prone positioning
Improved oxygenationImproved oxygenationNo difference in mortality, No difference in mortality, time on ventilatortime on ventilator
No difference in No difference in complicationscomplications
Gattinoni et al., Gattinoni et al., NEJM, 2001NEJM, 2001
Conflicting Evidence for Conflicting Evidence for Proning?Proning?
Mancebo, Am J of Resp & CCM, 2006Mancebo, Am J of Resp & CCM, 2006 136 adults, randomized to 20 h/day proning 136 adults, randomized to 20 h/day proning within 48h of intubation for severe ARDSwithin 48h of intubation for severe ARDS
Same ventilator treatment protocols in Same ventilator treatment protocols in both groupsboth groups
25 % relative reduction in ICU mortality25 % relative reduction in ICU mortality Curley, JAMA, 2005Curley, JAMA, 2005
Shorter proning times and multiple Shorter proning times and multiple protocols for vent mgt with lung-protocols for vent mgt with lung-protective stragegy and weaning, sedation, protective stragegy and weaning, sedation, nutrition, etcnutrition, etc
Only 8% mortality and no benefit from Only 8% mortality and no benefit from prone positioningprone positioning
Pharmacological Therapies Pharmacological Therapies in ARDSin ARDS
Surfactant Surfactant
iNOiNO
SteroidsSteroids
Partial Liquid VentilationPartial Liquid Ventilation
Surfactant in ARDSSurfactant in ARDS
ARDS:ARDS:
surfactant deficiencysurfactant deficiency
surfactant present is surfactant present is
dysfunctionaldysfunctional
Surfactant replacement improves Surfactant replacement improves
physiologic functionphysiologic function
Calf’s Lung Surfactant Calf’s Lung Surfactant Extract in Acute Pediatric Extract in Acute Pediatric
Respiratory FailureRespiratory Failure Multicenter trial-uncontrolled, observationalMulticenter trial-uncontrolled, observational
Calf lung surfactant (Infasurf) - Calf lung surfactant (Infasurf) -
intratrachealintratracheal
Immediate improvement and weaning in 24/29 Immediate improvement and weaning in 24/29
children with ARDS and 14% mortalitychildren with ARDS and 14% mortality
In several other studies, there is no evidence In several other studies, there is no evidence
for sustained benefit from Surfactant for sustained benefit from Surfactant
administrationadministration
Wilson et al, CCM, 24:1996
Wilson et al, JAMA, 2005
Steroids in ARDSSteroids in ARDS
Theoretical anti-inflammatory, Theoretical anti-inflammatory,
anti-fibrotic benefitanti-fibrotic benefit
Previous randomized studiesPrevious randomized studies
Acute use (1st 5 days)Acute use (1st 5 days)
No benefitNo benefit
Increased 2Increased 2 infection infection
Effects of Prolonged Effects of Prolonged Steroids in Unresolving Steroids in Unresolving
ARDSARDSRandomized, double-blind, Randomized, double-blind, placebo-controlled trialplacebo-controlled trial
Adult ARDS ventilated for Adult ARDS ventilated for >> 7 7 days without improvementdays without improvement
Randomized:Randomized:PlaceboPlaceboMethylprednisolone 2 mg/kg/day x 4 Methylprednisolone 2 mg/kg/day x 4 days, tapered over 1 monthdays, tapered over 1 month
Meduri et al, JAMA, 1998
Steroids in Unresolving Steroids in Unresolving ARDSARDS
By day 10, steroids improved:By day 10, steroids improved:PaOPaO22/FiO/FiO22 ratios ratiosLung injury/MOD scoresLung injury/MOD scoresStatic lung complianceStatic lung compliance
Steroids decreased procollagen Steroids decreased procollagen metabolitesmetabolites
24 patients enrolled; study 24 patients enrolled; study stopped due to survival stopped due to survival differencedifference
Meduri et al, JAMA, 1998
Steroids in Steroids in Unresolving ARDSUnresolving ARDS
0102030
4050607080
90100
ICUsurvival
Hospitalsurvival
Steroid Placebo
* *
p<.01*
What about after first 28 What about after first 28 days?days?
NHLBI ARDS Clinical Trials Network, NHLBI ARDS Clinical Trials Network, NEJMNEJM, 2006, 2006
180 adult patients with ARDS >7 180 adult patients with ARDS >7 daysdays
No difference in mortality with No difference in mortality with steroidssteroidsEXCEPT, if the patient was entered EXCEPT, if the patient was entered into the study after 14 days of ARDSinto the study after 14 days of ARDS
THEN, there was an increase in 60 and THEN, there was an increase in 60 and 180 day mortality180 day mortality
Inhaled Nitric Oxide in Inhaled Nitric Oxide in Respiratory FailureRespiratory Failure
NeonatesNeonatesBeneficial in term neonates with Beneficial in term neonates with PPHNPPHN
Decreased need for ECMODecreased need for ECMO
Adults/PediatricsAdults/PediatricsBenefits - lowers PA pressures, Benefits - lowers PA pressures, improves gas exchangeimproves gas exchange
Randomized trials: No difference Randomized trials: No difference in mortality or days of in mortality or days of ventilationventilation
ECMO and NO in NeonatesECMO and NO in Neonates
ECMO improves survival in ECMO improves survival in
neonates with PPHN (UK study)neonates with PPHN (UK study)
iNO decreases need for ECMO in iNO decreases need for ECMO in
neonates with PPHN: 64% vs 38% neonates with PPHN: 64% vs 38%
Clark et al, NEJM, Clark et al, NEJM,
20002000
Effects of Inhaled Nitric Effects of Inhaled Nitric Oxide In Children with Oxide In Children with
AHRFAHRFRandomized, controlled, blinded Randomized, controlled, blinded
multi-center trialmulti-center trial
108 children, median age 2.5 108 children, median age 2.5
yearsyearsEntry: OI Entry: OI >> 15 x 2 15 x 2
Randomized: Inhaled NO 10 ppm Randomized: Inhaled NO 10 ppm
vs. mechanical ventilation alonevs. mechanical ventilation aloneDobyns, et al., J. Peds, 1999
Inhaled NO and HFOV In Inhaled NO and HFOV In Pediatric ARDSPediatric ARDS
5853
58
71
0
10
20
30
40
50
60
70
80
Survival %
CMV
CMV + NO
HFOV
HFOV + NODobyns et al., Dobyns et al., J PedsJ Peds, ,
20002000
Partial Liquid Partial Liquid VentilationVentilation
Mechanisms of actionMechanisms of action oxygen reservoiroxygen reservoir recruitment of lung volumerecruitment of lung volume alveolar lavagealveolar lavage redistribution of blood redistribution of blood flowflow
anti-inflammatoryanti-inflammatory
Liquid VentilationLiquid Ventilation
Pediatric trials started in Pediatric trials started in 19961996Partial: FRC (15 - 20 cc/kg)Partial: FRC (15 - 20 cc/kg)Study halted 1999 due to lack of Study halted 1999 due to lack of benefitbenefit
Adult study 2001 Adult study 2001 no effect on outcomeno effect on outcome
ARDS- “Mechanical” ARDS- “Mechanical” TherapiesTherapies
Low tidal volumes Outcome benefit Low tidal volumes Outcome benefit in in large study large study
Prone positioningProne positioning Unproven outcome Unproven outcome benefit benefit
Open-lung strategyOpen-lung strategy Outcome benefit Outcome benefit in in small studysmall study
HFOVHFOV Outcome benefit in Outcome benefit in small studysmall study
ECMOECMO Proven in neonates Proven in neonates unproven in childrenunproven in children
Pharmacologic Pharmacologic Approaches to ARDS: Approaches to ARDS: Randomized TrialsRandomized Trials
Steroids
- acute no benefit
- fibrosing alveolitis lowered mortality, small study
Surfactant possible benefit in children
Inhaled NO no benefit
PLV no benefit
“…“…We must discard the old We must discard the old approach and continue to approach and continue to
search for ways to improve search for ways to improve mechanical ventilation. mechanical ventilation. In the meantime, there is In the meantime, there is
no substitute for the no substitute for the clinician standing by the clinician standing by the
ventilator…”ventilator…”Martin J. Tobin, MD
If you think about If you think about ECMO, ECMO,
it is worth a call it is worth a call to consider ECMOto consider ECMO
Pediatric ECMOPediatric ECMO
Potential candidatesPotential candidatesNeonate - 18 yearsNeonate - 18 yearsReversible disease processReversible disease processSevere respiratory/cardiac Severe respiratory/cardiac failurefailure
< 10 days mechanical ventilation< 10 days mechanical ventilationAcute, life-threatening Acute, life-threatening deteriorationdeterioration
Impact of ECMO on Impact of ECMO on Survival in Pediatric Survival in Pediatric Respiratory FailureRespiratory Failure
Retrospective, multicenter cohort Retrospective, multicenter cohort analysisanalysis
331 patients, 32 hospitals331 patients, 32 hospitalsUse of ECMO associated with survival Use of ECMO associated with survival (p < .001)(p < .001)
53 diagnosis and risk-matched pairs:53 diagnosis and risk-matched pairs:
ECMO decreased mortality (26% vs ECMO decreased mortality (26% vs 47%, p < .01)47%, p < .01)
-Green et al, CCM, 24:1996