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)

Phases of ARDSPhases of ARDS

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

Is turning the Is turning the ARDS patient ARDS patient

“prone” helpful?“prone” helpful?

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

Impact of ECMO on Survival Impact of ECMO on Survival in Pediatric Respiratory in Pediatric Respiratory

FailureFailure

0

10

20

30

40

50

60

70

80

90

<25% 25-50% 50-75% >75%

ECMO

Non-ECMO% Mortality

p<0.05

Green et al, CCM, 1996mortality risk quartile