Classifying ARDSClassifying ARDSClassifying ARDSClassifying ARDSThe Role of EVLWThe Role of EVLW

Ch l Philli MDCharles Phillips MDOregon Health and Science University Portland, Oregon USA

ARDS 2013• Incidence High

– 150,000 – 200,000 per year in US alone.

• Mortality persists at 30-45%

• Evidence that early detection of lung injury can• Evidence that early detection of lung injury can improve outcome

– More sensitive and specific markers of disease severity

ARDS Inflammatory ResponsePrecipitating

eventLeading to deterioration

f

S a ato y espo se

eventof patient’s condition

Increase inneutrophil

Impaired gasexchange and neutrophil

recruitmentexchange and

poor oxygenation

ProinflammatoryPulmonary Proinflammatoryeicosanoids and

free radicalsd d

Pulmonaryinflammation

with edema andt i ti producedvasoconstriction

Permission Paul Marik

Permeability injury

Thrombin TNF

Pulmonary capillary

Vessel Lumen

Cytokines

LPSTNF Reactive Oxygen/Nitrogen Species Stretch

Endothelium

Gap formationCell Activation

Endothelium

Epithelium

Alveoli

ALVEOLAREDEMA

Scanning EMEDEMA

ARDSARDS

EVLWEVLW

Calfee, C. S. et al. Chest 2007;131:913-920

The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.

NAECC - 19941. Acute onset

2 Bilateral radiograph2. Bilateral radiograph3. PaO2/FiO2

4 No CHF4. No CHF

Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24.

18 Years is a long timeBetter gBetter

Today1994

Today

Worse

1994 Today

SameSame

1994 Today1994 Today

18 Years is a long time18 Years is a long time

“After 18 years of applied research a number of issuesAfter 18 years of applied research, a number of issues regarding various criteria of the AECC definition have emerged”emerged– lack of explicit criteria for defining acute

– sensitivity of PaO2/FIO2 to different ventilator settings

– poor reliability of the chest radiograph criterionp y g p

– difficulties distinguishing hydrostatic edema

Chest radiogramsChest radiograms

# 22 3 4 6 13 15 19 11 20 1 14 7 16 18 21 5 23 24 8 17 2

T f ld diff b t d

% +

36 43 43 46 46 46 46 57 57 57 61 61 61 64 64 68 68 68 71 71 71

•Two-fold difference between readers

•К of 0.55 – moderate agreement

•Full agreement < half

•Lower lung zones consolidation

•Atelectasis

•Small lung volumes

•Pleural effusions

One half of patients

went from ARDS to ALIwent from ARDS to ALI

within 6 hours of

applying PEEP

•21 pts with ARDS < 5 days

•67% moved from ARDS to ALI with

O2/F

iO2

67% moved from ARDS to ALI with ↑FiO2 0.5 to 1.0

PaO

orr)

PaO

2/FiO

2(T

o

FiO2

PaO /FiO poorly reflects disease severityPaO2/FiO2 poorly reflects disease severity

Parameter AUCEVLW 0 988 ±0 019EVLW 0.988 ±0.019

Vd/Vt 0.869 ±0.112

PaO2/FiO2 0.643 ±0.137

Phillips, CR, Smith SM CCM Vol 1 2008

1. Met in Berlin – came up with a working p gdiagnosis of ARDS stressing:a) Feasibility – can be applied widely

b) Reliability – Agreement on case identification

) V lidit fl t di itc) Validity - reflects disease severity, predicts outcome, identifies those who ‘look’ like they have ARDS, captures all relevant aspects of syndrome

2. Formally evaluated using large cohort from 7 studies 4 multicenter and 3 single centerstudies - 4 multicenter and 3 single-center prospective studies enrolled by AECC

a) studies collected data necessary to applya) studies collected data necessary to apply the draft Berlin Definition and the AECC definition

Variables testedVariables tested

Criterion Rationale Reason not included

More quadrants on CXR Improved validity Poor reliability, no effect PPV

PEEP ≥ 10 mmHg Improved validity No effect PPV

CRS ≤ 40 ml/cm H2O Improved validity No effect PPV

VECORR ≥ 10L/min =minute ventilation X PaCO2/40)

Surrogate of Vd/VtImproved validity

No effect PPVventilation X PaCO2/40) Improved validity

Variable consideredVariable consideredC it i R ti l R t i l d dCriterion Rationale Reason not included

Vd/Vt Improved validity Not feasibleAss. Mortality

Plateau pressure Improved validityAss. Mortality

Not feasibley

EVLW Improved validityPPV - MortalitySensitive marker

Not feasible

Sensitive marker disease severity

Biologic markers Improved validity Not feasible, no standard

2012 Berlin Definition

1 Acute onset – 1 week1. Acute onset  1 week

2. Bilateral CXR opacities or CT radiograph ‐ samples

3 No CHF – clinician judgment verification (echo) if3. No CHF  clinician judgment  verification (echo) if no risk factors

4. NO ALI – those were the days4. NO ALI  those were the days 

5. ARDS                PaO2/FiO2 

Mild 201‐300 PEEP/CPAP≥5Mild                          201 300          PEEP/CPAP≥5

Moderate          101‐200              PEEP≥5

Severe                       ≤ 100 PEEP≥5

• Unified definition of a disease– Epidemiologic studiesp g– Better examine therapy

Best practices– Best practices• Berlin

– Clarified acute– Conducting validation study kept definitionConducting validation study kept definition

simple

ARDSBerlin - 2012

1 Acute onset ≤ 7d1. Acute onset ≤ 7d

2. Bilateral radiograph or CT

3. PaO2/FiO2 – min PEEP- Mild, moderate, severe ARDS

4. No CHF – echo to confirm

– lack of explicit criteria for defining acute

– sensitivity of PaO2/FIO2 to different ventilator settings

– poor reliability of the chest radiograph criterion

– difficulties distinguishing hydrostatic edemag g y

New DefinitionsNew Definitions

• Will it facilitate recognition of the disease?

Time domain– Time domain

– Epidemiologically

• Will it help to improve underlying pathophysiology?

• Will it improve prognostic ability?

• Will it change therapy?

What’s Wrong?

• The radiological criteria are still not sufficiently sensitive or specific

• Pao2/FiO2 is still too insensitive and too confounded 2

• Has poor PPV for outcome

• Ignored FiO effect• Ignored FiO2 effect

• Min PEEP– Ignored effect of PEEP on severity classification

– Ignored APRV, Bi-level, HFOV

– The disease does not exist unless it is being treated (min - PEEP)

The Problems• Insensitive non-specific criteria p

– Missed treatment

– Inhomonogous treatment groups

• Cant have the syndrome unless receiving advanced medical care

• Hydrostatic edema

The Problem of Hydrostatic EdemaThe Problem of Hydrostatic Edema

• AECC excluded ARDS if you had CHF• Berlin – no risks factors must confirm normal

heart function – ECHO, CO• Berlin – if you have risks factors for ARDS and aBerlin if you have risks factors for ARDS and a

high clinical suspicion you have ARDS

Edema

ARDS-CMARDS PERMEABILITY

CHFHydrostatic

65%Day 1 65%

29%

18%

Day 1

0-6hrs

06-hrs

60%

20%

46%

Day 1-3

?

12hrs 46%12hrs

EVLWEVLWIn order to better identify and properly classify ARDS we need a way to quantify both permeability and hydrostatic edema and determine their relative contribution toedema and determine their relative contribution to pathophysiology .

Extravascular lung water

ll h li id i h l i h l l l

Extravascular lung water

All the liquid in the lung not in the vascular or pleural space

Interstial, alveolar, lymph and airway “water”MucousS f t t} 20 25%SurfactantEdemaLymph

} 20-25%10%Lymph 

Intercellular “water”PMN’s  } 65%

10%

MacrophagesEndothelial and epithelial cells

} 65%

WET DRY

Injury ARDS Sepsis

WET DRY

Permeability ↑↑↑ ↑↑

Hydrostatic ↑↑ ↑↑

Oncotic Gradient ↑in ↑↑in

Alveolar clearance ↓↓↓ ↓↑EVLW

Lymph clearance ↑↑ ↑↑↑

Vascular dysfunction ↑↑ ↑↑↑

Transpulmonary ThermodilutionInjectThermodilutionTranspulmonary

Th dil ti

j

Thermodilution

Femoral Artery th i tthermister

EVLW goal directed Rx of ALIg

• Prospective randomized studyProspective, randomized study

• 48 subjects in ICU with SBP < 90 felt to require PAC

R ti EVLW d i t• Routine vs EVLW driven management

Subgroup: EVLW > 14, PAOP <  18 (ARDS)

– Mortality     33% (13/48) vs. 100% (35/48)   (p<0.05)

EVLW PACEVLW                 PAC

• No correlation of EVLW and PAOP: r2 = 0.026, n = 290

• Poor correlation of x‐ray reads with EVLW

Eisenberg et al, Am Rev Respir Dis 1987;136

•Retrospective 373 pts

•Sepsis

•ARDS

•Severe head trauma

•Intracranial hemorrhage•Intracranial hemorrhage

•Hemorrhagic shock

•EVLW 14.3ml/kg vs. 10.2ml/kg

AUC EVLW 0.988 ±0.019

Vd/Vt 0.869 ±0.112

PaO2/FiO2 0.643 ±0.137

EVLW > 16 near 100% mortality

Phillips, CR, Smith SM CCM Vol 1 2008

44 pts with ARDS

34% septic

PBW Improved predictive value p p

Cutoff value of 16 ml/kg PBW

EVLW in patients at risk for ALIEVLW in patients at risk for ALI

2.6

LeTourneau, J, Phillips, CR CCM 2012

EVLWEVLW•Detected lung injury 2.6 days before meeting criteriabefore meeting criteria

•Discriminated those who got it vs those who didn’tvs. those who didn t

•Better predicted progression to ALIALI

LeTourneau, J; Phillips, CR

EVLW/PBV

EVLW indexed to central blood volume can discriminate hydrostatic edema from ARDSARDSPVPI ≥ 3 85%sensitivty, 100%specificity

The Case for EVLWThe Case for EVLWEVLW is at the center of the pathogenesis of ARDS

Targeting EVLW improves outcomeTargeting EVLW improves outcome

EVLW has good PPV for outcome

Progression to ARDS

Mortalityy

PVPI can be used to discriminate hydrostatic from permeability PEp y

Feasible?A box or a module available to plug into most bedside pt monitors

A central lineA t i l liAn arterial line

ConclusionConclusion• We need more sensitive and specific• We need more sensitive and specific

mechanistic criteria • Earlier and more sensitive detection

• Discriminate from other infiltrative lung processesDiscriminate from other infiltrative lung processes

• Discriminate type and etiology of lung injury so we may better classify severity and target diseasemay better classify severity and target disease processes

EVLW and PVPI can provide this and should beEVLW and PVPI can provide this and should be incorporated into a definition of ARDS

Extravascular lung water 

Dynamic balance

Fluid and cells in Fluid and cells out

WET DRY

Fl id I t L L h O tFluids Into Lung Lymph Out

• Subgroup: EVLW > 14, PAOP <  18 (ARDS)

– Mortality:

33% (13/48) 100% (35/48) ( <0 05)33% (13/48) vs. 100% (35/48)              (p<0.05)

EVLW                 PAC

• No correlation of EVLW and PAOP: r2 = 0.026, n = 290

• Poor correlation of x‐ray reads with EVLW

Eisenberg et al, Am Rev Respir Dis 1987;13

EVLW•Detected lung injury 2.6 days before meeting criteria

•Discriminated those who got it vs. those who didn’tgot t s t ose o d d t

•Better predicted progression to ALIprogression to ALI 

LeTourneau, J; Phillips, CR, CCM 2012

f f• Analyzed modifications in fluid and vasoactive drug therapy when including EVLW

• 42 pts with hypotension or hypoxemia, felt to be euvolemic

• Initial decisions based on – CVP, GEDI, SVV, Blood pressure, CXR, COCVP, GEDI, SVV, Blood pressure, CXR, CO

• Asked to follow a protocol based on EVLW and record differencesrecord differences

Modified more than half ofModified more than half of therapeutic decisions

Of th 22 ith difi dOf the 22 with modified rx -it was effective in 18

13 i d d d fl id13 received reduced fluids or more diuretic - 12 of 13 improvedimproved

More negative fluid balance

CVP and GEDI was not useful in distinguishing groupsgroups

ARDS and Hydrostatic edemaARDS and Hydrostatic edema • # 1 cause of ARDS is sepsis

• Cardiac dysfunction in sepsis is characterized byy p y– ventricular dilatation– reduction in ejection fraction j– reduced contractility– can occur very early even during the ‘‘hyperdynamic’’can occur very early even during the hyperdynamic

phase

• Sepsis cardiomyopathy is commonSepsis cardiomyopathy is common

150 Pts on ventilators

EVLW as a preload metric

EVLW

CO

Large increase in EVLW

Small increase in CO

Preload

Determining EVLWDetermining EVLW

Temp-1

Time

∆ Down slope time

The Modern Era of ALI/ARDSThe Modern Era of ALI/ARDS• DaNang Lung Shock Lung Post Traumatic LungDaNang Lung, Shock Lung, Post Traumatic Lung

– WWII– Korea– Vietnam

• Acute Respiratory Distress in Adults , Ashbaugh, DG , Lancet 1967

C i f t t th– Cyanosis refractory to oxygen therapy– Pulmonary edema, atelectasis diffuse infiltrates on the chest radiograph – Vascular Congestion

Hyaline membranes– Hyaline membranes

• 1970 - 1980’s – increased vascular permeability studiesBrigham– Brigham

– Ohkuda– Fein

The Good1. Can “drown” with only 200‐300 ml extra lung water

2. No good surrogate markers of EVLW

3. EVLW Predicts mortality in ARDS

EVLW predicts progression to ALI in patients at riskEVLW predicts progression to ALI in patients at risk

EVLW driven protocols only approach shown to improve mortalitymortality

4. The promise of better outcomesGoal directed therapy

Better preload  management

The BadThe BadSli htl ti t i l• Slightly over-estimates in normals

• Slightly under-estimates in disease• Low CI < 1.5 • AneurysmsAneurysms• Pulmonary Vascular obstruction

High PEEP– High PEEP – PE

A t i h t• Anatomic shunt• Focal injury

Critics SayCritics SayE l R i l ti• Early Recirculation– Occurs before thermal indicator fully distributes

• Heterogeneous perfusion of injured lungs– Deadspacep– Changes in pulmonary blood volume

• Heterogeneous downslope timesHeterogeneous downslope times– Central blood volume and extravascular lung

water are not single compartments and do not g pmonoexponentially empty

The UglyThe Ugly

• Not using it

ConclusionsThe foundation for clinical use of EVLW has been establishedbeen established

We should be measuring all goals of therapyWe should be measuring all goals of therapy in a tailored comprehensive approach

Fluids SV EVLWFluids – SV, EVLWVasoactive meds – MAP, SVRInotropes – SV, CO, contractilityInotropes SV, CO, contractility

Can do this simply, at the bedside with TPT for the ‘cost’ of an arterial catheterfor the cost of an arterial catheter

Berlin definitionBerlin definition

The Modern Era of ALI/ARDSThe Modern Era of ALI/ARDSU til 1990 li bl d• Up until 1990 – normalize blood gases– High oxygen concentrations – Large tidal volumesLarge tidal volumes– High pressures

44 pts with ARDS

34% septic

PBW Improved predictive value

Cutoff value of 16 ml/kg PBW

The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.

Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24.

• 1. Plateau pressure – rejected as not feasible

• 2.

Minerva Anestesiol. 2012 Aug 3. [Epub ahead of print]

What's new in the 'Berlin' definition ofWhat s new in the Berlin definition of Acute Respiratory Distress Syndrome?Camporota L, Ranieri VM.

SVSV

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