Acute Respiratory Acute Respiratory Distress syndromeDistress syndrome

Meron YimenMeron Yimen

PGY 3PGY 3

Historical BackgroundHistorical Background

Since WWI physicians have recognized a syndrome of Since WWI physicians have recognized a syndrome of respiratory distress, diffuse lung infiltrates and respiratory distress, diffuse lung infiltrates and respiratory failure in pt with various medical conditions respiratory failure in pt with various medical conditions including from battle trauma to severe sepsis, including from battle trauma to severe sepsis, pancreatitis, massive transfusions etcpancreatitis, massive transfusions etc

In 1967, Ashbaugh et al become the first to describe the In 1967, Ashbaugh et al become the first to describe the syndrome which they referred to as adult respiratory syndrome which they referred to as adult respiratory distress syndrome in 12 such patients (1)distress syndrome in 12 such patients (1)

Historical BackgroundHistorical Background

in 1971, Ashbaugh and Petty further defined the in 1971, Ashbaugh and Petty further defined the syndrome in a form that summarized the clinical features syndrome in a form that summarized the clinical features well (but lacked specific criteria to identify pts well (but lacked specific criteria to identify pts systematically) (2)systematically) (2)

                -  severe dyspnea-  severe dyspnea        -  cyanosis refractory to O2        -  cyanosis refractory to O2        - decreased pulm compliance        - decreased pulm compliance        - diffuse alveolar infiltrates on CXR        - diffuse alveolar infiltrates on CXR        - atelectasis, vascular congestion, hemorrhage,         - atelectasis, vascular congestion, hemorrhage, pulm edema and hyaline membranes at autopsypulm edema and hyaline membranes at autopsy

Historical BackgroundHistorical Background

in 1988, a more expanded definition was proposed that in 1988, a more expanded definition was proposed that quantified the physiologic respiratory impairment through quantified the physiologic respiratory impairment through the use of 4-point lung injury scoring system (3)the use of 4-point lung injury scoring system (3)        - level of PEEP        - level of PEEP        - P/F RATIO            - P/F RATIO            - static lung compliance        - static lung compliance        - degree of infiltration on CXR        - degree of infiltration on CXR        - *also included nonpulm organ dysfunction        - *also included nonpulm organ dysfunction

This definition still had its shortcomings in that it specific This definition still had its shortcomings in that it specific criteria to r/o cardiogenic pulm edema and is not criteria to r/o cardiogenic pulm edema and is not predictive of outcomespredictive of outcomes

Historical BackgroundHistorical Background 1994 American - European Consensus Conference 1994 American - European Consensus Conference

Committee (AECC)  came up with definition that became Committee (AECC)  came up with definition that became widely acceptedwidely accepted

also changed the name to acute respiratory distress also changed the name to acute respiratory distress syndrome from adult respiratory distresssyndrome from adult respiratory distress

defined it as a spectrum of ALIdefined it as a spectrum of ALI        - Acute onset        - Acute onset        - bilateral infiltrates on CXR        - bilateral infiltrates on CXR        - PCWP =< 18 mmHg        - PCWP =< 18 mmHg        - P/F ratio =< 200        - P/F ratio =< 200( ALI if P/F ratio =< 300 )( ALI if P/F ratio =< 300 )

EpidemiologyEpidemiology the problem has always been how to identify the casesthe problem has always been how to identify the cases

attempts at extrapolating incidences based on the variousattempts at extrapolating incidences based on the variousdefinitions offered above have resulted in various numbers (1.5-8.3 - definitions offered above have resulted in various numbers (1.5-8.3 - 75/100,000)75/100,000)

the first study using the 1994 AECC definition was done inthe first study using the 1994 AECC definition was done inScandinavia (reported incidence of Scandinavia (reported incidence of 17.6/100,000 for ALI and17.6/100,000 for ALI and13.5/100,000 for ARDS13.5/100,000 for ARDS (4) (4)

More recently the ARDSNet study (done in King County, More recently the ARDSNet study (done in King County, Washington 4/1999-7/2000) reported much higher numbers for age-Washington 4/1999-7/2000) reported much higher numbers for age-adjusted incidence (5)adjusted incidence (5)        -  ALI -         -  ALI - 86.2/100,000 person-yrs86.2/100,000 person-yrs (reaching 306 in ages 75-84) (reaching 306 in ages 75-84)        -  estimated annually cases base on these stats 190,600        -  estimated annually cases base on these stats 190,600        -  mortality 74, 500/yr        -  mortality 74, 500/yr

Morbidity and MortalityMorbidity and Mortality

prior to ARDSNet study - mortality rate for ARDS prior to ARDSNet study - mortality rate for ARDS has been estimated at 40-70%has been estimated at 40-70%

ARDSNet found a much lower overall mortality ARDSNet found a much lower overall mortality rate 30-40% (6)rate 30-40% (6)

notable that MR increases with age: 24 % ages notable that MR increases with age: 24 % ages 15-19 and 60 % in > 85 yrs15-19 and 60 % in > 85 yrs

2/2 co-morbid conditions2/2 co-morbid conditions Mortality is attributable to sepsis or multiorgan Mortality is attributable to sepsis or multiorgan

dysfunctiondysfunction

Morbidity and MortalityMorbidity and Mortality

MorbidityMorbidity

- prolonged hospital course- nosocomial - prolonged hospital course- nosocomial infections especially VAPinfections especially VAP

- wt loss- wt loss - muscle weakness- muscle weakness - functional impairment in months following- functional impairment in months following

CausesCauses

DIRECT LUNG INJURYDIRECT LUNG INJURYCOMMONCOMMON PNAPNA AspirationAspiration

LESS COMMONLESS COMMON Pulm contusionPulm contusion Fat emboliFat emboli Near-drowningNear-drowning Inhalation injuryInhalation injury Reperfusion injury (transplant Reperfusion injury (transplant

etc)etc)

INDIRECT LUNG INJURYINDIRECT LUNG INJURYCOMMONCOMMON Sepsis*Sepsis* Severe trauma with shock and Severe trauma with shock and

multiple transfusionsmultiple transfusions

LESS COMMONLESS COMMON Cardiopulm bypassCardiopulm bypass Acute pancreatitisAcute pancreatitis TransfusionsTransfusions Drug overdoseDrug overdose

PathophysiologyPathophysiology

Diffuse alveolar damageDiffuse alveolar damage

Lung capillary damageLung capillary damage

Inflammation/pulm edema*Inflammation/pulm edema*

Resulting severe hypoxemia and Resulting severe hypoxemia and decreased lung compliancedecreased lung compliance

PathophysiologyPathophysiology

Occurs in stagesOccurs in stages

1.1. Exudative ( Acute Phase)Exudative ( Acute Phase)

2.2. ProliferativeProliferative

3.3. FibroticFibrotic

4.4. RecoveryRecovery

Exudative phase (Acute Phase)Exudative phase (Acute Phase)

Alveolar-capillary barrier is formed by Alveolar-capillary barrier is formed by microvascular endothelium and alveolar microvascular endothelium and alveolar epitheliumepithelium

Under normal conditions epithelial barrier Under normal conditions epithelial barrier is much less permeable than endotheliumis much less permeable than endothelium

Epithelium is made up of type I and II cellsEpithelium is made up of type I and II cells Type I cells are injured easily and Type II Type I cells are injured easily and Type II

cells are more resistantcells are more resistant

Exudative PhaseExudative Phase

In ALI/ARDS – damage to either one occurs In ALI/ARDS – damage to either one occurs resulting in increased permeability of the barrierresulting in increased permeability of the barrier

influx of protein-rich edema fluid into the alveolar influx of protein-rich edema fluid into the alveolar spacespace

Injury of Type I cells results loss of epithelial Injury of Type I cells results loss of epithelial integrity and fluid extravasation (edema)integrity and fluid extravasation (edema)

Injury of Type II cells then impairs the removal of Injury of Type II cells then impairs the removal of the edema fluidthe edema fluid

Exudative PhaseExudative Phase

Dysfunction of Type II cells also leads to Dysfunction of Type II cells also leads to reduced production and turnover of surfactant reduced production and turnover of surfactant which leads to alveolar collapsewhich leads to alveolar collapse

If severe injury to epithelium occurs – If severe injury to epithelium occurs – disorganized/insufficient epithelial repair occurs disorganized/insufficient epithelial repair occurs resulting in fibrosisresulting in fibrosis

In addition to inflammatory process, there is In addition to inflammatory process, there is evidence that the coagulation system is also evidence that the coagulation system is also involvedinvolved

Exudative PhaseExudative Phase

Fibrotic PhaseFibrotic Phase

After acute phase, some pt will have After acute phase, some pt will have uncomplicated course and rapid resolutionuncomplicated course and rapid resolution

Some pts will progress to fibrotic lung Some pts will progress to fibrotic lung injuryinjury

Such injury occurs histologically as early Such injury occurs histologically as early as 5-7 daysas 5-7 days

Fibrotic PhaseFibrotic Phase

Intense inflammation leads to obliteration of the Intense inflammation leads to obliteration of the normal lung architecturenormal lung architecture

Alveolar space is filled with mesenchymal cells Alveolar space is filled with mesenchymal cells and their productsand their products

Reepithelialization and new blood vessel Reepithelialization and new blood vessel formation occurs in disorganized mannerformation occurs in disorganized manner

Fibroblasts also proliferate, collagen is Fibroblasts also proliferate, collagen is deposited resulting in thickening of interstitiumdeposited resulting in thickening of interstitium

Fibrosing alveolitisFibrosing alveolitis and cyst formation and cyst formation

Proliferative PhaseProliferative Phase

With intervention (mechanical ventilation) With intervention (mechanical ventilation) there is clearance of alveolar fluid there is clearance of alveolar fluid

Soluble proteins are removed by diffusion Soluble proteins are removed by diffusion between alveolar epithelial cellsbetween alveolar epithelial cells

Insoluble proteins are removed by Insoluble proteins are removed by endocytosis and transcytosis through endocytosis and transcytosis through epithelial cells and phagocytosis through and phagocytosis through macrophagesmacrophages

Proliferative PhaseProliferative Phase

Type II cells begin to differentiate into Type II cells begin to differentiate into Type I cells and reepithelialize denuded Type I cells and reepithelialize denuded alveolar epitheliumalveolar epithelium

Further epithelialization leads to increased Further epithelialization leads to increased alveolar clearancealveolar clearance

Proliferative PhaseProliferative Phase

ConsequencesConsequences

Impaired gas exhangeImpaired gas exhange leading to severe leading to severe hypoxemia - 2/2 ventilation-perfusion mismatch, hypoxemia - 2/2 ventilation-perfusion mismatch, increase in physiologic deadspaceincrease in physiologic deadspace

Decreased lung complianceDecreased lung compliance – due to the – due to the stiffness of poorly or nonaerated lungstiffness of poorly or nonaerated lung

Pulm HTNPulm HTN – 25% of pts, due to hypoxic – 25% of pts, due to hypoxic vasoconstriction, Vascular compression by vasoconstriction, Vascular compression by positive airway compression, airway collapse positive airway compression, airway collapse and lung parenchymal destruction and lung parenchymal destruction

Clinical FeaturesClinical Features

Pts are critically illPts are critically ill develop rapidly worsening tachypnea, dyspnea, develop rapidly worsening tachypnea, dyspnea,

hypoxiahypoxia requiring high conc of O2 requiring high conc of O2 Occurs within hours to days ( usually12-48 Occurs within hours to days ( usually12-48

hours) of inciting eventhours) of inciting event Early clinical features reflects precipitants of Early clinical features reflects precipitants of

ARDSARDS Physical exam shows cyanosis, tachycardia, Physical exam shows cyanosis, tachycardia,

tachypnea and diffuse rales and other signs of tachypnea and diffuse rales and other signs of inciting eventinciting event

Work UpWork Up

ARDS is a clinical diagnosis ARDS is a clinical diagnosis No specific lab abnormality beyond No specific lab abnormality beyond

disturbance in gas exchange is evidentdisturbance in gas exchange is evident Radiologic findings may be consistent but Radiologic findings may be consistent but

not diagnosticnot diagnostic w/u therefore is useful in identifying w/u therefore is useful in identifying

inciting event or excluding other causes of inciting event or excluding other causes of lung injurylung injury

Work UpWork UpUseful diagnostic workup may includeUseful diagnostic workup may include

- - CBC, Renal panel, Coags, LFTs, pancreatitic enzymes, CBC, Renal panel, Coags, LFTs, pancreatitic enzymes, UAUA

- Blood cx, urine cxBlood cx, urine cx

- Tox screenTox screen

- BNP (low BNP may point to ARDS) (8)BNP (low BNP may point to ARDS) (8)

- TTETTE

- CXRCXR

- CTCT

- Bronchoscopy/BALBronchoscopy/BAL

- CVP, PCWPCVP, PCWP

CXR findingsCXR findingsdiffuse, fluffy alveolar infiltrates with prominent air diffuse, fluffy alveolar infiltrates with prominent air

bronchogramsbronchograms

CT findingsCT findings

TreatmentTreatment

No specific therapy for ARDS existsNo specific therapy for ARDS exists

Mainstay of treatment is supportive careMainstay of treatment is supportive care

Treat underlying/inciting conditionsTreat underlying/inciting conditions

Treatment – FluidsTreatment – Fluids

ARDSNet study comparing a conservative and a ARDSNet study comparing a conservative and a liberal fluid stategies (9)liberal fluid stategies (9)

Rationale behind this study is decreasing pulm Rationale behind this study is decreasing pulm edema by restricting fluidsedema by restricting fluids

Randomized, using explicit protocols applied for Randomized, using explicit protocols applied for 7 days in 1000 pts in ALI7 days in 1000 pts in ALI

Randomization was into fluid liberal vs fluid Randomization was into fluid liberal vs fluid conservative conservative

Primary end point was death at 60 daysPrimary end point was death at 60 days Secondary end points included vent-free days, Secondary end points included vent-free days,

organ failure free daysorgan failure free days

Treatment – FluidsTreatment – Fluids

Study did not show any significant difference in 60 day Study did not show any significant difference in 60 day mortalitymortality

However pts treated with fluid conservative strategy had However pts treated with fluid conservative strategy had an improved oxygenation index and lung injury score an improved oxygenation index and lung injury score

In addition, there was an increased in vent-free days In addition, there was an increased in vent-free days without increase in nonpulm organ failureswithout increase in nonpulm organ failures

Also noted in this study is that in fluid conservative group Also noted in this study is that in fluid conservative group the fluid balance was more even than negative which the fluid balance was more even than negative which may indicate the observed benefit may be may indicate the observed benefit may be underestimated underestimated

Treatment - VentilationTreatment - Ventilation

Goals of ventilation in ARDS are to:Goals of ventilation in ARDS are to: Maintain oxygenation by keeping O2 sats Maintain oxygenation by keeping O2 sats

at 85-90%at 85-90% Avoiding oxygen toxicity and Avoiding oxygen toxicity and

complication of mechanical ventilation – complication of mechanical ventilation – decreasing FiO2 to less than 65% within decreasing FiO2 to less than 65% within the 1the 1stst 24-48 hours 24-48 hours

Treatment - VentilationTreatment - Ventilation

Known – TV in normal persons at rest is 6-Known – TV in normal persons at rest is 6-7ml/kg7ml/kg

But historically TV of 12-15ml/kg was But historically TV of 12-15ml/kg was recommended in ALI/ARDSrecommended in ALI/ARDS

It was also recognized this strategy of high It was also recognized this strategy of high TV causes Vent-associated lung injury as TV causes Vent-associated lung injury as early as 1970searly as 1970s

Then came the land mark ARDSNet study Then came the land mark ARDSNet study which compared traditional TV to lower TVwhich compared traditional TV to lower TV

Treatment – VentilationTreatment – VentilationARDSNet ( low vs traditional TV)ARDSNet ( low vs traditional TV)

861 pts with ALI/ARDS at 10 centers861 pts with ALI/ARDS at 10 centers Patients randomized to tidal volumes of 12 Patients randomized to tidal volumes of 12

mL /kg or 6 mL /kg or 6 ml/kg (volumeml/kg (volume control, assist control, assist control)control)

In group receiving lower TV, plateau In group receiving lower TV, plateau pressure cannot exceed 30 cm H2Opressure cannot exceed 30 cm H2O

22% reduction in mortality in patients 22% reduction in mortality in patients receiving smaller tidal volumereceiving smaller tidal volume

Number-needed to treat: 12 patientsNumber-needed to treat: 12 patients

ARDSNet ARDSNet

6ml/kg 12m/kg PaCO2 43 ± 12 36 ±9 Respiratory rate 30 ± 7 17 ± 7 PaO2/F /FIO2 160 ± 68 177 ± 81 Plateau pressure 26 ± 7 34 ± 9 PEEP 9.2 ± 3.6 8.6 ± 4.2

ARDSNet low vs traditional TVARDSNet low vs traditional TVprotocolprotocol

* Calculated predicted body weight(pbw)* Calculated predicted body weight(pbw) male: 50+2.3[height(inches)-60]male: 50+2.3[height(inches)-60] female: 45.5+2.3[height(inches)-60]female: 45.5+2.3[height(inches)-60]Mode: Volume assist-controlMode: Volume assist-controlChange rate to adjust minute ventilation (not>35/min)Change rate to adjust minute ventilation (not>35/min)PH goal 7.30-7.45PH goal 7.30-7.45Plateau press<30cmh20Plateau press<30cmh20PaOPaO22 goal: 55-80mmhg or SpO goal: 55-80mmhg or SpO22 88-95% 88-95%FiOFiO22/PEEP combination to achieve oxygenation goal./PEEP combination to achieve oxygenation goal.

Treatment - Ventilation Treatment - Ventilation What about PEEP?What about PEEP?

Another ARDS net study compared higher Another ARDS net study compared higher vs lower PEEP in ARDSvs lower PEEP in ARDS

This study was conducted because of the This study was conducted because of the observation that low tidal volume pt observation that low tidal volume pt required high PEEP and this may have required high PEEP and this may have contributed improved survivalcontributed improved survival

In the same token, there has always been In the same token, there has always been a concern that high levels of PEEP may a concern that high levels of PEEP may contribute to vent-associated lung injurycontribute to vent-associated lung injury

Treatment - Ventilation Treatment - Ventilation What about PEEP? What about PEEP?

Another multicentered, randomized study involved 549 Another multicentered, randomized study involved 549 ptspts

Low Tidal volume strategy - calculated predicted body Low Tidal volume strategy - calculated predicted body weight (pbw)weight (pbw)

male: 50+2.3[height(inches)-60]male: 50+2.3[height(inches)-60] female: 45.5+2.3[height(inches)-60]female: 45.5+2.3[height(inches)-60]Mode: Volume assist-controlMode: Volume assist-controlChange rate to adjust minute ventilation(not>35/min)Change rate to adjust minute ventilation(not>35/min)PH goal 7.30-7.45PH goal 7.30-7.45Plateau press<30cmh20Plateau press<30cmh20PaOPaO22 goal: 55-80mmhg or SpO goal: 55-80mmhg or SpO22 88-95% 88-95%FiOFiO22/PEEP combination to achieve oxygenation goal/PEEP combination to achieve oxygenation goal

Treatment - Ventilation Treatment - Ventilation What about PEEP?What about PEEP?

Result of the study showed no benefit from Result of the study showed no benefit from higher levels of PEEP in either mortality or higher levels of PEEP in either mortality or secondary outcomes ( vent- free days, icu-secondary outcomes ( vent- free days, icu-free stays or organ failure)free stays or organ failure)

No significant increase in lung injury was No significant increase in lung injury was noted either noted either

So PEEP really does not matter!So PEEP really does not matter!

How to select vent settingsHow to select vent settings

PEEP/FiOPEEP/FiO22 relationship to maintain relationship to maintain adequate PaOadequate PaO22/SpO/SpO22

PaOPaO22 goal: 55-80mmHg or SpO2 88-95% goal: 55-80mmHg or SpO2 88-95% use FiO2/PEEP combination to achieve use FiO2/PEEP combination to achieve oxygenation goaloxygenation goal

How to select vent settingsHow to select vent settings

other ventilation strategiesother ventilation strategies

Recruitment maneuversRecruitment maneuvers

ProneProne

Inhaled nitric oxideInhaled nitric oxide

High frequency oscillationHigh frequency oscillation

Treatment Treatment

Treatment strategy is one of low volume and high frequency Treatment strategy is one of low volume and high frequency ventilation (ARDSNet protocol)ventilation (ARDSNet protocol)- Low Vt (6ml/kg) to prevent over-distention- Low Vt (6ml/kg) to prevent over-distention- increase respiratory rate to avoid very high level of hypercapnia- increase respiratory rate to avoid very high level of hypercapnia- PaCO- PaCO22 allowed to rise, usually well tolerated allowed to rise, usually well tolerated- May be beneficial- May be beneficial- low CVPs - low CVPs

Search for and treat the underlying cause; surgery if neededSearch for and treat the underlying cause; surgery if needed Ensure adequate nutrition and place on GI/DVT prophylaxisEnsure adequate nutrition and place on GI/DVT prophylaxis Prevent and treat nosocomial infxPrevent and treat nosocomial infx Consider short course of high dose steroids in pts w/ severe dz that Consider short course of high dose steroids in pts w/ severe dz that

is not resolvingis not resolving. .

ARDSnet and Long-term outcomeARDSnet and Long-term outcome

120pts randomized to low Vt or high Vt 120pts randomized to low Vt or high Vt a) 25%mortality w/ low tidal volumea) 25%mortality w/ low tidal volume b) 45% mortality w/ high tidal volumeb) 45% mortality w/ high tidal volume 20% had restricitve defect and 20% had obstructive defect 1 yr after 20% had restricitve defect and 20% had obstructive defect 1 yr after

recoveryrecoveryAbout 80% had DLCO reduction 1 yr after recoveryAbout 80% had DLCO reduction 1 yr after recoveryStandardized tested showed health-related quality of life lower than Standardized tested showed health-related quality of life lower than

normalnormalNo difference in long-term outcomes between tidal volume groupNo difference in long-term outcomes between tidal volume group

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Lancet 1967; 2: 319-23Lancet 1967; 2: 319-232. Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors 2. Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors

influencing prognosis and principles of management. Chest 1971; 60:233-9influencing prognosis and principles of management. Chest 1971; 60:233-93. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of adult respiratory 3. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of adult respiratory

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6.6. Davidson TA, Caldwell ES, Curtis JR. Reduced quality of life in survivors of acute Davidson TA, Caldwell ES, Curtis JR. Reduced quality of life in survivors of acute respiratory distress syndrome compared withcritically ill control patients. JAMA. Jan 27 respiratory distress syndrome compared withcritically ill control patients. JAMA. Jan 27 1999;281(4):354-601999;281(4):354-60

7.7. Ware LB, Matthay MA. The acute respiratory distress syndrome. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J MedN Engl J Med. May . May 4 2000;342(18):1334-49.4 2000;342(18):1334-49.

8. Levitt JE, Vinayak AG, Gehlbach BK, et al. Diagnostic utility of BNP in critically ill patients 8. Levitt JE, Vinayak AG, Gehlbach BK, et al. Diagnostic utility of BNP in critically ill patients with pulmonary edema: a prospective cohort study. Crit Care 2008; 12: R3with pulmonary edema: a prospective cohort study. Crit Care 2008; 12: R3

ReferencesReferences9.9. The NHLBI ARDS Clinical Trials Network. Comparison of two fluid-management The NHLBI ARDS Clinical Trials Network. Comparison of two fluid-management

strategies inacute lung injury. strategies inacute lung injury. N Engl J MedN Engl J Med. Jun 15 2006;354(24):2564-75. Jun 15 2006;354(24):2564-75

10.10. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distres syndrome. respiratory distres syndrome. N Engl J MedN Engl J Med. May 4 2000;342(18):1301-8. May 4 2000;342(18):1301-8

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