JOURNAL READING STASE PULMONOLOGI

Background
Pulmonary Edema
Cardiogenic (CPE)
= Hydrostatic =
Haemodynamic

Differentiating
is challenging

Non Cardiogenic = Acute

Lung Injury (ALI) = Acute
Respiratory Distress
Syndrome (ARDS)

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Background

✘ ARDS Clinical Trial Network : fluid management to decrease cardiogenic fluid

retention and the effects of lung permeability and edema, will shorten the
duration of mechanical ventilation and intensive care without increasing non-
pulmonary organ failure

✘ The differentiation between ALI/ARDS and CPE is important in order to avoid

delaying treatment of fluid retention and avoiding unnecessary testing

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Aim of Study

Several Biomarkers to distinguish ALI/ARDS

and CPE have been reported

Systematic Review

To review published studies of potential

biomarkers to distinguish ALI/ARDS from CPE

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Methods : Systematic Review
Conducted using Guidelines : PRISMA (Preffered Reporting Items
for Systematic Reviews and Meta-analyses) & MOOSE (Meta-
analysis of Observational Studies in Epidemiology

Prospective, retrospective Cohort Studies (Pubmed, Cochrane) Full Texts

are evaluated by three investigators

Study design, sample size, diagnostic methods, assessed markers, mean

value of the markers, area under the receiver operator characteristic curve
(AUC), sensitivity, specificity

Based on guidelines for following items : selection, performance, detection,

attriction, and publication bias. Each study was reviewed for quality
(GOOD, MODERATE, POOR) based on Hayden’s Criteria

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Result: Database Research

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Systemic Biomarker
✘ BNP, most commonly assessed biomarker. The discriminatory ability varied among 4
studies (AUC 0.67–0.83)
✘ Komiya and colleagues showed that CRP (AUC was as good as BNP), and combination
of BNP and CRP was significantly higher than either BNP or CRP alone
✘ The levels of plasma CRP in patients with ALI/ARDS were significantly higher
✘ ST-2, HBP, Copeptin in single studies showed high predictive value
✘ Arif and colleagues reported that pulmonary leak index was significantly higher in
ARDS. AUC for ARDS was 0.98 for transferrin, 0.95 for total protein, and 0.80 for albumin
levels in plasma
✘ Other studies compared mean value of mucin-associated antigen in serum, or
arteriovenous differences in lactate between ALI/ARDS and CPE but the sample size for
each of these studies was small, and the methods used as the standard for diagnosis
were unclear.

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Lung Biomarker
✘ Ware and colleagues showed that the fluid-to-plasma protein ratio had
a high AUC and good sensitivity and specificity. Value > 0.65 was
associated with higher mortality and more days requiring mechanical
ventilation
✘ Schutte and colleagues reported that the protein concentration in BALF
from ALI/ARDS subjects was higher
✘ Laminin gamma-2 fragments are parts of laminin-5, which is a cellular
adhesion molecule expressed solely by epithelium, and promotes
epithelial cell migration and repair of injured epithelium The
concentration of these fragments in epithelial lining fluid from subjects
with ALI/ARDS was significantly higher and the concentration of laminin
gamma-2 fragments at 5 days after onset also was associated with
mortality
✘ In two studies, surfactant apoprotein (SP)-A was significantly greater in
BALF from subjects with CPE compared
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to those with ALI/ARDS
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Imaging
• By Chest US normal lung sliding is seen in subjects with CPE, it is absent or
decreased in subjects with ALI/ARDS.
• “B lines” on chest sonography (distinct from Kerly B lines on plain
radiography), are generated from the thickened interlobular septa (interstitial
edema) at the lung wall interface
• Sekiguchi and colleagues reported that a higher “B-line ratio” (proportion of
chest zones with positive B lines relative to all zones examined) was specific
for the diagnosis of CPE, and that findings of a left-sided pleural effusion >20
mm, moderate or severe left ventricle dysfunction, and minimal diameter of
inferior vena cava >23 mm were helpful to distinguish CPE from ALI/ ARDS
using a derived, simplified prediction score
• Some features on chest CT were reported to better differentiate ARDS from
CPE. Small ill-defined opacities, defined as patchy areas of groundglass
attenuation or airspace consolidation, and left dominant pleural effusion had
high specificity for ALI/ ARDS in a single-center retrospective study

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Discussion : Systemic
• Brain Natriuretic Peptide (BNP)
o Released from ventricle in response to volume expansion and pressure overload
o Most Common evaluated biomarker.
o Predictive ability was variable. Due to different characteristic in each study (time sampling, age, renal
failure, sepsis)  no meta analysis
• C- Reactive Protein (CRP)
o Widely used as marker of systemic inflammation.
o Not directly influenced by cardiac function
o CRP + BNP may have greater discriminatory ability than either BNP/CRP alone
• Suppresion of tumorigencity-2 (ST-2)
o IL-1 receptor familiy, mediator of inflammation and immunity
o Showed excellent discrimination
• Heparin-binding Protein (HBP)
o Antimicrobial protein stored in neutrophil granules  breakdown cell barriers and increase macromolecular efflux
• Copeptin
o C-terminal portion of AVP, secreted from neurohypophysis. Reflects inflammatory cytokine response and presence of
hemodynamic and osmoregulatory disturbances

These biomarkers appeared to be robust in discriminating ALI/ARDS vs CPE in single studies 

need to be replicated and validated

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Discussion : Lung Specific
✘ Sample size was small compared with systemic markers
✘ Airway sampling by BAL may be difficult in the ED
✘ Pulmonary edema fluid-to-plasma protein ratio has been
studied for decades as a tool in differentating ALI/ARDS
and CPE

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Discussion : Imaging

✘ Ultrasonography (US)
○ Combining Cardiac and Thoracic US 
Determining cause of Pulmonary Edema
○ Operator-skill dependent
✘ Chest CT Scan
○ Better than CXR
○ Rarely performed in ED

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Limitation of Study
Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L,
Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. Jama.
2012;307(23):2526–33.

 ALI/ARDS and CPE can coexist

Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, de Boisblanc B, Connors
Jr AF, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung
injury. N Engl J Med. 2006; 354(24):2564–75.

 Some degree of CPE is present in ALI/ARDS. PCWP is reported to be elevated 30% of ARDS
patients.
Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, de Boisblanc B, Connors
Jr AF, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung
injury. N Engl J Med. 2006; 354(24):2564–75.

 Unlike this study, mixed cases of ALI/ARDS dn CPE is included in ALI/ARDS group.
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Discussion
• ARDS Clinical Trial Network : fluid management to
decrease cardiogenic fluid retention and the effects of
lung permeability and edema, will shorten the duration
of mechanical ventilation and intensive care without
increasing non-pulmonary organ failure
• BNP could be useful for differentiating CPE from
ALI/ARDS and for initiating fluid restriction and diuretics
early to decrease the risk of CPE
• ST-2, BNP+CRP, HBP  high AUC in differentiating
ALI/ARDS from CPE. But only in one single study
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 Discussion
• All studies compared Biomarkers with clinical diagnosis
• No studies compared Clinical Diagnosis with Clinical
Diagnosis+Biomarkers
• In This study  Decision to classify as ALI/ARDS vs CPE was made by
clinical expert reviewing clinical information and response to
therapy

? Reliable in
clinical
presentation ? Decision to
therapy

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Discussion

• Given this limitation purpose of this review was to identify potential

biomarkers that would most closely correlate with expert clinical
judgement
• If these biomarkers could be then used for earlier detection and
intervention
• BNP appeared to be most useful when measured at the time of
presentation in ED and before initiating therapy

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Conclussions
• No identified biomarkers or tools with high-quality evidence for
differentiating ALI/ ARDS from CPE
• The eventual diagnosis was determined by post hoc expert
review, blinded to target marker
• However, differentiating the cause of pulmonary edema is
important because the therapy of ALI/ARDS and CPE are
fundamentally different

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Conclussions
• Although fluid restriction might be used to treat both CPE and
ARDS/ALI, early recognition of ALI/ARDS allows an emphasis on
lung-protective ventilation and in the treatment of the underlying
cause of the ARDS whilst recognition of CPE may lead to the
appropriate use of diuretics, inotropic therapy, and afterload
reduction
• Combining clinical criteria with validated biomarkers may
improve the predictive accuracy and improve the outcomes of
ALI/ARDS even it co-exists with CPE

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 THANK YOU…

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Critical Appraisal
Systematic Review
 Are The Results Valid ?
1. Was the search for relevant primary studies include in the review
detailed and exhaustive ?
2. Were the criteria used to select studies for inclusion in the review
appropriate ?
3. Were the included primary studies of high methodological quality ?
4. Were the assesments of the studies reproducible ?