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Summary Table

Domain	High-Yield Detail
Risk Factors	Sepsis (most common cause overall), pneumonia, aspiration of gastric contents, acute pancreatitis, polytrauma, near-drowning, transfusion-related acute lung injury (TRALI), smoke inhalation, drug overdose
Etiology	Diffuse alveolar damage from direct pulmonary insult (pneumonia, aspiration) or indirect systemic insult (sepsis, pancreatitis, transfusion) leading to non-cardiogenic pulmonary edema
Patient Presentation	Acute onset of progressive dyspnea and hypoxemia developing within 1 week of a recognized clinical insult; refractory to supplemental oxygen
Classic Physical Exam	Tachypnea, labored breathing with accessory muscle use, diffuse bilateral crackles on auscultation, cyanosis; notably absent jugular venous distension, S3 gallop, or peripheral edema (distinguishing from cardiogenic pulmonary edema)
Key Diagnostic Results	$PaO_2/FiO_2 \leq 300$ mmHg on PEEP $\geq 5$ cmH$_2$O; bilateral opacities on chest radiograph not explained by effusion or atelectasis; ABG showing hypoxemia with widened $A\text{-}a$ gradient
Management	Low tidal volume ventilation ($6\ mL/kg$ ideal body weight), plateau pressure $< 30$ cmH$_2$O, prone positioning for severe cases, conservative fluid strategy, treat underlying cause
Keywords	"Bilateral white-out," "refractory hypoxemia," "non-cardiogenic pulmonary edema," "recent sepsis/pneumonia/aspiration," "diffuse alveolar damage," "hyaline membranes"

1. Pathophysiology

ARDS represents the lung's stereotyped inflammatory response to a variety of insults, whether originating from within the lung (direct injury) or from distant organ systems (indirect injury). The unifying pathology is diffuse alveolar damage (DAD), which progresses through three overlapping phases.

In the exudative phase (days 1 to 7), the triggering insult activates alveolar macrophages and recruits neutrophils into the pulmonary microvasculature. These neutrophils release reactive oxygen species, proteases, and pro-inflammatory cytokines (IL-1, IL-6, IL-8, TNF-alpha) that injure both the capillary endothelium and the alveolar epithelium. This dual injury disrupts the normally tight alveolar-capillary barrier, allowing protein-rich edema fluid to flood the alveolar spaces. The leaked plasma proteins, combined with necrotic cellular debris from damaged type I pneumocytes, polymerize along the alveolar surface to form hyaline membranes, which are the histological hallmark of ARDS. Simultaneously, injury to type II pneumocytes reduces surfactant production, increasing alveolar surface tension and promoting widespread alveolar collapse (atelectasis).

This combination of flooded and collapsed alveoli creates regions of the lung where blood flows through capillaries but encounters no ventilated alveolar units. This is true intrapulmonary shunt ($V/Q = 0$), which is the reason hypoxemia in ARDS is refractory to supplemental oxygen. Unlike hypoxemia from V/Q mismatch (which responds to increased $FiO_2$), shunt-mediated hypoxemia cannot be corrected by simply delivering more oxygen because the gas never reaches the blood. This concept is central to understanding why these patients require positive pressure ventilation with PEEP rather than a nasal cannula or face mask.

During the proliferative phase (days 7 to 21), the lung attempts repair. Type II pneumocytes proliferate and differentiate into type I cells to re-establish the alveolar lining. Fibroblasts begin organizing the intra-alveolar exudate. Some patients recover during this phase, while others progress.

In the fibrotic phase (beyond day 21), a subset of patients develops extensive interstitial fibrosis and architectural distortion. This leads to reduced lung compliance, persistent ventilator dependence, and a poor prognosis. The presence of this late fibrotic remodeling explains why survivors of prolonged ARDS may have lasting impairment in pulmonary function.

2. Classification and Clinical Manifestation

Berlin Definition Classification (2012)

The Berlin criteria replaced the older American-European Consensus Conference (AECC) definition. Classification is based entirely on the severity of oxygenation impairment, measured by the $PaO_2/FiO_2$ (P/F) ratio while the patient receives a minimum PEEP of $\geq 5$ cmH$_2$O.

Severity	$PaO_2/FiO_2$ Ratio	Mortality	Clinical Implication
Mild	$200 < P/F \leq 300$	~27%	May be managed with non-invasive ventilation in select cases; often underrecognized
Moderate	$100 < P/F \leq 200$	~32%	Requires invasive mechanical ventilation; consider prone positioning
Severe	$P/F \leq 100$	~45%	Mandatory prone positioning; consider neuromuscular blockade and ECMO referral

Berlin Criteria Components

Criterion	Requirement
Timing	Onset within 1 week of a known clinical insult, or new/worsening respiratory symptoms
Chest Imaging	Bilateral opacities on CXR or CT not fully explained by pleural effusions, lobar collapse, or nodules
Origin of Edema	Respiratory failure not fully explained by cardiac failure or volume overload; requires objective assessment (e.g., echocardiography) if no identifiable risk factor is present
Oxygenation	$PaO_2/FiO_2 \leq 300$ mmHg with PEEP (or CPAP) $\geq 5$ cmH$_2$O

Direct vs. Indirect Causes

Type	Mechanism	Examples
Direct (Pulmonary)	Insult originates within the lung parenchyma	Pneumonia (bacterial, viral, fungal), aspiration of gastric contents, pulmonary contusion, inhalation injury, near-drowning
Indirect (Extrapulmonary)	Systemic inflammatory response damages the lung remotely	Sepsis (non-pulmonary source), severe acute pancreatitis, TRALI, major burns, fat embolism, DIC

3. Diagnostic Workup

Test	Purpose	Key Findings
Arterial Blood Gas (ABG)	Quantify oxygenation and ventilation	Hypoxemia ($PaO_2 < 60$ mmHg), widened $A\text{-}a$ gradient, early respiratory alkalosis progressing to respiratory acidosis
Chest Radiograph (CXR)	Identify bilateral opacities	Diffuse bilateral infiltrates ("white-out"), absence of cardiomegaly
CT Chest	Characterize distribution of disease	Heterogeneous pattern: dependent consolidation, non-dependent ground-glass opacities, normal-appearing lung interspersed
Echocardiography	Exclude cardiogenic cause	Normal LV function, no elevated left atrial pressure, absence of severe valvular disease
BNP / NT-proBNP	Differentiate from heart failure	Low or normal values favor ARDS over cardiogenic edema
Pulmonary Artery Catheter	Measure wedge pressure (rarely used now)	PCWP $\leq 18$ mmHg confirms non-cardiogenic origin
Cultures / Infectious Workup	Identify treatable underlying cause	Blood cultures, sputum culture, respiratory viral panel, procalcitonin

The diagnostic approach to ARDS is fundamentally clinical, meaning there is no single confirmatory laboratory test or biopsy required. The diagnosis is established by demonstrating that the patient meets all four Berlin criteria simultaneously.

The best initial step when you suspect ARDS is obtaining an ABG and a chest radiograph together. The ABG will reveal the degree of hypoxemia and allow calculation of the P/F ratio, which is the cornerstone of diagnosis and severity classification. The $A\text{-}a$ gradient will be elevated, confirming that the hypoxemia is due to a parenchymal process rather than hypoventilation. Early in the course, the ABG often shows a respiratory alkalosis (low $PaCO_2$) from compensatory tachypnea; progression to respiratory acidosis indicates fatigue or worsening disease.

The chest radiograph should show bilateral opacities that cannot be fully accounted for by pleural effusions, atelectasis, or lung nodules. In classic presentations, the CXR demonstrates diffuse "white-out" involving both lung fields. However, early or mild ARDS may present with patchy bilateral infiltrates that can be subtle.

A CT scan of the chest is not required for diagnosis but provides important information. It reveals the heterogeneous nature of ARDS: consolidation predominates in dependent (posterior) lung regions due to gravitational effects on the edematous lung, while non-dependent (anterior) regions may show ground-glass opacities or even relatively normal-appearing lung. This heterogeneity is the physiological rationale behind prone positioning, as flipping the patient redistributes perfusion toward the better-aerated anterior lung.

Echocardiography is essential to exclude cardiogenic pulmonary edema, which is the primary differential diagnosis. The Berlin criteria require objective exclusion of cardiac failure if no clear ARDS risk factor is identified. Echo showing normal LV systolic function and no evidence of elevated left-sided filling pressures supports ARDS. A low BNP or NT-proBNP further supports the non-cardiogenic origin, though values can overlap in critically ill patients.

The pulmonary artery catheter (Swan-Ganz) demonstrating a pulmonary capillary wedge pressure (PCWP) $\leq 18$ mmHg was previously considered a defining feature under the AECC criteria. The Berlin definition no longer mandates catheterization, but the concept remains testable: ARDS produces low-pressure pulmonary edema in contrast to heart failure.

Finally, identifying the underlying cause is critical for management. Blood cultures, sputum cultures, and relevant imaging should be pursued to guide targeted therapy (e.g., antibiotics for pneumonia or sepsis).

4. Management and Treatment

Intervention	Details	Key Trial / Evidence
Low Tidal Volume Ventilation	$V_T = 6\ mL/kg$ ideal body weight; plateau pressure $< 30$ cmH$_2$O	ARDSNet / ARMA trial
PEEP Titration	Higher PEEP to recruit collapsed alveoli; target $SpO_2$ 88-95% or $PaO_2$ 55-80 mmHg	ARDSNet PEEP-$FiO_2$ table
Prone Positioning	$\geq 16$ hours/day for moderate-severe ARDS ($P/F < 150$)	PROSEVA trial
Conservative Fluid Strategy	Target even to negative fluid balance once hemodynamically stable	FACTT trial
Neuromuscular Blockade	Cisatracurium 15 mg bolus then 37.5 mg/hr for 48 hours in severe ARDS	ACURASYS trial (supported); ROSE trial (less definitive)
Corticosteroids	Dexamethasone 20 mg IV daily x 5 days, then 10 mg IV daily x 5 days; or methylprednisolone in early persistent ARDS	Villar (2020), Meduri studies
ECMO	Venovenous ECMO for refractory hypoxemia ($P/F < 80$) despite optimal ventilatory management	EOLIA trial
Treat the Underlying Cause	Antibiotics, source control, cessation of transfusion, etc.	Foundational principle

Acute stabilization centers on two parallel priorities: supporting gas exchange through protective mechanical ventilation and treating the precipitating cause.

Lung-protective ventilation is the single most important intervention with proven mortality benefit. The ARDSNet protocol mandates a tidal volume of $6\ mL/kg$ of ideal (predicted) body weight, NOT actual body weight. Ideal body weight is calculated using height:

$$IBW_{male} = 50 + 2.3 \times (height\ in\ inches - 60)$$

$$IBW_{female} = 45.5 + 2.3 \times (height\ in\ inches - 60)$$

The rationale is that ARDS lungs have markedly reduced aerated volume (the "baby lung" concept), so delivering conventional tidal volumes ($10\text{-}12\ mL/kg$) overdistends the remaining functional alveoli, causing ventilator-induced lung injury (VILI) through volutrauma and biotrauma. The plateau pressure must be maintained below 30 cmH$_2$O to prevent overdistension. Permissive hypercapnia (tolerating elevated $PaCO_2$ up to ~50-60 mmHg, pH $\geq 7.25$) is accepted as a trade-off for protective ventilation.

PEEP is titrated using the ARDSNet PEEP-$FiO_2$ tables to maintain $SpO_2$ between 88-95% (or $PaO_2$ 55-80 mmHg). Higher PEEP recruits collapsed alveoli, improves V/Q matching, and allows reduction in $FiO_2$ (thereby reducing oxygen toxicity). The oxygenation target is deliberately conservative; there is no benefit to achieving supranormal $PaO_2$.

Prone positioning should be initiated early (within 12 to 24 hours) in patients with moderate-to-severe ARDS ($P/F < 150$ mmHg). The PROSEVA trial demonstrated a mortality reduction from approximately 33% to 16% when patients were placed prone for at least 16 hours per day. Proning works by redistributing ventilation toward dorsal lung regions that receive preferential perfusion, reducing V/Q mismatch and improving recruitment of dependent atelectatic zones.

Conservative fluid management (as demonstrated in the FACTT trial) aims for an even or negative fluid balance once the patient is hemodynamically stable. Excess intravascular volume worsens pulmonary edema and prolongs ventilator dependence. This does not apply during active septic shock resuscitation, where initial fluid resuscitation takes priority.

Neuromuscular blockade with cisatracurium (15 mg IV bolus followed by a continuous infusion of 37.5 mg/hr for 48 hours) may be considered in early severe ARDS ($P/F < 150$). The ACURASYS trial showed mortality benefit, though the subsequent ROSE trial using a light sedation strategy in the control group did not replicate this. Blockade prevents ventilator dyssynchrony and reduces oxygen consumption, but prolonged use carries the risk of ICU-acquired weakness.

Corticosteroids remain an evolving area. Dexamethasone (20 mg IV daily for 5 days, then 10 mg IV daily for 5 days) showed mortality benefit in early moderate-to-severe ARDS. Methylprednisolone (1 mg/kg/day with taper over 2 to 3 weeks) has also been studied for persistent ARDS beyond day 7. A critical caveat: steroids should not be initiated after day 14 of ARDS onset, as late administration has been associated with worse outcomes.

Venovenous ECMO is a rescue therapy for patients with refractory hypoxemia (typically $P/F < 80$) who fail to improve despite optimal ventilation, proning, and adjunctive measures. It is best offered at experienced ECMO centers and should be considered early rather than as a last resort.

Throughout all of this, treating the underlying cause (antibiotics for infection, surgical source control, stopping a causative transfusion or drug) is non-negotiable.

Contraindications and Cautions

Scenario	Consideration
Active hemorrhagic shock	Liberal fluid resuscitation takes priority over conservative fluid strategy
Elevated intracranial pressure	Permissive hypercapnia is contraindicated; prone positioning requires caution
Unstable spine injury	Prone positioning is relatively contraindicated
Pregnancy	Use lung-protective ventilation; lateral decubitus (left lateral) positioning is preferred over prone; target $PaO_2 \geq 70$ mmHg to ensure fetal oxygenation

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Cardiogenic Pulmonary Edema	Bilateral opacities on CXR, acute dyspnea, hypoxemia	Elevated BNP, S3 gallop, JVD, peripheral edema, cardiomegaly on CXR, elevated PCWP ($> 18$ mmHg); responds to diuretics and afterload reduction
Diffuse Alveolar Hemorrhage (DAH)	Bilateral infiltrates, acute hypoxemia, may follow systemic illness	Hemoptysis (though may be absent), dropping hemoglobin without external bleeding, increasingly bloody returns on serial bronchoalveolar lavage, often in the setting of vasculitis or anticoagulation
Acute Eosinophilic Pneumonia (AEP)	Bilateral infiltrates, acute respiratory failure, young patient	Recent-onset smoking or new environmental exposure, BAL showing $> 25%$ eosinophils, dramatic response to corticosteroids, peripheral eosinophilia (may be absent initially)
Bilateral Pneumonia without ARDS	Bilateral infiltrates, hypoxemia, fever	Hypoxemia corrects with supplemental oxygen ($P/F > 300$), does not meet Berlin oxygenation criteria, lobar or segmental distribution rather than diffuse
Cryptogenic Organizing Pneumonia (COP)	Bilateral patchy infiltrates, dyspnea, may mimic ARDS on imaging	Subacute course (weeks, not days), "migratory" infiltrates, excellent response to corticosteroids, no identifiable precipitating insult in the preceding week
Pulmonary Vasculitis (e.g., GPA)	Bilateral pulmonary infiltrates, respiratory failure	Cavitary lesions, upper airway involvement (sinusitis, saddle nose), positive c-ANCA/PR3, renal involvement with active urine sediment
Transfusion-Related Acute Lung Injury (TRALI)	Bilateral infiltrates, acute hypoxemia, non-cardiogenic	Onset within 6 hours of transfusion (particularly plasma-containing products like FFP or platelets); technically a cause of ARDS but the temporal relationship to transfusion is the distinguishing feature

6. Traps and High-Yield Pearls

The most common way students miss ARDS questions is by confusing it with cardiogenic pulmonary edema. Both present with bilateral white-out on CXR and acute hypoxemia. The vignette will embed clues to differentiate: a patient with cardiogenic edema will have a history of heart failure, jugular venous distension, an S3 gallop, and peripheral edema, and will respond to diuretics. The ARDS vignette, by contrast, will describe a preceding insult (sepsis, pneumonia, pancreatitis, trauma, aspiration) with no signs of volume overload. If the question mentions a normal echocardiogram or a low BNP, it is steering you toward ARDS.

A second common trap involves the tidal volume calculation. Students frequently select $6\ mL/kg$ of actual body weight, which overestimates the appropriate tidal volume in obese patients. Lung size correlates with height, not weight. The exam will present an obese patient and test whether you calculate tidal volume using ideal body weight derived from height. An 80 kg woman who is 5'4" has an ideal body weight of approximately 54.5 kg, yielding a target tidal volume of approximately 327 mL, not 480 mL.

A third area of confusion is the oxygenation target. Students trained to normalize oxygen saturation may select interventions aiming for $SpO_2$ of 100%. In ARDS, the accepted target is $SpO_2$ 88-95% (or $PaO_2$ 55-80 mmHg). Driving for higher targets requires either higher $FiO_2$ (risking oxygen toxicity) or higher pressures (risking barotrauma and VILI), both of which worsen outcomes.

Finally, students forget the timing criterion of the Berlin definition. ARDS must develop within one week of a recognized clinical insult. A patient with bilateral infiltrates and hypoxemia developing gradually over several weeks does not meet the definition and should prompt consideration of alternative diagnoses such as interstitial lung disease, cryptogenic organizing pneumonia, or lymphangitic carcinomatosis.

The core competency tested across ARDS questions is the ability to recognize non-cardiogenic pulmonary edema following a systemic or pulmonary insult, apply the Berlin classification correctly, and select lung-protective ventilation with the appropriate tidal volume calculation as the first-line intervention.

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