Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS)

ARDS (Acute Respiratory Distress Syndrome) is a diffuse inflammatory lung injury characterized by:

Increased alveolar-capillary permeability
Non-cardiogenic pulmonary edema
Severe hypoxemia
Reduced lung compliance

Leading to acute respiratory failure requiring oxygen or ventilatory support.

Table of Contents

Berlin Definition (2012) — Diagnostic Criteria

Criterion	Requirement
Timing	Within 1 week of clinical insult or worsening respiratory symptoms
Chest Imaging	Bilateral opacities not fully explained by effusion, collapse, or nodules
Origin of edema	Respiratory failure not fully explained by cardiac failure or fluid overload or atelectasis.
Oxygenation (PEEP ≥5 cmH₂O)	Used to classify severity

Severity Classification

Severity	PaO₂/FiO₂	Mortality
Mild	200–300	~27%
Moderate	100–200	~32%
Severe	<100	~45%

(PaO₂ measured with PEEP ≥5 cmH₂O)

New Global Definition of ARDS (2023)

Developed by international critical care experts led by Luciano Gattinoni and the European Society of Intensive Care Medicine task force.

Why Was a New Definition Needed?

Limitations of the Berlin Definition:

Excluded patients on HFNC/NIV
Required PEEP ≥5 cmH₂O
Required arterial blood gas (PaO₂)
Required bilateral infiltrates on chest imaging
Poor applicability in low-resource settings
Did not recognize “early ARDS” on noninvasive support

Criterion	Requirement
Timing	Acute onset within 7 days of clinical insult OR new/worsening respiratory symptoms
Imaging	Bilateral opacities on CXR, CT, or lung ultrasound(B-lines/Consolidation)
Origin of edema	Respiratory failure not fully explained by cardiac failure or fluid overload or atelectasis.
Oxygenation impairment	Hypoxemia with positive pressure ventilation (IMV or NIV) having PEEP/CPAP ≥5 cmH₂O OR HFNC ≥30 L/min

If arterial blood gas unavailable:

SpO₂/FiO₂ (S/F ratio) may be used(when patient is on HFNC or or NIV/CPAP with at least 5 cm H 2 O PEEP and if Sp O 2 ≤ 97%)

Severity	SpO₂/FiO₂
Mild	~235–315
Moderate	~148—235
Severe	<148

Only PaO₂/FiO₂ 201–300 mmHg with PEEP/CPAP ≥5 cm H₂O(Mild ARDS) Can be diagnosed on NIV/CPAP.
For moderate -severe ARDS intubation Required.

Epidemiology

Incidence: ~10% of ICU admissions
~23% of mechanically ventilated patients

Cause	Frequency
Pneumonia	Most common
Sepsis	Second most common
Aspiration	Common
Trauma	Frequent in surgical ICU

Etiology

Direct Lung Injury (Pulmonary ARDS)	Indirect Lung Injury (Extrapulmonary ARDS)
Pneumonia (bacterial/viral/fungal)	Sepsis
Aspiration of gastric contents	Pancreatitis
Pulmonary contusion	Massive transfusion (TRALI)
Near drowning	Burns
Inhalational injury	Drug overdose
Fat embolism	Severe trauma
Reperfusion lung injury	Cardiopulmonary bypass

Pathophysiology

ARDS progresses through three overlapping phases.

Exudative Phase (Day 1–7)

Histological Hallmark-Diffuse Alveolar Damage (DAD)

Hyaline membranes
Alveolar edema
Neutrophilic infiltration

Mechanism	Effect
Capillary leak	Pulmonary edema
Surfactant dysfunction	Alveolar collapse
Neutrophil injury	Increased permeability
Fibrin deposition	Hyaline membrane formation

Proliferative Phase (Day 7–21)

Repair phase involving:

Type II pneumocyte proliferation
Fibroblast activation
Partial resolution of edema

Fibrotic Phase (Late ARDS)

Occurs in ~30–40% of patients.

Features:

Interstitial fibrosis
Pulmonary hypertension
Severe reduction in lung compliance

Pathophysiological Feature	Details
Shunt Physiology (Major Mechanism of Hypoxemia)	The dominant mechanism of hypoxemia in ARDS. Alveoli are filled with fluid, inflammatory exudate, or collapsed, while pulmonary perfusion continues. Blood passes through non-ventilated alveoli, resulting in a true intrapulmonary shunt that is often poorly responsive to oxygen therapy.
V/Q Mismatch	Some lung regions have poor ventilation but preserved perfusion, leading to ventilation-perfusion mismatch. This contributes to hypoxemia in addition to shunt physiology.
Reduced Lung Compliance	The ARDS lung becomes stiff and difficult to inflate. Causes include alveolar edema, atelectasis (alveolar collapse), and later fibrosis. Increased lung stiffness results in higher work of breathing and increased ventilatory pressures.
Pulmonary Hypertension	Common in moderate-to-severe ARDS. Mechanisms include hypoxic pulmonary vasoconstriction, pulmonary microthrombi, endothelial injury, and vascular remodeling, leading to increased pulmonary vascular resistance and right ventricular strain.
ARDS Lung Mechanics (“Baby Lung Concept”)	Introduced by Luciano Gattinoni. The functional lung available for ventilation is markedly reduced, resembling the size of a “baby lung.” Only a small portion of the lung remains aerated and available for gas exchange. Consequently, normal tidal volumes may overdistend the remaining healthy alveoli, causing ventilator-induced lung injury (VILI). This concept forms the basis for low tidal volume ventilation (≈6 mL/kg predicted body weight) in ARDS.

Clinical Features

Symptoms

Dyspnea
Tachypnea
Hypoxemia

Signs

Finding	Explanation
Tachypnea	Respiratory distress
Diffuse crackles	Alveolar edema
Cyanosis	Severe hypoxemia
Accessory muscle use	Increased work of breathing

Investigations

Arterial Blood Gas

Early:Respiratory alkalosis

Late:Severe hypoxemia—Possible respiratory acidosis

Chest X-ray

Bilateral diffuse infiltrates
“White lung”

CT Scan

Gold standard imaging. Findings:

Region	Appearance
Dependent lung	Consolidation
Nondependent lung	Ground glass
Aerated lung	“Baby lung”

Lung Ultrasound

Sign	Meaning
Multiple B-lines	Interstitial edema
Consolidation	Severe disease
Pleural line abnormalities	ARDS

Hemodynamic Assessment

To exclude cardiogenic edema.Methods:

Echocardiography
Pulmonary artery catheter (rarely used)

Differential Diagnosis

Condition	Distinguishing Feature
Cardiogenic pulmonary edema	Elevated PCWP
Diffuse alveolar hemorrhage	Hemoptysis
Acute interstitial pneumonia	Idiopathic
Pulmonary vasculitis	Autoimmune markers

Management

Lung Protective Ventilation
Established by the ARDSNet ARMA Trial.
No ventilator mode has been proven superior.The priority is lung-protective ventilation, not the specific mode.
Volume Assist-Control (VC-CMV / VC-AC)—Most commonly used mode in ARDS trials

Predicted Body Weight Formula

Male:PBW = 50 + 0.91(height cm − 152.4)
Female:PBW = 45.5 + 0.91(height − 152.4)

High-Frequency Oscillatory Ventilation(HFOV)

Trials:OSCILLATE,OSCAR Results:No benefit,Possible harm

Airway Pressure Release Ventilation (APRV),Pressure-Regulated Volume Control (PRVC)—No proven mortality benefit

Parameter	Target
Tidal volume	4–6 mL/kg PBW
Plateau pressure	<30 cmH₂O
Driving pressure	<15 cmH₂O
PEEP	Moderate–high
SpO₂:	88–95%
PaO₂:	55–80 mmHg
pH	7.30 to 7.45
respiratory rate (RR)	35 bpm(maximum)
inspiratory-to-expiratory time ratio	less than 1

What about Peak Pressure?-Although not guideline-mandated:

Ppeak <35–40 cmH₂O is commonly accepted.
If Ppeak >40–45 cmH₂O, investigate:Secretions—Bronchospasm—ETT obstruction—Pneumothorax—Excessive tidal volume—Excessive PEEP

The key question is always:What is the plateau pressure?

Peak airway pressure has no specific guideline limit because it is heavily influenced by airway resistance and does not reliably reflect alveolar overdistension.

PEEP Strategy

Purpose:Prevent alveolar collapse —Reduce atelectrauma—Reduce FiO₂ requirement—Achieve lung recruitment safely—Improve oxygenation—Reduce shunt fraction

Evidence for High vs Low PEEP

Major trials:ALVEOLI—LOVS—EXPRESS

Findings:

No major mortality benefit overall
Moderate-severe ARDS may benefit from higher PEEP
Better oxygenation and fewer rescue therapies

Meta-analysis:Severe ARDS likely benefits more from higher PEEP

Methods to Set Optimal PEEP

Optimal PEEP -The PEEP at which Driving pressure is lowest or Changes minimally despite increasing PEEP.Best physiologic marker of optimal PEEP = Highest compliance (lowest elastance)

1. ARDSNet PEEP-FiO₂ Table

Disadvantages:Can not be applicable to focal ARDS

2. Compliance Method

Increase PEEP gradually and identify best compliance.
Compliance improves with recruitment but worsens with overdistension.
Optimal PEEP:Highest static compliance
Static compliance formula: Cstat =(Pplat −PEEP)/VT
Higher compliance suggests better recruitment without excessive overdistension.

3. Driving Pressure Guided PEEP

Driving pressure:ΔP=Pplat −PEEP
Goal:Keep driving pressure < 15 cm H₂O
Lower driving pressure associated with improved survival.
If increasing PEEP:

Decreases driving pressure → beneficial recruitment
Increases driving pressure → overdistension likely

Example:Before recruitment

PEEP = 8 and Pplat = 24 and Driving pressure = 16

After increasing PEEP:PEEP = 12,Pplat = 25 but Driving pressure = 13(Driving pressure falls → recruitment occurred → beneficial.)

4. Pressure-Volume Curve Method

Identify:Lower inflection point (LIP) and Upper inflection point
Set PEEP: Slightly above LIP
Limitations: In ARDS, lung recruitment (opening of collapsed alveoli) does not occur only at the lower inflection point of the pressure-volume curve. Instead, alveoli may continue to open throughout the entire curve, even at pressures above the upper inflection point.At the same time, some already-open alveoli may become overdistended (overstretched), leading to hyperinflation, which is commonly seen on CT scans.

5. Esophageal Pressure Guided PEEP

Uses esophageal balloon to estimate pleural pressure.
Transpulmonary pressure:PL =Paw −Ppl

Useful in:

Obesity
Elevated abdominal pressure
Severe ARDS

Goal:End-expiratory transpulmonary pressure around 0–5 cm H₂O

Disadvantage-Unfortunately, a larger follow-up multicenter

randomized trial of esophageal pressure–directed PEEP for patients with moderate-to-severe ARDS failed to demonstrate a difference of mortality or ventilator free days compared with conventional PEEP titration strategies.

Permissive Hypercapnia

Allowed in ARDS ventilation.
Reason:Low tidal volume leads to CO₂ retention.
Acceptable:pH ≥ 7.20
Contraindications:Raised ICP,Severe pulmonary hypertension

Prone Positioning

Supported by the PROSEVA Trial
Indication:PaO₂/FiO₂ <150
Protocol:≥16 hours/day

Effect	Mechanism
Improves oxygenation	Better V/Q matching
Reduces mortality	Lung recruitment
Improves secretion clearance	Drainage

Neuromuscular Blockade

Used early in severe ARDS.during the first 48 hours

Evidence:ACURASYS Trial

Drug:Cisatracurium infusion (48 hrs)

Benefits:

Reduced ventilator asynchrony
Improved oxygenation

Fluid Strategy

Trial: FACTT Trial
Approach:Restrict fluid strategy after initial stabilization,can Use diuretics
Benefits:Shorter ventilation duration

Parameter	Target
Daily balance	0 to -500 mL/day
CVP	<4-8 mmHg
PAOP (if PAC used)	<8 mmHg
EVLW (PiCCO)	Reduce progressively
Lung ultrasound	Decreasing B-lines

Assess Fluid Responsiveness Before Giving Fluids

Static measures such as CVP are poor predictors.

Prefer dynamic indices:

Test	Positive Response
Passive Leg Raise	↑ SV >10%
Stroke Volume Variation	>12-13%
Pulse Pressure Variation	>13%
Echocardiography	↑ VTI >10-15%
Mini-fluid challenge	SV increase

Only give fluid if responsive.

Type of Fluids

Preferred Balanced Crystalloids

Ringer Lactate
Plasma-Lyte

Advantages:

Less hyperchloremia
Less renal vasoconstriction

ECMO

Used in refractory hypoxemia.

Evidence: EOLIA Trial

Indications:

Parameter	Threshold
PaO₂/FiO₂	<50 for >3 hrs
PaO₂/FiO₂	<80 for >6 hrs
pH	<7.25 with PaCO₂ >60

Type:VV ECMO

Recruitment Maneuvers

Transient increase in airway pressure.

Examples:

Sustained inflation(PEEP 35–45 cmH₂O and Sustained inflation 30–60 sec)
Staircase recruitment

Evidence: uncertain benefit(RMs can neither be recommended nor discouraged for all patients, but can be considered on an individualized basis for patients with life-threatening hypoxemia.)

Corticosteroids

Evidence evolving.
Recent guidelines suggest:
Dexamethasone or methylprednisolone
Benefits:

Reduced ventilation duration
Possible mortality reduction

Stress Index

Used during volume-controlled ventilation.

Evaluates the shape of the inspiratory pressure-time curve.

Interpretation

Stress Index	Meaning
<1	Tidal recruitment/collapse	Pressure curve bends downward—More alveoli opening during inspiration .Under-recruitment
1	Optimal inflation	Straight line-Meaning: Appropriate recruitment Desired target
>1	Overdistension	Pressure curve bends upward

Mechanical Power

Definition-Total energy transferred from ventilator to lung per minute.Represents cumulative risk of VILI.

Components

Mechanical power integrates:

Tidal volume
Respiratory rate
Driving pressure
PEEP
Flow
Airway pressure

into a single variable.

Simplified Formula (Volume Control)

MP=0.098×RR×VT×(Ppeak −0.5×ΔP)

Where:

MP = Mechanical Power (J/min)
RR = Respiratory Rate
VT = Tidal Volume (L)
ΔP = Driving Pressure

Interpretation

Mechanical Power	Risk
<12 J/min	Lower VILI risk
12–17 J/min	Intermediate
>17 J/min	Higher VILI risk
>20 J/min	Significant VILI risk

Why Important?

A patient may have: Safe VT or Safe Pplat but High RRo r High PEEP leading to excessive energy delivery.

Mechanical power captures the combined effect of all ventilator settings.

Adjunctive Therapies

Therapy	Role
Inhaled nitric oxide	Temporary oxygenation improvement
Prostacyclin	Pulmonary vasodilation
HFOV	Not routinely recommended

Complications

Secondary infections
ICU myopathy
Delirium
Fibrosis

ARDS Mortality Causes

Most deaths due to:

Sepsis
Multi-organ failure

NOT hypoxemia alone.

Emerging Concepts

ARDS Phenotypes

Two biological phenotypes identified:

Phenotype	Features
Hyperinflammatory	High cytokines, worse outcome
Hypoinflammatory	Better prognosis

Precision Medicine

Future therapy may involve:

Biomarker-guided treatment
Personalized ventilation

Trials in ARDS

Trial	Finding
ARDSNet ARMA	Low tidal volume reduces mortality
PROSEVA	Prone positioning improves survival
ACURASYS	Early paralysis helpful
FACTT	Conservative fluids beneficial
EOLIA	ECMO for refractory ARDS

Reference

1. Irwin & Rippe’s Intensive Care Medicine (9th Edition)

Lilly CM, Kelly WF, Irwin RS, Boyle WA III, editors. Irwin and Rippe’s Intensive Care Medicine. 9th ed. Philadelphia: Wolters Kluwer; 2023.

2. The Washington Manual of Critical Care (4th Edition)

Kollef MH, Despotovic V, Kraft BD, McDonald RK, Nguyen N, editors. The Washington Manual of Critical Care. 4th ed. Philadelphia: Wolters Kluwer; 2024.

3.Ohs manual of critical Care