Last edited: 11/5/2021

13. ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)

Acute Respiratory Distress Syndrome (ARDS) Medical Editor: Sohani Kashi Puranic

OUTLINE

I) OVERVIEW
II) DEFINITION
III) CAUSES
IV) PATHOPHYSIOLOGY
V) DIAGNOSIS
VI) TREATMENT
VII) SUMMARY
VIII) APPENDIX
IX) REVIEW QUESTIONS
X) REFERENCES

I) OVERVIEW Figure 1. Pneumonia causing ARDS

Diffuse damage to the alveolar capillary interface is the (2) Aspiration Pneumonia
main cause of Acute Respiratory Distress Syndrome Aspiration of gastric contents
(ARDS) o Gastric acid, bacteria→ Injury to lung parenchyma
It is often secondary to a variety of disease processes
including sepsis, infection, shock, trauma, aspiration,
pancreatitis, DIC, hypersensitivity reactions and drugs
Treatment includes addressing the underlying cause and
ventilation
[Pathoma]

II) DEFINITION
ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) is a
manifestation of severe ACUTE LUNG I NJURY (ALI)
ALI is characterized by the abrupt onset of hypoxemia
and bilateral pulmonary edema in absence of cardiac Figure 2. Aspiration Pneumonia causing ARDS
failure (non- cardiogenic pulmonary edema)
(3) Lung Contusions
Trauma→ Injury to lung parenchyma

The major underlying pathology in ARDS is

DIFFUSE ALVEOLAR DAMAGE

[Robbins]
Figure 3. Lung Contusions causing ARDS
III) CAUSES
(4) Near Drowning
ARDS is produced as a consequence of Acute Lung
Injury (i) Drowning in Sea Water
Injury to the lung can be
a. Direct
b. Indirect

(A) DIRECT CAUSES

(1) Pneumonia
(ii) Drowning in Fresh Water
(i) Streptococcus pneumoniae
(ii) Staphylococcus aureus
(iii) Pneumocystis jiroveci

(iv) SARS- CoV-2

(v) Mycobacterium tuberculosis

Figure 4. Near Drowning causing ARDS

Acute Respiratory Distress Syndrome (ARDS) RESPIRATORY PATHOLOGY: Note #13. 1 of 12

(5) Toxic Smoke (2) Pancreatitis

(i) Oxygen toxicity Can cause ARDS by:

(ii) Smoke (i) Release of Cytokines
(iii) Irritant gases and Chemicals (ii) Release of Pancreatic Enzymes

Both cause

(i) Capillaries to become leaky, due to:

(a) Vasodilation
(b) ↑ Vascular Permeability
(ii) Damage to:
(a) Capillary endothelium
Figure 5. Toxic Smoke causing ARDS (b) Alveolar epithelium
(B) INDIRECT CAUSES Damaged and leaky capillaries cause
Indirect causes of ARDS include systemic conditions
where there is:

These cause damage to capillary endothelium and

subsequently, alveolar epithelium
(1) Sepsis
Infectious pathogen enters the body

 IL-1
 IL-6
 TNF-α Figure 7. Acute Pancreatitis causing ARDS
(3) Multiple long bone Fractures
(i) Capillaries to become leaky, due to: Due to multiple fractures, fat globules from the medulla
leak out
(a) Vasodilation
(b) ↑ Vascular Permeability
(ii) Damage to:
(a) Capillary endothelium Damaged and leaky capillaries cause
(b) Alveolar epithelium

SEPSIS is the MOST COMMON cause of ARDS

Figure 8. Long bone fractures causing ARDS

Figure 6. Sepsis causing ARDS

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 (4) TRALI (A) INJURY TO PNEUMOCYTES
T RANSFUSION ASSOCIATED LUNG I NJURY (1) Pneumocytes
Most commonly seen in transfusions of:
Type 1 Type 2
(i) Fresh Frozen Plasma Pneumocyte Pneumocyte
(ii) Cryoprecipitate Cell Type Simple Squamous Cuboidal
Number 95% 5%
Function Production of
Gas Exchange
Surfactant
Consequence
No Gas Exchange Alveolar Collapse
of Damage
Ability to Yes, they are
No- Amitotic
Divide Stem cells
Appearance
(a) Cytokines
(b) Proteases
(c) Reactive Oxygen Species (ROS)
(2) Injury to Pneumocytes
The etiological agents cause damage to the Type I and
Type II Pneumocytes. Due to this:

(i) Triggers release of Cytokines/ Recognition particles

(ii) Cytokines activate Alveolar Macrophages
 Alveolar macrophages are activated
1. By Cytokines
2. Directly by the pathogen
 Macrophages then release:
1. IL-1
2. IL-6
3. IL-8
4. TNF-α
Figure 9. TRALI resulting in ARDS
(5) Drugs (i) Affect Endothelium
(i) Cocaine o ↑ Capillary Permeability
o ↑ Cell Adhesion Molecule (CAM)
(ii) Opioids expression
(iii) Aspirin toxicity
(ii) Activate Neutrophils
(iii) Damage channels on Type II
Pneumocytes
o When there is ↑ fluid in alveoli, the fluid is
taken up by Type II Pneumocytes by
channels and then expelled from the
alveoli
o When these channels are damaged, the
excess fluid accumulated is not
reabsorbed

(iii) These processes cause INFLAMMATION & EDEMA

Figure 10. Drugs causing ARDS

IV) PATHOPHYSIOLOGY

Figure 11. Time course for development and resolution of

ARDS
[Harrison's Principles of Internal Medicine, p. 2031 Fig. 294-1]

Figure 12. Injury to Pneumocytes

Acute Respiratory Distress Syndrome (ARDS) RESPIRATORY PATHOLOGY: Note #13. 3 of 12

 (B) EXUDATIVE PHASE
(1) IL-1, IL-6, TNF-α

(i) ↑ Capillary Permeability

(ii) ↑ Expression of Cell Adhesion Molecules

(2) IL-8
Causes Chemotaxis Figure 13. Diffuse alveolar damage. Hyaline Membrane shown
by arrows.
[Robbins & Cotran Pathologic Basis of Disease. p. 677 Fig. 15.4]
(3) Neutrophils in Alveoli

(i) Neutrophils enter Alveoli

 By action of IL-1, IL-6, TNF-α, IL-8

(ii) Degranulation of Neutrophils

 Neutrophils then release:

(a) Reactive Oxygen Species (ROS)

(b) Proteases
(c) Neutrophil Extracellular Traps (NETs)
 These damage Type I & Type II Pneumocytes

(iii) Damage of alveolar epithelium

(iv) Fluid accumulates in Alveoli
 Fluid collected in interstitium leaks into alveoli
through damaged epithelium

(v) Formation of Hyaline Membrane

 Fluid from interstitium accumulates in alveoli
 This edematous fluid contains Proteins, which
also accumulates
 Fibrin deposition occurs Figure 14. Exudative Phase with Formation of Hyaline
 Cellular debris (dead cells) collects as Type I & II Membrane
Pneumocytes are destroyed
 WBCs accumulate as they are recruited (C) PATHOGENESIS OF SIGNS AND SYMPTOMS
 Few RBCs are collected (1) Hypoxemia

(i) Damage to Type II Pneumocytes

(vi) Hypoxemia
 When Oxygen enters the alveoli, it has to pass
through a greater distance due to formation of (ii) Fluid accumulating in alveoli washes away
hyaline membrane surfactant
(iii) Surface Tension ↑

Hyaline Membrane =

Edematous Fluid + Proteins+ Fibrin+

Cellular Debris + WBCs + RBCs

Figure 15. Surfactant

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 (D) PHASE OF PROLIFERATION
(1) Resolution
LAPLACE LAW
(i) Re-epithelialization
𝟐𝟐𝟐𝟐  Repair of Type I & Type II Pneumocytes
𝑷𝑷 =
𝑹𝑹
P= Collapsing Pressure
T= Surface Tension
(ii) Removal of fluid from alveoli
R= Radius of Alveoli
 Type II Pneumocytes reabsorb the fluid and
expel it from the alveoli
When T↑, P also ↑ as it is directly
(E) PHASE OF FIBROSIS
proportional
In some cases, is granulation tissue doesn’t resolve, it
leads to fibrosis
(2) Consequences of Hypoxemia o Macrophages, Neutrophils

(i) Cyanosis
 Bluish discoloration of mucus membranes

(ii) Reflex Compensatory Mechanisms

(i) Compression of vessels
(a) Tachypnoea (ii) Makes lungs very rigid
(iii) Decreased lung compliance

(b) Tachycardia

(iii) ‘Crackles’ on Auscultation

 Fluid accumulation in alveoli
 ↑ work of respiration

Figure 17. Resolution and Fibrosis

Figure 16. Signs and Symptoms of ARDS

Acute Respiratory Distress Syndrome (ARDS) RESPIRATORY PATHOLOGY: Note #13. 5 of 12

 V) DIAGNOSIS

BERLIN CRITERIA FOR ARDS

(1) Acute Respiratory Failure

o Diagnose the initial cause. Ex, for Sepsis:

Figure 18. Acute Respiratory Failure

(2) Bilateral Opacities Figure 20. Chest X-Ray in ARDS

(ii) CT
o Imaging includes:
 GROUND- GLASS APPEARANCE
 Bilateral consolidation

Figure 19. Bilateral Opacities

(i) Chest X-Ray

CHEST X-RAY
Indications: all patients suspected of having ARDS
Findings:

(i) Acute findings (1–7 days)

 Often normal in the first 24 hours
 Diffuse bilateral symmetrical infiltrates Figure 21. CT Scan in ARDS
 In severe cases: bilateral attenuations that make
the lung appear white on x-ray (“WHITE LUNG”)
 Air bronchograms may be visible (iii) Ultrasound
 B- LINES
(ii) Intermediate (8–14 days) to late (> 15 days)
findings  Supportive evidence for ARDS:
 Typical course: Acute features remain stable, then
resolve
 Fibrotic course: RETICULAR OPACITIES begin to
appear and may become permanent

(iii) Findings supportive of ARDS rather than CHF

 Predominantly peripheral opacities
 Small or absent pleural effusions
 No cardiomegaly or septal lines
[AMBOSS]

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 (3) ↓P/F Ratio (4) Non-Cardiogenic Pulmonary Edema
Rule out cardiogenic causes of respiratory failure
𝑃𝑃 𝑃𝑃𝑃𝑃𝑃𝑃2
= (i) ECHO
𝐹𝐹 𝐹𝐹𝐹𝐹𝐹𝐹2  Left Ventricular Ejection Fraction (LVEF)- should
PAO2= Partial Pressure of Oxygen be normal
FIO2= Fraction of Inspired Oxygen
Example, normally: (ii) BNP
𝑃𝑃 100  Should be normal
= = 476
𝐹𝐹 0.21  Increased in Congestive Heart Failure (CHF)

(i) Mild ARDS

 P/F: 200-300 (iii) PCWP
𝑃𝑃 100  Pulmonary Capillary Wedge Pressure- should be
= = 250
𝐹𝐹 0.40 <18mmHg
(ii) Moderate ARDS
 Estimated by Swan Ganz Catheter
 P/F: 100-200
𝑃𝑃 100
= = 166
𝐹𝐹 0.60

(iii) Severe ARDS

 P/F: <100
𝑃𝑃 90
= = 90
𝐹𝐹 1

Figure 23. Non-Cardiogenic Pulmonary Edema

Mnemonic for Berlin Criteria
“ARDS”
Abnormal Chest X-Ray
Respiratory Failure that ensues <1 week of initial cause
Decreased P/F ratio
Should exclude CHF

Figure 22. Decreased P/F ratio

Figure 24. Diagnostic Criteria for ARDS

[Harrison's Principles of Internal Medicine, p. 2031 Table. 294-2]

Acute Respiratory Distress Syndrome (ARDS) RESPIRATORY PATHOLOGY: Note #13. 7 of 12

 VI) TREATMENT

Figure 25. Treatment of ARDS

Mild ARDS
(B) NIPPV
(1) Hemodynamically Stable
NON-I NVASIVE POSITIVE PRESSURE VENTILATION
(1) High Flow Nasal Canula (HFNC)
(2) Hemodynamically Unstable (i) ↑ flow rate of oxygen
 (50-60L/min)

(ii) ↓ Dead space

(iii) ↑ PEEP
Intubation- Lung Protective Ventilation
 POSITIVE -END EXPIRATORY PRESSURE
(1) If P/F< 150:

(i) Reduces work of breathing

(ii) Improves Oxygenation
(2) If patient has COVID, additional medications should
be given: (iv) Can control FIO2
 up to 100%
(2) Bi- Level Positive Airway Pressure (BIPAP)
Used if there is atelectasis

(i) IPAP + EPEP (PEEP)

 IPAP= I NSPIRATORY P OSITIVE AIRWAY
PRESSURE

 EPAP= EXPIRATORY P OSITIVE AIRWAY

PRESSURE

(ii) Can control FIO2

 up to 100%
Disadvantage:

 BIPAP would push the mucus down the airway,

forming a plus
 This would cause ↓↓ SpO2

Figure 26. Algorithm for Management of ARDS

[Harrison's Principles of Internal Medicine, p. 2034 Fig. 294-5]

Figure 27. NIPPV

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 (C) LUNG PROTECTIVE VENTILATION (3) FIO2

(1) Tidal Volume (TV)

Goal: ↑ FiO2
Ideal: ≥ 60%
Goal: Low TV Strategies
SpO2 target: 85-95%
Ideal: 4-6cc/kg of Ideal Body
Weight

Augments oxygenation
Tidal Volume is the best indicator for mortality

(i) Consequences of ↑ TV

(ii) Consequences of ↓ TV

Figure 29. Lung Protective Ventilation

MAINTENANCE OF PRESSURES

(i) Plateau Pressure (PPLAT)

 For measurement of degree of lung injury
 ↑ PPLAT

i. T IDAL V OLUME - most significant

ii. PEEP- when highly increased, it raises
PPLAT

 Causes lung injury

 Lower TV
Figure 28. P-V curve of lungs in a patient undergoing  If TV is at minimum, then lower PEEP
Mechanical Ventilation
[Harrison's Principles of Internal Medicine, p. 2036 Fig. 295-1] (ii) Driving Pressure (DP)
(2) Positive End-Expiratory Pressure (PEEP)  DP = PPLAT – PEEP
 When DP= 15 cmH2O, there is reduced mortality

Goal: ↑↑ PEEP
Ideal: ≥ 5cm H2O

PEEP is the pressure at the END of expiration

Function:

(i) During Inspiration

(ii) During Expiration

• This ↓ work of breathing

• Augments oxygenation
↑ PEEP ⇒ ↑O2

Acute Respiratory Distress Syndrome (ARDS) RESPIRATORY PATHOLOGY: Note #13. 9 of 12

 (D) PRONE POSITIONING (F) PARALYTICS
Prone positioning reduces mortality Lung Protective Ventilation adopts a low TV strategy
The dependent position of lungs is the Posterior Lung
Fields  Due to decreased oxygen concentration, the
patient’s body tries to respire OVER the ventilator
(1) Supine Position
 This is achieved by:
In supine position, heart presses on consolidated lung
(1) Sedation
tissue
(i) Propofol
(2) Prone Position (ii) Midazolam
In prone position, heart presses anteriorly (iii) Opioid bolus
(2) Paralysis of Respiratory Muscles

(i) Cisatracurium besylate

Figure 30. Prone Positioning

(E) INHALED PULMONARY VASODILATORS

(i) Nitric Oxide

(ii) PGI2
Figure 32. Paralytics

(G) ECMO
EXTRA CORPOREAL MEMBRANE OXYGENATION

Figure 31. Inhaled Pulmonary Vasodilators

Figure 33. ECMO

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 VII) SUMMARY
(A) CAUSES
(C) DIAGNOSIS
(1) Direct Causes Berlin Criteria
Pneumonia Acute Respiratory Failure
Aspiration pneumonia Bilateral opacities
Lung Contusions Decreased P/F ratio
Near drowning Should exclude cardiogenic causes of pulmonary edema
Toxic smoke
(D) TREATMENT
(2) Indirect causes
NIPPV
Sepsis
Pancreatitis
Multiple long bone fractures
TRALI Intubation
Drugs Lung Protective Ventilation

(B) PATHOGENESIS
Prone positioning
Inhaled pulmonary vasodilators

Paralytics

ECMO

VIII) APPENDIX

Figure 34. Pathogenesis of ARDS

The normal alveolus (left side) compared with the injured alveolus in the early phase of acute lung injury and acute respiratory distress
syndrome. IL-1, Interleukin-1; ROS, reactive oxygen species; TNF, tumor necrosis factor. (Modified with permission from Matthay MA, Ware LB, Zimmerman GA: The
acute respiratory distress syndrome, J Clin Invest 122:2731, 2012.)
[Robbins & Cotran Pathologic Basis of Disease. p. 677 Fig. 15.3]

Acute Respiratory Distress Syndrome (ARDS) RESPIRATORY PATHOLOGY: Note #13. 11 of 12

 IX) REVIEW QUESTIONS
6) A 62-year-old woman was diagnosed with ARDS was
1) What is the main pathomechanism of ARDS? put on mechanical ventilation. What is the long-term
a) Thickening of pleura complication due to her condition?
b) Diffuse alveolar damage a) Increased compliance of lung
c) Granuloma formation b) Interstitial lung disease
d) Autoimmune mechanism c) Granuloma formation
d) Sepsis
2) What does Hyaline Membrane comprise of?
a) Hyaline cartilage of trachea present within alveoli 7) A 48-year-old man comes to the ER with complaints
b) Transudate, fibrin and cellular debris of sudden onset abdominal pain, which radiates
c) Exudate, fibrin and necrotic epithelial cells through the back to the shoulders. He gives history
d) Aspirated fluid, fibrin, WBCs, RBCs of vomiting the previous day. He also complains of
nausea and dyspnea. What is the most likely finding
in this patient?
3) Which is the most common cause of ARDS?
a) Myocardial ischemia
a) Sepsis
b) Accumulation of fluid in interstitial spaces of alveoli
b) Acute Pancreatitis
c) Heart failure
c) Pneumonia
d) Thickening of pleura and accumulation of fluid in
d) Trauma
pleural cavity

4) Which is the most significant factor for maintaining

8) A patient with ARDS is started on oxygen therapy.
Plateau Pressure?
His hypoxemia however, does NOT improve. What
a) Tidal Volume
could be the reason for this, owing to the disease?
b) PEEP
a) Ventilation-perfusion mismatch
c) FIO2
b) Low concentration of oxygen given
d) Both a & b
c) Block in the tracheobronchial tree
d) Past history of asthma
5) All are signs & symptoms of ARDS, EXCEPT:
a) Cyanosis X) REFERENCES
b) Tachypnoea ● Kumar, V., Abbas, A. K., & Aster, J. C. (2021). Robbins and
c) Respiratory acidosis Cotran pathologic basis of disease (tenth edition.). Philadelphia, PA:
d) Respiratory alkalosis Elsevier/Saunders.
● Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL,
Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth
Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical; 2018
● Pathoma.com (2021)
● Le, Tao; Bhushan, Vikas; and Sochat, Matthew. First Aid for the
USMLE Step 1 2021. New York: McGraw-Hill Education, 2021.

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