Acute Lung Injury

Question 1

What is the Berlin Defintiion (2102) for ARDS with regards to:

Timing

Hypoxaemia

Origin of Oedema

Radiological abnormalities

Answer 1

Timing:

Acute onset within 1 week of known clinical insult

Hypoxaemia:

• MILD: 200 < PaO2/FiO2 ≤ 300 ; PEEP ≤ 5
• MODERATE: 100 < PaO2/FiO2 ≤ 200 ; PEEP 5-10
• SEVERE: PaO2/FiO2 ≤ 100 ; PEEP ≥ 10

Origin of Oedema:

Respiratory failure not explained by cardiac failure or fluid overload

Radiological Abnormalities:

Bilateral opacities - not explained by effusions, atelectasis or nodules

Question 2

Name some pulmonary/direct insults that increase the risk of ARDS

Answer 2

Common:

• Pneumonia
• Aspiration pneumonitis

Uncommon:

• Inhalation Injury
• Fat Emboli
• Near Drowning
• Reperfusion Injury (Iatrogenic?)

Question 3

Name some extrapulmonary/indirect insults that increase the risk of ARDS

Answer 3

Common:

• Sepsis
• Severe Trauma

Uncommon:

• Acute Pancreatitis
• Cardiopulmonary Bypass
• Transfusion-Related ALI (TRALI)
• DIC
• Burns
• Drug Overdose

Question 4

What is the biggest single risk factor for ARDS and what comes second to it?

Answer 4

Sepsis Syndrome

Transfusions

Question 5

Mortality of ARDS is 31% - 74%. The variability is due to the definition used and the fact that cause of death is usually _____. Early death is usually caused by the underlying illness or injury whilst late deaths are caused by _____ or multiorgan dysfunction.

Answer 5

Mortality of ARDS is 31% - 74%. The variability is due to the definition used and the fact that cause of death is usually non-respiratory. Early death is usually caused by the underlying illness or injury whilst late deaths are caused by sepsis or multiorgan dysfunction.

Question 6

Describe the ‘sponge’ lung concept

Answer 6

Lung parenchyma affected by the pulmonary oedema.

Gravity pulls the fluid downwards so that there is gravity-dependent atelectasis

Question 7

Patients with ARDS will almost certainly require mechanical ventilation for oxygenation. Describe how this can lead to Ventilator-Induced Lung Injury

Answer 7

VILI = Iatrogenic causes of lung injury due to:

1. Volutrauma = Lung stretch
2. Barotrauma = ↑pressure
3. Atelectorauma = repeated collapse-recruitment of lung

Question 8

Descirbe the ‘Baby’ lung concept and how this is releveant to current management

Answer 8

The baby lung refers to the small areas of lung which are aerated and that can ventilate

Ventilation pressures need to be carefully selected to avoid VILI in the aerated lungs -> lung protective ventilation (lung rest)

Question 9

The ARDS Network’s landmark study showed what?

Answer 9

Low Tidal volumes led to reduced mortality (6ml/kg vs 12ml/kg)

Question 10

Name the current treatment/supportive strategies for ARDS

Answer 10

1. Mechanical Ventilation
   
   1. ↓Tidal Volume
   2. PEEP (lung recruitment)
   3. Prone Positioning
2. ECMO
3. Pharmacological
   
   1. Neuromuscular Blockade
   2. Sedatives
   3. Inhaled NO
   4. B2 agonists (↑AFC)

ECMO = Extracorporeal Membrane Oxygenation

Question 11

How does ECMO work?

Answer 11

Catheter is inserted through the femoral vein into theinferior vena cava

Takes deoxygenated blood to an external oxygenator where gas exchange occurs

Oxygenated blood is pumped back into the heart through the internaljugular vein and superior vena cava.

Question 12

Outline the role of the pulmonary epithelium in ARDS and explain how it achieves this

Answer 12

Regulate fluid across the alevolar-capillary membrane

1. Tight Junctions
   
   1. Prevent fluid leakage in between cell spaces
   2. Tight junctions, adherens junctions, desmosomes
   3. Tight junctions linked to actin - active process to resist tension
2. Sodium transport
   
   1. ENaC takes Na from alveolar space into alveolar epithelial cell
   2. Na/K ATPase transport the Na into the capillary
   3. H2O follows

Question 13

Describe the role of neutrophils in ARDS

Answer 13

Insult to the lungs lead to CXCL8 release (neutrophil chemoattractant)

Neutrophil moves via diapedesis

It can produce elastase or MMP to break through the tight junctions between cells so that it can translocate to the parenchyma

Inhibition of these mediators do not have an effect on ARDS severity

Question 14

B2 agonists were looked at in the BALTI study to enhance alveolar fluid clearance. What was the proposed mechanism and did this work?

Answer 14

B2 agonist increased vectorial transport of Na across the epithelium

Reduced fluid BUT no improvements in:

• Oxygenation
• Mortality or ventilator-free days

Question 15

Broadly describe the resolution process in ARDS (3 phases)

Answer 15

1. Early Phase
   
   1. Removal of signal
   2. ↓Oedema
   3. ↓Inflammatory mediators
   4. ↓Leukocyte recruitment
      
      1. Neutrophil death leads to resolution of inflammation
2. Clearance Phase
   
   1. Apoptosis of recruited leukocytes
   2. Removal of cell debri
      
      1. Nautrophil uptake by macrophages leads to release of pro-resolving mediators (M2 phenotype?)
3. Restoration of function
   
   1. Proliferation
   2. Bioenergetics

Question 16

What can affect the resolution of inflammation in ARDS?

Answer 16

Secondary Insults (from VILI, Infection, aspiration)

Question 17

The alveolar epithelial cells release mediators as they are stretched. These mediators do not cuase disease until there is decompartmentalisation. Explain this concept.

Answer 17

Insults to the lung leads to the spillage of mediators into the circulation

Can lead to multi-organ failure

Question 18

Describe some feautres of the acute exudative phase of ARDS

Answer 18

1. Alveolar Capillary Membrane dysfunction
   
   1. ↑permeability
   2. ↓AFC
2. Epithelial Apoptosis
   
   1. ↑leakage past tight junctions
3. Leukocyte Recruitment
   
   1. Inflammation
4. Macrophage Activation
5. Intraalveolar coagulation

Question 19

Describe some limitations in modeling ARDS in animals

Answer 19

• Heterogeneous condition
• Species differences
  
  • Metabolism
  • Signalling
  • Cellular Phenotypes
• Difficult modeling of co-morbidities

Question 20

Describe the fibro-proliferative phase of ARDS

Answer 20

Pro-inflammatory mediators activate macrophages

ACM damage leads to fibroblast deposition of collagen

There is vascular remodelling to repair area -> Pulmonary HTN and RHF

Cellular Inflammation and cell infiltration

Question 21

Long-term recovery involves lung inflammation resolution. What other outcome needs to be fixed?

Answer 21

Muscle mass

ARDS requires a lot of energy and disuse in ARDS leads to muscle metabolism