Acute Respiratory Distress Syndrome

1. ACUTE RESPIRATORY DISTRESS
SYNDROME
Presenter: Dr. SATYAJIT HAJONG
Moderator: Dr .Th. BROJENDRO

2. The Berlin Definition Of ARDS
• A clinical syndrome of acute onset dyspnea , severe
hypoxemia, diffuse pulmonary infiltrates and decreased
respiratory system compliance leading to respiratory failure
in absence of evidence of congestive heart failure

3. First described in 1967 by Ashbaugh and Petty in The Lancet
Incidence (per 1,00,000 person years)-
Total- 86.2
Moderate and severe- 64
Dramatically increases between age 75 to 84 yrs - 306

4. OLDER DEFINITION
According to American European Consensus Conference – acute onset of illness ,
bilateral chest radiographic infiltrates consistent with pulmonary Oedema , poor
systemic oxygenation and absence of evidence for left atrial hypertension
• PaO2/FiO2 if is < 300- Acute Lung Injury, if < 200 then ARDS
• Cardiogenic pulmonary oedema must be excluded by clinical criteria/ PCWP
lower than 18 mm Hg
• Limitations- subjective variability of CXR interpretation, variable PaO2/FiO2 with
PEEP

5. THE BERLIN DEFINITION OF ARDS 2012
Clinical variables Parameters
Onset Within 1 week of inciting event
Chest radiograph
(CXR/ CT chest)
B/L opacities, not explained by effusion, atelectasis or nodules
Non-cardiac aetiology Respiratory failure not fully explained by cardiac failure or fluid
overload
Hypoxemia (PaO2/FiO2) </= 300 mmHg at PEEP >/= 5 cm H2O

6. ARDS Severity
ARDS Severity PaO2/FiO2 in mmHg
(at PEEP>/= 5cm H2O)
Mortality
Mild 200-300 26%
Moderate 100-200 32%
Severe <100 45-58%

7. Etiology
Direct causes Indirect causes
• Pneumonia(40 to 50)%
• Aspiration of gastric contents
• Pulmonary contusion
• Fat , amniotic fluid or air embolism
• Near drowning
• Inhalational injury
• Reperfusion injury
• High altitude pulmonary oedema
• Neurogenic pulmonary oedema
• Re-expansion pulmonary oedema
• Sepsis- most common cause
• Multiple Trauma
• Burns
• Acute pancreatitis
• Post cardiopulmonary bypass
• Toxic ingestions- aspirin, TCAs
• Transfusion of blood products

8. Factors Influencing The Risk and Mortality
• Advanced age
• Chronic liver disease
• Hypoproteinaemia
• Increased severity and extent of illness as measured by APACHE score
• Hyper transfusion of blood products
• Chronic alcohol abuse
• Cigarette smoking
• Long hospital stay prior to the development of ARDS

9. The natural history of ARDS is marked by three phases
 1.Exudative (First 7 days)
 2.Proliferative (After 7-21 days)
 3.Fibrotic (After 3-4 weeks)
Pathophysiology

10. Initial “Exudative"
phase-diffuse
alveolar damage
within the first
week

11. Alveolar capillary
membrane(ACM)
integrity is lost,
interstitial and
alveolus fills with
proteinaceous fluid,
surfactant can no
longer support
alveolus
Ware et al. NEJM 2000; 342:1334

12. Direct or indirect
injury to the
alveolus causes
alveolar
macrophages to
release pro-
inflammatory
cytokines
Ware et al. NEJM 2000; 342:1334

13. Cytokines attract
neutrophils into
the alveolus and
interstitum, where
they damage the
alveolar-capillary
membrane (ACM).
Ware et al. NEJM 2000; 342:1334

14. Most patient recover in this stage
 Signs of resolution and lung repair
* Neutrophil to lymphocytes predominant infiltrates
* Type II pneumocytes proliferation and differentiation into type I pneumatocytes
* New pulmonary surfactant
Proliferative phase

15. Require long term airway support(mechanical/supplemental O2)
Histologically-alveolar duct and interstitial fibrosis
Pulmonary hypertension from intimal fibroproliferation
Pulmonary fibrosis= increased mortality
Fibrotic phase

16. Stages of ARDS
EXUDATIVE PROLIFERATIVE FIBROTIC
• 0-6 days
• Accumulation of excess fluid in
the lung
• Hypoxemia is maximum at this
stage
• Some individuals recover from
this stage
• 3 stages of oedema-
• Stage 1- drained by lymphatic
• Stage2- interstitial
• Stage 3- alveolar
• 7-21 days
• Connective tissue, fibroblasts
proliferation
• Termed as stiff lung/ shock lung
• Abnormally enlarged air spaces
and fibrotic tissue are
increasingly apparent
• > 21 days
• Oxygenation improves and
extubation becomes possible
• Lung function continue to
improve over as long as 6-12
months
• Varying levels of residual
fibrotic changes remain

17. Resolution of ARDS
Removal of alveolar oedema fluid (10-20% per hour) via 5 routes- lymphatics, blood
vessels, airways, pleural space and mediastinum
• Mechanism- activated NaCl transporter
• Protein removal- (1-2% per hour)- mostly as intact- f/b phagocytosis
• Removal of interstitial fluid- in blood vessels or mediastinum
• 25-30% of oedema fluid- leaves into pleural space- pleural effusion

20. Clinical Presentation
• Acute dyspnoea within 7 days of an inciting event
• Hypoxemia resistant to oxygen therapy (d/t large R->L shunt)- Need for high fraction of
inspired O2(*FiO2) to maintain O2 saturation
• Tachypnoea (earliest sign), tachycardia, cyanosis
• Restlessness, confusion, disorientation
• Hypertension or low BP when in shock
• Bilateral fine crepitation on chest auscultation
• Other manifestations of the underlying cause

22. Differential Diagnosis
Most common Less frequent
• Cardiogenic pulmonary oedema
• Diffuse pneumonia
• Alveolar haemorrhage
• Acute interstitial lung disease
• Hypersensitivity pneumonitis
• Radiation pneumonitis
• B/L lower lobe atelectasis
• Severe U/L lower lobe atelectasis
• Massive pulmonary embolism

23. Chest Radiograph in ARDS
• Diffuse bilateral lung infiltrates extending to the lung margins
• Early in the course infiltrates may have patchy peripheral distribution
• CT scan of chest- more informative
• Drawbacks- oedema may not be visible until lung water increases upto
30% and upto 12 hours after onset of dyspnoea

26. Normal
chest x ray

28. Chest x ray in ARDS

29. Arterial Blood Gas
• Hypoxemia- PaO2/FiO2 <300 mm Hg
• Initially respiratory alkalosis
• However if ARDS is due to sepsis- metabolic acidosis with or without
respiratory compensation
• As the condition progresses the work of breathing increases and pCO2
begins to rise- respiratory acidosis

30. Broncho alveolar lavage
• Most reliable to confirm or exclude ARDS
• Neutrophils- in normal individuals <5% whereas in ARDS upto 80%
• Total protein- lavage fluid rich in protein is evidence of inflammation
• When protein in lavage fluid expressed as a fraction of serum protein
concentration-
• If <0.5 indicates hydrostatic oedema
• If >0.7 indicates lung inflammation

31. Other Investigations
• CBC- leukopenia/ leucocytosis, thrombocytopenia (in DIC)
• RFT and LFT- deranged in acute tubular necrosis and hepatocellular injury respectively
• Cytokines- IL-1, IL-6, IL-8 levels are elevated
• Pro calcitonin- marker of sepsis
• Von Willebrand Factor & plasma angiopoietin 2 : markers of impending ARDS with non
pulmonary sepsis- poor outcome
• Plasma BNP- to exclude cardiogenic pulmonary oedema
• <100 pg/ml- unlikely heart failure
• >500 pg/ml- heart failure is likely
• Echocardiography - to exclude cardiogenic pulmonary edema

32. Complications
COMMON OTHERS
• Nosocomial pneumonia
• Barotrauma
• SIRS and MODS
1. Renal- 40-55%
2. Liver- reversible , enzyme changes in 95%,
fulminant hepatitis in 10%
3. Myocardial depression by TNF- 10-23%
4. DIC- 26%
5. GIT- 7-30% as haemorrhage, ileus,
malabsorbtion
• Oxygen toxicity
• Stress ulcers
• Tracheal ulcerations
• Deep vein thrombosis
• Pulmonary embolism
• Pressure sores

33. Management of ARDS
Goals :
• To diagnose and treat the precipitating cause
• To maintain oxygenation
• To prevent ventilator induced lung injury (VILI)
• Hemodynamic management
• To keep pH in normal range without compromising goal to prevent VILI
• Prevention of other complications

35. Mechanical Ventilation
• No role of NIPPV (Only one comparative study by Ferrer et.al)
• To enhance patient ventilator synchrony and patient comfort by sedation,
amnesia, opioid analgesia, antipyretics and pharmacological paralysis- also
decreases oxygen consumption
• To apply PEEP to maximize alveolar recruitment & minimize cyclic
atelectasis
• Wean from mechanical ventilation when patient can breathe without
assisted ventilation to the earliest

36. 1. Maintaining adequate oxygenation-
• Positive end expiratory pressure (PEEP) is employed
• When utilized in sufficient amount PEEP allows lowering of FiO2 from high, potentially toxic
concentrations
• Lung protective mechanical ventilation-
• Mechanical ventilation using limited tidal volume
• The goal is to avoid injury to the alveoli
1. By overexpansion during inspiration (volu-trauma)
2. Due to repetitive opening and closing during inspiration and expiration (atelecta-trauma)

37. Low Tidal Volume Ventilation
• Calculate ideal body weight (IBW) in pounds
1. Males- 106 + [ 6 x (height in inches – 60 inches)]
2. Females- 105 + [ 5 x (height in inches – 60 inches)]
• Convert into kg by multiplying with 0.453
• Set initial tidal volume to 6 ml/kg IBW
• Set respiratory rate to < 35 per minute to match baseline minute ventilation

38. Ventillator Mode - Volume Assist / control
Tidal Volume (VT)– 6ml/kg of IBW
Measure pleatue pressure (Pplat 0.5 sec inspiratory pause ) every 4hrs and after
each change in PEEP and VT
• Goal is to maintain plateau pressure(Pplat) </= 30 cm of H2O
If Pplat rises above 30cm of H2O decrease tidal volume to 5 or to 4ml/kg IBW
• If Pplat is below 25cm of H2O increase tidal volume by 1ml /kg IBW to keep
Pplat >25cm of H2O

39. • Positive end expiratory pressure (PEEP) is employed
• I:E ratio -1: to 1:3
• Maintain PaO2 : ( 50 to 60) mm of Hg
• SpO2 : ( 88 to 95) %
FiO2 30
to
40 %
40% 50% 60% 70% 80% 90% 100
%
PEEP 5to8 8 to
14
8 to
16
10
to
20
10
to
20
14
to
22
16
to
22
18
to
25

40. Acidosis management
If pH < 7.3 increase RR until pH >7.3 or RR 35
If pH remains < 7.3 with RR 35 consider bicarbonate infusion
If pH < 7.15, VT may be increased( (Pplat may exceed 30cm of water)

41. Alkalosis management
If pH >7.4 and paient not triggering ventillator decrease set RR but not
below 6/min

42. Weaning from Mechanical Ventillation
• Daily interruption of sedation
• Daily screen for spontenous breathing trial
• Give spontenous breathing trial when all of the following criteria are present
• 1. FiO2<40% PEEP <8cm of H2O
• 2. Not receiving neuro mascular blocking agent
• 3.Patient is awake and following commands
• 4.Systolic arterial pressure >90mm of Hg without vasopressors
• 5.Tracheal secretions are minimal and patient have a good cough and gag reflex

43. Spontaneous Breathing Trial
• 1. Place patient on 5mm Hg pressure support with 5mm of Hg PEEP
• 2. Monitor HR , RR, SPO2 for 20 to 30 min
• 3. Extubate if there is no signs of distress ( tachycardia , tachypnea , agitation ,
diaphoresis )

46. Open Lung Ventilation
• Combines LTVV with enough applied PEEP
• LTTV- mitigates alveolar over distention and PEEP- minimizes cyclic
atelectasis
• PEEP is set at least 2 cm above the lower inflection point of the pressure
volume curve
• If the point is uncertain- PEEP of 16 cm of H2O is to be applied
• Drawback -it has the potential to cause barotrauma and decrease cardiac
output

47. Adjuncts to lung protective ventilation
1. Permissive hypercapnia
• LTVV causes reduction of CO2 elimination- allowing this to persist in favour of
maintaining lung protective LTVV is known as permissive hypercapnia
• Can be minimized by highest respiratory rate that does not induce auto PEEP
• Also by changing from a heat & moisture exchanger to a heated humidifier
• Can cause hyperventilation (brainstem stimulation)- neuromuscular blockade
• Data shows arterial pCO2 levels of 60-70 mmHg is safe

48. 2. Recruitment manoeuvres- intermittent increase of PEEP, by maintaining
CPAP of 35 to 40cm of H2O for 30 seconds
3. Prone positioning-
• About 66% of the patients improve oxygenation with this
• Mechanisms - 1. Increase in functional residual capacity
2. Change in regional diaphragmatic motion
3. Perfusion redistribution
4. Improve clearance of secretions

49. Extra Corporeal Membrane Oxygenation
• Modified heart lung machine- gas exchange and circulatory support
• Veno-venous(VV) ECMO- for gas exchange
• Veno-arterial(VA) ECMO- for both gas exchange and circulatory support
• ARDS with pneumonia is the commonest situation needing ECMO

50. Newer therapeutic strategies
1. Intra venous mesenchymal stromal (stem) cells(START Trial) – being
tested in phase 2 clinical trial – have pleotropic protective and reparative
effect in the lungs
2. Use of pulmonary vasodialators - inhaled nitric oxide and prostacyclin
3. Glucocorticoids ( methylprednisolone ) – hastens resolution of late
fibroproliferative ARDS – not recommended for routine use

51. Fluid management
• Golden rule- hydrostatic pressure to be kept as low as possible provided that
oxygen delivery to the tissues is not compromised
• Tailored systemic fluid restriction to achieve lowest intravascular volume that
maintain adequate tissue perfusion
• The lung infiltration in ARDS is an inflammatory process- diuretics don’t reduce
this , but helps in lowering intra vascular volume
• To maintain CVP < 4𝑐𝑚 𝑜𝑓 𝐻2𝑂 ,MAP> 65 mmHg and Urine output > 0.5
ml/kg/hour

52. Nutrition
• High fat and low carbohydrate diet reduces the duration of
mechanical ventilation by reduction in carbon dioxide production and
reduction in respiratory quotient

53. Other agents
Agent Mechanism of action Recommendation
Glucocorticoids Anti-inflammatory NO
Neuromuscular blockers Promotes ventricular synchrony,
decrease oxygen consumption
YES
Statins Antagonising inflammatory
cytokines
Under experimentation
Beta-agonists Fluid removal by activated
sodium pump via cAMP
NO
Macrolide antibiotics Unknown Under experimentation

54. Mortality and Functional Recovery
Mortality-
ARDS Network published in 2012 , 60 day mortality was 23%
1 year mortality is 41%
32% for mild ARDS , 58 to 60 % for moderate to severe ARDS
Early death - due to the underlying cause of ARDS most commonly
• Death in later course- nosocomial pneumonia and sepsis causing MODS

55. Mortality and Functional Recovery
• Functional recovery-
• Maximum lung function- by 6 months
• One year after extubation over 33% survivors have normal spirometry
and diffusion capacity
• Most of the remaining survivors have only mild abnormalities- others
low exercise capacity
• Significant rate of post traumatic stress disorder in the form of
depression and anexity

56. Conclusion
• ARDS is a multisystem syndrome
• Characterised by accumulation of fluid in the lungs with resulting hypoxemia and
some degree of fibrotic changes
• The most frequent causes - sepsis, pneumonia, aspiration and severe trauma
• Treatment- supportive, ventilation and oxygenation strategies
• Despite many theoretical therapies the best proven strategy to improve survival is
LOW TIDAL VOLUME VENTILATION
• Despite all advances mortality is still very high ranging from 26-58%

57. References
• Fishman’s Pulmonary Diseases and Disorders 5th Edition
• Harrison’s Principles of Internal Medicine 20th edition
• The ICU book,3rd edition- Paul L. Marino
• JAMA, June 20th, 2012- vol 307, no 23: Berlin definition
• Finks Textbook of Critical care 7th edition

58. THANK YOU

59. Pathophysiology
• Normally small amount of fluid leaking into the interstitium is drained by lymphatic
system
• In ARDS- diffuse alveolar injury (T1 pneumocytes)-> release of cytokines-> recruitment
and activation of neutrophils
• Neutrophils release toxic mediators (ROS, proteases)-> capillary endothelium and
alveolar epithelium damage-> protein loss into interstitium
• Loss of oncotic gradient-> fluid pours into interstitium overwhelming the lymphatic
system
• Epithelial breakage- alveoli get filled with oedema fluid and debris

60. • In addition surfactants are lost resulting in alveolar collapse
• These result in impaired gas exchange, decreased compliance and increased pulmonary
arterial pressure
• Physiological shunt- continued perfusion of non ventilated alveoli (V/Q=0)
• Microscopically-
1. Widespread alveolar and interstitial oedema, inflammation & haemorrhage
2. Hyaline membrane composed of plasma proteins, fibrin & necrotic debris- the
footprint of a pathologic finding- diffuse alveolar damage (DAD)
• MODS- due to increased concentration of biologically active soluble Fas ligand (sFasL 45
kD)- apoptosis

62. Time course of evolution of ARDS

65. • Effective anti sepsis interventions
• Antibodies against macrophage migration inhibitory factor
• Antibodies against high mobility group B1 protein
• Stem cell therapy- Human Mesenchymal Stem Cells for Acute Respiratory Distress
Syndrome (START trial)