ARDS

1. Acute respiratory distress
syndrome
Dr md abdullah saleem
MBBS, MD (pulmonology)
Dept. of Respioratory Medicine

2. ARDS
• Golden anniversary : 1967 , Ashbaugh
• Rapidly progressive form of acute respiratory failure characterized by
severe hypoxemia and non hydrostatic pulmonary edema and stiff
lungs.
• Considered to be prototype disorder managed in the ICU.
• Mortality is high if not recognized in time and if not managed
appropriately.
• Hallmark of ARDS – heterogenous distribution . Nothing called as
‘typical ARDS’

3. Epidemiology
• Incidence was 86 per 100,000 person-years for individuals with an
arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) ratio
≤300 mmHg and 64 per 100,000 person-years for individuals with a
PaO2/FiO2 ≤200 mmHg.
• 10 to 15 percent of ICU patients and up to 23 percent of mechanically
ventilated patients meet criteria for ARDS.

4. ARDS - Definition
• Key components : Time of onset , Hypoxemia , Non cardiogenic
pulmonary edema
• Ashbaugh 1967
• AECC 1994
• Berlin 2012
• Kigali Modification ??
• Still under recognized – early identification has shown to increase the
use of PEEP.

5. AECC – Definition

6. AECC definition Criticisms

7. Berlin Definition
JAMA. 2012;307(23):2526-2533
The mortality rate was 27% for mild, 32% for moderate and
45% for severe ARDS

8. Etiology
ARDS network N Engl J Med 2000; 342:1301
Pneumonia
35%

9. Risk Factors For ARDS
DIRECT
• Pneumonia
• Aspiration of gastric
contents
• Inhalational injury
• Pulmonary contusion
• Pulmonary vasculitis
• Drowning
INDIRECT
• Non-pulmonary sepsis
• Major trauma
• Pancreatitis
• Severe burns
• Non-cardiogenic shock
• Drug overdose
• Multiple transfusions

10. Pulmonary vs Extra pulmonary
PULMONARY
• Less common cause
• Epithelial injury
• Inhomogenous
distribution
• Not always recruitable
and RM may be harmful
• Worse outcomes
EXTRAPULMONARY
• More common cause
• Endothelial injury
• Homogenous in
distribution
• Recruitment possible
and beneficial
• Better outcomes

11. Pathophysiology
• Imbalance between.
• Pro - and anti-inflammatory cytokines,
• Oxidants and antioxidants,
• Procoagulants and anticoagulants,
• Neutrophil recruitment and activation and mechanisms of neutrophil
clearance,
• Proteases and protease inhibitors.

12. Pathophysiology
• Pulmonary or systemic insult
• Endothelial and epithelial
injury
• Diffuse alveolar damage
• Alveolar and interstitial
edema
• Pulmonary fibrosis
• Heterogenous areas of lung

13. HISTOLOGY
Diffuse alveolar damage Normal lung

14. Phases of pathogenesis
Exudative phase (0-7 days) Proliferative phase(7-14 days) Fibrotic phase (after 14 days)
Alveolar wall damage
with Flooding
Hyaline membrane
Type II alveolar cell hyperplasia
Myofibroblast proliferation
Resolution of edema
Extensive fibrosis with
Loss of normal lung architecture
All these phases overlap no clear distinction

15. Mortality in ARDS
Phua et al. AJRCCM 2013;179:220

16. Ventilatory Management
• Principle of doing no harm applies here especially in ventilatory
management.
• Keeping alveoli open at all times and Preventing derecruitment is the key.
• Avoiding excessive tidal volumes is the most effective measure.
• Minimizing biotrauma - the current line of thinking.
• VILI – major determinant of outcomes .
• Engineering studies have suggested that it is not the individual breath
parameters – Vt , PEEP , Pplat which determine the development of VILI ,
but the combination of factors and their effect on the dynamic strain
which seems to be the major determinant of VILI

17. Ventilator-Induced Lung Injury (VILI)
• Over distentionVolutrauma
• Repeated recruitment and collapseAtelectetrauma
• Inflammatory mediatorsBio trauma
• High-pressure induced lung damageBarotrauma
• FiO2Oxygen toxic effect

18. Ventilatory Management
• Tidal volume
• PEEP
• Plateau pressure
• Respiratory rate
• I:E ratio
• Driving pressure
• Recruitment
• Prone ventilation
• Advanced modes
} Lung protective ventilation

19. Tidal Volume
• All data suggest 6-8ml/kg of predicted body weight
• Higher tidal volumes are associated with worse outcomes.
• Increase in Paco2 up to 60 mmHg is acceptable
( target pH ) Hickling and colleagues 1990
• Monitoring plateau pressure is crucial
N Engl J Med 2000;342:1301-8.

20. ARDSnet Tidal Volume Study
NEJM 2000;342:1301-8.

21. PEEP
• Most misunderstood and misused entity in ventilation of ARDS
• Protective effects by preventing tidal derecruitment
• Best PEEP ???? Better PEEP !!!! Best technique ???
• 8-12 cm is ideal range for ARDS.
• PEEP<6 is likely to be ineffective.
• PEEP>14 likely to do more harm than good
• PEEP should be based on severity and pathology.
• Keep volume status in mind when PEEP causes hemodynamic instability
• Hypoxia should be managed by manipulation of PEEP and not tidal
volume.
ALVEOLI :N Engl J Med 2004;351:327-36.
Mercatt,M,et al.JAMA.2008;299(6):646-655

22. Airway Pressures
• ARDS is a disease of compliance
• Peak plateau gradient in narrowed
• Keeping plateau pressures less than 30 cm H2O is crucial ( higher in
patients with decreased chest wall compliance )
• Airway pressures are not transmitted to intracranial compartment in
ARDS
Terragni et al. Am J Resp Crit Care Med. 2007; 175(2):160

23. PEEP

24. Driving pressure ∆P
• Whats wrong with Pplat- does not take into account extrapulmonary
• Driving pressure (ΔP) = (Pplat – PEEP).
• Respiratory system compliance. CRS = VT / Pplat – PEEP = VT / ΔP
• Driving pressure , ΔP = VT/CRS.
• caveat – we want a tidal volume normalized to lung compliace rather
than CRS

25. • ΔP was the ventilation variable that best stratified risk.
• Decreases in ΔP owing to changes in ventilator settings were strongly
associated with increased survival.
N Engl J Med 2015;372:747-55.

27. • Better predictor than VT or PPlateau alone
Not the only contributor to VILI
Amplified junctional forces
Tidal opening & closure
Frequency & minute ventilation
Inspiratory flow and flow profile
Vascular pressures & flows
• May overestimate risk
– Stiff chest wall
– Unmeasured auto-PEEP
• May underestimate risk
• – Spontaneous breathing efforts

28. Respiratory Rate
• Conventional respiratory rates to start with
• Higher RR are required when PCO2 is elevated
• Upper limit is generally around 35/min
• Rates always have to be compared with I:E ratio
• Using higher rates will need deep sedation

29. I:E Ratio
• 1:2 is the default setting
• However most patients will require 1:1.5 to 1:1 ratio
• Inverse ratio ventilation known to be beneficial
• PCV is the preferred mode when inverse ratio is used
• Use inverse ratio ventilation with caution when patient has COPD /
Asthma

30. Recruitment
• Ability to open alveoli by transient application of higher airway
pressures
• Recruit ability determines most interventions in ARDS
• Extra pulmonary ARDS more likely to be associated with recruitment
• Recruitment with CPAP VS PC
• Controversial !!!
• Hemodynamic monitoring is essential during recruitment
• Avoid derecruitment at all times

31. Methods
• Sustained inflation
• Sigh ventilation
• Step ladder recruitment
• APRV
• HFOV
• Prone?

32. Contraindications for RM
• Hemodynamic compromise
• Existing barotrauma
• Increased intracranial pressure
• Predisposition to barotrauma

33. Position of patient – Effect on Recruitment
• Prone positioning may not only contribute to the success of
recruitment maneuvers, but should itself be considered as a
recruitment maneuver.
• In the prone position, the transpulmonary pressure in dorsal lung
areas increases, opening alveoli and improving gas exchange
• The development of VILI due to excessively high VT seems to be
delayed during prone compared to supine positioning

34. Recruitment - conclusions
• Evidence is lacking that the use of recruitment maneuvers improves
patient outcomes.
• Alveolar recruitment is desirable if it can be achieved safely, but there
is variable potential for recruitment among patients with ARDS.
• A stepwise recruitment maneuver is preferred over sustained
inflation.
• If a recruitment maneuver is effective, sufficient PEEP is necessary to
maintain the recruitment.
• Evidence is not sufficient to recommend the routine use of
recruitment maneuvers as standard practice.

35. Prone Ventilation
• Has strong physiological basis and evidence base recommendation
• Low cost intervention with high impact value in ARDS.
• Skilled manpower is however needed
• Meticulous care of pressure areas is important
• Can be prolonged for 18 – 21 hrs /day

36. Prone Ventilation – Rationale
• Optimisation of V/Q match .
• Increase in FRC.
• Decreased atelectasis .
• Less lung deformation – more homogeneity .
• Weight of heart on sternum and not on the left lung .
• Plateau pressure is more uniformly distributed in the prone position .
• Alteration in the chest wall mechanics , allowing lungs to inflate at.
lower pressures.
• Drainage of secretions better .

37. Prone Ventilation

38. Practical Considerations
Contraindications
• Spine instability
• Hemodynamic instability
• Arrhythmias
• Thoracic and abdominal
surgeries
• Increased intracranial
pressure
Complications
• Extubation
• Selective intubation
• ETT obstruction
• Dislodging CVCs
• Facial edema
• Pressure sores

39. HFOV
• HFOV is also a method of recruitment.
• Special equipment and dedicated staff needed.
• Almost always causes hypercapnia.
• Contraindicated in raised ICP and head injury.
• Current evidence is not convincing and may be harmful.

40. HFOV
• OSCILLATE trial terminated early due to increased in‐hospital
mortality in the HFOV arm (47% versus 35%)
• OSCAR trial demonstrated no difference in 30‐day mortality
between groups: HFOV was not superior

41. HFNC
• Also called vapotherm or mini cpap.
• Delivers adequately heated and humidified gas upto 60 lit/min.
• Difference from NIV
• Active humidification
• Interface different
• Decrease in dead space
• Difference with nasal canula
• With normal nasal canula – flow max 4 to 5 lit /min
• No constant Fio2 at low flows
• No proper humidification

43. FLORALI study
• In patients with
nonhypercapnic acute
hypoxemic respiratory failure,
treatment with high-flow
oxygen, standard oxygen, or
noninvasive ventilation did not
result in significantly different
intubation rates.
• There was a significant
difference in favor of high-flow
oxygen in 90-day mortality

44. HFNC
• Mild to moderate ARDS
• Can provide a PEEP OF ~ 5 cm H20.
• Alternative or bridge to NIV
• Patients who don’t tolerate NIV or are being weaned.
• Not to be used in severe ARDS.

45. NON VENTILATORY MANAGEMENT

46. NO PHARMACOLOGICAL TREATMENT FOR ARDS YET
• Ashbaugh et al described “using
a clinical trail of variety of drugs ,
respirators and fluid regimens
with limited success”

47. Non Ventilatory Strategies
• Fluids
• NMBs
• Corticosteroids
• Nutritional therapy
• ECMO
• Preventing second HIT
• Future therapies

48. Fluids
• Many conditions causing ARDS are associated with hemodynamic
instability and need fluid administration .
• Conflicting practices between sepsis egdt and ards resuscitation.

49. • Positive fluid balance is associated with worse outcomes in
ARDS .
Crit Care Med 2006 Vol. 34, No. 2

51. • Conservative strategy had
significant ventilator free days
(14.6 vs 12.1) and improvement
in pulmonary physiology.
• More ICU free days. 13.4 vs 11.2.
• 2.9 % reduction in 60 day
mortality but not statistically
significant

52. • Five-day protocolized regimen of 25 g of human serum
albumin every 8 hrs with continuous infusion furosemide
titrated to achieve a daily weight loss of > 1 kg/day.
• Diuresis and weight loss over 5 days (5.3 kg more in the
treatment group, p=.04) was accompanied by
improvements in the PaO2/FIO2 ratio in the treatment
group within 24 hrs (from 171 to 236, p=.02)

53. Fluids - conclusion
• Conservative fluid management
• Improves lung function and
• Shortens mechanical ventilation times and ICU days.
• Without increasing non pulmonary organ failures.
• Monitoring EVLW may tell whether fluid administration will worsen
pulmonary edema.

54. Steroids
• 4 RCTs investigated early use of high dose of corticosteroids for
prevention of ARDS in septic shock or confirmed ARDS.
• Significantly reduced duration of mechanical ventilation.
• No benefit in terms of prevention or improvement of ARDS and
no effect or even an including in mortality with CS

55. Steroids in early ARDS
• Bacterial Pneumonias
• Pneumocystis pneumonia
• Eosinophillic pneumonia
• Other systemic autoimmune conditions

56. • Methylprednisolone-induced down-regulation of systemic inflammation was
associated with significant improvement in pulmonary and extrapulmonary
organ dysfunction and reduction in duration of mechanical ventilation and ICU
length of stay

57. • Therapy with methylprednisolone is associated with
improvement in lung injury score.

58. • 180 pts pts with ARDS of > 7 days
• No difference in 60 day or 180 day
mortality
• Methylprednisolone is associated
with increased mortality in pts
enrolled with > 14 days of ARDS.
• MP increased number of ventilator
free days and shock free days.
• No increase in infectious
complication rate.
• Increase in NM weakness.

59. • Early therapy (< 3 d of mechanical ventilation) appeared more
strongly associated with mortality than late administration.
• Patients receiving steroids had more acquired pneumonia and a trend
to a longer duration of ventilation.

60. • Methylprednisolone group had fewer patients
who died before achieving UAB (12 vs. 29 %;
p0.001)
• Hospital mortality was decreased in MP group
(20 vs. 33 %; p = 0.006),

61. Steroids – conclusions
• Not to be used for viral pneumonias
-Am J Respir Crit Care Med Vol 183. pp 1200–1206, 2011
• Not to be used in 2nd week of ARDS onwards. Increased mortality rate
if Initiation 2 or more weeks after onset of ARDS
Late steroid rescue study (LaSRS) (2000)
• Have got some role in bacterial pneumonias when used early in 1st
week .
Meduri et al (CHEST 2007; 131:954–963)
• Increased risk of CIP. No increase infection.

62. Neuromuscular blockers
• Short term paralysis-
• Facilitate pt-vent synchrony in the setting of lung protective
ventilation
• Eliminates pt triggering, active exp.muscle activity.
• May serve to limit-overdistension(volutrauma) & cyclic alveolar
collapse(atelectrauma)
• May also act to lower metabolism & overall vent demand

63. • Severe ARDS,P/F<150,PEEP>5, TV = 6-8 mL/kg
• 48 hrs cisatracurium vs placebo
• 10% absolute reduction in mortality.
• Crude 90-day mortality was 31.6% in cisatracurium group &
40.7% in placebo group.
• No comparative increase in CIM.

65. Nutritional therapy
• Maintain glycemic control between 130-150 mg/dl
• Caloric requirement increases during ARDS 25 – 28 Kcal /kg/day.
• Role of omega-3-fatty acids is questionable.
• Trace element deficiencies crucial in weaning phase
• Hypophosphatemia is an important factor.

66. ECMO
• ECMO is a rescue therapy and is not intended as a
primary ARDS treatment.

67. • 63% of patients allocated to consideration for treatment by ECMO
survived to 6 months without disability compared with 47% of those
allocated to conventional management.
• Extracorporeal Membrane Oxygenation for Severe Acute Respiratory
Distress Syndrome (EOLIA)

68. ECMO
• ECMO or Extra Corporeal Membrane Oxygenation –
• External artificial circulation carries venous blood from the patient to a gas
exchange device (oxygenator) where blood becomes enriched with oxygen
and has carbon dioxide removed.
• This blood then re-enters the patient circulation.
• Does not treat the underlying cause
• Allows support while disease resolves
• Only appropriate if underlying pathology is potentially reversible

69. INDICATIONS
• Hypoxemic respiratory failure
• Hypercapnic respiratory failure
• Refractory cardiogenic shock (myocardial infarction, right
ventricular failure,myocarditis)
• Cardiac arrest
• Failure to wean from cardiopulmonary bypass after cardiac
surgery
• Bridge to cardiac transplantation or placement of a ventricular
assist device
• Other indications like cardiotoxicity

70. Contraindications
• Age > 65 years
• Prolonged Mechanical ventilation > 7 days
• Significant neurological injury
• Active bleeding/coagulation disorder
• Multiple organ dysfunction >2 major system failure
• Terminal disease with short life expectancy
• Severe chronic lung disease
• Unwitnessed arrest or CPR for 30 minutes
• Uncontrollable metabolic acidosis
• Pulmonary fibrosis
• Malignancy and or chemotherapy
• Immunosuppression
• Positive HIV status

71. Criteria for ECMO in ARDS
• ECMO should be considered when the risk of mortality is 50% or greater,
and is indicated when the risk of 80% or greater .
• 50% mortality risk can be identified by a PaO2/FiO2 < 150 on FiO2 > 90%
and/or Murray score 2-3
• 80% mortality risk can be identified by a PaO2/FiO2 < 100 on FiO2 > 90%
and Murray score 3-4 despite optimal care for ≥ 6 hours.
• CO2 retention on mechanical ventilation despite high Pplat (>30 cm H2O)
• A-a oxygen gradient > 600 mm Hg.

73. Other Criteria
• CO2 retention due to asthma or permissive hypercapnia with a PaCO2 >
80 – ph < 7.2
• Severe air leak syndromes
• Need for intubation in a patient on lung transplant list
• Immediate cardiac or respiratory collapse (PE, blocked airway,
unresponsive to optimal care)
• Inadequate tissue perfusion manifested as hypotension and low cardiac
output despite adequate intravascular volume

74. Preventing Second Hit
• Hand wash
• Head end elevation
• Closed suction catheters
• Subglottic suction tubes
• Chlorhexidine mouth wash
• Appropriate DVT prophylaxis

75. Case … contd
• Emergency LSCS
• Proned next day
• ECMO for 11 days
• Discharegd home after 2 wks
• Still in follow up.

76. Future therapies
• Phase 3 – Interferon beta-1a.
• Phase 2 – KGF , Aspirin , MSC therapy.
• Phase 1 – ACE 2 , nebulised heparin.
• Preclinical studies – sialic acid Nano particles.

77. Interferon beta-1a (Traumakine)
interferon-beta
increases CD73
expression
resulting in
increased local
adenosine.
Subsequently high
local adenosine
levels reduce
capillary leakage
and increase lung
function.

78. • Interferon beta-1a (Traumakine)
for acute respiratory distress
syndrome – first line
• On day 28, 3 (8%) of 37 patients
in the treatment cohort and 19
(32%) of 59 patients in the
control cohort had died.
Lancet
Respir Med 2014;2: 98–107

79. Keratinocyte growth factor - KGF
• By giving hKGF – it has been
shown in ex vivo model
lungs that administration
100ng of hKGF was
associated with improved
alveolar fluid clearance and
decrease epithelial
dysfunction.

80. Keratinocyte growth factor - KGF
KGF increases alveolar surfactant
protein D
KGF increases apoptotic epithelial cell
phagocytosis p=0.02

81. Mesenchymal stem cell therapy

82. Mesenchymal stem cell therapy

83. Mesenchymal stem cell therapy

84. Sialic acid Nano particles
Science Translational
Medicine 02 Sep 2015:Vol.
7, Issue 303, pp. 303ra140

85. Sialic acid Nano particles
Science Translational
Medicine 02 Sep 2015:Vol.
7, Issue 303, pp. 303ra140

86. Sialic acid Nano particles

87. Summary non ventilatory strategies
Conservative fluid strategy
Neuromuscular blockade
Steroids
Prone ventilation
ECMO
Nutrition
Prevention of 2nd HIT
Nebulised heparin
Future therapies.
×Surfactant
×Beta agonists
×Ketoconazole
×Nitric oxide
×Prostaglandins
×Statins
×Pharmaco nutrients
×Aspirin

88. Take home messages
• P rotective ventilation strategy
• P EEP - protective against VILI
• P – delta : driving pressure
• P rone ventilation
• P aralysis
• P erfusion (fluid balance)
• P rotocolised weaning
• P reventing second hit and
• ECMO - consider early

89. THANK YOU