The document defines acute hypoxaemic respiratory failure and ARDS according to the Berlin Definition. It then discusses issues with the Berlin definition and the old criteria. The direct and indirect causes of ARDS are outlined. Details are provided about the pathophysiology, effects, biomarkers, outcomes, and various treatment strategies for ARDS including ventilation measures, prone positioning, recruitment maneuvers, and oxygenation targets. Mortality rates associated with ARDS are also summarized.

2. Definition
1a
Digitally signed by Dr.Sherif Badrawy
DN: cn=Dr.Sherif Badrawy, o=KKUH,
ou=Critical Care,
email=sherif_badrawy@yahoo.com, c=SA
Date: 2015.02.25 18:17:25 +03'00'

3. Acute hypoxaemic respiratory failure due
to bilateral and diffuse alveolar damage
1b

4. New Berlin Definition (JAMA 2012):
2a

5. ◆ acute: within 1 week of insult or respiratory ⇊
◆ Bilateral opacities
◆ Respiratory failure not fully explained by HF or fluid overload (PAOP removed ➜ ↓use of
PACs)
◆ Oxygenation:
Mild: PaO2/FiO2 from 201 - 300 with PEEP or CPAP >= 5 (27% mortality)
Moderate: 101 - 200 with PEEP >= 5 (32% mortality)
Severe: <= 100 (45% mortality)
◆ The term acute lung injury (ALI) has been discarded
◆ 4 other variables
✫ compliance <= 40
✫ PEEP >= 10
✫ Expired minute volume > 10
✫ Radiographic severity
◆ an "objective assessment" (e.g. echo) should be done
if there is no clear cause such as trauma or sepsis
2b

6. Issues é the Berlin definition
3a

7. ◔ ability to predict mortality is still poor, but slightly better
◔ doesn't include underlying aetiology & lacks a direct measure of lung injury
◔ use of vasopressors at the time of Dx of ARDS is associated é a much higher
mortality regardless of the PF ratio (not accounted for in the Berlin definition)
◔ Does not allow early identification of Pts who may be amenable to Rx before
ARDS becomes established
◔ still allows CXR to be used for Dx, ῶ compared poorly é CT chest ῳ studied by
Figueroa-Casa et al, 2013
◔ Berlin definition has low sensitivity ῳ compared to autopsy findings.
3b

8. Old Criteria:(Old Definition)
4a

9. ☆ Acute
☆ PaO2/FiO2 < 300 (ALI) or < 200 (ARDS)
☆ CXR: B/L infiltrates ➜ pulmonary oedema sparing
costophrenic angles
☆ PAOP: < 18 mmHg or no ↑LAP
◆ Weaknesses were:
◕ NO definition of acute, and the effect of PEEP
◕ variations in PiO2/FiO2 ratio
◕ Not specific about radiologic criteria
4b

10. Direct causes of ARDS (ie alveolar
insult):
5a

11. ☆ Pneumonia (46%), aspiration(29%),
lung contusion
(34%), fat embolism, near drowning,
inhalational injury, reperfusion injury
5b

12. Indirect causes of ARDS(ie capillary
insult):
6a

13. ☆ non-pulmonary sepsis (25%), multiple
trauma (41%), massive transfusion
(34%), pancreatitis (25%),
cardiopulmonary bypass
6b

14. X-ray in ARDS
7a

15. ☆ depending on the stage of the disease
☆ MC findings are bilateral, predominantly peripheral, asymmetrical
consolidation with air bronchograms
☆ ±Septal lines and pleural effusions 7b

16. CT in ARDS
8a

17. ☆ dorsal dependent ↑lung density
☆ reverses with a shift from supine to prone
☆ Groundglass appearance ➜ fibrosis
☆ 2nd week ➜ cysts or pneumatoceles
☆ Abscess formation, empyema
☆ pneumothorax 8b

18. Long term outcomes
9a

19. ☆ Exercise tolerance dt critical illness
neuropathy and myopathy
☆ Depression, anxiety and PTSD
☆ cognitive impairments dt desaturation
< 90% (cautions against permissive
hypoxaemia)
9b

20. Pathogenesis of ARDS
10a

21. ☆ Injury
☆ Exudative: alveolar capillary membrane disruption +
inflammatory cell infiltrate
☆ Proliferative: Type 2 alveolar cells and inflammatory cells
☆ Fibrotic: infiltration with fibroblasts
☆ Resolution: slow and incomplete repair
☆ The alveolocapillary barrier ➜ damage é bidirectional flow
(proteins & fluid in to alveoli, surfactant & alveolar cytokines
into plasma)
☆ surfactant dysfunction ↓activity ➜ ↓in pulmonary
compliance
10b

22. Effects of ARDS
11a

23. ♙ hypoxaemia (V/Q mismatch, impaired hypoxic pulmonary
vasoconstriction)
♙ ↑in dependent densities (surfactant dysfunction, alveolar
instabilities)
♙ ↓compliance (surfactant dysfunction, ↓lung volume,
fibrosis)
♙ collapse/consolidation (↑compression of dependent lung)
♙ ↑minute ventilation (↑in alveolar dead space)
♙ ↑WOB (↑elastance, ↑minute volume requirement)
pulmonary HTN (VC, microvascular thrombi, fibrosis, PEEP)
11b

24. Neutrophils in ALI:
12a

25. ☆ Most abundant cell type in early ALI
☆ release reactive O2 ➜ tissue damage
☆ However, ALI occurs in neutropenic patients
Other cell types:
Microvascular thrombosis ➜ PHTN
Alveolar macrophages ➜ TGF α & PDGF
12b

26. Biological markers
13a

27. ➜ Stiff lungs (↓compliance) ➜ trauma with ventilation,
impaired ventilation (↑CO2) and V/Q mismatch
Changes are not uniform
TNF-α, IL-1β, IL 6 and IL 8 most important.
Measurement of cytokines is not predictive of ALI or
mortality
ferritin and serum surfactant protein B ➜ predictive
Biopsy ➜ fibrosing alveolitis after 5 days.
13b

28. Mortality in ARDS is up to 40% is due to:
14a

29. Multiorgan failure
Severe hypoxaemia: alveoli perfused
but not ventilated (shunt)
Some argue ARDS is largely a hospital
acquired iatrogenic injury dt delayed Abs,
↑fluid and poor ventilation
14b

30. Mechanisms of Ventilator Associated
Lung Injury
15a

31. ✩ Volutrauma
✩ Barotrauma
✩ Biotrauma
✩ Atelectrauma
✩ Shearing injury
✩ Oxygen toxicity
15b

32. Definition of Volutrauma
16a

33. ✩ dt over-distension of normal alveoli to
transpulmonary pressures ≥ 30 cm
✩ Non-homogenous lung injury
✩ disruption of the lung architecture
✩ ↑alveolar-capillary permeability,
✩ activation or stretch responsive
inflammatory pathways
16b

34. Causes of Volutrauma
17a

35. Alveolar rupture ➜ interstitial
emphysema, mediastinal emphysema,
pneumothorax, pneumoperitoneum and
SC emphysema ➜ HD & respiratory
compromise
17b

36. Rx of Volutrauma
18a

37. Lung protective strategies: ↓Vt,↓RR,
↓mean Aw P (by ↓PEEP), avoid auto-
PEEP
Drain collections of gas
Double lumen tubes (differential lung
ventilation)
18b

38. Barotrauma
19a

39. ↑trans-pulmonary pressures > 50 cm ➜
disruption of BM ➜ gross air leaks
19b

40. Biotrauma
20a

41. tissue disruption ➜ ↑chemokines &
cytokines ➜ WBC activation ➜
pulmonary & systemic inflammatory
response
20b

42. Atelectrauma
21a

43. Recruitment/de-recruitment injury: the
weight of oedematous lung ➜ collapse of
the dependant portions of the lung ➜
repeated opening and closing with Vt
21b

44. Shearing injury:
22a

45. at the junction of the collapse lung and
ventilated lung, ➜ ventilate lung moving
against the relatively fixed collapsed lung
➜ ↑shearing force and subsequent
injury.
22b

46. Oxygen toxicity
23a

47. ✬ Lung toxicity:
◒ ↑FiO2 ➜ cellular damage (?by O2 free radicals over whelming scavenging systems)
➜ progressive ↓compliance + interstitial oedema ➜ fibrosis. The safe concentration
/duration is unknown. "Safe" periods > 50% vary from 16 to 30 hours.
◒ ↑O2 ➜ ↑atelectasis & bronchoalveolar distension ➜ Absorption atelectasis at FiO2
as low as 0.3 - 0.5 ➜ ↑V/Q mismatch
◒ ↑PaO2 ➜ pulmonary vasoconstriction ➜ worse V/Q mismatch ➜ ↑dead space
ventilation ➜ ↑PaCO2
◒ Alters tracheal flora in favour of pseudomonas & Proteus
✬ ↑PaO2 ➜ ↓coronary artery blood flow
✬ CNS effects (incl seizures) with O2 > 3 atmospheres
✬ ↓innate immunity in lab studies
✬ Fire risk: turn off O2 when defibrillating - sparks cause fires
23b

48. Ventilation measures in ARDS
24a

49. ↓Tidal volume
Limit plateau pressure
Slow respiratory rate
FiO2, aim for < 60%
Optimise recruitment
Optimise blood flow to ventilated alveoli: Inhaled NO or prostacyclin
Permissive hypercapnea
Spontaneous ventilation
Transpulmonary pressure monitoring
▤ Last resorts:
Decrease circuit dead space (lower CO2)
HFOV
ECMO
24b

50. Optimise recruitment in ARDS
25a

51. ↑PEEP: ↑surface area for gas
exchange, ↓atelectasis, ➜ redistribute lung
water
Lung recruitment
↑I:E ratio towards 1:1
Inverse ratio ventilation: use autoPEEP
to ↑FRC and area for gas exchange
25b

52. NIV in ARDS
26a

53. Role of NIV uncertain - > complications, delays
intubation. Current data do not support the routine
use of NIV in undifferentiated hypoxaemic ARF
NIV vs intubation in haematological malignancy
and ARDS. ➜ No difference in mortality bw NIV and
intubated patients. 71% mortality overall
26b

54. ARDS Network study (NEJM 2000)
27a

55. ✾ P/F ratio < 300 in the first 36 hours ➜ Strict PEEP & FiO2
protocol ,
✾ AC mode to avoid excessive spontaneous Vt
✾ Average RR ~ 30/min in low mortality group.
✾ Pplat target was < 30
✾ Showed 6 ml/kg LBW (with plateau pressures < 30) better
than 12 ml/kg LBW (with plateau pressures < 30) - mortality
reduced by 22% show that over-distension is bad
✾ Meta-analysis showed Vt < 7.7 ml predicted body weight was
protective.
✾ Now called "Lung Protective Ventilation"
27b

56. Invasive Ventilation in ARDS
Tidal Volume: Avoidance of overstretch
28a

57. ★ Vt need to be reduced in proportion to the
reduction in aerated lung otherwise aerated lung
will over stretch. It is lung stretch, not Paw, that
leads to volutrauma
★ Normal lung fully inflated at a transpulmonary
pressure of ~30 cmH2O. Pplat, the elastic
distending pressure, should not exceed 30 - 35.
28b

58. measurement of transpulmonary
pressure
29a

59. ★ Vt limitation > practical than PSV or
measurement of
transpulmonary P.
★ By oesophageal P. monitoring with an
oesophageal balloon ➜ exclude effect of the chest
wall.
★ better when chest wall pressures are abnormal
(↑obesity , chest wall trauma, etc.)
29b

60. MV mode in ARDS
30a

61. PC has theoretical advantage that Ppk
~ Pplat but HD stability & mean Aw P ➜
no difference
Inverse ratio ventilation: small
decrease in CO2 but ↑mean Aw P &
↑risk of HD consequences
30b

62. HFOV in ARDS:
31a

63. early studies showed no benefit
31b

64. Heavy sedation +/- paralysis: in ARDS:
32a

65. ACURASYS Study ➜48- hour infusions of
cisatracurium ↓mortality & barotrauma, no
effect on ICU-acquired weakness
Minimise O2 consumption/CO2 production &
eliminate dyssynchrony
Improved ventilation/perfusion relationships
32b

66. Permissive Hypercapnea in ARDS
33a

67. pH > 7.1 (problematic in head injury & PHTN)
Low Vt ➜ ↑PaCO2 unless ↑rate ➜ > tidal
stretch & possibly alveolar injury ➜ ↑PCO2 may
not be that harmful as - if it occurs slowly‫ز‬
↑ CO2 may ➜ ↓inflammatory response
(↓neutrophil function, ↓proinflammatory
cytokines).
33b

68. Should I ↑RR to ↓CO2 in ARDS ?
34a

69. ✯ ARDS Net aimed at normocapnea with
RR up to 35 to minimize acidosis.
✯ ARDSNET tried to avoid hypercapnea
by ↑RR & giving NaHCO3
✯ Augmenting RR to combat rises in
CO2 may augment mechanical & bio-
trauma to the lung
34b

70. Advantages of PEEP in ARDS
35a

71. ✯ ↑O2 & ↓VILI (dt tidal opening & closing of
alveoli).
✯ ↑PaO2 by ↑FRC ➜ recruiting alveoli but may↓VR
✯ ARDSNet protocol titrates PEEP to PaO2/FiO2 ➜
tidal over-inflation in 1/3.
✯ Lower inflection point of a volume-pressure curve
used to set PEEP as it was thought this reflected
recruitment
35b

72. Disadvantages of PEEP in ARDS
36a

73. ✾ ↓VR ➜ ↓COP even though O2 rises
✾ over-inflation of non-dependent alveoli
(+ recruitment of dependent alveoli).
✾ Less likely if alveolar distending
pressure is < 30 - 35 cmH2O, or change
in driving pressure is < 2cmH2O when Vt
is constant
36b

74. Reasonable approach for Ideal PEEP ?
37a

75. Use a scale similar to the ARDS Network
protocol
Titrate PEEP to PaO2, ➜ a PEEP of ~15
cmH2O, levels up to 25 cm H20 in severe ARDS
the delta-PEEP technique indirectly assesses
excess stress as PEEP is ↑at a constant Vt
37b

76. Recruitment manoeuvres in ARDS
38a

77. Recruitment is not homogenous ➜ will preferentially distend
normal lung
Unclear whether they add anything to PEEP ➜ largest trial
showed no effect. ?Only effective in early ARDS when lower
levels of baseline PEEP used
Apply 30 - 40 cm CPAP in an apnoeic patient for 30 - 40
seconds
May lead to improved oxygenation. May also cause
hypotension in an under-filled patient
Stretch above resting Vt powerful stimulus for surfactant
release
38b

78. Oxygenation in ARDS
39a

79. Balance bw damage from ↑Aw P &
↑FiO2 is unknown - generally FiO2
regarded as less damaging
Start at FiO2 of 1 & titrate down to <
0.6
SaO2 > 90% & PaO2 > 60 reasonable
targets
39b

80. Prone Position in ARDS
40a

81. For persisting severe hypoxia
Prone position ➜ ↓chest wall compliance. So in
PCV should have ↑recruitment at same levels of
pressure
Theoretically ↑secretion drainage (dorsal ventral
orientation of large airways)
Debate over who should be proned, when in their
course, duration of proning, how many days to persist
40b

82. Evidence of Prone Position in ARDS
41a

83. ✰ MRCT ➜ French ICUs proning, early in illness, 16
hours prone at a time vs supine, in PF ratio of < 150
persisting > 24 hours. 28 day morality 16% vs 32%.
Complications the same. Guerin et al, NEJM 2013.
Very dramatic result - is it true? Influenced by
number of H1N1 patients?
✰ MRCT comparing supine with prone for 6 h per
day. ↑PaO2 in 70% No improvement in mortality -
but ↑in the most hypoxic ➜ use as a rescue therapy.
41b

84. Disadvantages of Prone Position in
ARDS
42a

85. potential for dislodgement of tube/lines,
problems with airway access, ➜ new
pressure sores, ↑ICP, ↓enteral feed
tolerance, difficult or CI in spinal
trauma/abdo surgery /pelvic
fractures/pregnancy.
42b

86. Advantages Pulmonary Vasodilators in
ARDS (iNO/ Inhaled Nitric oxide)
43a

87. ↓shunt & ↓RV afterload (↑CO is unusual).
Delivered to well ventilated lung ➜ VD
pulmonary circulation & redistribute blood away
from poorly ventilated lung
Bind Hb inactivates NO so systemic
complications modest
Technically easier than proning & HFVO
For temporary rescue only
43b

88. Disadvantages Pulmonary Vasodilators
in ARDS (iNO/ Inhaled Nitric oxide)
44a

89. Risk of opening circulation to poorly aerated
lung ➜ ↑shunt ➜ ↓PO2
Expensive ➜ $2,000 per day
Toxicity with NO2 ➜ Met Hb
Coagulopathy ➜ Risk of pulmonary Hge dt
platelet inhibition & ↑bleeding time
rebound PAH & hypoxia with discontinuation
↑renal failure & nosocomial infection
44b

90. INDICATIONS of iNO/ Inhaled Nitric
oxide
45a

91. (1) controversial role in ARDS
(2) PHTN (adults & newborn)
(3) Rt HF (e.g. post-cardiac surgery ,
heart transplant)
45b

92. Evidence of iNO/ Inhaled Nitric oxide:
46a

93. ✪ "Routine use should be discontinued",
at least until trials indicate any subgroup
that may benefit.
✪ RCTs in ARDS ➜ short term
oxygenation benefits up to 72 hours, ➜
no change in length of ventilation or
mortality
46b

94. Mechanism of iNO/ Inhaled Nitric oxide
47a

95. ✪ Smooth-muscle relaxant via cAMP ➜ local
pulmonary VD ➜ ±improving VQ mismatch &
↓PHTN, ± immuno-modulation (↓neutrophil
adhesion & platelet aggregation)
✪ Physiological improvement in PHTN & heart
transplant but no longer term benefits
47b

96. Monitoring of efficacy of iNO/ Inhaled
Nitric oxide
48a

97. PAP/PaO2 and/or Pulmonary Vascular
Resistance (via pulmonary artery catheter or
TEE)
↑PaO2 of 20% a positive response - continue
iNO at the minimum effective dose
May be no fall in PA pressure (though PVR
has fallen). Positive response may be seen in
CO,SvO2 and/or CVP
48b

98. Requirements of iNO/ Inhaled Nitric
oxide
49a

99. Cylinders contain 800 ppm +
nitrogen. complex equipment to monitor
PO2, PAP, Met Hb & NO & nitrogen
dioxide
Delivery via mixed NO/N2 - measure
inspiratory concentrations of each
Commonly used doses are 1 - 60 ppm
49b

100. Inhaled prostaglandins/Inhaled
PGI2:(Iloprost)
50a

101. improves oxygenation as effectively as iNO.
Continuously jet nebulised dt short half life
May be better than iNO. in (PAH & RV
function)
Given via ultrasonic nebuliser.
Doesn't cause systemic hypotension that IV
would.
Neither has been shown to improve outcomes.
50b

102. Fluid management in ARDS
51a

103. Limit CVP to PEEP + 2 maximum. Consider
frusemide if CVP > PEEP + 5
ARDSNET, NEJM 2006, ➜ fluid, diuretics &
vasoactive infusions to achieve CVP of 10 - 14
mmHg or < 4. ➜ No difference in 60 day
mortality. ?reduced duration of ventilation in
dry/conservative group.
51b

104. surfactant replacement therapy in ARDS
52a

105. theoretically good, improves O2 but no
improvement in
mortality, problems é distribution to
alveoli
52b

106. Steroids in ARDS:
53a

107. Menduri study: ↓Lung injury score, ↓LOS, ↓duration of
IPPV
ARDSNET 7 - 28 days to placebo vs methylprednisolone
(ie late in the disease process). ➜ no change in 60 day
mortality but ↑O2, ↑ventilator free days & shock free days,
offset by neuromuscular complications & ↑reintubation
Another study ➜ initiation after 2 weeks ➜ ↑mortality
Overall, not recommended
53b

108. Possible reasons for no positive trials of
Steroids in ARDS despite experimental
evidence:
54a

109. Given too late. need to be early to
↓inflammation ? Trials have often
started after ARDS established
SEs outweigh benefits
54b

110. ketoconazole in ARDS:
55a

111. antifungal that inhibits thromboxane
synthase & 5-lipooxygenase ➜ early data
but not confirmed
55b