ARDS IN NUTSHELL WITH RECENT EVIDENCES

1. ACUTE RESPIRATORY
DISTRESS SYNDROME
Dr. Abhinov K
MBBS DNB FNB

2. ARDS
 HISTORY
 DEFINITION
 ETIOLOGY
 EPIDEMIOLOGY
 PATHOGENESIS
 CLINICAL FEATURES
 DDX
 MANAGEMENT
 PROGNOSIS

3. HISTORY
 In 1821, in “A Treatise on Diseases of the Chest”
Laennec described the gross pathology of the
heart and lungs and described idiopathic
anasarca of the lungs; pulmonary edema without
heart failure.
 Double pneumonia
 Respirator lung

4. HISTORY
 In 1967 in a landmark article published in Lancet, that
Ashbaugh, Bigelow, Petty, and Levine first described the
clinical entity that they called “acute respiratory distress in
adults” This article recognized for the first time that ARDS
was a constellation of pathophysiologic abnormalities
common to a relatively large number of patients but that
were initiated by a wide variety of unrelated insults.
 1971 Petty and Ashbaugh used the term “adult”
respiratory distress syndrome in another publication
probably to address the perception of ARDS as an
adult version of the previously described infant
respiratory distress syndrome (IRDS).

5. CLINICAL TERMS
SYNONYMOUS WITH ARDS
 Adult hyaline-membrane disease
 Adult respiratory insufficiency syndrome
 High output respiratory failure
 Congestive atelectasis
 Hemorrhagic lung syndrome
 Da Nang lung
 Stiff-lung syndrome
 Shock lung
 White lung
 Transplant lung
 Non cardiogenic pulmonary edema
 Diffuse alveolar damage

6. Need for definition
 Facilitate research into pathogenesis
 Stantardise treatment modalities
 Allow comparison of various trials
 Assist with outcome prognostication

7. Lung Injury Score
 1988, Murray and colleagues, attempted to expand
the definition of ARDS
 incorporated risk factor, relative acuteness of the
disease process and measures of severity
 severity was graded using a Lung Injury Score
(LIS) considering 4 parameters.

9. DEFINITION
 In 1994 the American European Consensus Conference
(AECC) defined as
 “a syndrome of inflammation and increased permeability that is
associated with a constellation of clinical, radiologic, and
physiologic abnormalities that cannot be explained by, but may
coexsist with, left atrial or pulmonary capillary hypertension” and
“is associated most often with sepsis syndrome, aspiration,
primary pneumonia, or multiple trauma and less commonly with
cardiopulmonary bypass, multiple transfusions, fat embolism,
pancreatitis, and others.”
 Acute respiratory distress syndrome was defined as a subset of
ALI patients with more severe oxygenation deficit.

10. AECC Definition 1994
 AECC 1994- a joint American-European Consensus Conference.
ALI ARDS
ONSET ACUTE ACUTE
OXYGENATION P/F <300mmHg <200mmHg
CHEST RADIOGRAPH BILATERAL ALVEOLAR
OR INTERSTITIAL
INFILTRATES
BILATERAL ALVEOLAR
OR INTERSTITIAL
INFILTRATES
ABSENCE OF LA HTN PCWP<18mmHg or NO
CLINICAL EVIDENCE OF
ELEVATEDLAP
PCWP<18mmHg or NO
CLINICAL EVIDENCE OF
ELEVATEDLAP

11. Shortcomings of AECC definition.
 Acute was ill defined.
 P/F ratio can be manipulated by adjusting PEEP.
 CXR interpretation is unreliable.
 PACs are rarely used.
 PCWP may oscillate above and below the cut-off and may
be elevated for reasons other than heart failure
 ALI was used inconsistently.

12. ARDS Berlin definition 2012
 ARDS is an acute diffuse, inflammatory
lung injury, leading to increased
pulmonary vascular permeability,
increased lung weight, and loss of
aerated lung tissue along with hypoxemia
and bilateral radiographic opacities,
associated with increased venous
admixture, increased physiological dead
space and decreased lung compliance.

13. ARDS Berlin definition

14. Limitations of Berlin criteria.
 Ability to predict mortality is still poor.
 4 ancillary variables for severe ARDS were assessed but
did not have additional predictive value, so were not
included in the definition:
— radiographic severity, respiratory system compliance
(≤40 mL/cm H2O), positive end-expiratory pressure (≥10
cm H2O), and corrected expired volume per minute (≥10
L/min)

15. Limitations of Berlin criteria.
 Berlin definition doesn’t include underlying etiology
and lacks a direct measure of lung injury
 use of vasopressors at the time of diagnosis of ARDS
is associated with a much higher mortality regardless
of the P/F ratio (not accounted for in the Berlin
definition)
 Does not allow early identification of patient's who
may be amenable to therapies before ARDS becomes
established
 Berlin definition still allows CXR to be used for
diagnosis, which compared poorly with CT chest
when studied by Figueroa-Casa et al, 2013:

16. Limitations of Berlin criteria.
 The Berlin definition has low sensitivity when
compared to autopsy findings:
— Thille et al (2013) found that the Berlin
Definition had a sensitivity of 89% and specificity
of 63% to identify ARDS, based on autopsies of
356 patients with clinical criteria for ARDS using
evidence of diffuse alveolar damage as the gold
standard

17. Etiology
Direct Indirect
 Pneumonia
 Aspiration of gastric
contents
 Lung contusion
 Fat embolism
 Amniotic fluid embolism
 Near drowning
 Inhalational injury
 Reperfusion injury
 Non-pulmonary
sepsis
 Multiple trauma
 Massive transfusion
 Pancreatitits
 Salicylate or narcotic
overdose
 Cardiopulmonary
bypass

18. EPIDEMIOLOGY
●The age-adjusted 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.
● The incidence increased with patient age from 16 per
100,000 person- years among individuals 15 to 19 years of
age to 306 per 100,000 person-years among individuals 75
to 84 years of age.
●Extrapolation of the data suggested that there are
approximately 190,000 cases of ARDS in the United States
each year.

19.  The incidence of ARDS may be decreasing.
 A prospective cohort study from a single
institution reported that the incidence of ARDS
decreased from 82.4 cases per 100,000 person-
years in 2001 to 38.9 cases per 100,000 person-
years in 2008.
 This was attributable to a decline in hospital-
acquired ARDS, since the incidence of ARDS at
hospital presentation did not change.

20. Mortality according to severity
ARDS Severity PaO2/FiO2 Mortality
Mild 200 – 300 27%
Moderate 100 – 200 32%
Severe < 100 45%
Acute Respiratory Distress Syndrome-The Berlin Definition
The ARDS Definition Task Force*
JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669.

21. Pathogenesis

22. Edema •Diminished aeration
•Atelectasis
•Decreased Compliance
Intra pulmonary shunting and Hypoxia
Increased work of breathing, Dyspnea

23.  Microvascular occlusion (Microthrombi)
Reduced PBF to ventilated portion of lung
Increased Dead
Space Ventilation
Pulmonary HTN
HYPERCAPNIA

24.  Injury- edema-Exudative phase
 Proliferative phase
Resolution
Fibrotic Phase

25. Host factors increasing the risk
 Clinical variables found to be associated with an
increased risk of ARDS are
 Chronic alcohol abuse
 Hypoproteinemia
 Advanced age,
 Increased severity and extent of injury or illness as
measured by injury severity score (ISS) or APACHE
score
 Multiple transfusions of blood products
 Cigarette smoking.

26. Signs and Symptoms
Disease specific
 Fever, Hypotension,
Tachycardia in Sepsis
 Abdominal Pain in
Pancreatitis
Related to DAD
 Tachypnea,
 Dyspnea
 Hypoxemia
 Cyanosis
 Rales and crypts on
auscultation
 Raised Pap
 Pulm HTN
 Raised A-a Gradient

27. DDx
 Cardiogenic pulmonary edema
 Diffuse pneumonia, pneumothorax, Effusions
 Diffuse Alveolar hemorrhage
 Acute interstitial lung disease
 Neurogenic Pulmonary Edema
 Acute immunologic lung injury

28. CARDIOGENIC NON-CARDIOGENIC

31. Management of ARDS.
A) VENTILATORY MANAGEMENT:
 Conventional strategies:
o NIV
o lung protective ventilation
o PEEP
 Non conventional strategies:
o Recruitment manoeuvres
o Prone ventilation
o HFOV
o ECMO
B) NON VENTILATORY MANAGEMENT:
 Fluid management.
 Pharmacotherapy.
 Nutrition.

32. Baby Lung Concept
 Gattinoni and Antonio done serial CT
examinations of lungs in patients with ARDS,
which showed in this patients the aerated tissue
is about the size of the lung of 5-6 yrs old.
 He states that ARDS lung is not stiff but instead
small.
 It is a functional concept, not anatomical concept.
 Normally aerated, poorly aerated, overinflated,
non aerated tissues are seen in ARDS lungs

33. Complex interplay
 pulmonary oedema from damage to the
alveolocapillary barrier
 inflammatory infiltrates
 surfactant dysfunction
 NOTE: It is essential to understand that although
ALI is a diffuse process, it is also a heterogeneous
process, and not all lung units are affected equally:
normal and diseased tissue may exist side-by-side.

35. Effect of mechanical ventilation/
lung injury
 Barotrauma: high ventilating pressure and
alveolar over distension
 Atelectotrauma: repeatedly opening and closing
of lung units at tidal ventilation. (Whenever lung
units collapse, stretching adjacent, non-
atelectatic lung units and create damaging shear
forces)
 Volutrauma: regional overinflation can result in a
stretch injury leading to DAD.
 Biotrauma: release of inflammatory mediators and
bacterial translocation, which may incite end-
organ failure.
 High FiO2 causing oxygen toxicity.

36. NIV for ARDS?
 they conducted a prospective, randomized
trial of noninvasive positive-pressure
ventilation as compared with endotracheal
intubation with conventional mechanical
ventilation in 64 patients with hypoxemic
acute respiratory failure who required
mechanical ventilation.

37.  They found out- 20 of 32 patients (62 percent) in the
noninvasive-ventilation group and 15 of 32 (47 percent) in
the conventional- ventilation group had an improved ratio of
the partial pressure of arterial oxygen to the fraction of
inspired oxygen (PaO2 :FiO2 (P=0.21).
 Ten patients in the noninvasive-ventilation group
subsequently required endotracheal intubation.
 23 patients in noninvasive-ventilation group (72 percent)
survived their stay in the intensive care unit (odds ratio, 0.4;
95 percent confidence interval, 0.1 to 1.4; P=0.19)
 conventional-ventilation group had serious complications
(66 percent vs. 38 percent, P=0.02)
 Among the survivors, patients in the noninvasive-
ventilation group had shorter periods of ventilation
(P=0.006) and shorter stays in the intensive care unit
(P=0.002)

38. NIV for ARDS?

39.  Among 113 patients receiving NIV for AHRF, 82 had
acute respiratory distress syndrome (ARDS) and 31 had
non-ARDS.
 Intubation rates significantly differed between ARDS and
non-ARDS patients (61% versus 35%, P = 0.015) and
according to clinical severity of ARDS: 31% in mild, 62%
in moderate, and 84% in severe ARDS (P = 0.0016).
 Among patients with moderate ARDS, NIV failure was
lower among those having a PaO2/FiO2 >150 mmHg
(45% vs. 74%, p = 0.04).
 NIV failure was associated with active cancer, shock,
moderate/ severe ARDS, lower Glasgow coma score
and lower positive end-expiratory pressure level at NIV
initiation.
 Among intubated patients, ICU mortality rate was 46%
overall and did not differ according to the time to

40.  In conclusion- With intubation rates below 35%
in non-ARDS and mild ARDS, NIV stands as the
first-line approach
 NIV may be attempted in ARDS patients with a
PaO2/FiO2 > 150.
 By contrast, 84% of severe ARDS required
intubation and NIV did not appear beneficial in
this subset of patients.
 However, the time to intubation had no influence
on mortality.

41. NIV in ARDS?
 Respir Care 2010 Dec;55(12):1653-60.
 Role of noninvasive ventilation in acute lung
injury/acute respiratory distress syndrome: a
proportion meta-analysis.
Agarwal g et al.
CONCLUSIONS:13 STUDIES(540 PATIENTS)
 Our results suggest an almost 50% NIV failure rate in
patients with ALI/ARDS, so NIV should be cautiously
used in patients with ALI/ARDS. There is a need for a
uniform NIV protocol for patients with ALI/ARDS.

42. Invasive ventilation
 Main goals and management strategies during
mechanical ventilation are:
 avoid over distending lung units by limiting the
inflation volume and pressure.
 avoid repetitive opening and collapse by applying
adequate positive end expiratory pressure
(PEEP).
 Mechanical ventilation is initiated according to
ARDSNet protocol defined protocol.

43.  Compared 6 ml/kg ideal body weight (IBW) tidal volume versus 12 ml/kg IBW tidal
volume
 Each patient group also had their respective Pplat restrictions (< 30 for 6ml/kg and < 50
cm H20 for 12 ml/kg)
 Results:
 The trial was stopped after the enrollment of 861 patients because mortality was lower in
the group treated with lower tidal volumes than in the group treated with traditional tidal
volumes (31.0 percent vs. 39.8 percent, P=0.007).
 Also there was reduction in measured plasma biomarkers (TNF 1r, IL-6, and IL-8),
inflammatory mediators typically reflective of more severe lung injury.

47. Which mode of ventilation is better?

48.  3 RCTs that randomly assigned a total of 1089 participants
recruited from 43 ICUs in Australia, Canada, Saudi Arabia,
Spain and the USA.
 For mortality in hospital, the RR with PCV compared with VCV
was 0.83 (95% CI 0.67 to 1.02; three trials, 1089 participants;
moderate-quality evidence),
 For mortality in the ICU, the RR with PCV compared with VCV
was 0.84 (95% CI 0.71 to 0.99; two trials, 1062 participants;
moderate-quality evidence)
 The difference in effect on barotrauma between PCV and VCV
was uncertain
 Data from one trial with 983 participants for the mean duration
of ventilation, and from another trial with 78 participants for the
mean number of extrapulmonary organ failures that developed
with PCV or VCV, were skewed.
 Thus at currently available data from RCTs are insufficient to
confirm or refute whether PCV or VCV offers any advantage
for people with ARDS. More studies including a larger number
of people given PCV and VCV may provide reliable evidence
on which more firm conclusions can be based.

49. PEEP in ARDS.
 The 3 core RCTs include:
 the ARDSnet ALVEOLI study reported by Brower
and colleagues.
 the Canadian/Australian LOVS trial reported by
Meade and colleagues.
 and the French EXPRESS trial reported by
Mercat and colleagues.

50.  HIGH VS LOWER PEEP IN ARDS- ALVEOLI STUDY
 549 PATIENTS
 MEAN PEEP LOWER -8.3
HIGHER -13. 2
 CLINICAL OUTCOMES SIMILAR IN BOTH GROUPS.

51.  LOVS study.
 Interventions The control strategy included target tidal volumes of 6 mL/kg of predicted body
weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of
positive end-expiratory pressure (n = 508). The experimental strategy included target tidal
volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O,
recruitment manoeuvres, and higher positive end-expiratory pressures (n = 475).
 Conclusions For patients with acute lung injury and acute respiratory distress syndrome, a
multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no
significant difference in all-cause hospital mortality or barotrauma compared with an established
low-tidal-volume protocolized ventilation strategy. This “open-lung” strategy did appear to
improve secondary end points related to hypoxemia and use of rescue therapies.

52.  EXPRESS trial:
 Intervention: Tidal volume was set at 6 mL/kg of predicted
body weight in both strategies. Patients were randomly
assigned to a moderate PEEP strategy (5-9 cm H2O) (minimal
distension strategy; n = 382) or to a level of PEEP set to
reach a plateau pressure of 28 to 30 cm H2O (increased
recruitment strategy; n = 385).
 Conclusions: A strategy for setting PEEP aimed at increasing
alveolar recruitment while limiting hyperinflation did not
significantly reduce mortality. However, it did improve lung
function and reduced the duration of mechanical ventilation and
the duration of organ failure.

53. Meta-analysis on PEEP in ARDS.
 Conclusions: Treatment with higher vs lower levels of
PEEP was not associated with improved hospital survival.
However, higher levels of PEEP groups were associated
with improved survival among the subgroup of patients with
ARDS (usually is severe ARDS refractory to conventional
methods)

54.  In summary, it appears that for patients with less
severe lung injury the low-PEEP table from the
ARDSNet study is most appropriate.
 In patients with severe ARDS and refractory
hypoxemia, either the higher-PEEP table or
individualizing the PEEP to respiratory mechanics
may be beneficial

55. Limitations in Use of Plateau Pressure
for ARDS
 Patients with reduced chest wall compliance --
most commonly due to obesity -- may have higher
plateau pressures at baseline. Titrating tidal
volumes to plateau pressures < 30 cm H2O may
be inadequate and result in worsened
hypoventilation.
 In such situations Esophageal manometry is
considered superior to plateau pressures through
its measurement of transpulmonary pressure,
considered a more precise measure of potentially
injurious pressures in the lung.

56. Permissive hypercapnea in ARDS
 In low tidal volume ventilation – decrease minute
ventilation - increase in PaCO2 which leads to a
strategy of permissive hypercapnia.
 Its an acceptable practice when necessary to limit
tidal volumes.
 CO2 has anti inflammatory properties.
 Contraindicated in raised ICP.
 PaCO2 levels upto 80 mm Hg are acceptable
 When pH falls below 7.20, many physicians
choose to administer sodium bicarbonate,
Carbicarb, or THAM to maintain blood pH between
7.15 - 7.20.

57. Preserving spontaneous ventilation
 Experimental lung injury models of ARDS
demonstrated that preserving spontaneous
breathing was associated with:
 1) reduced markers of lung inflammation and
epithelial cell damage;
 2) improved tidal ventilation, gas exchange and
oxygen delivery and
 3) increased systemic blood flow.

58.  NEUMANN et al. and PUTENSEN et al. demonstrated that
partial ventilatory support with APRV promoted alveolar
recruitment in juxta-diaphragmatic areas, improved
ventilation/perfusion matching and gas exchange, and
increased oxygen delivery in comparison with controlled
mechanical ventilation.
 It should be noted that among the studies described
above, the study populations had a mild-to-moderate
degree of lung injury.
 The impact of spontaneous breathing in severe ARDS may
be completely different and may be harmful.

59.  YOSHIDA and co-workers found that
spontaneous breathing in a model of severe lung
injury caused high transpulmonary pressure,
worsened oxygenation and lung damage, and
could also cause local injury by internal
redistribution of volume.

60. RECRUITMENT MANEUVERS
INDICATIONS:
 As a rescue measure to improve oxygenation
 After disconnections in ventilator circuit( if responsive to
recruitment maneuvers)
 Post intubation to assess recruitability

61. RECRUITMENT MANEUVERS
 Systematic review analyzed 40 studies that evaluated RMs; 4
RCTs, 32 prospective studies and 4 retrospective cohort
studies.
 The sustained inflation method CPAP of 35–50 cm H2O for
20–40 seconds) was used most often (45%), followed by high
pressure control (23%), incremental PEEP (20%), and a high
VT/sigh (10%).
 Oxygenation was significantly increased after an RM but was
generally short lived.
 Adverse events included hypotension (12%) and
desaturation (8%)- generally transient
 Barotrauma (1%) and arrhythmias (1%) infrequent
Fan E Am J Respir Crit Care Med 2008;178(11):1156–
63.

62. RECRUITMENT MANEUVERS
 Current evidence suggests that RMs should not be routinely
used on all ARDS patients unless severe hypoxemia persists.
 RMs might be used as a rescue manoeuvre to overcome
severe hypoxemia, to open the lung when setting PEEP or
following evidence of acute lung derecruitment such as a
ventilator circuit disconnect.
 RM is useful only if recruitable lung is left behind.

63. RECRUITMENT MANEUVERS
STEPS:
1. The patient should be well sedated/paralyzed.
2. The patient should be adequately hydrated.
3. The patient should be hemodynamically stable and
no arrhythmias.
4. Avoid in patients with severe chronic respiratory
disease, intracranial hypertension, morbid obesity
and pregnancy
METHOD Ι:
 Keep the patient in CPAP mode and deliver 40cm
H2O pressure for up to 30 s at FiO2 of 1.

64. RECRUITMENT MANEUVERS
METHOD ΙΙ:
 Put patient in pressure control mode
 FiO2 of 1
 Inspiratory pressure 40-50 cm H2O
 PEEP 20-30 cm H2O
 Rate 8-20/min
 Inspiratory time 1-3 s
 Duration 1-2 min
 start with lower inspiratory pressure (40) and PEEP
(20) and if there is no response go to higher pressure.

65. PRONE VENTILATION.
 Improves oxygenation.
Mechanisms –
 Improve V/Q matching.
 Decreases shunt flow.
 Gravitational distribution of blood flow.
 Changes the regional diaphragm motion.
 Less compression from heart (1-4% in PV vs 16-42% in
SV).
 VALI - reduction.
 Better response to PPV.

66. PRONE VENTILATION.
 A representative computed tomography scan of a
patient with acute respiratory distress syndrome in
the supine position (left) and prone position (right).
Prone positioning redistributes opacities from dorsal
to ventral zones.

68.  PROSEVA trial ( N engl J Med 2013 May)
 Multi center prospective randomized controlled trial
 466 patients
 Severe ARDS defined as – P/F ratio <150 with FIO2 of 0.6 &
peep of 5cm of H2O.
T.V of 6ml /kg PBW.
 prone-positioning sessions of at least 16 hours or to be left in the
supine position.
 primary outcome 28 day mortality
 237- prone group. 229 –supine group
 The 28-day mortality was 16.0% in the prone group and
32.8% in the supine group (p<0.001).

69. PRONE VENTILATION.
Absolute contraindications:
 spinal instability and
 unmonitored increased intracranial pressure.
Relative contraindications:
 open abdominal wounds,
 multiple trauma with unstabilized fractures,
 pregnancy.
 severe hemodynamic instability.
 high dependency on airway and vascular access.
Complications:
 Facial edema.
 transient desaturation,
 transient hypotension,
 accidental extubation,
 catheter displacement,
 pressure ulcers,
 Vomiting.
 need for increased sedation.
 Compression of nerves and retinal vessels.

70. HFOV (high frequency oscillatory
ventilation)
 Ventilator strategy – small vts 1 ml/kg @ high
frequencies 1-15 hz(1 hz= 60 breaths/minute).
 Gas is actively pushed in and actively withdrawn.
 Tidal volumes generated with HFOV are often
smaller than anatomic dead space.
 Therefore, unlike conventional ventilation,
which relies principally upon bulk flow of gas to
the alveoli, ventilation during HFOV is
accomplished largely by enhanced gas
mixing within the lung.

71. OSCAR TRIAL

72. OSCILLATE TRIAL.

73. HFOV
 Compared HFOV to a lung protective strategy that employed
low tidal volume and higher PEEP levels to fully recruit the
lung.
 In the OSCAR study 398 patients were randomized to HFO
and 397 patients to a conventional lung protective strategy.
There was no difference in mortality between the two groups
(HFOV 42% vs. conventional ventilation 41%).
 In the OSCILLATE study, an excess mortality was reported
in the HFOV arm and the trial was stopped early after
enrolling 548 patients instead of planned 1,200 patients.
 In-hospital mortality was 47% in the HFO group compared to
35% in the control group (relative risk of death with HFO, 1.33;
95% confidence interval, 1.09 to 1.64; P=0.005).
 In addition, 11% of patients in the conventional arm crossed
over to HFOV arm for refractory hypoxemia and despite this
the death rates due to refractory hypoxemia were not
different between groups.

74. HFOV
 Oscar study:
Conclusion
 The use of HFOV had
no significant effect on
30-day mortality in
patients undergoing
mechanical ventilation
for ARDS.
 Oscillate study:
Conclusion
 In adults with moderate-
to-severe ARDS, early
application of HFOV, as
compared with a
ventilation strategy of
low tidal volume and
high positive end-
expiratory pressure,
does not reduce, and
may increase, in-
hospital mortality.

75.  10 RCTs (n = 1850); almost all participants had moderate or severe
ARDS.
 In participants randomized to HFO, there was no significant
difference in hospital or 30- day mortality (risk ratio (RR) 0.92, 95% )
(P = 0.46) compared with conventional ventilation.
 This systematic review suggest that HFO does not reduce hospital and 30-
day mortality due to ARDS; the quality of evidence was very low. Thus
cant be used as first line of therapy for severe ARDS.

76. ECMO (extracorporeal membrane
oxygenation)
 Randomized 180 patients with ARDS and a
Murray Lung Injury Score > 3 or a pH <
7.20 to either conventional therapy or
transfer to an ECMO center for consideration
of ECMO.

77. CESAR TRIAL- JUL’01- AUG’06
 Findings:
 766 patients were screened; 180 were enrolled and randomly
allocated to consideration for treatment by ECMO (n=90
patients) or to receive conventional management (n=90). 68
(75%) patients actually received ECMO; 63% (57/90) of
patients allocated to consideration for treatment by
ECMO survived to 6 months without disability compared
with 47% (41/87) of those allocated to conventional
management (relative risk 0·69; 95% CI 0·05–0·97,
p=0·03).
 Interpretation:
 We recommend transferring of adult patients with severe but
potentially reversible respiratory failure, whose Murray score
exceeds 3·0 or who have a pH < 7·20 on optimum
conventional management, to a centre with an ECMO-based
management protocol to significantly improve survival without
severe disability.

78. Liquid ventilation in ARDS
 401 participants, 170 received 'high'-dose partial liquid ventilation (i.e. a
mean dose of at least 20 mL/kg), 99 received 'low-dose' partial liquid
ventilation (i.e. a dose of 10 mL/kg) and 132 received conventional
mechanical ventilation (CMV).
 No evidence indicated that 'high'-dose PLV either reduced mortality at 28 d
(risk ratio (RR) 1.21, 95% confidence interval (CI) 0.79 to 1.85, P = 0.37) or
increased the number of days free of CMV at 28 d (mean difference (MD) -
2.24, 95% CI -4.71 to 0.23, P = 0.08).
 Pooled estimates of effect for the following adverse events- hypoxia,
pneumothorax, hypotension and cardiac arrest- all showed a non significant
trend towards a higher occurrence of these events in those treated with PLV.
 No evidence supports the use of PLV in ALI or ARDS; some evidence
suggests an increased risk of adverse events associated with its use.

79. Non ventilatory stratergies

80. FLUID MANAGEMENT
 In ARDS patients, alveolar edema formation caused by
increased vascular permeability may be worsened by
higher hydrostatic pressure as a consequence of fluid
overload.
 Independent risk factors for mortality in critically ill
patients:
 positive fluid balance.
 higher values of central venous and capillary wedge
pressures.

81. FACTT trial- Fluids and Catheters Treatment Trial

82. Martin GS et al. Albumin and furosemide therapy
in hypoproteinemic patients with acute lung injury.
Crit Care Med 2002; 30:2175–2182
 randomized 37 patients with ALI and a serum protein
concentration of < 5.0 gms/ dL to receive either
furosemide and albumin every 8 h for 5 days or
double placebo.
 intervention group had improved oxygenation, fluid
balance, and hemodynamics, reduction in ventilator
time and ICU & hospital length of stay.
 No differences in mortality were seen.

83. Martin GS et al. A randomized, controlled trial of furosemide
with or without albumin in hypoproteinemic patients with acute
lung injury. Crit Care Med 2005; 33:1681–1687.
 Comparing the administration of furosemide with
albumin to that of furosemide without albumin, ALI
patients treated with a combination of albumin and
furosemide had significantly greater improvements in
oxygenation.
 Addition of albumin to furosemide therapy promoted
diuresis while reducing hypotension and shock from
furosemide monotherapy .
 Combination group had lower SOFA scores and an
increased number of shock-free and ventilator-free days

84. SAFE STUDY
 The use of albumin or other colloids in the ICU
has decreased because of prior meta analyses
and the SAFE study which revealed no
difference in mortality and other significant
clinical endpoints for patients resuscitated with
albumin, as compared to those resuscitated with
normal saline.
 However, large randomized studies of albumin
use only in ARDS patients may throw some light
on its benefits.

85. PHARMACOTHERAPY
STEROIDS IN ARDS
 Corticosteroids - inhibition of the transcription of
proinflammatory cytokines, inhibition of neutrophil
activation.
 A synergic action with anti-inflammatory cytokines
 Suppression of the synthesis of phospholipase A2,
cyclooxygenase, and inducible NO synthase
 Corticosteroids have an inhibitory effect on fibroblast
proliferation and collagen deposition, including in the lung.

86.  180 patients with ARDS of at least seven days’ duration
randomly assinged to receive either methylprednisolone
or placebo in a double-blind fashion.
 The primary end point was mortality at 60 days.
 Secondary end points included the number of ventilator-
free days and organ-failure–free days, biochemical
markers of inflammation and fibroproliferation, and
infectious complications.

87. RESULTS
 At 60 days, the hospital mortality rate was 28.6 percent in the
placebo group and 29.2 percent in the methylprednisolone
group(p = 1.0) and at 180 days, the rates were 31.9 percent
and 31.5 percent (P = 1.0)
 Methylprednisolone was associated with significantly increased
60- and 180-day mortality rates among patients enrolled at
least 14 days after the onset of ARDS.
 Methylprednisolone increased the number of ventilator-free
and shock free days during the first 28 days, improvement in
oxygenation, respiratory-system compliance, fewer days of
vasopressor therapy.
 As compared with placebo, methylprednisolone did not
increase the rate of infectious complications but was
associated with a higher rate of neuromuscular weakness.

88.  91 patients were randomized to methylprednisolone infusion (1
mg/kg/d) vs placebo group. The duration of treatment was up to
28 days.
 Treatment was associated with a reduction in the duration
of mechanical ventilation (p 0.002), ICU stay (p 0.007), and
ICU mortality (20.6% vs 42.9%; p 0.03). Treated patients
had a lower rate of infections (p 0.0002),and infection
surveillance identified 56% of nosocomial infections in
patients without fever.
 Conclusions:
Methylprednisolone-induced down-regulation of systemic
inflammation was associated with significant improvement
in pulmonary and extrapulmonary organ dysfunction.
 reduction in duration of mechanical ventilation and ICU
length of stay.
(CHEST 2007; 131:954–963

89. STEROIDS IN ARDS can be used
 1-7 days (ideally within 72 hrs).
 Methylprednisolone 1mg/kg IV bolus, then 1 mg/kg/day
continuous IV for 14 days. Taper after 14 days over 2
weeks.
 If paralytics used, delay using concomitant steroids.
 If no clear physiological or radiologic benefit in 3-5 days
then stop steroids.
 7-14 days:
 Benefit less certain.
 > 14 days:
 No role. May increase mortality.

90. NEUROMUSCULAR BLOCKERS(NMBS)
 Facilitation of mechanical ventilation and control of
patient/ventilator asynchrony.
 The presence of ARDS criteria, high plateau
pressure, use of prone positioning, high PEEP
levels, or nonconventional modes of ventilation,
such as high-frequency oscillatory ventilation
 Decrease in VILI, as suggested by the decreased
incidence of barotrauma and pneumothoraces

91. ACURASYS trial.(339 pt, 48 hrs, P/F <150)

92. NEUROMUSCULAR BLOCKERS(NMBS)
 Administration of NMBAs in patients with early ARDS
improves oxygenation and decreases 90-day in-hospital
mortality, particularly in the most hypoxaemic patients
(i.e. when Pao2/F ratio is <120 mmHg).
 The mechanisms involved could include better adaptation
to protective ventilation with less VILI and diminution of
inflammation.
 NMBAs do not appear to be an independent risk factor
for ICU-acquired weakness if they are not given with
corticosteroids or in patients with hyperglycaemia.

93. Surfactant
 In Adults current evidence less compelling than pediatric.
 In a multi-institutional, randomized, controlled, and masked
trial Adult subjects within 48 h of initiation of mechanical
ventilation for direct ARDS were randomized to receive up to
three interventions with instilled CALFACTANT VS AIR
PLACEBO. The primary outcome was 90-day all-cause
mortality.
 Administration of calfactant was not associated with improved
oxygenation or longer-term benefits relative to placebo in this
randomized, controlled, and masked trial. At present,
exogenous surfactant cannot be recommended for routine
clinical use in ARDS.

94. INHALED NITRIC OXIDE
 Inhaled nitric oxide (iNO) selectively vasodilates the pulmonary
vasculature in ventilated alveoli, which improves:
 Ventilation-perfusion matching and hypoxemia
 Lowers pulmonary arterial pressure.
 Administration via the inhaled route and its very short half-life
minimize systemic effects (i.e., hypotension)
 iNO IS USED AS A RESCUE THERAPY IN SEVERE
HYPOXEMIA.
 A maximal oxygenation benefit typically occurs with
doses as low as 0.1 to 2 ppm. Worsening of oxygenation dose
>20ppm.

95. Severe ARDS
 n = 329, six trials
 RR 1.01; 95% CI 0.78 to 1.32; p =
0.93
 No mortality benefit
Mild to Moderate ARDS
 n = 740, seven trials
 RR1.12, 95% CI 0.89 to 1.42; p =
0.33
 No mortality benefit
Nitric oxide does not reduce
mortality in adults or
children with acute
respiratory distress
syndrome, regardless of the
degree of hypoxemia.

96. IV beta 2 agonists
 BALTI 2 STUDY.
 326 ARDS patients
 PaO2/FiO2 < 200 mmHg
 IV salbutamol vs placebo
28 day mortality
 salbutamol: 34% vs
Control 23%
 RR 1∙47, 95% CI 1∙03 to
2∙08

97. Beta 2 agonists.
 CONCLUSIONS:
Treatment with I.V. salbutamol early in the course
of ARDS was poorly tolerated, is unlikely to be
beneficial and could worsen outcomes.

98. Use of statins in ARDS
 Rosuvastatin- no mortality benefit but increased
adverse hepatic and renal damage.
 Simvastatin- no mortality benefit but less adverse
effects. Improvement in organ dysfunction in ALI.

99.  A randomized, double-blinded, placebo controlled trial in
patients with ALI. Patients received 80mg simvastatin or
placebo until cessation of mechanical ventilation or up to 14
days.
 At Day 7, there was no difference in extravascular lung water.
 By Day 14, the simvastatin-treated group had improvements in
non pulmonary organ dysfunction. Oxygenation and Respiratory
mechanics improved, although these parameters failed to reach
statistical significance.
 Treatment group- less CRP, IL-8.
 BUT NO MORTALITY BENEFIT.

100. NUTRITION
 Critically ill, mechanically ventilated patients typically
have elevated metabolic rates.
 High carbohydrate diet increases respiratory quotient
and minute ventilation demand (by increase in CO2
production).
 typically 50% of the non-protein portion of caloric intake
should consists of lipid

101. ASPEN/SCCM Guidelines 2016
 Either trophic or full nutrition by Enteral Nutrition is
appropriate for patients with acute respiratory
distress syndrome (ARDS) / acute lung injury (ALI)
and those expected to have a duration of mechanical
ventilation ≥72 hours as these 2 strategies of feeding
have similar patient outcomes over the first week of
hospitalization.
[Quality of Evidence: High]

102. OMEGA 3 STUDY

103. OMEGA 3 STUDY
 Basis :
The omega-3 (n-3) fatty acids docosahexaenoic acid and
eicosapentaenoic acid, along with γ-linolenic acid and
antioxidants, may modulate systemic inflammatory
response and improve oxygenation and outcomes in
patients with acute lung injury.
 272 pts, within 48 hrs of developing ALI, received twice
daily supplements of omega 3 vs placebo.

104. OMEGA 3 STUDY

105. ASPEN/SCCM Guidelines 2016
 No recommendation at this time regarding the
routine use of an enteral formulation
characterized by an anti inflammatory lipid profile
(eg, omega-3 FOs, borage oil) and antioxidants in
patients with ARDS and severe ALI given
conflicting data.
 [Quality of Evidence: Low to Very Low]

106. PROGNOSIS
Mortality- respiratory-16% ; non respiratory-
30-50%.
Leading cause of death – sepsis
Sepsis preceding ARDS- abdomen
predominant source.
Sepsis occurring after onset of ARDS-
pulmonary source.
VAP- 55% WITH ARDS VS 28% NON
ARDS.

107.  Predictors of poor outcome
 Age >75 mortality 60% vs <45 age 20%.
 Underlying cause of ARDS-
 Trauma related – lower likelihood of death at 90 days.
 Younger, less chronically ill, less severe lung epithelial and
endothelial injury .
 Apache score.
 Treatment with steroids.
 PRBC transfusion.
 Linear correlation between dead space ventilation and
mortality- for every 0.05 increase in dead space fraction
the odds ratio of death increases by 45% , nejm 2002;apr
25;346(17)1281-6.

108. Outcome scoring
AGE, PAO2/FIO2, AND PLATEAU PRESSURE
SCORE: A PROPOSAL FOR A SIMPLE
OUTCOME SCORE IN PATIENTS WITH THE
ACUTE RESPIRATORY DISTRESS SYNDROME
 Critical Care Medicine:
 July 2016 - Volume 44 - Issue 7 - p 1361–1369
 doi: 10.1097/CCM.0000000000001653

109.  A prospective, multicenter, observational, descriptive, and
validation study
 Six-hundred patients meeting Berlin criteria for moderate
and severe acute respiratory distress syndrome enrolled
in two independent cohorts treated with lung-protective
ventilation.
 They found out that a 9-point score based on patient’s
age, PaO2/FIO2 ratio, and plateau pressure at 24 hours
after ARDS diagnosis was associated with death.
 Patients with a score greater than 7 had a mortality of
83.3% (relative risk, 5.7; 95% CI, 3.0–11.0),
 whereas patients with scores less than 5 had a mortality
of 14.5% (p < 0.0000001).

110. Prevention
 Many clinical risk factors are associated with the
development of ARDS such as sepsis, shock,
pneumonia, pancreatitis, aspiration, high-risk
trauma and surgery, and multiple blood
transfusions.
 Many patients, therefore, develop ARDS during
hospital admission because of a second-hit, but
from potentially preventable exposures

111.  This was a population-based, nested, case-control
study
 consecutive adult patients who developed ARDS
from January 2001 through December 2010 during
their hospital stay (cases) were matched to similar-
risk patients without ARDS (controls).
 They were matched for 6 baseline characteristics.

112.  Adverse events were highly associated with
ARDS development (odds ratio, 6.2; 95% CI, 4.0-
9.7), as
 They were inadequate antimicrobial therapy,
 mechanical ventilation with injurious tidal volumes
 hospital-acquired aspiration
 volume of blood products transfused and fluids
administered.
 Incidence of ARDS decreased during the
study period.

113.  Thus we must try to avoid stated adverse event
even before development of ARDS
 Adopting lung protective ventilation in non ARDS
patient is beneficial.