The document provides an overview of acute respiratory distress syndrome (ARDS). It begins with a case presentation of a patient exhibiting symptoms of ARDS and then outlines the learning objectives which include understanding the definition, pathology, ventilation strategies, and adjunct therapies for ARDS. It reviews the history and evolving definitions of ARDS from 1967 to the current Berlin Definition from 2012. Key aspects of the Berlin Definition are described. The document discusses the incidence, outcomes, risk factors, pathophysiology involving different phases, clinical features, investigations, management goals and therapies for ARDS. Images are included showing histology, chest x-rays and CT scans of ARDS patients.

1. Updates on Acute respiratory distress syndrome
Hamdi Turkey - chest physician

2. I hope you are still awake at the end
of this lecture !

3. Case presentation
A 35 year old male patient was
r u s h e d i n t o t h e E R
complaining of SOB for the
past 3 days, he has fever,
Tachypnea, pulse 110 bpm,BP
80/50 mmHg, pallor and
cyanosed, normal JVP, normal
S1 and S2 with no added
sounds, on chest auscultation
there was bilateral diffuse
crackles.
SpO2 on room air was 60, ABG
: PaO2= 40, Pco2= 40, pH=7.3
What's the diagnosis?

4. Learning Objectives
To know the new definition of ARDS
To understand the pathology and pathophysiology of ARDS
To devise a ventilation strategy for these patients.
To introduce the concept of ventilator induced lung injury
To address adjunct and rescue therapy for patients with
resistant hypoxemia.

5. History
I n 1 9 6 7 A s h b a u g h a n d
colleagues published a case
series in the Lancet which
described a clinical syndrome,
which they (later) termed “Adult
R e s p i r a t o r y D i s t r e s s
Syndrome” (ARDS). The 12
patients involved complained of
acute respiratory distress,
cyanosis refractory to oxygen
t h e r a py, d e c r e a s e d l u n g
c o m p l i a n c e a n d d i f f u s e
pulmonary infiltrates on chest
x-ray.

6. Trauma doctors involved in treating victims of war had
long been familiar with this syndrome, which came to be
known as “wet lung”, “shock lung” or “Da-nang lung”.
This problem had been identified during World War II but
with the advent of advanced trauma (M.A.S.H. units
during the Vietnam war) the prevalence of this form of
respiratory failure was truly recognized.
Over the past 30 or so years, this syndrome has come to
be one of the central problems of intensive care: lung
injury arising from a variety of different etiologies, each
characterized by bilateral diffuse infiltrates on x-ray,
hypoxemia, and non-cardiogenic pulmonary edema.
History

7. In 1988, an expanded definition was
proposed that quantified the
physiologic respiratory impairment
through the use of a four-point lung-
injury scoring system that was based
on:
level of positive end-expiratory
pressure
ratio of the partial pressure of
arterial oxygen to the fraction of
inspired oxygen
static lung compliance
degree of infiltration evident on
chest radiographs.
History

8. Before research into the pathogenesis and
treatment of this syndrome could proceed, it was
necessary to formulate a clear definition of the
syndrome. Such a definition was developed in 1994
by the American-European Consensus Conference
(AECC) on acute respiratory distress syndrome
(ARDS).
The term “acute respiratory distress syndrome”
was used instead of “adult respiratory distress
syndrome” because the syndrome occurs in both
adults and children.
History

9. The Berlin Definition of ARDS
(published in 2012) has replaced the
American-European Consensus
Conference’s definition of ARDS
(published in 1994). However, it should
be recognized that most evidence is
based upon prior definitions.
History

10. Other terms
Shock lung
Pump lung
Traumatic wet lung
Post traumatic
atelectasis
Adult hyaline
membrane disease
Progressive respiratory
distress
Acute respiratory
insufficiency syndrome
Haemorrhagic
atelectasis
Hypoxic
hyperventilation
Postperfusion lung
Oxygen toxicity lung
Wet lung
White lung
Transplant lung
Da Nang lung
Diffuse alveolar injury
Acute diffuse lung
injury
Noncardiogenic
pulmonary edema.
Progressive
pulmonary
consolidation

11. AECC Past definition of ARDS
ARDS was defined as:
the acute onset of respiratory failure, bilateral
infiltrates on chest radiograph, hypoxemia as
defined by a PaO2/FiO2 ratio ≤200 mmHg, and no
evidence of left atrial hypertension or a pulmonary
capillary pressure <18 mmHg (if measured) to rule
out cardiogenic edema. In addition, Acute Lung
Injury (ALI), the less severe form of acute
respiratory failure, was different from ARDS only
for the degree of hypoxemia, in fact it was defined
by a 200 < PaO2/FiO2 ≤300 mmHg.

12. The 1994 AECC definition
became globally accepted, but
had limitations
The current definition is the
‘Berlin Definition’ published
in 2013, which was created by
a consensus panel of experts
convened in 2011 (an initiative
of the European Society of
Intensive Care Medicine
endorsed by the American
Thoracic Society and the
Society of Critical Care
Medicine)
AECC Past definition of ARDS

13. ARDS BERLIN DEFINITION
ARDS is an acute diffuse, inflammatory
lung injury, leading to increased pulmonary
vascular permeability, increased lung
weight, and loss of aerated lung tissue…
[ w i t h ] h y p o x e m i a a n d b i l a t e r a l
radiographic opacities, associated with
increased venous admixture, increased
physiological dead space and decreased
lung compliance.

14. The goal of developing the Berlin definition was to try
and improve feasibility, reliability, face and predictive
validity
ARDS BERLIN DEFINITION

15. Timing of acute onset
The timing of acute onset of respiratory
failure to make diagnosis of ARDS is clearly
defined in Berlin definition.
It defines the exposure to a known risk factor
or worsening of the respiratory symptoms
within one week.
It is important to identify risk factors that
explain the context of acute respiratory
failure arised from

16. Oxygenation
In the Berlin definition, there is no use of the term
Acute Lung Injury (ALI).
The committee felt that this term was used
inappropriately in many contexts and hence was
not helpful.
In the Berlin definition, ARDS was classified as
mild, moderate and severe according to the value
of PaO2/FiO2 ratio. Importantly, the PaO2/FiO2
ratio value is considered only with a CPAP or PEEP
value of at least 5 cmH2O.

17. The chest radiograph is characterized by bilateral
opacities involving at least 3 quadrants that are not
fully explained by pleural effusions, atelectasis and
nodules.
In the absence of known risk factors, a cardiogenic
origin of edema is to be excluded by objective
evaluation of cardiac function with echocardiography.
Consequently, the wedge pressure measurement was
abandoned because ARDS may coexist with
hydrostatic edema caused by fluid overload or cardiac
failure.
Chest X-ray

18. Key components
acute, meaning onset over 1 week or less
bilateral opacities consistent with pulmonary edema
must be present but may be detected on CT or chest
radiograph
PF ratio <300mmHg with a minimum of 5 cmH20 PEEP
(or CPAP)
must not be fully explained by cardiac failure or fluid
overload,” in the physician’s best estimation using
available information — an “objective assessment“ (e.g.
echocardiogram) should be performed in most cases if
there is no clear cause such as trauma or sepsis.

19. Severity
*on PEEP 5+; **observed in cohort
ARDS is categorized as being mild, moderate, or severe:
ARDS Severity PaO2/FiO2* Mortality**
Mild 200 – 300 27%
Moderate 100 – 200 32%
Severe < 100 45%

20. Changes from the 1994 AECC
definition
the term acute lung injury was abandoned
measurement of the PaO2/FIO2 ratio was changed to
require a specific minimum amount of PEEP
3 categories of ARDS were proposed (mild, moderate, and
severe) based on the PaO2/FIO2 ratio
Radiographic criteria were changed to improve interrater
reliability
PCWP criterion was removed and additional clarity was
added to improve the ability to exclude cardiac causes of
bilateral infiltrates

21. 1994 AECC
DEFINITION
Now
obsolete

22. Shortcoming of the AECC
definition
acute is ill defined
PF 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, just PF ratio 200 to 300,
or all patients <300 including ARDS?

24. Incidence and outcome
■ 20-75 per 100,000
■ 30% mortality
■ Recovery may take 6-12 months
■ Residual:
Restriction
Obstruction
Gas- Exchange Abnormalities
Reduced Quality of Life

25. Direct
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
Indirect
Risk factors

26. Cardiogenic Vs non cardiogenic
pulmonary edema
Cardiogenic Non-Cardiogenic
Patchy infiltrates in
bases
Effusions
Kerley B lines
Cardiomegaly
Pulmonary vascular
redistribution
Excess fluid in alveoli
Homogenous fluffy
shadows
No effusion
No Kerley B lines
No cardiomegaly
No pulmonary vascular
redistribution
Protein, inflammatory cells,
fluid

27. Cardiogenic Non-Cardiogenic

28. Cardiogenic Non-Cardiogenic

29. Pathophysiology
Classical phases
Injury
Exudative – alveolar capillary membrane disruption with
inflammatory cell infiltrate and high protein exudate to form
hyaline membranes
Proliferative – proliferation of abnormal Type II alveoli cells and
inflammatory cells
Fibrotic – infiltration with fibroblasts which replace alveoli and
alveolar ducts with fibrosis
Resolution – slow and incomplete repair and restoration of
architecture

31. Pathophysiology
Based on the histological appearance -
Exudative phase (0-4 days)
• Alveolar and interstitial edema
• Capillary congestion
• Destruction of type I alveolar cells
• Early hyaline membrane formation
Proliferative Phase (3-10 days)
• Increased type II alveolar cells
• Cellular infiltration of alveolar septum
• Organisation of hyaline membranes
Fibrotic Phase (>10 days)
• Fibrosis of hyaline membranes and alveolar septum
• Alveolar duct fibrosis

32. Findings on Light Microscopy and Electron Microscopy
during the Acute Phase (Panels A and D) and the Fibrosing-
Alveolitis Phase (Panels B, C, and E) of Acute Respiratory
Distress Syndrome.

33. Pathophysiology
Mechanisms in early phase -
• Release of inflammatory cytokines – TNF alpha, IL-
1,6,8
• Failure of alveolar edema clearance, epithelial and
endothelial damage
• Increased permeability of alveolo – capillary membrane
• Neutrophil migration and oxidative stress
• Procoagulant shift – fibrin deposition
• Surfactant dysfunction
Mechanism in late (repair) phase –
• Fibroproliferation -TGF beta, MMPs, thombospondin,
plasmin, ROS
• Remodelling - matrix and cell surface proteoglycans,
MMP, imbalance of coagulation and fibrinolysis.

34. Pathophysiology

35. Complex interplay
pulmonary oedema from damage to the alveolocapillary barrier
inflammatory infiltrates
surfactant dysfunction
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.

36. Effects
hypoxaemia (V/Q mismatch, impaired hypoxic pulmonar y
vasoconstriction)
increase in dependent densities (surfactant dysfunction, alveolar
instabilities)
decreased compliance (surfactant dysfunction, decreased lung volume,
fibrosis)
collapse/consolidation (increased compression of dependent lung)
increased minute ventilation (increased in alveolar dead space)
increased work of breathing (increased elastance, increased minute
volume requirement)
pulmonary hypertension (vasoconstriction, microvascular thrombi,
fibrosis, PEEP)

37. Host factors increasing the risk of
ARDS
Clinical variables found to be associated with an increased
risk of ARDS
Diabetes mellitus decreases the risk of ALI.
chronic alcohol abuse
hypoproteinemia
advanced age,
increased severity,and extent of injury or illness as
measured by injury severity score (ISS) or
APACHEscore
hyper-transfusion of blood products
cigarette smoking.

38. Causative factors in ARDS
Primary injury Host response
Consequences of
therapy

39. Clinical features

40. Symptoms
Acute respiratory distress syndrome (ARDS) is characterized by the
development of acute dyspnea and hypoxemia within hours to days of an
inciting event, such as trauma, sepsis, drug overdose, massive transfusion, acute
pancreatitis, or aspiration. In many cases, the inciting event is obvious, but, in
others (eg, drug overdose), it may be harder to identify.
Patients developing ARDS are critically ill, often with multisystem organ
failure, and they may not be capable of providing historical information.
Typically, the illness develops within 12-48 hours after the inciting event,
although, in rare instances, it may take up to a few days.
With the onset of lung injury, patients initially note dyspnea with exertion. This
rapidly progresses to severe dyspnea at rest, tachypnea, anxiety, agitation, and
the need for increasingly high concentrations of inspired oxygen.

41. Physical findings
Physical findings often are nonspecific and include tachypnea, tachycardia, and the
need for a high fraction of inspired oxygen (FIO2) to maintain oxygen saturation.
The patient may be febrile or hypothermic. Because ARDS often occurs in the
context of sepsis, associated hypotension and peripheral vasoconstriction with cold
extremities may be present. Cyanosis of the lips and nail beds may occur.
Examination of the lungs may reveal bilateral rales. Rales may not be present
despite widespread involvement. Because the patient is often intubated and
mechanically ventilated, decreased breath sounds over 1 lung may indicate a
pneumothorax or endotracheal tube down the right main bronchus.
Manifestations of the underlying cause (eg, acute abdominal findings in the case of
ARDS caused by pancreatitis) are present.

42. Symptoms
and signs
that
suggest a
cause of
ARDS

43. Laboratory investigations
Routine blood counts
RFT
LFT
Blood culture
BNP
ABG
BAL
ECHO
Chest CT scan
PCWP

44. Classic Chest X Ray of a patient with ARDS, although the
lung injury appears diffuse, when you look at the CT scan
of the same patient on the right you can see that the lower
lobes are densely consolidated and the upper lobes
relatively spared. Nevertheless, this patient was severely
hypoxic, and responded well to prone positioning.

45. Management

46. Therapy- goals
Treatment of the underlying cause
Cardio-pulmonary support
Specific therapy targeted at lung therapy
Supportive therapy

47. Diagnosis and appropriate treatment of the underlying cause
to minimise physiological impact of cause (drain collection,
antibiotics, resuscitate, splint fractures)
Nutritional support
Standard ICU prophylaxis
Stress ulcer prophylaxis
Prevention of nosocomial infections
CVP monitoring with CV line with appropriate fluid therapy
General measures

48. Goal of
management
of a patient
with ARDS

49. Treatable
inciting
causes of
ARDS

50. Lung protective strategy in ARDS
A myth or a fact!

51. Mechanical ventilation

52. Therapy- mechanical ventilation
The Problem: Ventilator- Induced Lung Injury
■ High volumes and pressures: Stress
( barotrauma)
■ Overdistension & Alveolar Cracking
( volumtrauma)
■ Cyclic Opening and closing of atelectatic
alveoli ( atelectrauma)
Cause increased permeability and alveolar
damage

53. The Problem: Oxygen Toxicity
■ Free Radicals
■ Oxygen Washout and De-Recruitment
High FiO2 can lead to further alveolar
damage
Therapy- mechanical ventilation

54. ■ Intubation almost always necessary
■ In past, goal was to normalize pH,
PaCO2, PaO2
■ High volumes and pressures were used
■ Worse outcomes
Therapy- mechanical ventilation

55. Lung protective strategy
Amato et al. 1998, Effects of a protective-
ventilation strategy on mortality in the acute
respiratory distress syndrome. N. Engl. J. Med.
338:347-54
■ 53 pts with early ARDS
■ Compared “conventional” ventilation of 12ml/kg
to “protective” 6ml/kg
■ Low PEEP. PaCO2 35-38
■ Improved survival at 28 days
■ Higher percentage of ventilator weaning
■ Less barotrauma

56. The Acute Respiratory Distress Network. 2000.
Ventilation with lower tidal volumes as compared with
traditional tidal volumes for acute lung injury and the acute
respiratory distress syndrome. N. Engl. J. Med. 342:1301-8
■ Larger Trial. 861 patients
■ Compared 12 ml/kg vs. 6ml/kg ventilation.
■ Plateau pressures 50 cm H2O vs. 30 cm H2O.
■ Trial ended early:
■39.8% mortality vs. 31% mortality
THIS HAS CHANGED CLINICAL PRACTICE
Lung protective strategy

57. Mechanical ventilation
ARDS Network protective lung ventilation strategy (from the
ARMA study)
controlled ventilation
TV 6mL/kg
avoid overstretch (volutrauma) and inadequate recruitment
(atelectrauma)
PEEP 5-15
Plateau pressure <30 cmH20 (higher than this contributes
to VILI from overstretching and hyperinflation of the
functional ‘baby lung’)

58. mode of ventilation: generally no difference
PCV tends to be used c/o plateau pressure
approximates peak pressure, with VC plateau
pressure needs to be measured
no role for inverse ratio ventilation (I:E ratio > 1) ->
increased mean airway pressure + haemodynamic
instability + regional hyperinflation
oxygenation target: SpO2 88-95%, PaO2 > 55-80 mmHg
carbon dioxide target: ARDSnet aimed for a normal
CO2 -> but lung is exposed to repeated tidal stretch,
ideally hypercapnia should be minimised but there
isn’t compelling data to suggest it is harmful unless
there is an obvious reason (raised ICP, pregnancy).

59. Ventilator
strategy
in ARDS

60. Ventilator settings
for lung protection

61. Complications
related to MV

63. Other techniques to improve oxygenation
prone posture: improves oxygenation and mortality in
severe ARDS
recruitment manoeuvres (e.g. PEEP 30-40cmH2O held
for 30 seconds or staircase recruitment manouvre) ->
can improve oxygenation but controversial, not
everyone responds
inhaled iNO: optimisation of V/Q mismatch,
1-60ppm, on 40-70% will respond, monitor for metHb
inhaled prostacycline (PGI2): optimisation of V/Q
mis-match, 1-50ng/kg/min, as effective as iNO

64. Pharmacological therapy
surfactant replacement therapy: theoretically good, improves
oxygenation but no improvement in mortality, problems with
distribution to alveoli
Diuretics : liberal vs conservative strategy
glucocorticoids: improvement in ventilator free days and shock,
no improvement in mortality and increase in weakness
ketoconazole: antifungal that inhibits thromboxane synthase and
5-lipooxygenase -> early data but not confirmed.
others: cytokine antagonism, NSAIDS, scavengers of O2 radicals,
lisofylline -> no success
Seek and treat underlying causes and complications

65. A randomized, clinical trial determined that simvastatin, a
hydroxymethylglutaryl-coenzyme A reductase inhibitor, improved oxygenation
and respiratory mechanics in patients with ALI. Further studies are needed, but
treatment with simvastatin appears safe and may be associated with improved
organ dysfunction in patients with ALI.
Statins
Pharmacological therapy
Activated protein C
Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011. In
the Recombinant Human Activated Protein C Worldwide Evaluation in Severe
Sepsis (PROWESS)-SHOCK clinical trial, drotrecogin alfa failed to demonstrate a
statistically significant reduction in 28-day all-cause mortality in patients with
severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality
rate of 26.4% in patients treated with activated drotrecogin alfa compared with
24.2% in the placebo group of the study.

66. In these critically ill patients, pay careful
attention to early recognition of potential
complications in the intensive care unit (ICU),
including pneumothorax, IV line infections, skin
breakdown, inadequate nutrition, arterial
occlusion at the site of intra-arterial monitoring
devices, DVT and pulmonary embolism (PE),
retroperitoneal hemorrhage, gastrointestinal
(GI) hemorrhage, erroneous placement of lines
and tubes, and the development of muscle
weakness.

67. Prognosis
pulmonary function returns to normal at 6-12 months in
survivors
occasionally patient have severe restrictive lung disease
although this is the case, many patient have a severe
reduction and pulmonary QOL -> depression, anxiety
and PTSD are common
patient often have cognitive impairment -> these
correlate with the period and severity of hypoxia

70. Thank you