ACUTE RESPIRATORY DISTRESS SYNDROME AND HOW TO MANAGE Wahju Aniwidyaningsih Division of Interventional Pulmonology & Respiratory Critical Care Department of Pulmonology & Respiratory Medicine Faculty of Medicine University of Indonesia – Persahabatan Hospital Disampaikan pada acara PIT VI IDI Kota Bogor | 9 Nopember 2013

1. ACUTE RESPIRATORY DISTRESS SYNDROME
AND
HOW TO MANAGE
Wahju Aniwidyaningsih
Division of Interventional Pulmonology & Respiratory Critical Care
Department of Pulmonology & Respiratory Medicine
Faculty of Medicine University of Indonesia – Persahabatan Hospital

2. DEFINITION
• N Engl J Med 2000;342:1301–8
– The original description of ARDS included the
presence of bilateral infiltrates on the chest
radiograph
– Insult: pulmonary and non-pulmonary

3. Definitions of the Acute Respiratory Distress Syndrome
Ware, L. B. et al. N Engl J Med 2000;342:1334-1349

4. The American-European
Consensus Conference definition
• Recognizes the severity of clinical lung injury :
– Patients with less severe hypoxemia (as defined by a ratio of the partial
pressure of arterial oxygen to the fraction of inspired oxygen of 300 or
less) are considered to have acute lung injury
– Patients with more severe hypoxemia (as defined by a ratio of 200 or
less) are considered to have the acute respiratory distress syndrome
–  facilitate earlier management.
• Simple to apply in the clinical setting.
• Disadvantage not assessing underlying cause and whether other
organ systems are affected
Am J Respir Crit Care Med 149:818—824, 1994

5. Incidence
• Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome
(ARDS) are still common problems in many countries with high
morbidity and mortality
• In the United States over 100,000 individuals each year develop
Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome
(ARDS)
• No Indonesian data  need integrated epidemiological study
between centres and institutions in Indonesia
• Many studies suggest that ARDS mortality has improved during the
past two decades, but remains high, ranging between 25 and 50% in
the most current series

6. Underlying etiologies of pulmonary and extrapulmonary
acute respiratory distress syndrome
Eur Respir J 2003; 22: Suppl. 42, 48s–56s.

7. Pathophysiology of ARDS
• Driven by an aggressive inflammatory reaction
• Triggered by local events such as noxious inhalation or aspiration or
by systemic processes such as sepsis and pancreatitis  activate
,an infammatory response, many mediators are released into the
pulmonary and systemic circulations.
• Result  endothelial damage cause pulmonary edema and
disturbances of the pulmonary and systemic microcirculations.
• The neutrophil is a major component of this infammatory response,
• Key mediators eg TNFα promote neutrophil adherence to the
endothelium and neutrophil activation

8. • Other cytokines, such as interleukin (IL)-8 : neutrophil
chemoattractants and enhance neutrophil activation  degranulate
neutrophils, release proteases, reactive oxygen species
(ROS), leukotrienes.
• The lipid mediators and platelet activating factor (PAF) decrease
vascular reactivity and promote further inflammation.
• The coagulation and complement systems also are activated, with
enhanced coagulation and decreased fibrinolysis.
• Endothelial damage  leaky capillaries, formation of nonhemodynamic pulmonary edema and alterations in the pulmonary
microcirculation.
• The end result  respiratory failure, decreased systemic
oxygenation, and ultimately death.

9. Pathogenesis of ARDS
N Eng J Med 2000; 342:1334-1349

10. Clinical presentation
• ARDS developed rapidly, 12-18 hours from insulting injury up to 5
days
• Restlessness, agitation and hypoxemia.
• Pulmonary changes due to inflammation  reduced lung
compliance  small tidal volume, increased respiratory rate and
increased work of breathing
• If the patients still able to tolerate  respiratory alcalosis
• Worsening can occur in few hours & may need intubation and
mechanical ventilation  due to respiratory acidosis.

11. Supporting diagnostic procedure
• No laboratory findings are specific for ARDS other than
diagnostic criteria
• Blood gas analysis :
– In early phase  hypoxemia & respiratory alkalosis due to shunt
or low ventilation-perfusion ratio (V/Q)
– In late phase  increased deadspace ventilation & work of
breathing, reduced CO2 elimination  respiratory acidosis
• Hematological abnormalities
– Anemia, leucocytosis/leucopenia, thrombocytopenia due
systemic inflammation and endothelial injury
– DIC eg in sepsis, head trauma or severe trauma
– Increased von Willebrand's factor (VWF) antigen in serum

12. • Acute phase reactant :
– Increased ceruloplasmin
– Reduced albumin
• Proinflammatory cytokines:
– Increased tumor necrosis factor α (TNF- α) and IL-1, -6, -8
• BAL
– High neutrophils (>60%)
– High eosinophils (>15%–20%) : possibilities of eosinophilic
pneumonia
– High lymphocytes  differential diagnosis hypersensitivity
pneumonitis, sarkoidosis, cryptogenic organizing pneumonia
(bronchiolitis obliterans organizing pneumonia), other acute form
ILD (interstitial lung disease)
– High erythrocytes and hemosiderin laden macrophages :
pulmonary haemmorhage

13. • BAL should be processed for :
– Cultures for possible infection
– Cytological examination
– PCP
– Viral inclusion bodies
• Bronchoscopy with PSB, not suggested to
do TBLB (escp patients with mechanical
ventilation)

14. Principles of ARDS Management
• Standard supportive therapy for ALI/ARDS is
directed toward identification and management
of pulmonary and nonpulmonary organ
dysfunction
• Most common disease processes associated
with ALI include sepsis, pneumonia, aspiration of
gastric contents, trauma, multiple
transfusions, and ischemia reperfusion
• Treat the underlying etiology

15. • Careful evaluation
– Pulmonary etiology
– Nonpulmonary sources of infection or other
insult should be made.
• In many cases, inciting cause of lung
injury cannot be directly treated, such as
aspiration or multiple transfusions 
optimizing supportive care of the patient.

16. Mechanical Ventilation
• The mainstay of supportive care in ALI/ARDS is
positive pressure mechanical ventilation.
• Intrapulmonary shunt and ventilation-perfusion
imbalances  life-threatening hypoxemia.
• High work of breathing from increased alveolar
dead space and reduced respiratory system
compliance may cause ventilatory failure with
hypercapnia and respiratory acidosis.

17. • By stabilizing respiration, mechanical ventilation allows
time for administration of treatment for the underlying
cause of ALI/ARDS (eg, infection) and for the evolution
of natural healing processes.
• Arterial oxygenation can be supported by raising the
fraction of inspired oxygen (FIO2) and applying positive
end-expiratory pressure (PEEP).
• Ventilation can be supported with intermittent positive
airway pressure

18. Volutrauma & Atelectrauma
• Volutrauma
– Occurs when the lung is overinflated and alveoli are overstretched
– Tidal stretch, rate of stretch, and frequency of stretch.
• Atelectrauma
– Caused by the repetitive opening and closing of recruitable alveoli.
– In the injured lung, positive-pressure ventilation can force open some
airless alveoli, but on expiration these same alveoli again collapse. 
recruitment-derecruitment of alveoli.
– Shear stresses  trauma, resulting in disruption of the surfactant
monolayer, especially when the opening/closing cycle is repetitive.
– Loss or disruption of the surfactant monolayer  requirement for higher
pressures to achieve alveolar opening, and may affect the permeability
of the alveolar-capillary barrier to proteins and other solutes.

19. Airway pressure and lung
distension
• Inflation of the lung will cause damage if
airway pressures are high enough.
• The important issues for the clinician  ?
– What levels of airway pressure are dangerous
– Can they be avoided in the mechanical
ventilation of patients with stiff lungs, as in
ARDS?

20. Effects of the distribution of ventilation in two-unit lung models with
homogeneous mechanical properties, with abnormal compliance
distribution, and with abnormal resistance distribution.
Respir Care Clin 10 (2004) 309–315

21. Rat lungs ventilated for 1 hour at three pressure settings: 14/0; 45/10, and 45/0 cm H2O.
Lungs of the control animals (14/0 cm H2O) seem to be uninjured. The lungs ventilated at 45/
0 cm H2O are markedly congested and hemorrhagic, whereas the lungs ventilated at 45/10 cm
H2O seem only slightly edematous.
Am Rev Respir Dis 1974;110:556–65;

22. Lung protective ventilation
• Clinical hallmarks of ALI/ARDS is decreased respiratory system
compliance
• Traditional tidal volumes of 10 to 15 mL/kg are used in patients with
ALI/ARDS receiving mechanical ventilation  resulting airway
pressures are frequently elevated, reflecting overdistention of the
less-affected lung regions
• Ventilation with small tidal volumes and limited airway pressures can
reduce ventilator-associated lung injury from overdistention  may
cause complications acute respiratory acidosis
• Prospective studies  mortality was reduced substantially from 40%
(traditional strategy) to 31% (lower tidal volume strategy) in a larger
trial by the National Institutes of Health (NIH) ARDS Network

23. Support of Arterial Oxygenation
(PEEP)
• PEEP reduces intrapulmonary shunt and
improves arterial oxygenation  adequate
arterial oxygenation at a lower FiO2, reduce
pulmonary oxygen toxicity.
• Adverse effects of PEEP include decreased
cardiac output, increased pulmonary edema
formation,increased resistance of the bronchial
circulation, increased lung volume and stretch
during inspiration further lung injury or
barotrauma.

24. Support of Arterial Oxygenation
(FiO2)
• In animals, high levels of inspired oxygen cause physiologic and
pathologic changes that are similar to other forms of ALI.
• In humans, no detectable oxygen toxicity occurred in normal
subjects when the FIO2 was < 50%, but impaired gas exchange was
apparent after breathing 100% oxygen at sea level for approximately
40 h.
• Diseased lungs may be more susceptible to injury from moderate
hyperoxia.
• Relationship of FIO2 to oxygen-induced lung injury has not been
clearly defined in ALI/ARDS patients, an FIO2 < 0.6 is usually
considered to be safe.

25. When should we wean?
• The timing and method of discontinuation from
mechanical ventilation remains an important clinical
problem.
• Mechanical ventilation can result in life-threatening
complications and therefore should be discontinued as
soon as possible.
• However, premature attempts at weaning from
respiratory support can result in failure and reinstitution
of mechanical ventilation, which carries an enhanced risk
of morbidity and mortality.

26. Non-invasive ventilation
• Complications of endotracheal intubation :
– upper-airway injuries, tracheomalacia, tracheal stenosis, sinusitis, and
ventilator-associated pneumonia.
• Noninvasive positive-pressure ventilation (NIPPV)  alternative
modality to avoid these complications.
• Advantages of allowing some verbal communication by
patients, and some patients can eat during short respites from the
face mask.
• Studies in ALI/ARDS patients  fewer cases of nosocomial
pneumonia and shorter requirements for ventilator assistance in
patients who received NIPPV as compared to those who received
ventilation via endotracheal tubes.
• Not feasible in delirious or obtunded patients.

29. High-Frequency Ventilation
• Utilizes very small tidal volumes with very
high respiratory rates
• Achieves the two main lung-protective
objectives (avoiding both overdistention
and ventilation with atelectasis at endexpiration) while maintaining normal
PaCO2 as well as arterial oxygenation

30. High-Frequency Ventilation
• Am J Respir Crit Care Med 2002;166,801-808
– Multicenter Oscillatory Ventilation for ARDS Trial
– 148 ARDS patients were randomized to either conventional
ventilation with a VT of 5 to 10 mL/kg and PEEP 10 cm H2O or
to high-frequency oscillatory ventilation (HFOV).
– The patients in the HFOV group
• Ventilation at 5 breaths/s at a mean airway pressure of 5 cm H2O
higher than that observed during conventional ventilation.
• The pressure amplitude of ventilation was initially set to achieve
vibration of the chest wall and was adjusted along with frequency to
achieve PaCO2 from 40 to 70 mm Hg.
– After 30 days, mortality in the conventional group was
52%, whereas in the HFOV group it was 37% (p = 0.102).
• HFOV is a safe and effective mode of ventilation in
ARDS patients.

31. Management of infection
•
Patients with ALI/ARDS frequently die from uncontrolled
infection.
•
Infection may have been the initial cause of ALI/ARDS
•
High risk of developing nosocomial infections, such as
pneumonia and catheter-related sepsis.
•
Uncontrolled infection associated with the development
of multiple organ dysfunction, a major objective of
standard supportive care in patients with ALI/ARDS is to
identify, treat, and prevent infections.

32. Vasodilators
• Most ALI/ARDS patients have mild-to-moderate pulmonary arterial
hypertension.
• A progressive rise in pulmonary vascular resistance  patients die
from ALI.
• Etiology of pulmonary arterial hypertension is multifactorial, and may
include hypoxic vasoconstriction, destruction and/or obstruction of
the pulmonary vascular bed, and high levels of PEEP.
• Inhaled NO  encouraging result
• Inhaled NO at a concentration of 18 ppm reduced mean pulmonary
artery pressure from a mean of 37 to 30 mm Hg  associated with a
decrease in intrapulmonary shunt from 36 to 31% and an increase in
PaO2/FIO2

33. Antiinflamatory drugs
• ARDS  systemic inflammation
• Antiinflammatory drugs  controversies exist
– Glucocorticoid  controversies, which phase, early or
late
– Ketokonazole : leucotriene and thromboxane A2
inhibitor
– Lisofylline and Pentoxifylline : inhibitor
phosphodiesterase  inhibit chemoattractant of
neutrophil and TNFα
– Futher research

34. Antioxidant
• Reactive oxygen species play a major role in mediating
injury to the endothelial barrier of the lung in the
presence of endotoxin, bacterial sepsis, or hyperoxic
lung injury.
• Antioxidant therapy has been useful in the prevention
and the treatment of ALI in some animal models
• N-acetylcysteine and procysteine, oxygen free-radical
scavengers and precursors for glutathione, were
efficacious in some experimental studies
• Large scale study  failed to show improvement

35. Beta adrenergic agonist
• B-adrenergic stimulation is known to
reduce infammation
• Adrenergic agents can inhibit the
increased lung vascular permeability seen
in ARDS and favor resorption of edema.
• Increased sodium-chloride transport
transepithelial

36. Hemodynamic Management
• Optimal fluid management in patients with ALI/ARDS is a
controversial issue.
• Data from animal experimentation suggest that fluid
restriction may reduce pulmonary edema in patients with
increased pulmonary vascular permeability, as in
ALI/ARDS.
• Other experimental data suggest that ALI/ARDS patients
may benefit from a hemodynamic management strategy
that increases oxygen delivery, which may require
increased vascular volume.

37. • Tissue hypoxia: how to detect, how to
correct, how to prevent; consensus conference
(Am J Respir Crit Care Med 1996; 154:1573–
1578)
– The consensus committee concluded that "... timely
resuscitation and achievement of normal
hemodynamics is essential."
• Vasopressors ?
– Needed to support systemic BP or to increase cardiac
output in patients with shock.
– No clear evidence that any vasopressor or
combination of vasopressors is superior.

38. Surfactant therapy
• Surfactant  normally produced by type II
pneumocytes, decreases surface tension at the air-fluid
interface of small airways and alveoli.
• Without surfactant, alveoli may collapse and resist
opening, even with high airway pressures.
• In respiratory distress syndrome of premature
infants, surfactant production by the immature lung is
deficient and surfactant replacement therapy is
beneficial.
• In adult ?

39. Nutrition
•
The goals of nutritional support include the provision of adequate nutrients
for the patient’s level of metabolism, and the prevention and treatment of
deficiencies of macronutrients and micronutrients while attempting to
minimize complications related to the mode of nutritional support.
•
The route of administration of nutrition in ALI/ARDS will be influenced by the
individual patient’s condition and ability to tolerate enteral feeding.
•
Parenteral nutrition has been used frequently in ALI/ARDS patients, but
experimental and clinical trials suggest that enteral nutrition may be
superior.
•
Enteral nutrition  less complications
•
Which composition ?  further research

40. Prone Positioning
•
Prone positioning leads to substantial improvements in arterial oxygenation
in approximately 65% of ARDS patients
•
Improved ventilation to previously dependent (dorsal) regions in the prone
position.
•
In the supine position, pleural pressures were higher near the more
dependent dorsal regions due to hydrostatic gradients  reduced
transmural pressures of dependent bronchioles and alveoli, contributing to
the tendency for atelectasis in these lung zones.
•
In the prone position, pleural pressures appeared more uniform, allowing
some dorsal regions to open and participate in ventilation and gas
exchange could prevent VILI , more uniform distribution of tidal volume
and by recruiting dorsal lung regions, preventing repeated opening and
closing of small airways or excessive stress at margins between aerated
and atelectatic dorsal lung units.
•
How many hours a day?

42. Conclusion
• Management of ARDS still have great controversies
• Mechanical ventilation still play great role in ARDS
management
• Lung protective ventilation strategy
• Treat underlying etiologies
• Other alternatives of modalities
• Further researches

43. NIH ARDS Network Lower Tidal Volume Ventilation for ALI/ARDS Protocol Summary
Variables
Protocol
Ventilator mode
Volume assist-control
Tidal volume
6 mL/kg predicted body weight
Plateau pressure
30 cm H2O
Ventilation set rate/pH
goal
6–35/min, adjusted to achieve arterial pH
Inspiratory flow, I:E
Adjust flow to achieve I:E of 1:1–1:3
Oxygenation goal
55
F 2/PEEP (mm Hg)
combinations
0.3/5, 0.4/5, 0.4/8, 0.5/8, 0.5/10, 0.6/10, 0.7/10, 0.7/12, 0.7/14,
0.8/14, 0.9/14, 0.9/16, 0.9/18, 1.0/18, 1.0/22, 1.0/24
Weaning
Attempts to wean by pressure support required when
F 2/PEEP .40/8
IO
Pa 2
O
mm Hg or 88
Sp 2
O
7.30 if possible
95%
IO
• Sp 2 = oxyhemoglobin saturation by pulse oximetry.
O
• Further increases in PEEP to 34 cm H2O allowed but not required.

44. Lung Injury Score