Adult Respiratory Distress

Syndrome
Mazen Kherallah, MD, FCCP

The Inexact Definition for ARDS

Contributes to difficulty in management
ARDS and ALI consensus statement definitions
Acute onset (not specified)
Po2/FiO2 ratio <200 (300 for ALI)
Bilateral infiltrates on chest radiograph (highly
variable)
PAWP<18 mm Hg or absence of clinical evidence of
volume overload

Bernard GR et al, Am J Resp Crit Care Med. 1994;149:818-824

The Nature of Acute Lung Injury

Pulmonary events
Infection
Bleeding
Aspiration

Extrapulmonary events
Sepsis
Pancreatitis
Trauma
Intestinal ischemia and reperfusion

Acute Inflammatory Response in the Lung

Physiologic cascades may be different
and responses to different therapies

Mediators of the Acute Inflammatory Process

Bacterial products
Reactive oxygen intermediates
Proinflammatory cytokines (high mobility
group protein 1)
Activated neutrophils, macrophages,
epithelium, endothelium, and platelets.
Complements

Mechanisms of the Acute

Inflammatory Process
Activation of transcriptional factors
Initiation of proinflammatory cytokine
cascades
Activation of coagulation cascades
Activation of pulmonary cell population

Decline in ARDS Fatality Rate

80
70

Mortality 9%)

60
50
40
30
20
10
0
83

84 85

86 87 88

89 90
Years

91 92

93 94 95

96

Causes of Mortality in ARDS

1990
11%
6%
36%

4%
6%

15%
22%

Sepsis/MOF
CNS
Respiratory
Cardiovascular
Hepatic
GI
Others

Arterial Oxygenation and

Outcome in ARDS

Oxygenation

Outcome

Arterial |Oxygenation and

Outcome in ARDS

Oxygenation

Outcome

Management of ARDS
Does it really make a difference whether the
arterial PO2 is 50 or 100

Management ARDS: Traditional

Goals for Gas Exchange
Normal PaO2 (maximize PaO2/FiO2)
Normal PaCO2 and pH

Changes in ARDS Management

in the 1990s

Lower tidal volumes

Lower alveolar pressures
Acceptance of hypercapnia
Acceptance of acidosis

Multicenter study of effectiveness of two

Tidal Volumes for Ventilation
ARDS network study
Prospective, randomized, multicenter study to compare
the effectiveness of 2 tidal volumes in patients with ALI
and ARDS- 12 ml/kg and 6 ml/kg
429 subjects randomized to 12 ml/kg of ideal body weight
Airway plateau pressure < 50 cm H2O
432 subjects randomized to 6 ml/kg of ideal body weight
Airway plateau pressure < 30 cm H2O

NIH ARDS Network Trial

Mechanical Ventilation in ARDS
Vt=6

Vt=12

110
100
90

31% mortality
40% mortality

70
60
50

(%
)

Survivals

80

40
30
20
0

10

20

30

40

50

60

70

Time after onset of ARDS

80

90

100

NIH ARDS Network Trial

Mechanical Ventilation in ARDS
45

P = 0.0054

40

25
20
15
10

(%
)

Mortality

35
30

5
0
6 ml/kg

12 ml/kg

Median # Ventilator-Free Days

14
12
10
8
6
4
2
0
6 ml/kg

ARDSnet

12 ml/kg

PaO2/FiO2
200
190
180
170

12 ml/lg
6 ml/kg

160
150
140
130
120
0

INITIAL VENTILATOR TIDAL VOLUME AND RATE

ADJUSTMENTS
A.Calculate predicted body weight (PBW)
Male= 50 + 2.3 [height (inches) - 60] or 50 + 0.91
[height (cm) - 152.4]
Female= 45.5 + 2.3 [height (inches) - 60] or 45.5 + 0.91
[height (cm) - 152.4]
B.Mode: Volume Assist-Control
1.Set initial tidal volume to 8 ml/kg PBW
2.Reduce tidal volume to 7 ml/kg after 1-2 hours and
then to 6 ml/kg PBW after 1-2 hours
3.Set initial ventilator rate to maintain baseline minute
ventilation (not > 35 bpm)

SUBSEQUENT TIDAL
VOLUME ADJUSTMENTS
Plateau Pressure Goal: 30 cmH2O
Check inspiratory plateau pressure (Pplat) with 0.5 second
inspiratory pause at least every four hours and after each change in
PEEP or tidal volume.
If Pplat > 30 cmH2O, decrease tidal volume by 1 ml/kg PBW
steps to 5 or if necessary to 4 ml/kg PBW.
If Pplat < 25 cmH2O and tidal volume < 6 ml/kg, increase tidal
volume by 1 ml/kg PBW until Pplat > 25 cmH2O or tidal
volume = 6 ml/kg.
If breath stacking or severe dyspnea occurs, tidal volume may
be increased (not required) to 7 or 8 ml/kg PBW if Pplat
remains 30 cmH2O.

ARTERIAL OXYGENATION
GOAL: PaO2 55-80 mm Hg or SpO2 88-95%
Use these FiO2/PEEP combinations to achieve oxygenation goal.

FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20-24

RESPIRATORY RATE (RR) AND ARTERIAL pH

ARTERIAL pH GOAL: 7.30-7.45
A.Acidosis Management:
If pH 7.15-7.30:
Increase set RR until pH > 7.30 or PaCO2 < 25
(Maximum Set RR =35)
If set RR = 35 and pH < 7.30, NaHCO3 may be given (not
required)
If pH < 7.15:
Increase set RR to 35.
If set RR = 35 and pH < 7.15 and NaHCO3 has been
considered, tidal volume may be increased in 1 ml/kg
PBW steps until pH > 7.15 (Pplat target may be exceeded).
B.Alkalosis Management: (pH > 7.45):
Decrease set RR until patient RR > set RR.

I:E RATIO

GOAL: 1:1.0 - 1:3.0

Adjust flow rate and inspiratory flow wave-form to
achieve goal.

WEANING
1.Conduct A CPAP trial daily when:
a.1. FiO2 0.40 and PEEP 8, and
b.PEEP and FiO2 values of previous day, and
c.Patient has spontaneous breathing efforts (may decrease
vent set rate by 50% for 5 minutes to detect effort), and
d.Systolic BP 90 mm Hg without vasopressor support.
Conducting the CPAP Trial:
Set: CPAP = 5 cmH2O, FiO2 = 0.50.
If patient RR 35 for 5 min., advance to Pressure Support
Weaning (Section VI.B)
If patient RR > 35, return to previous A/C settings and
reassess for weaning next morning.

Pressure Support (PS) Weaning Procedure

a.Set PEEP = 5 and FiO2 = 0.50
b.Set initial PS based on RR during CPAP trial:
i.If CPAP RR < 25: set PS = 5 cmH2O and go to steps 3c-d.
ii.If CPAP RR = 25-35: set PS = 20 cmH2O, then reduce by 5 cmH2O at
5 min. intervals until patient RR = 26-35, then go to step c-i.
iii.If initial PS not tolerated: return to previous A/C settings.
c.REDUCING PS: (No reductions made after 1700 hrs)
i.Reduce PS by 5 cmH2O q 1-3 hr.
ii.If PS 10 cmH2O not tolerated, return to previous A/C settings (If
VI.A Criteria O.K., resume last tolerated PS level next morning and go to
step c-i).
iii.If PS = 5 cmH2O not tolerated, go to PS = 10 cmH2O. If tolerated, PS
of 5 or 10 cmH2O may be used overnight with further attempts at
weaning the next morning.
iv.If PS = 5 cmH2O tolerated for 2 hours, assess for ability to sustain
unassisted breathing.

UNASSISTED BREATHING
TRIAL
a.Place on T-piece, trach collar, or CPAP < 5 cmH2O
b.Assess for tolerance as below for two hours.
c.If tolerated, consider extubation.
d.If not tolerated, resume PS 5 cmH2O

Definition of Weaning
Intolerance
1.RR > 35 (may exceed 35 5 minutes), and
2.SpO2 < 88% (< 5 minutes at < 88% may be tolerated), and
3.Respiratory distress ( 2 of the following):
Pulse > 120% of rate at 6 A.M. > 5 minutes
Marked use of accessory muscles
Abdominal paradox
Diaphoresis
Marked complaint of dyspnea

Definition of Unassisted
Breathing Intolerance
1.RR > 35
2.SpO2 < 90 % and/or PaO2 < 60 mm Hg, and
3.Spontaneous tidal volume < 4 ml/kg PBW, and
4.Respiratory distress (any two of the following):
Pulse > 120% of usual rate for > 5 minutes
Marked use of accessory muscles
Abdominal paradox
Diaphoresis
Marked complaints of dyspnea

High-Frequency Ventilation:
Very small tidal volume and very high
respiratory rate
Achieves lung protective objectives
Results of large randomized controlled trial
of HFV in adults with ARDS were
disappointing ( was not designed to avoid
atelectasis and end-expiration)
More studies are needed
Carlon GC et al. Chest. 1983;84:551-559

Tracheal Gas Insufflation:

Physiological dead space is elevated in ARDS patients,
and small tidal volume ventilation frequently causes
hypercapnia and acute acidosis
Without TGI, the bronchi and trachea are filled with
CO2-laden gas which is forced back into the alveoli
during the next inspiration
TGI provides a stream of fresh gas which is insufflated
into the trachea and thus reduces dead space
It may cause desiccation of secretion and increased
auto-PEEP

Inverse-Ratio Ventilation
IRV causes shunt reduction and improved
arterial oxygenation
Short exhalation time may cause increased
auto-PEEP which may account for the
improved oxygenation
Many patients require heavy sedation and
paralysis

Prone Positioning
Improves ventilation to previously dependent regions
of the lung
Leads to substantial improvement in oxygenation in
65% of ARDS patients
Prevents ventilator-associated lung injury by
promoting more uniform distribution of tidal volume
and by recruiting dorsal lung regions
Clinical outcome did not improve in ARDS patients
randomized to prone positioning for at least 6h/d vs
patients randomized to remain supine*

*Gattinoni L et al. Lancet 1997;350:815

Nutrition
High-Fat, Low-Carbohydrate Diet
Reduces the duration of ventilation in
patients receiving mechanical ventilation
Reduces the respiratory quotient and the
level of carbon dioxide
Al-Saady NM, et al. Intensive Care Med.
1989;15:290-295

Nutrition
Immunomodulatory Nutrients
Amino acids such as arginine and
glutamine, ribonucleotides, and omega-3
fatty acids.
Meta Analysis: decrease in infectious
complications and duration of hospital stay
Hays SD. Ann Surg 1999;229:467-477

Nitric Oxide
Vasodilatory effects are restricted to the blood
vessels at the site of generation or administration
since it is rapidly inactivated
NO inhalation dilates pulmonary vessels perfusing
aerated lung units, diverting blood flow from
poorly ventilated or shunt regions
Potential treatment for pulmonary hypertension
and severe hypoxemia in ARDS

Nitric Oxide
Prospective, multicenter, randomized, double-blind,
placebo-controlled trial on inhaled nitric oxide in
ARDS
208 patients
Payen D et al. Intensive Care Med 1999;25:s166
No effect on mortality or the duration of mechanical
ventilation
There may be a role for NO in some ALI/ARDS
patients with severe refractory hypoxemia and
pulmonary arterial hypertension

Surfactant Replacement Therapy

Multicenter, randomized, placebocontrolled trial in 725 patients with sepsisinduced ARDS
Artificial protein-free surfactant given by
aerosol did not affect arterial oxygenation,
duration of mechanical ventilation, or
survival
Anzueto A et al: N Eng J Med 334:1417-1421, 1996

Extracorporeal Gas Exchange

Prospective, multicenter, randomized trial was
conducted to compare ECMO to conventional
ventilation alone, mortality in both groups of
patients was approximately 90%(1).
Prospective, randomized trial compared clinical
outcomes in 40 patients with severe ARDS who
received either conventional mechanical
ventilation or LFPPV with ECco2R. No significant
difference in mortality between the two treatment
groups(2).
(1)Zapol WM et al. JAMA 1979;242:2193-2196
(2)Morris AH et al. Am J Respir Crit Care Med 1994; 149:295-305

Fluorocarbon Liquid-Assisted
Gas Exchange
Fluorocarbon liquids can dissolve 17 times more oxygen
than water, have low surface tension, and spread quickly
over the respiratory epithelium. They are nontoxic,
minimally absorbed, and eliminated by evaporation.
Reduced tension improves alveolar recruitment, arterial
oxygenation, and increase lung compliance.
Partial liquid ventilation: lungs are filled to functional
residual capacity and gas ventilation is done through
conventional ventilation.
Trials are needed before adoptation.

Anti-inflammatory Strategies

Glucocorticoid therapy
Antioxidant therapy
Prostaglandin E1
Lisofylline and pentoxyfilline
Anti IL-8 therapy

Corticosteroid Therapy in the

Proliferative Phase of ARDS
24 patients, 16 in the methylprednisolone arm and 8 in
the placebo arm, Significant changes were observed
for PaO2/FIO2 ratio (262 vs 148, p <0.001), LIS (1.7
vs 3.0, p <0.001), mean pulmonary artery pressure
(22.5 vs 30.0 mm Hg, p = 0.01), and multiple-organ
dysfunction syndrome score (0.7 vs 1.8, p <0.001) in
the corticosteroid-treated group vs the placebo group,
respectively. ICU survival was 100% (16 of 16) in the
steroid group vs 37% (3 of 8) in the placebo group (p
= 0.002), while overall survival was 87% (14 of 16) vs
37% (3 of 8), respectively (p = 0.03).
1)

Meduri GU, Headley S, Golden E, et al. JAMA 1998; 280:159-165

Late Steroid Rescue Study

The late phase of ARDS is often characterized by excessive fibroproliferation leading to
gas exchange and compliance abnormalities. While corticosteroids are not effective in early
ARDS, several case reports and uncontrolled case series and one small randomized,
controlled trial suggest that corticosteroids may be useful in the management of late-phase
ARDS. To test this hypothesis, a randomized, double-blinded trial comparing
corticosteroids to placebo in severe, late-phase ARDS after seven days is proposed.
The objective is to determine if the administration of corticosteroids, in the form of
methylprednisolone sodium succinate, in severe late-phase ARDS, will reduce mortality
and morbidity. In addition, bronchoalveolar lavage and serum will be collected during the
first week of the study to search for inflammatory markers of fibroproliferation.
The study will accrue a maximum of 180 patients. The trial will be reviewed by an
independent Data and Safety Monitoring Board every 60 patients. The Board is preparing
for its second review.
To date, 125 patients have been enrolled in this trial.

Antioxidant Therapy
N-acetylcysteine and procysteine are
oxygen free-radical scavengers and
precursors for glutathione
Phase II clinical studies showed
encouraging results
Large, randomized, placebo-controlled trial
failed to show beneficial effects of
procysteine in patients with ALI/ARDS
Ware Lb et al, N Eng J Med 2000; 342:1334-1349

Prostaglandin E1
Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled,
randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group.

Total 350 patients

Critical Care Medicine, Volume 27 Number 8 August 1999

Ketoconazole

Mortality

Potent inhibitor of thromboxane and leukotriene synthesis

100
90
80
70
60
50
40
30
20
10
0

Total 234 Patient

34

35

Placebo

Ketoconazole

The ARDS Network. JAMA 2000;283:1995-2002

Lisofylline and Pentoxifylline:

Inhibits the release of free-fatty acids from cell
membranes under oxidative stress
Inhibits the release of TNF, IL-1, and IL-6

119 Placebo
116 lisofylline

The ARDS network. Crit Care Med 2002;30:1-6

Anti-IL-8 Therapy
IL-8 is a chemotactic stimulus for migration of
neutrophils from an intravascular to an extravascular
location
Substantial quantities of IL-8 are present in BAL fluid or
the pulmonary edema fluid of patients in the early phase
of ARDS.
Monoclonal antibodies that neutralize IL-8 reduces acidinduced lung injury in rabbits
Clinical trials of ant-IL-8 therapy for prevention in high
risk patients or in early ALI/ARDS may soon be
warranted

Enhanced Resolution of Alveolar

Edema: 2 Agonists
2 Agonists increases alveolar fluid
clearance either by acting on epithelial
sodium channels or the sodium/potassium
adenosine triphosphatase pumps, and
inhibits the increased vascular permeability
Controlled clinical trials are needed to
evaluate aerolized beta-adrenergic agonist
therapy in patients with ALI/ARDS

ALVEOLI Study
Prospective, Randomized, Multi-Center Trial of Higher End-expiratory Lung
Volume/Lower FiO2 versus Lower End-expiratory Lung Volume/Higher FiO2
Ventilation in Acute Lung Injury and Acute Respiratory Distress Syndrome.
This study is a prospective, randomized, controlled multi-center trial. The objective is
to compare clinical outcomes of patients with acute lung injury and acute respiratory
distress syndrome treated with a higher end-expiratory lung volume/lower FiO2 versus
a lower end-expiratory lung volume/higher FiO2 ventilation strategy.
The study will test the hypothesis that mortality from ALI and ARDS will be reduced
with a mechanical ventilation strategy designed to prevent lung injury from repeated
collapse of bronchioles and alveoli at end-expiration.
The study will accrue a maximum of 750 patients. The trial will be reviewed by an
independent Data and Safety Monitoring Board to determine if the study should stop
for futility, lack of safety or proven efficacy.
To date, the trial has enrolled 450 patients.

PAC Study
A maximum of about 1,000 patients will be enrolled.
Patients will be treated with the specific fluid
management strategy (to which they were randomized)
for 7 days or until unassisted ventilation, whichever
occurs first. Patients randomized to PAC will utilize this
catheter for at least 3 days and up to 7 days (depending on
protocol defined stability criteria) or until unassisted
ventilation, whichever occurs first. If the PAC is
discontinued according to protocol between day 3 and day
7, the fluid management strategy will continue and will be
guided by the CVC. Patients randomized to CVC will
utilize this catheter for 7 days or until unassisted
ventilation, whichever occurs first.

PAC Study
This is a Prospective, Randomized, Multi-Center Trial of
evaluating the use of a Pulmonary Artery Catheter (PAC)
versus a less invasive alternative, the Central Venous
Catheter (CVC) for Management of patients with Acute
Lung Injury (ALI) and Acute Respiratory Distress
Syndrome (ARDS). The study is combined with a second
study evaluating a "Fluid Conservative" vs. "Fluid
Liberal" Management strategy in patients with ALI or
ARDS. These studies are combined using a 2x2 factorial
design.

Therapeutic Modalities in ARDS

Not Useful

Uncertain Value

Useful

Lisofylline

-adrenergic agents

PEEP

Inhaled nitric oxide

Anticytokine therapy Open Lung

Strategies
PAF

Ketoconazole

N-acetylcysteine

Prostaglandin E1

Late steroids

Early steroids

Surfactant

ECMO/ ECco2E

Partial liquid
ventilation
Immunonutrition

APC