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 Extrapulmonary events

Infection Sepsis
Bleeding Pancreatitis
Aspiration 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

60
Mortality 9%)

50

40
30

20

10

0
83 84 85 86 87 88 89 90 91 92 93 94 95 96
Years
Causes of Mortality in ARDS

1990
%
% 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 1990’s
• 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= Vt=

31% mortality
Survivals

40% mortality
%
(
)

Time after onset of ARDS

 NIH ARDS Network Trial
Mechanical Ventilation in ARDS

P = 0.0054
Mortality

(%
)

ml/kg ml/kg
 Median # Ventilator-Free Days

ml/kg ml/kg

ARDSnet
PaO2/FiO2

ml/lg
ml/kg
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.
•Minimum set RR = 6/min.
 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 ³ 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 ³ 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 ³ 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 (³ 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, placebo-
controlled trial in 725 patients with sepsis-
induced 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
Potent inhibitor of thromboxane and leukotriene synthesis

Total 234 Patient

Mortality

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 acid-induced 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
PAF Strategies
Ketoconazole N-acetylcysteine APC
Prostaglandin E1 Late steroids
Early steroids Surfactant
ECMO/ ECco2E Partial liquid
ventilation
Immunonutrition