Chapter 7: Acute

Respiratory Distress
Syndrome
James D. Fortenberry, MD, FCCM, FAAP
Medical Director, Critical Care Medicine and
Pediatric/Adult ECMO
Childrens Healthcare of Atlanta at Egleston

ARDS: What Is It?

Term first introduced in 1967
Acute respiratory failure with non-cardiogenic
pulmonary edema, capillary leak after diverse insult
Adult RDS defined to differentiate from neonatal
surfactant deficiency
Problems with definition troubled literature
Murray score 1988: CXR, PEEP, Hypoxemia,
Compliance
Synonyms
Shock lung
Da Nang Lung
Traumatic wet lung

New and Improved

Adult Respiratory Distress
Syndrome

Acute Respiratory Distress

Syndrome

ARDS: New Definition

Criteria
Acute onset
Bilateral CXR infiltrates
PA pressure < 18 mm Hg
Classification
Acute lung injury - PaO2 : F1O2 < 300
Acute respiratory distress syndrome PaO2 : F1O2 < 200
- 1994 American - European
Consensus Conference

ARDS - Epidemiology
New criteria allow better estimate of
incidence
1994 criteria in Sweden: ALI
17.9/100,000; 13.5/100,000 ARDS
US: may be closer to 75/1000,000
Prospective data pending
Incidence in children appears similar
5-9% of PICU admissions

Clinical Disorders Associated with ARDS

Direct Lung Injury

Indirect Lung Injury

Common causes

Common Causes

Pneumonia
Aspiration of gastric
contents

Sepsis
Severe trauma with shock ,
multiple transfusions

Less common causes

Less common causes

Pulmonary contusion
Fat emboli
Near-Drowning
Inhalational injury
Reperfusion pulmonary
edema

Cardiopulmonary bypass
Drug overdose
Acute pancreatitis
Transfusions of blood products

The Problem: Lung Injury

Davis et al., J Peds 1993;123:35

Non-infectious Pneumonia
14%
Cardiac Arrest 12%
Infectious Pneumonia 28%

Hemorrhage 5%

Trauma 5%
Other 4%

Septic Syndrome 32%

Etiology In Children

ARDS - Pathogenesis
Instigation
Endothelial injury: increased
permeability of alveolar - capillary
barrier
Epithelial injury : alveolar flood, loss
of surfactant, barrier vs. infection
Pro-inflammatory mechanisms

ARDS Pathogenesis: Resolution Phase

Equally important
Alveolar edema - resolved by active
sodium transport
Alveolar type II cells - reepithelialize
Neutrophil clearance needed

ARDS - Pathophysiology
Capillary leak:non-cardiogenic pulmonary
edema
Inflammatory mediators
Diminished surfactant activity and airway
collapse
Reduced lung volumes
Heterogeneous
Baby Lungs
Altered pulmonary hemodynamics

ARDS:CT Scan View

ARDS - Pathophysiology:
Diminished Surfactant Activity
Surfactant production and composition
altered in ARDS: low lecithin-sphingomyelin
ratio
Components of edema fluid may inactivate
surfactant

ARDS - Pathophysiology:
Diminished Surfactant Activity
Surfactant product of Type II pneumocytes
Importance of surfactant:
P = 2T/r (Laplace equation; P: transpulmonary pressure, T: surface tension,
r: radius)
Surfactant proportions surface tension to
surface area: thus

ARDS - Pathophysiology: Lung

Volumes
Reduced lung volumes, primarily reduced FRC
FRC =

Nl =

Low FRC-large intrapulmonary shunt, hypoxemia

Implies
lower compliance = flatter PV curve
marked hysteresis
PV curve concave above FRC and inflection point at
volume > FRC
closing volume in range of tidal volume
resistance increased primarily due to mechanical
unevenness (vs. airway R): high flow rates helpful

ARDS - Pathophysiology: Lung

Volumes
FRC = Volume of gas in lungs at end of
normal tidal expiration; outward recoil of
chest wall = inward recoil of lungs
Normal FRC =
FRC decreased by 20-40% in ARDS
FRC decreased by 20-30% when supine:
elevate head!

ARDS - Pathophysiology:
Mediators
Massive literature
Mediators involved but extent of
cause/effect unknown
Cellular:
neutrophils-causative: depletion in models
can obliterate lesion; ARDS can occur in
neutropenic patient; direct endothelial
injury, release radicals, proteolytic
enzymes
macrophages-release cytokines

ARDS - Pathophysiology:
Mediators
Humoral:
Complement
Cytokines: TNF, IL-1
PAF, PGs, leukotrienes
NO
Coagulant pathways

ARDS - Pathophysiology:Pulmonary
Edema
Non-cardiogenic pulmonary edemaStarling formula
What changes in ARDS?
Q = K(Pc - Pis) - ( pl - is)
Q =
K =
Pc =
=

; Pis =

pl = ; is =

Phases of ARDS
Acute - exudative, inflammatory: capillary congestion,
neutrophil aggregation, capillary endothelial swelling,
epithelial injury; hyaline membranes by 72 hours

(0 - 3 days)
Sub-acute - proliferative: proliferation of type II
pneumocytes (abnormal lamellar bodies with decreased
surfactant), fibroblasts-intra-alveolar, widening of
septae

(4 - 10 days)
Chronic - fibrosing alveolitis: remodeling by collagenous
tissue, arterial thickening, obliteration of pre-capillary
vessels; cystic lesions

( > 10 days)

ARDS - Outcomes
Most studies - mortality 40% to 60%;
similar for children/adults
Death is usually due to sepsis/MODS
rather than primary respiratory
Mortality may be decreasing
53/68 %

39/36 %

ARDS - Principles of Therapy

Provide adequate gas

exchange
Avoid secondary injury

Therapies for ARDS

Mechanical
Ventilation

Innovations:
NO
PLV
Proning
Surfactant
ARDS
AntiInflammatory
Extrapulmonary Gas Exchange

ECMO

IVOX
IV gas
exchange

Gentle ventilation:
Permissive
hypercapnia
Low tidal volume
Open-lung
HFOV

AVCO2R

Total
Implantable
Artificial Lung

The Dangers of Overdistention

Repetitive shear stress
Injury to normal alveoli

inflammatory response

air trapping

Phasic volume swings: volume trauma

The Dangers of Atelectasis

compliance

intrapulmonary shunt

FiO2

WOB

inflammatory response

Lung Injury Zones

Lung Volume (ml/kg)

Overdistentio
n
20
10

Sweet
Spot
Atelectasis

0
13

33
Airway Pressure (cmH20)

38

ARDS: George H. W. Bush Therapy

Kinder, gentler forms of
ventilation:
Low tidal volumes (6-8 vs.10-15
cc/kg)
Open lung: Higher PEEP, lower
PIP
Permissive hypercapnia: tolerate
higher pCO2

Lower Tidal Volumes for ARDS

Multi-center trial, 861 adult ARDS
Randomized:
Tidal volume 12 cc/kg
Plateau pressure < 50 cm H2O
vs
Tidal volume 6 cc/kg
Plateau pressure < 30 cm H2O
ARDS Network,
NEJM, 342: 2000

Lower Tidal Volumes for ARDS

40

22

35

e
d
%

as
e
r
c

Traditional
Lower

30
25
Percent

20
15

10

Vent free
days

* p < .001

Death

5
0

ARDS Network,
NEJM, 342: 2000

Is turning the
ARDS patient
prone to be
helpful?

Prone Positioning in ARDS

Theory: let gravity improve matching
perfusion to better ventilated areas
Improvement immediate
Uncertain effect on outcome

Prone Positioning in Adult ARDS

Randomized trial
Standard therapy vs. standard + prone
positioning
Improved oxygenation
No difference in mortality, time on
ventilator, complications
Gattinoni et al., NEJM, 2001

Prone Positioning in Pediatric ARDS:

Longer May Be Better
Compared 6-10 hrs PP vs. 18-24 hrs
PP
Overall ARDS survival 79% in 40 pts.
Relvas et al., Chest 2003

Brief vs. Prolonged Prone Positioning

in Children
25

Oxygenation
Index (OI)

20

15

**
*

10
5
0
Pre-PP

Brief PP

Prolonged PP

- Relvas et al., Chest 2003

High Frequency
Oscillation:
A Whole Lotta
Shakin Goin On

Its not absolute pressure,

but volume or pressure
swings that promote lung
injury or atelectasis.
- Reese Clark

High Frequency Ventilation

Rapid rate
Low tidal volume
Maintain open lung
Minimal volume swings

High Frequency Oscillatory Ventilation

HFOV is the easiest way to

find the ventilation
sweet spot

HFOV: Benefits Vs. Conventional

Ventilation

HFOV vs. CMV in Pediatric

Respiratory Failure: Results
Greater survival without severe lung
disease
Greater crossover to HFOV and
improvement
Failure to respond to HFOV strong
predictor of death
Arnold et al, CCM, 1994

HFOV vs. CMV in Pediatric

Respiratory Failure
Survival with CLD%

40

20

*
0
HFOV

CV

CV to
HFOV

HFOV to
CV

- Arnold et al, CCM, 1994

HFOV: Outcomes of Randomized

Controlled Trials
HFOV

Reduces need for ECMO, chronic lung

disease in neonates
Improves survival without CLD in
pediatric ARDS

Pediatric ECMO
Potential candidates
Neonate - 18 years
Reversible disease process
Severe respiratory/cardiac failure
< 10 days mechanical ventilation
Acute, life-threatening deterioration

Impact of ECMO on Survival in

Pediatric Respiratory Failure
Retrospective, multi-center cohort analysis
331 patients, 32 hospitals
Use of ECMO associated with survival (p < .001)
53 diagnosis and risk-matched pairs:
ECMO decreased mortality (26% vs 47%,
p < .01)
-Green et al, CCM, 24:1996

Impact of ECMO on Survival in

Pediatric Respiratory Failure

90
80
70
60
5
0
Mortality%40
30
20
10
0 <25%
p < .05

ECMO
Non-ECMO
*

25-50
%

5075%

>75%

- Green et al., CCM, 1996

Pediatric Respiratory ECMO Childrens Healthcare of Atlanta

Diagnosis

Number

Survival %

ARDS/ARF

38

71

ELSO Survival
%
51

Bacterial
Pneumonia
Viral
Pneumonia
Trauma

85

79

24

86

53

80

63

Burns

75

52

TOTAL

86

79%

62%

Other Cost Intensive Therapies

Therapy

Cost/Patient

Pediatric ECLS

$ 232, 941

Pediatric Liver Transplant

$ 206, 375

Pediatric Heart Transplant

$ 126,695

ECMO: Comparison to Other

Expensive Therapies

(Thousands of Dollars)

Cost/Life - Year

70

62.5

60
50

43.5

40
26.5

30

16.3

20
10
0

4.19
ECLS

Vats et al., CCM, 1998

Liver

Bone Cardiac Renal

Marrow

If you think about ECMO,

it is worth a call to consider
ECMO

Surfactant in ARDS
ARDS:
surfactant deficiency
surfactant present is dysfunctional
Surfactant replacement improves
physiologic function

Calfs Lung Surfactant Extract in

Acute Pediatric Respiratory Failure
Multi-center trial-uncontrolled,
observational
Calf lung surfactant (Infasurf) intratracheal
Immediate improvement and weaning in
24/29 children with ARDS
14% mortality
-Willson et al,CCM, 24:1996

Surfactant in Pediatric ARDS

Current randomized multi-center
trial
Placebo vs calf lung surfactant
(Infasurf)
Childrens at Egleston is a
participating center-study closed,
await results

Steroids in ARDS
Theoretical anti-inflammatory, antifibrotic benefit
Previous studies with acute use (1st 5
days)
No benefit
Increased 2 infection

Effects of Prolonged Steroids in

Unresolving ARDS
Randomized, double-blind, placebocontrolled trial
Adult ARDS ventilated for > 7 days without
improvement
Randomized:
Placebo
Methylprednisolone 2 mg/kg/day x 4 days,
tapered over 1 month
Meduri et al, JAMA 280:159, 1998

Steroids in Unresolving ARDS

By day 10, steroids improved:
PaO2/FiO2 ratios
Lung injury/MOD scores
Static lung compliance
24 patients enrolled; study stopped
due to survival difference

Meduri et al, JAMA, 1998

Steroids in Unresolving ARDS

100
90
80
70
60
50
40
30
20
10
0

Steroid
Placebo

ICU
survival

- Meduri et al., JAMA, 1998

Hospital
survival

* p<.01

Inhaled Nitric Oxide in

Respiratory Failure
Neonates
Beneficial in term neonates with PPHN
Decreased need for ECMO
Adults/Pediatrics
Benefits - lowers PA pressures,
improves gas exchange
Randomized trials: No difference in
mortality or days of ventilation

ECMO and NO in Neonates

ECMO improves survival in neonates
with PPHN (UK study)
NO decreases need for ECMO in
neonates with PPHN: 64% vs 38%
(Clark et
al, NEJM, 2000)

Effects of Inhaled Nitric Oxide In

Children with AHRF
Randomized, controlled, blinded multicenter trial
108 children with OI > 15
Randomized: Inhaled NO 10 ppm vs.
mechanical ventilation alone
Dobyns, Cornfield, Anas,
Fortenberry et al., J. Peds, 1999

Inhaled NO and HFOV In Pediatric

ARDS
80

Survival %

70

71

60
50 58
40

53

58

30
20
10
0

Dobyns et al.,

J Peds, 2000

Partial Liquid
Ventilation

Partial Liquid Ventilation

Mechanisms of action
oxygen reservoir

recruitment of lung volume

alveolar lavage
redistribution of blood flow
anti-inflammatory

Liquid Ventilation
Pediatric trials started in 1996
Partial: FRC (15 - 20
cc/kg)
Study halted 1999 due to
lack of benefit
Adult study (2001): no
effect on outcome

ARDS- Mechanical Therapies

Prone positioning

- Unproven outcome
benefit

Low tidal volumes

- Outcome benefit in
large study

Open-lung strategy

- Outcome benefit in
small study

HFOV

-Outcome benefit in
small study

ECMO

- Proven in neonates
unproven in children

Pharmacologic Approaches to
ARDS: Randomized Trials
Glucocorticoids
- acute

- no benefit

- fibrosing alveolitis

- lowered mortality,
small study

Surfactant

- possible benefit in
children

Inhaled NO

- no benefit

Partial liquid ventilation

- no benefit

We must discard the old approach

and continue to search for ways to
improve mechanical ventilation. In
the meantime, there is no substitute
for the clinician standing by the
ventilator
- Martin J. Tobin, MD