1. Chapter 7: Acute Respiratory Distress Syndrome
James D. Fortenberry, MD, FCCM, FAAP
Medical Director, Critical Care Medicine and Pediatric/Adult ECMO
Children’s Healthcare of Atlanta at Egleston

2. 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

3. New and Improved Adult Respiratory Distress Syndrome
Acute Respiratory Distress Syndrome

4. 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
American - European
Consensus Conference

5. 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

6. Clinical Disorders Associated with ARDS

7. 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%

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

9. ARDS Pathogenesis: Resolution Phase
Equally important
Alveolar edema - resolved by active sodium transport
Alveolar type II cells - re-epithelialize
Neutrophil clearance needed

11. 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

12. ARDS:CT Scan View

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

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

17. 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

21. 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!

22. 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

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

24. ARDS - Pathophysiology:Pulmonary Edema
Non-cardiogenic pulmonary edema-Starling formula
What changes in ARDS?
Q = K(Pc - Pis) -  (pl - is)
Q =
K =
Pc = ; Pis =
 =
pl = ; is =

26. 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
( days)
Chronic - fibrosing alveolitis: remodeling by collagenous tissue, arterial thickening, obliteration of pre-capillary vessels; cystic lesions
( > 10 days)

28. 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 % /36 %

29. ARDS - Principles of Therapy
Provide adequate gas exchange
Avoid secondary injury

31. Therapies for ARDS Mechanical Ventilation Innovations: NO
PLV
Proning
Surfactant
Anti-Inflammatory
Gentle ventilation:
Permissive hypercapnia
Low tidal volume
Open-lung
HFOV
ARDS
Extrapulmonary Gas Exchange
Total Implantable Artificial Lung
IVOX
IV gas exchange
AVCO2R
ECMO

32. The Dangers of Overdistention
Repetitive shear stress
Injury to normal alveoli
inflammatory response
air trapping
Phasic volume swings: volume trauma

33. The Dangers of Atelectasis
compliance
intrapulmonary shunt
FiO2
WOB
inflammatory response

34. Lung Injury Zones
Overdistention
“Sweet Spot”
Atelectasis

35. ARDS: George H. W. Bush Therapy
“Kinder, gentler” forms of ventilation:
Low tidal volumes (6-8 vs cc/kg)
“Open lung”: Higher PEEP, lower PIP
Permissive hypercapnia: tolerate higher pCO2

37. 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

38. Lower Tidal Volumes for ARDS
22% decrease * *
ARDS Network,
NEJM, 342: 2000
* p < .001

39. Is turning the ARDS patient “prone” to be helpful?

40. Prone Positioning in ARDS
Theory: let gravity improve matching perfusion to better ventilated areas
Improvement immediate
Uncertain effect on outcome

42. 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

43. Prone Positioning in Pediatric ARDS: Longer May Be Better
Compared 6-10 hrs PP vs hrs PP
Overall ARDS survival 79% in 40 pts.
Relvas et al., Chest 2003

44. Brief vs. Prolonged Prone Positioning in Children* **
Oxygenation Index (OI) *
- Relvas et al., Chest 2003

45. High Frequency Oscillation: A Whole Lotta Shakin’ Goin’ On

46. It’s not absolute pressure, but volume or pressure swings that promote lung injury or atelectasis.
- Reese Clark

47. High Frequency Ventilation
Rapid rate
Low tidal volume
Maintain open lung
Minimal volume swings

48. High Frequency Oscillatory Ventilation

50. HFOV is the easiest way to find the ventilation
“sweet spot”

51. HFOV: Benefits Vs. Conventional Ventilation

52. 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

53. HFOV vs. CMV in Pediatric Respiratory Failure*
- Arnold et al, CCM, 1994

54. HFOV: Outcomes of Randomized Controlled Trials
Reduces need for ECMO, chronic lung disease in neonates
Improves survival without CLD in pediatric ARDS

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

58. 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

60. Pediatric Respiratory ECMO - Children’s Healthcare of Atlanta

61. Other Cost Intensive Therapies
Therapy Cost/Patient
Pediatric ECLS $ 232, 941
Pediatric Liver Transplant $ 206, 375
Pediatric Heart Transplant $ 126,695

62. ECMO: Comparison to Other Expensive Therapies
Vats et al., CCM, 1998

63. If you think about ECMO, it is worth a call to consider ECMO

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

65. Calf’s Lung Surfactant Extract in Acute Pediatric Respiratory Failure
Multi-center trial-uncontrolled, observational
Calf lung surfactant (Infasurf) – intra-tracheal
Immediate improvement and weaning in 24/29 children with ARDS
14% mortality
-Willson et al,CCM, 24:1996

66. Surfactant in Pediatric ARDS
Current randomized multi-center trial
Placebo vs calf lung surfactant (Infasurf)
Children’s at Egleston is a participating center-study closed, await results

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

68. Effects of Prolonged Steroids in Unresolving ARDS
Randomized, double-blind, placebo-controlled 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

69. 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

70. Steroids in Unresolving ARDS* * *
p<.01
- Meduri et al., JAMA, 1998

71. 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

72. 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)

73. Effects of Inhaled Nitric Oxide In Children with AHRF
Randomized, controlled, blinded multi-center trial
108 children with OI > 15
Randomized: Inhaled NO 10 ppm vs. mechanical ventilation alone
Dobyns, Cornfield, Anas, Fortenberry et al., J. Peds, 1999

75. Inhaled NO and HFOV In Pediatric ARDS*
Dobyns et al.,
J Peds, 2000

76. Partial Liquid Ventilation

77. Partial Liquid Ventilation
Mechanisms of action
oxygen reservoir
recruitment of lung volume
alveolar lavage
redistribution of blood flow
anti-inflammatory

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

79. 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

80. 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

81. “…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