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
Pneumonia Aspiration of gastric contents

Common Causes
Sepsis Severe trauma with shock , multiple transfusions

Less common causes

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

Less common causes

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% Trauma 5%

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

Innovations: NO PLV Proning Surfactant AntiInflammatory
Mechanical Ventilation

ARDS

Gentle ventilation: Permissive hypercapnia Low tidal volume Open-lung HFOV Total Implantable Artificial Lung

Extrapulmonary Gas Exchange

ECMO

IVOX IV gas exchange

AVCO2R

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

Overdistention
Lung Volume (ml/kg)

20

Sweet Spot

10

Atelectasis

0 13 Airway Pressure (cmH20) 33 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 35 30 25 Percent 20 15 10 5 0 Traditional Lower

ARDS Network, NEJM, 342: 2000

Death

Vent free days

* p < .001

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 20

Oxygenation Index (OI)

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

40
Survival with CLD%

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 Mortality % 50 40 30 20 10 0
< 25% 25 - 50 % 50 75% > 75%

ECMO Non-ECMO

p < .05

- Green et al., CCM, 1996

Pediatric Respiratory ECMO Childrens Healthcare of Atlanta

Diagnosis ARDS/ARF Bacterial Pneumonia Viral Pneumonia Trauma Burns Number 38 9 24 5 4 Survival % 71 85 86 80 75

ELSO Survival % 51 79 53 63 52

TOTAL

86

79%

62%

Other Cost Intensive Therapies

Therapy Pediatric ECLS Pediatric Liver Transplant Pediatric Heart Transplant Cost/Patient $ 232, 941 $ 206, 375 $ 126,695

ECMO: Comparison to Other Expensive Therapies

70 62.5

(Thousands of Dollars)

60 50 40 26.5 30 16.3 20 10 0
ECLS Liver Bone Cardiac Renal Marrow

Cost/Life - Year

43.5

4.19

Vats et al., CCM, 1998

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

Hospital survival

- Meduri et al., JAMA, 1998

* 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 70

*
71 53 58

Survival %

60 50 58 40 30 20 10 0

NO

NO

HF O

CM

Dobyns et al.,

HF O

CM

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

Open-lung strategy HFOV ECMO

- Outcome benefit in large study

- Outcome benefit in small study -Outcome benefit in small study - Proven in neonates unproven in children

Pharmacologic Approaches to ARDS: Randomized Trials

Glucocorticoids
- acute - fibrosing alveolitis Surfactant Inhaled NO Partial liquid ventilation - no benefit - lowered mortality, small study - possible benefit in children - no benefit - 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