1. What’s New In Pediatric ARDS
Nancy G. Hoover, MD
Medical Director, PICU
Walter Reed AMC

2. New and Improved Acute Respiratory Distress Syndrome
Ashbaugh, Lancet, 1967
Adult Respiratory Distress Syndrome
To distinguish from neonatal HMD/RDS
American-European Consensus conference, 1994
Ashbaugh first described the syndrome of severe respiratory failure similar to infant hyline membrane disease

3. 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
PCWP higher than 18 mmHg are generally considered to be c/w left-heart failure and may be the cause of cargiogenic pulmonary edema.
1994 American-European
Consensus Conference

4. Clinical Disorders Associated with ARDS
Direct Injury
Common Causes
Pneumonia
Gastric aspiration
Less Common Causes
Pulmonary contusion
Fat emboli
Near drowning
Inhalational injury
Indirect Injury
Common Causes
Sepsis
Shock after severe trauma
Less Common Causes
Cardiopulm. bypass
Drug overdose
Acute pancreatitis
Massive blood transfusions

5. The Problem: Lung Injury
Davis et al., J Peds 1993;123:35
Noninfectious Pneumonia 14%
Cardiac Arrest 12%
Infectious Pneumonia 28%
Hemorrhage 5%
Trauma 5%
Other 4%
Septic Syndrome 32%

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

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

8. ARDS - Pathophysiology
Decreased compliance
Alveolar edema
Heterogenous
“Baby Lungs”
Gattinoni “Concept of Baby Lung”, Intensive Care Medicine, 2005:
The "baby lung" concept originated as an offspring of computed tomography examinations which showed in most patients with acute lung injury/acute respiratory distress syndrome that the normally aerated tissue has the dimensions of the lung of a 5- to 6-year-old child ( g aerated tissue).
DISCUSSION: The respiratory system compliance is linearly related to the "baby lung" dimensions, suggesting that the acute respiratory distress syndrome lung is not "stiff" but instead small, with nearly normal intrinsic elasticity. Initially we taught that the "baby lung" is a distinct anatomical structure, in the nondependent lung regions. However, the density redistribution in prone position shows that the "baby lung" is a functional and not an anatomical concept. This provides a rational for "gentle lung treatment" and a background to explain concepts such as baro- and volutrauma.
CONCLUSIONS: From a physiological perspective the "baby lung" helps to understand ventilator-induced lung injury. In this context, what appears dangerous is not the V(T)/kg ratio but instead the V(T)/"baby lung" ratio. The practical message is straightforward: the smaller the "baby lung," the greater is the potential for unsafe mechanical ventilation.

9. Axial CT of an experimental model of ARDS showing the heterogeneous distribution of
lung disease. The gravitationally nondependent lung region (ventral) is relatively spared,
whereas the dependent lung region (dorsal) exhibits greater involvement

11. Phases of ARDS Acute - exudative, inflammatory
(0 - 3 days)
Subacute - proliferative
( days)
Chronic - fibrosing alveolitis
( > 10 days)

12. Phases of ARDS

13. ARDS - Outcomes Most studies - mortality 40% to 60%
Majority of deaths sepsis or MOD rather than primary respiratory
Outcomes similar for adults and children
Mortality may be decreasing
53/68 % /36 %

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

15. It would seem ironic that the very existence of humans is fully dependent on a gas that, in excess quantities, is toxic and lethal
Lynn D. Martin

16. Mechanical Ventilation
Therapies for ARDS
Mechanical Ventilation
Innovations:
iNO
PLV
Proning
Surfactant
Anti-Inflammatory
Gentle ventilation:
Permissive hypercapnia
Low tidal volume
Open-lung
HFOV
ARDS
Extrapulmonary techniques
ECMO
IVOX
IV gas exchange
Total Implantable Artificial Lung
Extrapulmonary Gas Exchange

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

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

19. Lung Injury Zones
Overdistention
“Sweet Spot”
Atelectasis

20. “Mechanical” Therapies in ARDS
Lower tidal volumes but avoidance of atelectasis with higher PEEP
Permissive hypercapnia
HFOV
Prone positioning

21. 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

22. Lower Tidal Volumes for ARDS
22% decrease * *
40% vs. 31% mortality
Vent-free days in the first 28 days was significantly higher in the low tidal volume group (12 +/- 11 vs. 10 +/-11;p=0.007
ARDS Network,
NEJM, 342: 2000
* p < .001

23. Ventilator Goals
Set the PEEP slightly higher than the lower inflection point
Lower tidal volume (generally < 6 mL/kg)
Static peak pressure <40 cm H20
Wean oxygen to <60%
In Stewart’s study, If peak pressure is <30 and tidal volume is <8 mL/kg, then there was no difference in mortality.

24. Permissive Hypercapnia
Defined: presence of hypercapnia in the setting of a mechanically ventilated patient receiving limited inspiratory pressures and reduced tidal volumes
Hickling, Intensive Care Med 1990
Hickling, Int Care Med, 1990

25. Physiologic Effects of Hypercapnia
RESP: Net effect is improvement in oxygenation by
enhancing hypoxic pulmonary vasoconstriction and decreases intrapulmonary shunting
Right-shift of oxygen-hemoglobin dissociation curve
When hypercapnia is produced through the limitation of tidal volumes and inspiratory airway pressures without adequate
PEEP, the Qs/Qt ratio increases secondary to progressive derecruitment of alveolar units. Under such conditions, oxygenation will be further impaired
by the hypercapnia-induced increase in cardiac output. This increase in cardiac output induces a worsening Qs/Qt ratio as blood flow increases
preferentially to the gravitationally dependent, poorly ventilated lung regions and results in additional intrapulmonary shunting
The increase in Qs/Qt can frequently be counteracted through the optimization of lung volume by means of recruitment maneuvers and application of suitable
levels of PEEP.
Hypercapnic acidosis enhances hypoxic pulmonary vasoconstriction, thus improving ventilation-perfusion matching, decreasing Qs/Qt, and increasing the PaO2.
Hypercapnic acidosis positively affects oxygen availability to tissues by promoting a right shift in the oxygen–hemoglobin dissociation curve.
Net effect is improvement in oxygenation

26. Physiologic Effects of Hypercapnia
CV: Net effect is often hemodynamic compromise
Sympathetic stimulation with increased C.O.
Increased HR and SV, decreased SVR
Intracellular acidosis of cardiomyocyte is reversible when due to hypercarbia compared to metabolic acidosis
When combined with high PEEP strategy, can lead to severely decreased preload and cardiovascular compromise
Hypercapnic acidosis has been shown to cause marked sympathetic stimulation with predictable increases
in cardiac output due to the augmentation of heart rate and stroke volume secondary to decreased systemic vascular resistance

27. Physiologic Effects of Hypercapnia
RENAL:
Compensatory bicarb reabsorption
Acidosis leads to direct renal vasoconstriction
Sympathetic-meditated release of norepinephrine (NE)
Indirectly, hypercapnia causes a decrease in SVR that in turn releases NE, stimulates the renin-angiotensin-aldosterone system, leading to a further decrease in renal blood flow
Within hours of the onset of sustained hypercapnic acidemia, the kidneys initiate compensatory net reabsorption of sodium bicarbonate, generally returning blood pH to physiologic levels within 2 days.

28. Permissive Hypercapnia Is it worth it?
Early adult ARDS trial showed a reduction in expected mortality of 56% to an actual mortality of 26%
Included in adult trauma patients protocol for mechanical ventilation
Several pediatric studies showing benefit when used in conjunction with low TV and high PEEP
Caution in patients with elevated ICP
Hickling, CCM, 1994
Nathens, J Trauma, 2005
Sheridan, J Trauma, 1995
Paulson, J Pediatr, 1996

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

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

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

32. Differences Between CMV and HFOV

33. 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

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

35. HFOV: Outcomes of Randomized Controlled Trials
Reduces cost, severity of chronic lung disease and decreases airleak in neonatal RDS
Decreases need for ECMO in eligible neonates
Improves survival without CLD in pediatric ARDS

36. Indications for HFOV Severe persistent airleak Neonatal: HMD (*)
Pneumonia
Meconium aspiration
Lung hypoplasia
Acute respiratory distress syndrome

37. Is turning the ARDS patient “prone” helpful?

38. Prone Positioning in ARDS
Theory: let gravity improve matching perfusion to well-ventilated lung
Improvement is immediate
Decreased shunt: improved PaO2 but variable (75%)
Uncertain effect on outcome

39. Effect of prone position on ventilation distribution
Effect of prone position on ventilation distribution. In the supine position, the distribution of ventilation is preferentially distributed to the ventral regions. When the patient is prone, the stiffness of the dorsal chest wall favors the distribution of ventilation to the dorsal regions, facilitating reinflation in this area.

41. Prone Positioning in Adult ARDS
Randomized trial
Standard therapy vs. standard + prone positioning
Improved oxygenation
No difference in mortality, time on ventilator
No difference in complications
Post-hoc analysis showed an improvement in 10-day mortality in the prone group but overall ventilator-free days, ICU discharge and length of hospitalization was unchanged
Gattinoni et al., NEJM, 2001

42. Conflicting Evidence for Proning?
Mancebo, Am J of Resp & CCM, 2006
136 adults, randomized to 20 h/day proning within 48h of intubation for severe ARDS
Same ventilator treatment protocols in both groups
25 % relative reduction in ICU mortality
Curley, JAMA, 2005
Shorter proning times and multiple protocols for vent mgt with lung-protective stragegy and weaning, sedation, nutrition, etc
Only 8% mortality and no benefit from prone positioning
In the study by Curely et al, you probably won’t see a benefit because with all of the other therapies, the mortality was so low, it would take a huge number of patients to show a mortality difference.

43. Pharmacological Therapies in ARDS
Surfactant
iNO
Steroids
Partial Liquid Ventilation

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

45. Calf’s Lung Surfactant Extract in Acute Pediatric Respiratory Failure
Multicenter trial-uncontrolled, observational
Calf lung surfactant (Infasurf) - intratracheal
Immediate improvement and weaning in 24/29 children with ARDS and 14% mortality
In several other studies, there is no evidence for sustained benefit from Surfactant administration
Wilson et al, CCM, 24:1996
Wilson et al, JAMA, 2005

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

47. 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, 1998

48. Steroids in Unresolving ARDS
By day 10, steroids improved:
PaO2/FiO2 ratios
Lung injury/MOD scores
Static lung compliance
Steroids decreased procollagen metabolites
24 patients enrolled; study stopped due to survival difference
Meduri et al, JAMA, 1998

49. Steroids in Unresolving ARDS* * *
p<.01

50. What about after first 28 days?
NHLBI ARDS Clinical Trials Network, NEJM, 2006
180 adult patients with ARDS >7 days
No difference in mortality with steroids
EXCEPT, if the patient was entered into the study after 14 days of ARDS
THEN, there was an increase in 60 and 180 day mortality

51. 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

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

53. Effects of Inhaled Nitric Oxide In Children with AHRF
Randomized, controlled, blinded multi-center trial
108 children, median age 2.5 years
Entry: OI > 15 x 2
Randomized: Inhaled NO 10 ppm vs. mechanical ventilation alone
Dobyns, et al., J. Peds, 1999

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

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

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

58. ARDS- “Mechanical” Therapies
Low tidal volumes Outcome benefit in large study
Prone positioning Unproven outcome benefit
Open-lung strategy Outcome benefit in small study
HFOV Outcome benefit in small study
ECMO Proven in neonates unproven in children

59. Pharmacologic Approaches to ARDS: Randomized Trials
Steroids
- acute no benefit
- fibrosing alveolitis lowered mortality, small study
Surfactant possible benefit in children
Inhaled NO no benefit
PLV no benefit

60. “…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

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

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

64. Impact of ECMO on Survival in Pediatric Respiratory Failure
Retrospective, multicenter 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

65. Impact of ECMO on Survival in Pediatric Respiratory Failure
% Mortality
mortality risk quartile
Green et al, CCM, 1996
p<0.05