1. © The Children's Mercy Hospital, 2014. 03/14
TARA BENTON, MD MSCI
Pediatric Intensivist
Children’s Mercy Hospitals and Clinics
June 27, 2014
Pediatric ARDS: the old and the
new(-ish)

2. © The Children's Mercy Hospital, 2014. 03/142
Disclosures
• none

3. © The Children's Mercy Hospital, 2014. 03/143
Objectives
• Review history of ARDS
• Define acute lung injury and acute respiratory distress syndrome
• Discuss the epidemiology of pediatric ARDS
• Review relevant pathophysiology
• Discuss ventilator induced lung injury in the context of ARDS
• Discuss available treatment modalities
– In the context of pathophysiology
– Overview of research

4. © The Children's Mercy Hospital, 2014. 03/144
What I want you to get out of
this talk…
• ARDS is a very heterogeneous disease which makes it
difficult to study
• Many studies have been performed (mainly in adults) BUT
– ONLY LUNG PROTECTIVE VENTILATION HAS BEEN
ACCEPTED AS STANDARD THERAPY AND HAD MORTALITY
BENEFIT
• Reducing iatrogenic harm is important
• Children are not small adults
• If you want to do an RCT that people remember, you must
have a cool acronym

5. © The Children's Mercy Hospital, 2014. 03/145
The first
description of
ARDS?
• 1821 – Laennec (guy
who invented the
stethoscope)
described idiopathic
lung anasarca which
is pulmonary edema
without heart failure
in his text ‘A Treatise
on Diseases of the
Chest’

6. © The Children's Mercy Hospital, 2014. 03/146
History Lesson
• 1925 – Sir William Osler – considered cause and
pathophysiology in his textbook
– ‘uncontrolled septicemia leads to frothy pulmonary edema that
resembles serum, not the sanguinous transudative edema fluid
seen in dropsy or congestive heart failure’
• 1967 – “Adult” RDS was initially described by Ashbaugh et
al in a case series of 12 patients
– Pao2/FiO2 ratio of <300, diffuse bilateral disease, an identifiable
insult within 7 days, Pcwp <18 mmHg
– “A” was changed to acute by a consensus conference in 1994

7. © The Children's Mercy Hospital, 2014. 03/147
Definitions
 Acute lung injury and ARDS (acute respiratory
distress syndrome) are sydromes that represent
spectrum of lung disease
 Hallmarks of this disease – hypoxia, tachypnea,
decreased compliance
 Histology – diffuse alveolar damage

8. © The Children's Mercy Hospital, 2014. 03/148
Definitions
 1994- American-European Consensus Conference
o ARDS – acute noncardiogenic pulmonary edema with
bilateral pulmonary infiltrates on chest x-ray and a ratio
of PaO2 to FiO2 of ≤ 200
o ALI – same as above except P/F ratio 200-300
o Clinical parameters
 Acute onset
 Severe arterial hypoxemia resistant to oxygen therapy
alone (P/F ratios above)
 Diffuse pulmonary inflammation
 No evidence of left atrial hypertension

9. © The Children's Mercy Hospital, 2014. 03/149
The Berlin Definition 2011
Used consensus data as well as empirical data create “new” ARDS criteria

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Epidemiology
• ARDS occurs in 1-4% of PICU admissions
– As many as 10% of ventilated pts in PICU meet diagnostic criteria for ARDS
• Mortality 20-75% depending on coexisting conditions and risk factors
(immunocompromise, nonpulmonary organ failure)
– Seems to be decreasing since the standard practice of low tidal volume ventilation –
have been studies with mortality as low as 11%
– General peds mortality 22-26%
– SCT were found to have mortality rate of >75%
• PEDALIEN: 2012 Spain epidemiology study
– Mortality based on P/F ratio >300 = 0%, 200-300= 11.8%, 101-200 = 20.7%, <100
= 38.5%

11. © The Children's Mercy Hospital, 2014. 03/1411
Epidemiology of ARDS in
children
Pneumonia and sepsis most frequent etiologies identified

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Pathophysiology
Etiologies:
• Direct injury –
– pneumonia, aspiration
• Regional consolidation from destruction of the alveolar
architecture
• Indirect injury –
– sepsis, shock, cardiopulmonary bypass, transfusion
related acute lung injury (TRALI), pancreatitis
• Pulmonary vascular congestion, interstitial edema, and less
severe alveolar involvement

13. © The Children's Mercy Hospital, 2014. 03/1413
Alveolar-capillary
unit in ARDS
Injury →
Inflammatory
response →
Proteinaceous fluid
filled alveoli and
breaks down the
alveolar
epithelial barrier
→
Thick barrier
between
alveolus and
capillary

14. © The Children's Mercy Hospital, 2014. 03/1414
Pathophysiology
Phases of disease
Exudative (Acute) phase
 Acute development of decreased
pulmonary compliance and arterial
hypoxemia  tachypnea
Proinflammatory state
Fibroproliferative phase
 Increased alveolar dead space and
refractory pulmonary hypertension may
develop as a result of chronic inflammation
and scarring of alveolar-capillary unit
Recovery phase
 Restoration of the alveolar epithelial
barrier, gradual improvement in pulmonary
compliance and resolution of arterial
hypoxemia and eventual return to
premorbid pulmonary function

15. © The Children's Mercy Hospital, 2014. 03/1415
Diagnosis
• Clinical symptoms
– Hypoxia
– Tachypnea
– Eventual respiratory failure
– Other symptoms depend on inciting injury
• Imaging
– CXR – diffuse alveolar infiltrates, air bronchograms
– CT chest- “ground glass opacities,” consolidation along gravitational axis
• Remember diagnostic criteria for ARDS/ALI

16. © The Children's Mercy Hospital, 2014. 03/1416
Imaging
CXR

17. © The Children's Mercy Hospital, 2014. 03/1417
Imaging
CT images

18. © The Children's Mercy Hospital, 2014. 03/14
Targets of Therapy
• Decrease mortality and
morbidity
• Hasten recovery
• Optimize long-term
cognitive and respiratory
function
– Minimize profound
hypoxia that leads to
cell death and
damages developing
brain
• MINIMIZE HARM

19. © The Children's Mercy Hospital, 2014. 03/1419
Therapy options
• Supplemental O2
• NIPPV
– HFNC
– CPAP/BiPAP
• Invasive ventilation
– Conventional ventilation
– HFOV
• iNO
• Surfactant
• Steroids
• Prone positioning
• Fluid management
• ECMO

20. © The Children's Mercy Hospital, 2014. 03/1420
Summary of therapy
recommendations

21. © The Children's Mercy Hospital, 2014. 03/1421
Positive Pressure Ventilation
• Optimize oxygenation while minimizing lung injury
– PEEP to maintain FRC above closing volumes throughout the ventilator
cycle (atelectatrauma)
– Limit plateau pressure, Pplat (barotrauma)
– Avoid overdistention (volutrauma)
– Limit radical-related injury due to high concentrations of inspired O2
• Permissive hypercapnea
– Allow Pco2 to rise as long as pH >7.25 (?)

22. © The Children's Mercy Hospital, 2014. 03/1422
Ventilator Induced Lung Injury
• Results from injury to
the blood-gas barrier
caused by mechanical
ventilation
• Overall suggestion of
this study, limit tidal
volume (<10ml/kg) in
patients with or without
ARDS
• Lower rates
associated with less
VILI

23. NEJM 2013
Ventilator-Induced
Lung Injury

24. NEJM 2013
Ventilator-Induced
Lung Injury

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Permissive
hypercapnea
• Goal is to minimize
VILI
• General consensus is
that hypercapnea is
not harmful
• pH limit usually set
somewhere around
7.25
• Acidosis helps unload
oxygen from
hemoglobin

26. © The Children's Mercy Hospital, 2014. 03/1426
Lung Protective Ventilation
Strategy
ARDS Network of investigators
• the National Heart, Lung, and Blood Institute, National Institutes of Health,
initiated a clinical network to carry out multi-center clinical trials of ARDS
treatments
ARDS-Net Trial NEJM 2000
• Sentinel article for lung protective ventilation
• Multicenter RCT enrolled 861 patients with ARDS
– Randomized to low tidal volume (6ml/kg) and low Pplat (<30 cmH2o) vs
standard of care (12ml/kg and Pplat 50cm)
• Primary outcome mortality: 31% vs 39.8% p=0007
• Stopped early due to clear benefit of low tidal volume

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Lung Protective Strategy
• Meta-analysis of multiple RCTs looking at low vs high tidal
volume – Cochrane review 2012

28. © The Children's Mercy Hospital, 2014. 03/1428
Lung Protective Strategy -
meta-analysis

29. © The Children's Mercy Hospital, 2014. 03/1429
So what makes the difference, high PEEP
or low PIP (or Pplat)?
ALVEOLI – ARDS Net NEJM 2004
• RCT 549 with ALI/ARDS
– Low (~8) vs high PEEP (~13)
• Constant tidal volume 6ml/kg and Pplat <30
– Primary outcome – mortality – no difference
24.9 vs 27.5

30. © The Children's Mercy Hospital, 2014. 03/1430
So what makes the difference, high PEEP
or low PIP (or Pplat)?
EXPRESS - Mercat JAMA 2008
• Multicenter RCT 767 adults in France with ALI/ARDS P/F <300
– Minimal distention (PEEP and Pplat kept low) vs recruitment strategy
(PEEP adjusted based on airway pressure, Pplat kept <30)
– Primary outcome of mortality was not different between the groups
– Secondary outcomes
• Ventilator free days (7 vs 3 p=0.04)
• Organ failure free days (6 vs 2 p= 0.04)
• Higher compliance, better oxygenation, less use of adjunctive
therapies, larger fluid requirements

31. © The Children's Mercy Hospital, 2014. 03/1431
PEEP strategies
LOVS (lung open ventilation study investigators) JAMA 2008
• Compared established low-tidal-volume ventilation strategy vs
experimental strategy which combined low tidal volume, lung
recruitment, and high PEEP
– 983 adult patients met ARDS criteria
– Mortality 36.4% vs 40.4% ([RR], 0.90; 95% confidence interval [CI],
0.77-1.05; P = .19
– Lower rates of refractory hypoxemia, death with refractory hypoxemia,
and previously defined eligible use of therapies

32. © The Children's Mercy Hospital, 2014. 03/1432
PEEP and mortality
• Oxygenation Response to PEEP Predicts Mortality in ARDS: A
Secondary Analysis of the LOVS and ExPress Trials - Hot of the
presses- June 11, 2014 in press from AJRCCM
– Evaluated the physiologic response to PEEP (P/F ratio) and mortality
– Decreased mortality noted for those patients with >25mm Hg increase in
P/F ratio following increase in PEEP (OR 0.80, 95% CI 0.72-0.89)
• Stronger association with severe ARDS (P/F ratio <150)
– Findings were supported in data sets from 2 studies
• “We hypothesize that this association may be linked through the
physiological causal pathway of increased lung recruitment (reflected by
improved oxygenation), protecting against VILI, reducing pulmonary and
systemic organ failure, and ultimately lowering mortality.”

33. © The Children's Mercy Hospital, 2014. 03/1433
History of ARDS research in
children
• Why hasn’t a similar sentinel trial been performed in children?
– lack of clinical equipoise
• As in all pediatric research, traditional outcome measures (mortality) would require very
large sample size for an adequate study
– Mortality 10-15% most recent trials
– To power a study to detect 25% decrease in mortality -> would need over 2,000 patients
• To detect smaller decrease -> more patients
– PALIVE study – feasibility
• 4 years, 60 PICUs to enroll 800 children to use mortality as endpoint
• Pediatric Acute Lung Injury and Sepsis Investigators (PALISI)
– Collaborative group working on directing multicenter efforts
• Most recent outcome measure in pediatric trials (PALISI) = ventilator free days

34. © The Children's Mercy Hospital, 2014. 03/1434
High Frequency Oscillatory Ventilation (HFOV)
• Ultimate open lung strategy of ventilation
– very low tidal volume (1-2ml/kg/cycle), high mean airway pressure (low
PIP)
• Used frequently in pediatrics (adopted from NICU)
• Early data in adults indicated that HFOV might be beneficial (however
this was compared to high tidal volume conventional ventilation)
• Only one crossover trial in pediatrics (Arnold, et al CCM 1994)
comparing rescue HFOV with conventional ventilation
– HFOV associated with higher MAPs, improved oxygenation, reduced need
for O2 at 30 days

35. © The Children's Mercy Hospital, 2014. 03/1435
HFOV vs conventional
ventilation
• In adults, two recent RCTs of HFOV vs low tidal volume high PEEP
published in the NEJM demonstrated no mortality benefit and in one of
the trials may have shown harm (higher mortality)
– OSCILLATE – multicenter RCT – 39 ICUs in 5 countries
• Moderate to severe ARDS (P/F ratio <200, FiO2 >0.5)
• HFOV targeting lung recruitment vs conventional ventilation targeting lung
recruitment (low tidal volume, high PEEP)
• Primary outcome in-hospital mortality: HFOV 47% vs 35% (RR of death 1.33
with HFOV CI 1.09 to 1.64; p=0.005)
• Stopped early
• Should we be reconsidering our “lung protection”

36. © The Children's Mercy Hospital, 2014. 03/1436
Open Lung Ventilation –
adverse effects
• Important hemodynamic considerations
– Increases intrathoracic pressure
• Decrease venous return to right atrium (preload) –
lead to low cardiac output
• Support this with fluid, inotropes might be necessary
– Depending on how high MAP, might need
muscle relaxation

37. © The Children's Mercy Hospital, 2014. 03/14
Prone positioning
Goal of prone positioning is to improve V/Q
matching.

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Prone positioning
• Curley, et al. JAMA 2005
– Multicenter RCT 102 pediatric patients with ALI/ARDS
– Randomized to prone for 20hrs vs supine
– Stopped early due to futility
– No improvement in other secondary outcomes
• In adults, studies suggested that in the sub-group
of more severe ARDS, prone positioning might be
beneficial

39. © The Children's Mercy Hospital, 2014. 03/1439
Prone positioning
Guerin, et al in NEJM May 2013 (France and Spain)
– Multicenter prospective RCT – 466 pts with severe
ARDS (P/F <150, FiO2 >0.6, PEEP >5, tidal volume
6ml/kg, Pplat <30) , enrolled at <36hrs of ventilation
• Prone-positioning for at least 16 hours vs standard supine
• Primary outcome 28 day mortality
– Prone 16% vs supine 32.8% (p<0.001)
– HR for death with prone positioning 0.39 [95%CI 0.29-0.63]
• Unadjusted 90 day mortality = 23.6% prone vs 41% supine
(p<0.001)

40. © The Children's Mercy Hospital, 2014. 03/1440
Guerin, et al – early prone
position

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Inhaled Nitric Oxide (iNO)
• Potent selective vasodilator
– Goal is to improve V/Q
matching by directing blood
toward the more open
alveoli
• Meta-analysis of multiple
studies (children and adults)
– Improves oxygenation
without improving chosen
outcomes

42. © The Children's Mercy Hospital, 2014. 03/1442
iNO – mortality

43. © The Children's Mercy Hospital, 2014. 03/1443
iNO – oxygenation

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Surfactant
• Surfactant –produced by Type
II alveolar cell
– Reduces surface tension at
the air: fluid interface and
varies surface tension
during the respiratory cycle
– WOB minimized,
atelectasis at end
expiration prevented,
distribution of ventilation is
equal during inspiration
• Early studies showed promise

45. © The Children's Mercy Hospital, 2014. 03/1445
Surfactant
• PALISI study Calfactant in
pediatric ARDS – PCCM 2013
– Multicenter RCT 110 pts with
ARDS due to direct lung injury
– Randomized to calfactant vs
air within 48 hours of
intubation (up to 3 doses)
– Stopped early due to futility
– Overall mortality was 11%
– Not associated with
improvement in oxygenation

46. © The Children's Mercy Hospital, 2014. 03/1446
Steroids
• No studies in pediatrics
• Adult studies indicate no improvement with
treating in the acute phase (and might be
harmful if used for “prevention”)
• Outcomes contradictory in many other
studies (including meta-analysis)

47. Preventive steroids Therapeutic steroids
Steroids – meta-analysis Cochrane review
2008

48. © The Children's Mercy Hospital, 2014. 03/1448
Restrictive Fluid Management
• ARDSNet FACTT trial
– Conservative approach to
fluid management increase
VFDs and improves
oxygenation in adults with
ALI/ARDS when compared
to more liberal fluid
protocol
• Albumin + lasix - might be
helpful in adults
• Should only be used after
adequate initial resuscitation
from shock

49. © The Children's Mercy Hospital, 2014. 03/1449
Restrictive Fluid
Management
• Calfactant Trial
secondary analysis
• Guideline was for
conservative fluid
management based
on modified FACTT
trail
• Conclusion - In
pediatrics we are still
fairly liberal, those
patients that died
were more fluid
overloaded

50. © The Children's Mercy Hospital, 2014. 03/1450
Sedation and Muscle
Relaxation
• No studies about appropriate type of sedation
– RESTORE data hopefully coming soon?
• Muscle relaxation – associated with weakness
and critical illness myopathy in adult patients with
ALI
– If concurrent use with steroids -> increases this risk?
– Early might be ok, but not prolonged
– Only use if necessary for oxygenation or ventilation

51. © The Children's Mercy Hospital, 2014. 03/1451
ECMO
• Has been used as a rescue therapy for many years
• Recent adult study (CESAR Trial) showed benefit for ECMO use in
adults with ARDS
– Survival at 6 months in ECMO 63% vs Conventional group 47%
• Another trial (ECMO to Rescue Lung Injury in severe ARDS – EOLIA)
ongoing and anticipated to be completed this year
• Strategy and thoughts are changing about ECMO use
– What is lung rest?
– Extubation?
– Early mobilization
– Limit sedation/muscle relaxation

52. © The Children's Mercy Hospital, 2014. 03/1452
Novel Therapies
• Statins in sepsis induced ARDS (NEJM May, 2014)
– Statins are typically used to reduce cholesterol levels, but have been
found to reduce inflammation
– Animal models have suggested that statins can prevent ARDS
– Human studies have suggested that statins used in sepsis or other
inflammatory conditions improves outcome
– RCT of rosuvastatin vs placebo in adults with sepsis-induced ARDS
• Stopped for futility with ~75% of enrollment (745 patients)
• No mortality difference
• Increased incidence of renal and hepatic dysfunciton with statins

53. © The Children's Mercy Hospital, 2014. 03/1453
Novel Therapies
• Mesenchymal Stem Cells in
Mouse and Sheep ARDS
models have improved
oxygenation and decreased
pulm edema
– Mesenchymal stem cells have
been shown to modulate the
inflammatory response, augment
tissue repair, enhance pathogen
clearance, and reduce severity of
injury, pulmonary dysfunction, and
death

54. © The Children's Mercy Hospital, 2014. 03/1454
How are we practicing as pediatric
intensivists?
• PALIVE PCCM 2013
• Survey sent out to
multiple centers across
US and Europe
• 3 case scenarios asking
pediatric intensivists
parameters they would
use to manage the
patients
• Bottom line: most use
adult guidelines

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How do we practice?

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How do we practice?
Optimal PaCO2 levels Adjunctive treatments
considered

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How do we practice?
• The same group gathered actual data from the institutions
and there was a discrepancy between the survey results
and actual practice
– 25% of patients were ventilated with Vt >10ml/kg
– 16% had PIPs greater than 35cm H2O
• The conclusion of the group – though pediatric physicians
agree generally with the adult guidelines, it is difficult in
practice to maintain those parameters
– Even with protocols in clinical studies the compliance is usually
between 66-87%

58. © The Children's Mercy Hospital, 2014. 03/1458
Summary
• Pediatric ARDS is less common than in adults, but still accounts for a
large portion of our ventilated patients
• Most common etiologies are pneumonia and sepsis
• Lung protective ventilation is the ONLY therapeutic strategy that has
showed reproducible mortality benefit
– Low tidal volume, low Pplat, high PEEP
– Permissive hypercapnea
• Likely there are subgroups of patients (i.e. severe ARDS) that benefit
from additional therapeutic strategies (prone positioning, HFOV, iNO,
etc.)
• More pediatric research is needed but difficult to organize and perform

59. © The Children's Mercy Hospital, 2014. 03/1459
So what’s new?
• Trying to determine appropriate inclusion criteria for clinical trials and
appropriate clinical outcomes
– Thought is that many of the therapies that have been studies likely have
benefit if we can identify the right group of patients
• Think early about minimizing harm (lung protection)
• ECMO
– Using more protocolized lung protection to determine if this is a better
strategy and improves outcomes.
• Continuing search for biomarkers for ARDS to potentially help with
future studies
• Continuing search for novel therapies

60. © The Children's Mercy Hospital, 2014. 03/1460
References
• ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA
2012;307:2526-33.
• Lopez-Fernandex Y, et al. PED-ALIEN Network. Pediatric Acute Lung Injury Epidemiology and Natural History Study: Incidence
and outcome of the acute respiratory distress syndrome in children. Crit Care Med 2012:40 (12);3238-3245
• Smith LS, Zimmerman JJ. Mechanisms of Acute Respiratory Distress Syndrome in Children and Adults: A Review and
Suggestions for Future Research. Ped Crit Care Med 2013: 14; 631-643
• Biehl M, Kashiouris MG, Gajic O. Ventilator-Induced Lung Injury: Minimizing its Impact in Patients With or at Risk for ARDS.
Respir Care 2013;8(6): 927-934.
• Slutsky AS, Ranieri VM. Ventilatory-Induced Lung Injury. N Engl J Med 2013;369: 2126-2136
• Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory
distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301–1308
• Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome (Review). The Cochrane
Library 2013:2; 1-36
• Mercat A, Richard J, Vielle B, Jaber S. Positive end-expiratory pressure setting in adults with acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646–655.
• Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky
S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE, Lung Open Ventilation Study Investigators. Ventilation strategy using low
tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory
distress syndrome: a randomized controlled trial. JAMA 2008;299:637–645.

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References
• Ferguson ND, et al. OSCILLATE Trial Investigators and the Canadian Critical Care Trials Group. High-Frequency Oscillation in Early
Acute Respiratory Distress Syndrome. N Engl J Med 2013
• Goligher, et al. Oxygenation Response to PEEP Predicts Mortality in ARDS: A Secondary Analysis of the LOVS and ExPress Trials.
AJRCCM 2014 in press
• Guerin C, Reignier J, et al. PROSEVA Study Group. Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl J Med
2013: 368(23); 2159-2168
• Willson DF, et al. PALISI Network. Pediatric Calfactant in Acute Respiratory Distress Syndrome Trial. Ped Crit Care Med 2013: 14(7);
658-665
• Peter V, et al. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome in adults: meta-analysis. BMJ 2008
1-10
• Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med
2006;354:2564–2575
• Willson DF, et al. PALISI Network. The relationship of fluid administration to outcome in the Pediatric Calfactant in Acute Respiratory
Distress Syndrome Trial. Ped Crit Care Med 2013: 14(7); 666-672
• Rosuvastain for Sepsis-Associated Acute Respiratory Distress Syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J
Med 2014;370:2191-2200
• Assmussen S, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia.
Thorax 2014 Jun 2 in press
• Santschi M, Randolph A, et al. PALIVE, PALISI, and ESPNIC investigators. Mechanical Ventilation Strategies in Children with Acute
Lung Injury: A Survey on Stated Practice Pattern. Pediatr Crit Care Med 2012; 14:e332–e337

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Thank you!