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

What’s New In Pediatric
ARDS
Nancy G. Hoover, MD
Medical Director, PICU
Walter Reed AMC
New and Improved
Acute Respiratory Distress Syndrome
Ashbaugh, Lancet, 1967
Adult Respiratory Distress Syndrome
To distinguish from neonatal HMD/RDS
Acute Respiratory Distress Syndrome
American-European Consensus conference, 1994
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
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

The Problem: Lung Injury
Davis et al., J Peds 1993;123:35
Noninfectious 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

Proinflammatory mechanisms
ARDS Pathogenesis
Resolution

Equally important

Alveolar edema - resolved by active
sodium transport

Alveolar type II cells - re-epithelialize

Neutrophil clearance needed
ARDS - Pathophysiology
Decreased
Alveolar
compliance
edema
Heterogenous
“Baby
Lungs”
Phases of ARDS
 Acute
- exudative, inflammatory
(0 - 3 days)
 Subacute - proliferative
(4 - 10 days)
 Chronic - fibrosing alveolitis
( > 10 days)
Phases of ARDS
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 %
39/36 %
ARDS - Principles of Therapy
Provide adequate gas
exchange
Avoid secondary injury
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
Therapies for ARDS
Innovations:
iNO
PLV
Proning
Surfactant
AntiInflammatory
Mechanical
Ventilation
ARDS
Gentle
ventilation:
Permissive
hypercapnia
Low tidal volume
Open-lung
HFOV
Extrapulmonary Gas Exchange
The Dangers of Overdistention
 Repetitive
shear stress
inflammatory response
air trapping
 Phasic
volume swings: volutrauma
 Injury
to normal alveoli
The Dangers of Atelectasis
compliance
intrapulmonary shunt
FiO2
WOB
inflammatory response
Lung Injury Zones
Lung Volume (ml/kg)
Overdistention
20
10
“Sweet Spot”
Atelectasis
0
13
33
Airway Pressure (cmH20)
38
“Mechanical” Therapies in ARDS

Lower tidal volumes but avoidance of
atelectasis with higher PEEP

Permissive hypercapnia

HFOV

Prone positioning
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
Traditional
Lower
*
35
30
25
Percent
20
15
*
10
5
Vent free
days
* p < .001
Death
0
ARDS Network,
NEJM, 342: 2000
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%
Permissive Hypercapnia

Defined: presence of hypercapnia in the
setting of a mechanically ventilated
patient receiving limited inspiratory
pressures and reduced tidal volumes
Hickling, Int Care Med, 1990
Physiologic Effects of Hypercapnia

RESP: Net effect is improvement in
oxygenation by
 enhancing
hypoxic pulmonary vasoconstriction
and decreases intrapulmonary shunting
 Right-shift
curve
of oxygen-hemoglobin dissociation
Physiologic Effects of Hypercapnia

CV: Net effect is often hemodynamic
compromise
 Sympathetic
 Increased
stimulation with increased C.O.
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
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
Permissive Hypercapnia
Is it worth it?
Early adult ARDS trial showed a reduction
in expected mortality of 56% to an actual
mortality of 26%
Hickling, CCM, 1994
 Included in adult trauma patients protocol
for mechanical ventilation
Nathens, J Trauma, 2005
 Several pediatric studies showing benefit
when used in conjunction with low TV and
high PEEP
Sheridan, J Trauma, 1995

Paulson, J Pediatr, 1996
Caution
in patients with elevated ICP
High Frequency
Oscillation:
A Whole Lotta
Shakin’ Goin’ On
It’s not absolute pressure,
but volume or pressure
swings that promote lung
injury or atelectasis.
Reese Clark
High Frequency Ventilation
 Rapid
 Low
rate
tidal volume
 Maintain
 Minimal
open lung
volume swings
Differences Between CMV and
HFOV
Rate (BPM)
Tidal volume (cc/kg)
Alveolar pressure
swings (cmH20)
End exp. lung volume
CMV
0-120
4-20
5-50
HFV
120-1200
0.1-5
0.1-5
low
high
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

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
Indications for HFOV
 Severe
persistent airleak
 Neonatal: HMD (*)
Pneumonia
Meconium aspiration
Lung hypoplasia
 Acute respiratory distress syndrome
Is turning the ARDS
patient “prone”
helpful?
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
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
Gattinoni et al., NEJM, 2001
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
Pharmacological Therapies in ARDS

Surfactant

iNO

Steroids

Partial Liquid Ventilation
Surfactant in ARDS


ARDS:

surfactant deficiency

surfactant present is dysfunctional
Surfactant replacement improves
physiologic function
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
Wilson et al, CCM, 24:1996

In several other studies, there is no evidence for
sustained benefit from Surfactant administration
Wilson et al, JAMA, 2005
Steroids in ARDS

Theoretical anti-inflammatory, anti-fibrotic
benefit

Previous randomized studies

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, 1998
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
Steroids in Unresolving ARDS
100
90
80
70
60
50
40
30
20
10
0
Steroid
Placebo
*
ICU
survival
*
Hospital
survival
* p<.01
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
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)

iNO 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, 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
Inhaled NO and HFOV In Pediatric
ARDS
80
71
60
50 58
40
58
53
30
20
10
NO
V
+
V
HF
O
+
V
CM
HF
O
NO
V
0
CM
Survival %
70
Dobyns et al., J Peds, 2000
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
Low tidal volumes
Outcome benefit in
large study
Prone positioning
Unproven outcome benefit
Open-lung strategy
Outcome benefit in
small study
Outcome benefit in
small study
Proven in neonates
unproven in children
HFOV
ECMO
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
“…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
If you think about ECMO,
it is worth a call to consider
ECMO
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,
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
Impact of ECMO on Survival in
Pediatric Respiratory Failure
90
80
% Mortality
70
60
50
ECMO
Non-ECMO
40
30
20
10
0
<25%
25-50%
50-75%
mortality risk quartile
p<0.05
>75%
Green et al, CCM, 1996