Pediatric acute lung injury
P. Dahlem*, W.M.C. van Aalderen and A.P. Bos
Medical Center of Coburg, Children’s Hospital, Ketschendorferstr. 33, 96450 Coburg, Bayern, Germany
Clinical research on acute lung injury (ALI) and acute
respiratory distress syndrome (ARDS) is dominated by
studies performed in adult patients.1,2For example, a
Medline search including the terms ‘‘Respiratory Distress
Syndrome, Adult‘‘ OR ‘‘acute lung injury’’ resulted in 9607
clinical investigations (date: 25–1–2007); however, when
limited exclusively to children only 762 hits remained.
Therefore, our aim was to review the most relevant
publications on pediatric ALI.
We included relevant publications on children aged from 4
weeks to 18 years suffering from ALI accessible on the
were defined following the criteria recommended by an
American-European Consensus Conference in 1994
(Table 1).3Preference was given to randomized controlled
clinical trials (RCT) or nonrandomized case-control studies
published up to 31 December 2006. Studies involving
meta-analyses and systematic reviews were also reviewed.
Investigations on pediatric acute hypoxic respiratory failure
(AHRF) were only considered if sufficient information was
given to apply ALI criteria to the analysed patients. Where
appropriate, we have included investigations performed in
adult patients with ALI/ARDS and newborns with the
respiratory distress syndrome (RDS).
HISTORY OF ALI/ARDS - DEFINITION
In 1967 Ashbaugh et al. introduced the term ‘‘adult respira-
tory distress syndrome’’ (ARDS) for a spectrum of condi-
tions characterized by severe hypoxemia, reduced lung
complianceand new bilateralinfiltrates onchest radiograph
(Fig. 1), caused by an unrelated underlying critical illness
PAEDIATRIC RESPIRATORY REVIEWS (2007) 8, 348–362
acute respiratory distress
Summary Among ventilated children, the incidence of acute lung injury (ALI) was 9%;
of that latter group 80% developed the acute respiratory distress syndrome (ARDS). The
population-based prevalence of pediatric ARDS was 5.5 cases/100.000 inhabitants.
Underlying diseases in children were septic shock (34%), respiratory syncytial virus
infections (16%), bacterial pneumonia (15%), near-drowning 9%, and others. Mortality
ranged from18% to 27% for ALI (including ALI-non ARDS and ARDS) and from 29% to
50% for ARDS. Mortality was only 3%–11% in children with ALI-non ARDS. As risk
factors, oxygenation indices and multi-organ failure have been identified. New insights
into the pathophysiology (for example the interplay between intraalveolar coagulation/
fibrinolysis and inflammation and the genetic polymorphism for the angiotensin-con-
verting enzyme) offer new therapeutic options. Lung protective mechanical ventilation
with optimal lung recruitment is the mainstay of supportive therapy. New therapeutic
modalities refer to corticosteroid and surfactant treatment. Well-designed follow up
studies are needed.
? 2007 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +49 9561 225551;
Fax: +49 9561 225552.
E-mail address: PDahlem@hotmail.com (P. Dahlem).
1526-0542/$ – see front matter ? 2007 Elsevier Ltd. All rights reserved.
such as, for example, sepsis or aspiration pneumonia.4
However, the criteria were not clearly defined. Therefore,
in 1993 an American-European Consensus Conference
(AECC) provided a new definition of ALI and ARDS
(Table 1)3: ‘‘a syndrome of inflammation and increased
permeability that is associated with a constellation of
clinical, radiological, and physiological abnormalities that
cannot be explained by, but may co-exist with, left atrial
or pulmonary capillary hypertension’’ ... and ‘‘ ...is asso-
ciated most often with sepsis, aspiration, primary pneumo-
nia, or multiple trauma and less commonly with
cardiopulmonary bypass, multiple transfusions, fat embo-
lism, pancreatitis, and others’’. From that moment onwards
ALI came to represent the entire spectrum of this condi-
tion, and ARDS was reserved to apply to patients with
more severe hypoxemia. Because children may also be
affected, the AECC changed the ‘‘A’’ previously referring to
‘‘adult’’, to the ‘‘A’’ referring to acute (respiratory distress
Independently of age, ALI is characterized by an initial insult
which triggers cell-mediated mechanisms releasing a cas-
cade of a variety of mediators. They disturb the integrity
and function of the cellular linings of the alveolar-capillary
unit (Fig. 2). Hyaline membranes, flooded alveoli with
protein-rich edema fluid, infiltrates of polymorphnuclear
neutrophils (PMN), macrophages and erythrocytes are the
leading histological hallmarks of ALI (Fig. 3a and b).7,8Pro-
inflammatory mediators are expressed in lung alveolar and
endothelial cells which are associated with the onset,
severity and course of ALI.9The degree of inflammation
depends on the biologic activity and the imbalance
between pro- and anti-inflammatory cytokines, for exam-
ple interleukin (IL)-8 versus IL-1.9,10
A polymorphism in the gene encoding angiotensin-
converting enzyme (ACE) is linked to the susceptibility
and outcome of ARDS.11ACE cleaves angiotensin I to
generate angiotensin II which stimulates the production of
pro-inflammatory mediators like IL-8 and IL-6 in alveolar
epithelial cells.12Furthermore, angiotensin II is a potent
vasoconstrictor and a key factor in the Fas-induced apop-
tosis (programmed cell death) of alveolar epithelial cells in
vitro.13,14Animalswith ALI that were deficient for ACE had
reduced pulmonary edema formation and leukocyte infil-
Similar to bacterial sepsis, a close interrelationship exists
between inflammatory mediators and the coagulation cas-
cade in ALI.16,17Activation of pro-coagulative factors (tis-
sue factor) and inhibition of fibrinolysis (plasminogen
activator inhibitor (PAI) -1) have been identified to pro-
This interplay occurs both intra- and extravascularly, and in
depositions and alveolar hyaline membranes are the net
result.23–25Surfactant function is inactivated by plasma
proteins leakage and its production is further diminished
by damage of pneumocyst type II.26
For overall resolution (end of the first week) the
dynamic interaction between inflammation, coagulation,
restoration of water transport and cell function need to
be rebalanced and surfactant production restarted.27The
clearance of pulmonary edema fluid and transcapillary
water transport are crucial.1,10Apoptosis should be reba-
PEDIATRIC ACUTE LUNG INJURY349
shows progression to generalized infiltrates with pleural effusions.
A child with meningococcal septic shock. Day 1: the left-hand image shows bilateral infiltrates. Day 3: the right-hand image
definitions of ALI and ARDS
The American-European Consensus Conference
OxygenationALIPaO2/FiO2< 300 (regardless
of positive end expiratory
ARDS PaO2/FiO2< 200 (regardless
of positive end expiratory
Bilateral infiltration seen on
frontal chest radiograph
<18 mm Hg when measured
or no clinical evidence of
left atrial hypertension
lanced providing the clearance of inflammatory cells (e.g.
PMN). The exact mechanisms of repair are still under
investigation (Fig. 4).28–30
Unfortunately in some patients resolution is hampered.
Histologically, these patients show alveolar fibrosis along
with persistence of inflammatory cells and only partial reso-
lution of pulmonary edema.31Transforming growth factor
beta causes persistent depression of fibrinolysis and forma-
tion of fibrin depositions.32–36This pro-fibrosing milieu may
permanent abnormalities in respiratory function and
reduced health-related quality of life are observed.34,39–41
ALI/ARDS in adult patients are characterized as a restrictive
disease with reduced lung compliance caused by loss of
of interstitial/alveolar plasma leakage.6Newth et al. con-
firmed reduced lung compliance in children with ARDS, and
the decrease in lung compliance correlated with severity.42
Respiratory function measurements at the bedside might
appropriate respiratory function devices are not routinely
used and are not available on most of the pediatric intensive
care units (PICU). Therefore, implementation of this tech-
nique in daily routine has not yet occurred.
About 40% of critically ill children admitted to a PICU are
mechanically ventilated, and about 14% of them are suffer-
ing from AHRF.2,43Before the AECC publication in 1994,
only a limited number of retrospective studies paid atten-
tion to epidemiological data on children with acute hypoxic
respiratory failure (AHRF) or ARDS.
studies performed on a PICU and only one population-
based study performed in Germany.43–47In those five
studies, among the mechanically ventilated children the
incidence of ALI was 9%, and 80% of that group developed
ARDS resulting in an incidence of 7% to 8%.43,47In relation
to all PICU admissions the incidence of ARDS was calcu-
lated to be 3% to 4%.43,46The only population-based study
was conducted in a German district and reported a pre-
valence of pediatric ARDS of 5.5 cases/100,000 inhabitants
and an incidence of 3.2 cases per year/100,000 inhabi-
tants.44In contrast, a much higher incidence of ALI was
found in adults ranging from 18 to 86 cases per year/
100,000 inhabitants.48–50In general, comparisons between
studies are difficult and depend on the characteristics of the
study population enrolled.43For example, in the report by
Randolph et al. of the eight PICUs in North America, three
surgical and cardiac patients.47
children might predispose them to critical illness.51,52Data
from the ESPNIC ARDS database (www.meb.uni-bonn.de/
vs. 27) in the age group 0 < 12 months.53Therefore, it was
concluded that factors other than testosterone might be
involved in the male preponderance (low levels of male sex
hormones at this age). It is likely that differences in lung
mechanics between male and female infants (with disadvan-
tages to the male) might contribute to ALI/ARDS.54
350P. DAHLEM ET AL.
An illustration of the pathophysiology of acute lung injury (adapted from reference 1).
Mortality in children versus adults
Overall mortality in children suffering from ALI (including
ALI-non ARDS and ARDS), ranged from 18% to 27% and,
not surprisingly, mortality increased to 29%–50% when
children developed ARDS. In contrast, mortality was only
3% to 11% in those who did not develop ARDS.2,43,45In
adults with ALI mortality was higher; the in-hospital mor-
tality rate was 38.5% and mortality increased with age up to
60%.48–50Interestingly, for adult patients no differences
between those who developed ARDS and those who did
not develop ARDS (i.e. ALI-non-ARDS) were found.48
PEDIATRIC ACUTE LUNG INJURY 351
phase of ALI (Fig. 3b) there is formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are
marginating through the interstitium into the air space. Alveolar macrophages secrete interleukin-1, 6, 8, and 10, as well as tumor necrosis
factor alpha (TNF-a) which stimulate and activate neutrophils. Neutrophils release pro-inflammatory molecules (oxidants, proteases,
and, together with unresolved fibrin depositions, fibrin-rich hyaline membranes are formed.
Illustration showing the normal alveolus (Fig. 3a) and the injured alveolus (Fig. 3b) during acute lung injury (ALI). In the acute
Mortality in children with ARDS has been associated
with multi-organ failure; for example as demonstrated by
the Pediatric Risk of Mortality Score (PRISM, a validated
score to predict mortality of children immediately after
and/or cardio-circulatory failure rather than respiratory
failure was identified. In general, independently of the
severity of ALI/ARDS, a worse course was determined
based on the past medical history and the primary under-
lying disease (e.g., immunosuppression, severe cerebral
injury, inborn error of metabolism).43,45Therefore, it has
been proposed that ‘‘the presence of severe pre-existing
disease or associated pathology, rather than severity of
respiratory failure alone is associated with outcome’’.2
Studies reported a correlation between the PaO2/FiO2
ratio on day one and/or its further deterioration and
mortality.43,45However, other investigators were not able
respiratory variables and their association with outcome
parameters.2,45,55Much interest was also directed to bio-
validity improved when biological markers were used in
combination with the underlying clinical condition (e.g.
The factors which predispose the individual patient at
risk are not yet understood and the search for gene
candidates has been challenged.56,57For example, it was
demonstrated that the DD genotype for ACE was asso-
ciated with increased mortality in ALI patients.58,59
Despite these inconsistencies, efforts should still be
made to identify prognostic factors for use in the early
phase of ALI in order to define which patient might benefit
most from novel therapeutic strategies.
Independently of the possible risk factors associated
with ALI, in some situations the underlying disease may
determine outcome. For example, in one study 2 of 4
children and in another study 83.3% of children with
immunodeficiency died.43,53Dahlem et al. found that 7
of 11 patients who died had irreversible cerebral damage,
which might have had aconsiderableimpactonoutcome.43
Therefore, it was suggested that it is not helpful in all
circumstances to include these categories of patients when
calculation the risk factors for ALI.53
In adult patients, a variety of critical diseases may originate
ALI (Table 2).10The outcome differs depending on
352 P. DAHLEM ET AL.
cells occurs (on the right-hand side of the figure). For complete resolution it is important that water is moving via additional aquaporines
and by recovery of sodium and chloride channel function (ENaC) and sodium pump (Na+/K+–ATPase). Also intraalveolar protein must
be cleared by paracellular diffusion and secondarily by endocytosis. Furthermore, insoluble debris (protein, apoptotic neutrophils) is
removed by macrophages. Very important for complete recovery is the gradual remodeling and resolution of intraalveolar and interstitial
granulation tissue and fibrosis (left-hand side of the figure).
Illustration of the recovery from acute lung injury. During recovery de novo proliferation and differentiation of alveolar type II
whether the origin of lung injury was caused by direct (e.g.
aspiration pneumonia) or by indirect (e.g. sepsis) lung
With some differences compared to adult patients, the
common underlying diseases in children can be divided into
indirect lung injury e.g. caused by septic shock (up to 34%)
and direct lung injury caused by pulmonary disorders such
as respiratory syncytial virus infection (15.9%) and bacterial
pneumonia or aspiration pneumonia (up to 15%). Less
frequent are a variety of other conditions, including near-
drowning (9%), cardiac diseases, oncologic disorders and
Complications directly related to the severity of lung injury
are rare and include pneumothorax (8–9%) and failure of
conventional ventilation. In these situations of untreatable
respiratory failure, alternative and experimental treatment
options are applied (Table 3).43,45,62
The mainstay to treat hypoxic failure is controlled oxygen
supply with or without mechanical support. Prevention of
fluid overload and measures to stabilize circulation and the
patients comfort (by sufficient pain relief and sedation) are
essential supportive targets. In critical ill patients the meta-
bolic balance is shifted towards catabolism and protein
malnutrition. Early aggressive nutritional support will help
the patient to recover faster.63,64The following sections
address conventional and novel treatment options for
children with ALI.
Mechanical ventilation and ventilator-
induced lung injury
When conventional mechanical ventilation was introduced
for the treatment of respiratory failure in the 1960s and
were recommended to maintain arterial CO2values within
the normal range. However, life-threatening complications
such as pneumothorax occurred and mortality was high.65
With the introduction of positive end-expiratory pressure
(PEEP), oxygen uptake improved and the incidence of
pneumothoraces in ARDS patients was reduced dramati-
with a lower Vt (i.e. in stead of 10–15 mL/kg actual body
weight) reduced further mortality.69,70
In parallel with these clinical observations, patho-anato-
mical and computerized tomographic studies in the 1970s/
1980s informed physicians about the uneven distribution of
aerated areas and dense consolidated regions of the lung.71
The remaining alveolar surface for gas exchange (i.e., func-
tional residual capacity, total lung volume) was found to be
largely reduced in adult patients. Gattinoni et al. introduced
the term ‘‘baby lung’’ to symbolize this condition.72‘‘Nor-
mal’’ Vt of 10–15 mL/kg may cause a dramatic overdisten-
tionofthe‘‘babylung’’resulting inlossofcompliance dueto
the pressure volume relationship of the lung (Fig. 5).
PEDIATRIC ACUTE LUNG INJURY 353
Table 3Specific treatments (modified from reference 47)
ARDS n (%)
Inhaled nitric oxide
Extracorporeal life support
ARDS: acute respiratory distress syndrome.
lung.A, inflationlimb;B,deflation limb.On inflation(A)lungsneed
higher pressures to inflate than on deflation. On deflation (B), the
higher lung volume can be maintained on lower pressure. Thus,
once the lung is open it is more compliant. At the lower inflection
point the lung opens up, compliance improves and at the upper
inflection point optimal lung volume is achieved. At overinflation,
compliance decreases and lung injury occurs.
The hysteresis of the pressure-volume curve of the
(adapted from reference 10)
Disorders causing acute lung injury in adults
Direct lung injuryIndirect lung injury
Aspiration of gastric
Severe trauma with
shock and multiple
Less common causes
Transfusions of blood
Reperfusion pulmonary edema
after lung transplantation or
Based on these observations the concept of ventilator-
induced lung injury (VILI) evolved during the 1990s.
Ventilator-induced lung injury
VILI is now considered to initiate and to sustain lung injury
following a similar histo-morphological and inflammatory
pattern to that of the original ALI.73–75VILI also contributes
to multi-organ failure and death. The basic mechanisms of
VILI can be summarized as ‘‘barotrauma, volutrauma,
atelectrauma and biotrauma’’.73
Barotrauma is characterized by the fact that mechanical
forces (high pressure inflation) during artificial inflation
cause pressure-related ‘‘shear forces’’ on inhomogeneous
(partly aerated and partly consolidated) lung tissues.74On
microscopy, lungs show disruption of the alveolar capillary
sheets with air leaks.
Atelectrauma is defined as repetitive opening and closure of
alveolar units during mechanical ventilation with alveolar-
capillary stress failure.
Volutrauma: Large Vt cause disruption of alveolar-capillary
sheets, pulmonary edema, increased alveolar-capillary per-
meability, alveolar-capillary stress failure, and structural
abnormalities on electron microscopy.76,77
Biotrauma: Slutsky et al. and others developed the ‘‘bio-
trauma’’ hypothesis, which addressed the question why do
mechanically ventilated patients with ALI die.75,78,79VILI
shows biochemical characteristics similar to those of original
ALI.75,80Invasion of PMN and the presence of pro-inflam-
matory cytokines (e.g., tumor necrosis factor alpha, IL-6, IL-
10) play a major role. Additionally, mechanical stretch acti-
vates many signal transduction pathways (e.g. mitogen-acti-
vated pathway) which activate inflammatory mediators.
However, the exact relations between pro-inflammatory
and anti-inflammatory mediators and their balance are still
under debate: they might differ in children and may occur in
healthy as well as in pre-injured lungs (e.g. sepsis-induced
ALI).74,76,81Finally, theses pro-inflammatory mediators may
spill over from the pulmonary compartment to the systemic
major organs leading to multi-organ failure and death.73
Protective ventilation strategies
be prevented and high-pressure ventilation avoided.
It has been shown that atelectrauma (alveolar collapse)
could be prevented by sufficient PEEP above the lower
inflection point in combination with recruitment maneu-
vers (Fig. 5).62,82–84Furthermore, optimal PEEP has shown
to reduce biotrauma by preventing translocation of cyto-
kines (or even bacteria) from the alveolar compartment to
the systemic circulation. Without PEEP, however, this
compartmentalisation is lost and inflammatory mediators
as well as pathogenic microbes are distributed to other
organs and cells contributing to secondary sepsis, multi-
organ failure and death.73,75,80,85
Despite all the experimental rationales for applying
sufficient PEEP, recently published clinical results have
questioned the benefits concerning final outcome. In a
RCT of low versus high PEEP, the high PEEP group
(13 cmH2O) disappointingly did not show a significant
reduction of mortality.86One reason why differences
between the groups were not significant might have been
the surprisingly low overall mortality of below 26% due to
‘‘lung protective’’ basic ventilator settings in in accordance
with the ARDSnetwork recommendation: Vt <6 mL/kg
and positive inspiratory pressure (PIP) <30 cmH2O.
Therefore, additional benefits from a single parameter such
PEEP level of 13 cmH2O might have been not high enough.
It has been demonstrated that PEEP levels above
15 cmH2O are necessary to keep alveoli open and prevent
lung injury.87,88Third, when optimal PEEP was combined
with small Vt of less than 6 mL/kg and recruitment man-
euvers, the outcome of patients improved.89,90
Despite some limitations in study design, the ARDS
Network study set a new ventilation strategy as gold
standard89: Sufficient PEEP (titrated on FiO2or respiratory
function measurements), lung recruitment, avoiding PIP
above 30 cmH2O, and Vt not exceeding 6 mL/kg ideal
body.82,83,91Furthermore, Gattinoni et al. recommended
measured by computed
approach, the levels of inflammatory markers as well as
mortality in adult patients have been reduced.78,79,89
However, reliable data from children with ALI are
lacking. Even so, it is questionable, whether evidence from
adult patients can also apply to children; we have to
acknowledge that there are age-dependent differences in
e.g. respiratory tract anatomy, physiology, underlying dis-
eases, etc. However, conducting a well-designed trial in the
pediatric age group will be difficult due to the smaller
numbers of children with ALI. Moreover, the evidence
and practice derived from adult patients have already
entered and are being applied in the PICU.
Despite all the scientific evidence for lung protective
ventilation strategies (outside of clinical trials), overall
improvement will only be achieved when physicians are
aware of these principals in daily routine.92–94
FURTHER SUPPORTIVE TREATMENT
High-frequency oscillatory ventilation
High-Frequency Oscillatory Ventilation(HFOV) reduces Vt
to a minimum and applies a continuous distending pressure
354P. DAHLEM ET AL.
above PEEP. With HFOV, ventilation in the so-called safe
zone of the pressure/volume curve can be established
preventing volutrauma and atelectrauma (Fig. 5). There-
fore, one might expect that with HFOV important goals of
repetitive closure and re-opening of alveoli) may be
achieved. Most of the clinical HFOV studies were con-
ducted in newborns with neonatal RDS; however, no clear
benefit on mortality compared with conventional ventila-
tion (CV) was observed.95–99
In adult patients with ALI; reviews by leading experts in
the field and a Cochrane systematic review of RCTs found
that HFOV during the early phase of ALI seems to have no
benefits and that there might be a role for HFOV only in
For pediatric ALI/ARDS, only one prospective RCT on
HFOV has been conducted.95It was found that physiolo-
gical parameters, oxygenation and lung recruitment
improved. However, the duration of mechanical ventilation
and 30-day mortality did not differ between the HFOV and
control group. Therefore, no recommendation for routine
use can be made. Despite lacking sufficient evidence, the
frequency of its use varied from occasionally up to almost
During prone position, dependent lung regions are
recruited under the influence of gravity. Promising clinical
observations in adult ALI/ARDS patients demonstrated
that prone position improves oxygenation by 70–
80%.103–106A trend towards lower mortality was observed
when patients suffered from severe ARDS and when they
were put in prone position within 48 h after onset of ALI/
ARDS for at least 17 h per day lasting 7 days. Combining
prone position, HFOVorinhaled nitric oxide(INO) didnot
improve outcome and is only recommended for rescue
In pediatric patients, Numa et al. demonstrated that
prone position increases functional residual capacity,
improving lung compliance and oxygenation.108Many clin-
ical case series have shown that oxygenation improved in
children.108–118Oxygenation improves within a short per-
iod (1–2 h) after position change and can be sustained. For
example, Casado-Flores et al. showed in a prospective case
study that repetitive changes of positioning every 8 h
improved oxygenation in 18 of 23 children with ARDS;
however, mortality was not affected.113The largest pro-
spective multi-center RCT did not find any differences
between both groups on important outcome variables
such as ventilator-free days and mortality.111Despite these
disappointing findings, it has been shown that regular prone
position is able to ameliorate the degree of VILI.110,119–121
In summary, at the moment there is not enough evi-
dence to recommend prone position for routine use.
However, ‘‘turning the child round’’ in a more favorable
position/condition should not be disregarded based on all
the physiological/experimental rationales that have been
Selective pulmonary vasodilatation
Inhaled nitric oxide
Hypoxemia in ALI is mainly caused by ventilation/perfusion
mismatch with increased intrapulmonary shunting due to
dysregulation characterized by pulmonary vasodilatation in
non-ventilated (hypoxic) lung regions and vasoconstriction
in ventilated areas as well as pulmonary hypertension.
Inhaled nitric oxide (INO) has shown to be an ideal
selective pulmonary vasodilator improving oxygenation
and decreasing pulmonary artery pressure.123–127
In neonates with persistent pulmonary hypertension,
INO minimized the degree of respiratory failure and
reduced the need for the extracorporeal membrane oxy-
genation (ECMO).128In how far INO may reduce chronic
lung disease and mortality in preterm neonates is still a
matter of debate.129,130
About 60%–80% of adult patients with ALI/ARDS
improved in oxygenation with dosages between 2–
Only a small number of clinical studies have examined
INO in children.138,139One RCT found that oxygenation
was improved only in children with severe hypoxemia
(oxygenation index >25); however this effect was short-
lived.140In combination with HFOV further improvement
was achieved due to better lung recruitment.141Despite
these effects, mortality was not reduced. Therefore, after a
systematic review and a meta-analysis the conclusion was
not to recommend its use routinely because final outcome
has not been improved.135,136In a European Consensus
Conference, leading experts in this field subscribed to this
The indications for use of aerosolized prostacyclins (e.g.,
for INO, i.e. primary and secondary pulmonary hyperten-
sion. Inhaled prostacyclin (PGI2) can be applied easily by
means of a standard nebulizer system appropriate for
optimal alveolar deposition.143,144In 1993, Walmrath
et al. showed for the first time that aerosolized PGI2
selectively lowers pulmonary artery pressure, decreases
intrapulmonary shunts, and improves oxygenation in adult
patients with ARDS.144
Only one prospective double-blind RCT examined the
effect of PGI2in 14 children with ALI. Primary outcome
measure was oxygenation. It was found that oxygenation
was significantly improved by 26%.143The optimal dosage
in children for PGI2was 30 ng/kg/min and thus higher than
the recommended dosage in adult patients of 10 ng/kg/
PEDIATRIC ACUTE LUNG INJURY 355
min.145,146Motality was not measured in this study; there-
fore, based on its level of evidence its use may be only
reasonably justified. Regarding costs in a child weighing, for
example 18 kg, one hour of PGI2therapy of 30 ng/kg/min
costs $12 vs. $125 for INO (manufactures data).
In contrast to neonatal RDS, in ALI there is secondary
surfactant depletion and inactivation.6,147The best available
evidence concerning surfactant treatment in adult patients
with ALI/ARDS has been extensively reviewed recently,
showing improvement in oxygenation shortly after surfac-
tant instillation; however no effect on mortality.148
on surfactant treatment in children with ALI, the primary
outcome measure, ventilator-free days, did not differ
between the surfactant and placebo group.149Mortality,
the secondary outcome measure, was reduced in surfac-
tant-treated children 19% vs. 36%. Interestingly, a novel
surfactant preparation (Calfactant, 2 doses of 80 mL/m2
administered 12 h apart) with a high proportion of hydro-
phobic surfactant associated protein B (SP-B) was used,
which seems to be equal to natural surfactant and may
a final conclusion based on these results due to an uneven
distribution of the number of immunocompromised
patients in trial groups and an insufficient number of
patients for subgroup analysis.
Future trials should be sufficiently powered, should use
high and repetitive dosages of natural surfactant prepara-
tions with sufficient SP-B fraction, and should stratify for
relevant patient subgroups (e.g. indirect vs. direct lung
It was found that patients with ALI who exhibit early
fibroproliferation are at greater risk to die.27Therefore,
intravenous corticosteroid therapy has been considered
the most appropriate target pharmacotherapy for many
years.150However, several clinical trials of high-dose corti-
costeroids during the early phase of ARDS failed to show
improvements in survival.150–153In a large multi-center
double-blind RCT a moderate dose of corticosteroids
was delivered to patients with persistent ARDS for minimal
7 days.154Mortality did not improve at day 60 of follow-up
andin asubgroupofpatientsin whom corticosteroids were
started on day 14 after onset of ALI/ARDS mortality at day
180 was even higher. This observation raised serious
concerns about the appropriateness of corticosteroid ther-
apy in ALI/ARDS. It was speculated that the pro-inflam-
matory and anti-inflammatory processes during ALI/ARDS
do not occur at similar time points, and that the consider-
able genetic differences in each individual patient may also
play a role.155
To our knowledge, no RCT addressing corticosteroid
therapy in the pediatric age group has yet been published.
Extracorporeal Membrane Oxygenation
There are no RCTs exploring the benefits of ECMO in
children with ALI. Inaretrospective analysisofchildrenwith
severe pediatric AHRF (including ARDS patients only as a
subgroup) with a predicted mortality of 50% to 75%,
ECMO did reduce mortality.156,157
ECMO can be a life-saving tool in critical ill children
suffering from transient illness and who otherwise would
die (e.g. during meninogococcal septic shock and AHRF).158
Future research should identify patients at risk for ALI and
for VILI, by the discovery of new gene candidates or by
identifying clinically relevantrisk factors. Clinicaltrials should
attempt to include patients soon as early as ALI and VILI
develops in order to define new treatment strategies
preventing VILI and deterioration of ALI.45Furthermore,
studies should differentiate between patients with direct or
indirect lung injury and between adults and children.60
Distinct gene candidates have been identified which are
associated with lung injury induced by overdistention as a
possible cause for VILI.159As one of the novel mechanisms,
Woesten et al. found increased ACE activity in bronch-
oalveolar lavage fluid (BALF) of mechanically ventilated rats
triggering inflammation and apoptosis within hours. Pre-
treatment with an ACE inhibitor reduced ACE activity in
BALF, pulmonary inflammation and apoptosis (personal
communication, unpublished observation).
Differences in lung damage between children and adults
should be addressed. Kornecki et al. found that the still-
growing lung of animals had more capacity to recover and
to compensate early lung damage and seems therefore less
vulnerable to VILI than the fully grown adult lung.160
New treatment options such as corticosteroids, surfac-
tant and lung protective ventilation should be examined in
ing influence of underlying disease on outcome (conditions
with immunocompromise), novel therapeutic approaches
may nevertheless improve outcome of children with ALI
(e.g. the ARDS Network study protective ventilation strat-
egy).89Interestingly, in the study of Willson et al., surfactant
improved outcome in the subgroup of immunocompro-
mised children (50 vs. 60).149
For this subgroup (80%–100% mortality), DiCarlo et al.
reported in a small case study that hemofiltration
decreased mortality, when started from early onset of
ARDS due to improved fluid management and removal
of inflammatory mediators.161Larger series should confirm
Interventions in alveolar coagulation/fibrinolyis might
offer new therapeutic options. The interplay between
356P. DAHLEM ET AL.
inflammation and coagulation/fibrinolysis contributes sig-
turnover is disturbed and misbalanced towards an anti-
fibrinolytic intraalveolar milieu dominated by PAI-1.18–
20,163–166Fibrin depositions trigger de novo inflammation
and pulmonary fibrosis. Many coagulation inhibitors have
been tested to rebalance fibrin turn over including heparin,
antithrombin, tissue factor pathway inhibitor, factor VIIa,
activated protein C, and thrombomodulin in animal models
and/or humans with either sepsis or ALI.20,166So far, none
of these has achieved clinical approval. From the successful
experiencein thetreatmentofsepsis withactivatedprotein
C (APC), a promising pilot study in human volunteers after
endotoxin administration demonstrated the potential role
of APC in ALI.167,168
Due to the fact that VILI resembles original lung
injury in many ways, it was hypothesized that disturbed
fibrin turnover might play a role in VILI, preventing
resolution of alveolar fibrin depositions. First experimen-
tal evidence suggests that traumatic mechanical ventilator
settings may suppress alveolar fibrinolysis.169,170This
observation is important, because high levels of PAI-1
in pulmonary edema fluid (antifibrinolytic alveolar milieu)
correlate with mortality.171Interestingly, lung protective
ventilation attenuates intra-alveolar fibrin formation.172
These preliminary results should encourage investigating
the underlying pathomechanisms and novel treatment
We need more follow-up data on pediatric ALI. In
contrast to the scarcity of pediatric data, follow-up studies
in adults showed that a considerable percentage of patients
suffer lifelong sequelae (e.g. health-related quality of life,
neuro-cognitive dysfunction, and abnormal pulmonary
function testing).40,173–186The severity of lung injury, direct
vs. indirect lung injury and the duration of mechanical
ventilation correlate with persistent abnormalities of pul-
For the pediatric age groups, it is possible that ALI may
interfere with normal lung development thus causing
chronic lung disease.187A few small sized observational
cohort studies have reported respiratory sequelae of 33%–
Different kinds of respiratory function
abnormalities have been measured and most of them
are subclinical: obstructive and restrictive functional
abnormalities. For example, an observational follow-up
study of pre-school children (mean age 37 months) after
a period of septic shock and ARDS found that 2 of 7
children suffered from relevant respiratory sequelae.192
Three months after discharge almost all children experi-
enced restrictive and/or obstructive abnormalities and
recovery during the following months reached plateau
levels at the 12-month visit with no further improve-
ment.40,188,193Recovery is however limited to a period
of 6–12 months.40,193This shows that the timing of the
follow-up examination is crucial and mainly determines the
incidence of abnormalities (Fig. 6).
No specific therapy for respiratory function abnormal-
ities exists. Inhalation therapy with beta-2 adrenergic
bronchodilators for obstructive lung disease has been tried;
function tests were improved.188,192
The positive effects of lung protective ventilation stra-
tegies on prevention of respiratory function abnormalities
and long-term sequelae need to be determined.89,194
Future research should concentrate on the pediatric age
group, the complex and heterogeneous pathophysiology
(e.g. fibrinolysis), the repair mechanisms and the genetic
and gender-related conditions.73,170. Furthermore, pedia-
tric critical care physicians should be aware of and search
for the short-term and long-term sequelae of pediatric ALI.
Whether lung growth will put the child in a more favorable
situation compared with an adult (compensation of lung
damage by growth?) also needs to be answered. Therefore,
a concerted effort is still needed to address all these factors
related to pediatric ALI.
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