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.
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