C H A P T E R 6 5
Acute Respiratory Distress
Syndrome in Children
Jan Hau Lee Ira M. Cheifetz David A. Turner
Acute respiratory distress syndrome (ARDS) is character-
ized by severe hypoxemia and diffuse infiltrates on radio-
logic examination. ARDS represents the final common
pathway and clinical presentation of the most severe
acute lung injury (ALI), which may be precipitated by
various pulmonary (direct) or nonpulmonary (indirect)
insults. Infections are an important cause of ARDS in
children, with pneumonia and sepsis being most
common.39,116 ARDS is an important consideration in the
setting of pediatric infectious disease, given the wide
range of infections that may lead to this complication and
its associated morbidity and mortality.39,116 Morbidity,
mortality, and resource usage related to ARDS also
increase during outbreaks of infectious diseases, as seen
during the 2009 to 2010 global influenza H1N1 pan-
demic.36,87 This chapter will discuss the definition, patho-
physiology, presentation, and clinical management of
critically ill children with ARDS, with an emphasis on
aspects that may be of particular interest to pediatric
infectious disease specialists.
 65 Acute Respiratory Distress Syndrome in Children 867

TABLE 65-1 The Berlin Definition of Acute Respiratory Distress Syndrome 2011
Acute Respiratory Distress Syndrome

Criteria Mild Moderate Severe

Time of onset Within 1 week of known clinical insult or new or worsening respiratory symptoms
Degree of hypoxemia P/F ratio 201-300 with PEEP/CPAP 5 P/F ratio 200 with PEEP 5 P/F ratio 100 with PEEP 5
Origin of edema Risk factors for ARDS must be present. Respiratory failure that is not fully explained by cardiac
failure or fluid overload.*
Radiologic findings+ Bilateral opacities that are not fully explained by effusions, lobar or lung collapse, or nodules
(CXR or CT scan)

*If no risk factors are present, objective measures (e.g., echocardiography) are required to exclude hydrostatic edema.
ARDS, Acute respiratory distress syndrome; CPAP, continuous positive airway pressure; CT, computed tomography CXR, chest
radiography; PEEP, positive end-expiratory pressure.

DEFINITION TABLE 65-2 Causes of Acute Respiratory

Although first described by Ashbaugh and colleagues in
1967,11 no formal definition of ARDS was developed for
over 25 years. In 1994, the American-European Consen-
sus Conference (AECC) defined ARDS as follows15:
1. Acute onset of respiratory symptoms
2. Frontal chest radiograph with bilateral infiltrates
3. Partial pressure of oxygen (Pao2) to fraction of
inspired oxygen (Fio2) ratio (P/F ratio) 200mm Hg
or less
4. No clinical evidence of left atrial hypertension as
defined by a pulmonary capillary wedge pressure
less than 18mm Hg (if measured)
The AECC also designated the term acute lung injury
as a part of the spectrum of ARDS, and ALI is defined
by a P/F ratio between 201 and 300mm Hg. Despite the
limitations,111 these formal definitions have allowed for
standardization of terminology and led to landmark clini-
cal studies in ALI and ARDS that have contributed to
improved understanding of this spectrum of conditions
over the past 18 years.20,41,104
Recently, the Berlin Definition of ARDS was proposed
by the European Society of Intensive Care Medicine
(ESICM) in collaboration with the American Thoracic
Society (ATS) at the ESICM Congress in October,
2011.35,105 This new definition proposes that the term
ALI be removed and ARDS be considered a single entity
with three subgroups based on severity of hypoxemia
(i.e., mild, moderate, and severe). The Berlin Definition
of ARDS takes into account the timing of onset, degree
of respiratory support (positive airway pressure), and
overall fluid status. This new definition also allows for
the use of either computed tomography (CT) of the
chest or standard chest radiograph for determination of
ARDS (Table 65-1).
ETIOLOGY
Numerous insults that both directly and indirectly
affect the lung can lead to generation of inflammatory
mediators that contribute to development of ARDS
(Table 65-2). Direct pulmonary insults include pneumo-
nia, aspiration, chest trauma, near drowning, and smoke
Distress Syndrome
Indirect (Nonpulmonary)
Direct (Pulmonary) Causes Causes
Pneumonia Severe sepsis and septic
Bacterial shock
Viral H1N1, RSV Multiple trauma
Mycobacterium Severe hemorrhage
Fungal
Severe pancreatitis
Transfusion reaction
Aspiration Cardiopulmonary bypass
Near-drowning
Smoke or chemical inhalation
Pulmonary contusion
Fat embolism (rare in children)
inhalation. Indirect lung injury may be the result of gen-
eralized systemic conditions, such as sepsis, closed head
injury, multisystem trauma, transfusion reactions, pan-
creatitis, and hemorrhagic shock.
Infective etiologies account for a large proportion of
the causes for ARDS, with bacterial and viral infections
being the most common infectious etiologies of ARDS.14
Streptococcus pneumoniae and Pseudomonas aeruginosa are
common bacteria associated with severe pneumonia
potentially leading to sepsis and, subsequently, ARDS.14
Certain characteristics of these organisms have been
shown to be instrumental in initiating this injury; for
example, P. aeruginosa incites lung injury via the cytotoxic
activity derived from the patatin-like phospholipase
domain of ExoU toxin.75
Respiratory syncytial virus (RSV) infection is one of
the most common indications for admission to the pedi-
atric intensive care unit (PICU), especially during the
winter months.7 Although most critically ill children
present as severe RSV bronchiolitis, a significant propor-
tion (up to 27%) can present with ARDS; those with
preexisting conditions are at the highest risk.46 The influ-
enza viruses are the most common cause of viral-induced
ARDS, especially during an epidemic or pandemic.36,87
Bacterial coinfection in patients with the severe pandemic
868 SECTION XII Systemic Infectious Diseases
H1N1 viral infection has been shown to increase the
need for mechanical ventilation, duration of intensive
care unit (ICU) stay, and mortality.90 Specifically, coinfec-
tion with methicillin-sensitive Staphylococcus aureus at
admission was independently associated with almost a
threefold increase in mortality.90 There is a growing
concern of community-acquired methicillin-resistant S.
aureus (MRSA) infection leading to severe necrotizing
pneumonia and ARDS, even with non-H1N1 influenza
infection.53,69,107 A less common cause of viral-induced
ARDS is the coronavirus, such as the strain that caused
the severe acute respiratory syndrome (SARS) in 2003
and affected adults more severely than children.59,60
In addition to bronchiolitis and pneumonia, severe
sepsis is also a leading risk factor for ARDS in children.117
In critically ill adults, sepsis is also associated with an
approximately 40 percent risk for developing ARDS.77
Multiorgan dysfunction and other illnesses associated
with sepsis increase the risk for ARDS, and this risk is
further compounded by the presence of chronic condi-
tions or underlying comorbidities.50 In addition, genetic
differences, which regulate the immune responses of the
lungs to these precipitating factors, account for differ-
ences in the degree of severity in ARDS in individual
patients, even when similar risk profiles are present.80
One such example of genetic polymorphisms is that
related to nuclear factor-B (NF-B). Deletion polymor-
phism of the promoter region of this important transcrip-
tion factor leads to inappropriate upregulation of
proinflammatory genes, which has been shown to result
in an increase in ARDS severity and mortality.4,13
Limited data exist on the impact of the underlying
etiology of ARDS on clinical outcomes in children. In a
study involving 736 adults with ARDS, patients with
sepsis-related ARDS were more likely to have diabetes,
longer pre-ICU stay, and higher APACHE III (a measure
of severity of illness in critically ill adults) scores in con-
trast to those who had nonsepsis-related ARDS.97
However, after accounting for differences in clinical
characteristics, no difference was found in 60-day mortal-
ity between patients with sepsis-related ARDS and non
sepsis-related ARDS. Furthermore, no evidence exists to
suggest that the source of sepsis is an important determi-
nant of mortality in ARDS.96
INCIDENCE
In contrast to the incidence in adults, the incidence of
ARDS in critically ill children is not as well described but
does appear to be lower.106 In a study conducted in the
United States, 13 percent (828/6235) of patients who
required mechanical ventilation had ARDS. This inves-
tigation reported an incidence of 16/100,000 person-
years for those 15 to 19 years old and 306/100,000
person-years for adults 75 to 84 years old.94 In a follow-up
study involving children younger than 18 years, the inci-
dence was 12.8/100,000 person-years.117 Single-institution
studies previously reported that ARDS accounted for 2.7
to 4.3 percent of PICU admissions.28,43 In more recent
data involving multiple centers, ARDS accounted for
lower percentages (1.4% to 2.7%) of all PICU
admissions,49,116 making the conduct of clinical ARDS
trials in critically ill children particularly challenging.
CLINICAL COURSE
The initial clinical course of ARDS begins with direct or
indirect acute injury to the pulmonary parenchyma. In
the initial stage, the clinical symptoms and physical find-
ings vary depending on the etiology of the ALI. Children
with pulmonary etiologies of ARDS will have predomi-
nantly respiratory symptoms; those with nonpulmonary
etiologies of ARDS will have symptoms related to the
initial insult (e.g., acute abdomen for pancreatitis). Early
in the course of lung injury, patients may display mild
tachypnea and dyspnea but tend to have normal radio-
graphic findings.
After the inciting event and initial phase, a latent
period follows that may last for a variable period. During
this latent period, the patient may appear to be clinically
stable, but early signs of pulmonary insufficiency develop,
as manifested by hyperventilation with hypocarbia and
respiratory alkalosis. The chest radiograph may remain
clear or may begin to demonstrate a fine reticular pattern
related to the development of pulmonary interstitial fluid
(Fig. 65-1).33 With progression of the lung injury, acute
respiratory failure follows and is characterized by rapid
onset of hypoxemia that is often refractory to supplemen-
tal oxygen administration. Diffuse pulmonary edema and
worsening compliance cause significant atelectasis and
intrapulmonary shunting. Clinically, patients develop
rapid, shallow tachypnea with increased work of breath-
ing. The physical signs of respiratory failure will vary
with age and severity of illness, but usually include sub-
costal and supraclavicular retractions, grunting, and nasal
flaring. Lung examination usually reveals diffuse crackles
on auscultation. Radiographically, bilateral areas of con-
solidation with air bronchograms reflect alveolar filling
and atelectasis (Fig. 65-2). A significant percentage of
these children will require endotracheal intubation and
FIGURE 65-1 Early stage of acute respiratory distress
syndrome.
 65 Acute Respiratory Distress Syndrome in Children 869
FIGURE 65-2 Established acute respiratory distress syndrome.
mechanical ventilation with the application of positive
end-expiratory pressure (PEEP). However, noninvasive
ventilation may be an alternative for a subgroup of
patients.81
Mortality
Most studies indicate that mortality associated with
ARDS is due to nonrespiratory causes.38,68 In most cases,
early death (i.e., within 72 hours) is caused by the under-
lying illness or injury, whereas late death (i.e., beyond 72
hours) is caused by infection or multiorgan system failure.
Reported mortality rates for children with ARDS vary
greatly and range from 8 to 62 percent.* This variation
is likely due to the myriad of underlying causes of ARDS,
the differing degrees of ARDS severity, and the presence
or absence of concomitant organ failures. Some of the
factors that have been identified as predictors of mortality
in pediatric ARDS include P/F ratio, oxygenation index
([Fio2 mean airway pressure]/Pao2), pH, Pediatric Risk
of Mortality (PRISM) score (a severity index score com-
monly used in PICUs), and presence of multiorgan
failure.84 Despite the large reported variation in mortal-
ity, it is generally accepted that the overall mortality
rate of pediatric ARDS is lower than that of the adult
population.117
Recent studies suggest that mortality from ARDS may
be declining; however, the reason for this overall improve-
ment is not completely clear. The trend toward decreas-
ing ARDS mortality over time began over 20 years ago,
before the publication and widespread adoption of low
tidal volume ventilation strategy. Low tidal volume ven-
tilation is the only mechanical ventilation strategy that
has ever been clearly shown to decrease mortality in
ARDS in adult patients in the setting of a randomized
clinical study.104 The extent that protective mechanical
*References 16, 25, 28, 49, 84, 114.
ventilation strategy has on mortality in actual clinical care
remains to be determined, especially in the pediatric
population.2,66 Changes in organization of ICU care,
improvement in supportive care, and improved monitor-
ing capabilities may have accounted for the decreasing
trend between the early 1990s and late 1990s (66% vs.
34% mortality, respectively).2 More recent adult studies
in the era of low-volume ventilation still report mortal-
ity rates of approximately 40 percent in adults with
ARDS.79,110 Similar trends are noted in pediatric patients,
with mortality rates falling from 80 percent in the 1980s
to approximately 20 percent in the early 2000s and poten-
tially under 15 percent now.117
PATHOLOGY AND ROLE OF
IMMUNOMODULATORS
Pathology and Pathophysiology
The clinical stages of ARDS coincide with three patho-
logic stages: the exudative stage, the proliferative stage,
and the fibrotic stage. The exudative stage is character-
ized by accumulation of protein-rich edema fluid into the
alveoli. This fluid flux is secondary to diffuse injury to
the alveolar-capillary membrane by either direct or indi-
rect injury (see Table 65-1). Neutrophils play a predomi-
nant role in this stage of ARDS. In addition to influx of
inflammatory cells and mediators, formation of micro-
thrombi within the vasculature contributes further to the
ALI and alters the pulmonary vascular tone. Pulmonary
compliance is worsened by the presence of edema and
can result in widespread atelectasis. Pulmonary compli-
ance is further affected by the inactivation of surfactant
that results from the presence of plasma proteins, such as
fibrin, and inflammatory mediators, such as proteinases,
in the alveolar space.61,95 The development of micro-
thrombi within the pulmonary vasculature together with
the release of numerous vasoactive mediators from
inflammatory cells and the activated endothelium con-
tribute to the development of elevated pulmonary vascu-
lar resistance and further contribute to the ventilation/
perfusion abnormalities characteristic of ARDS. The
degree of epithelial injury and the subsequent ability to
clear edema fluid, along with the reversibility of pulmo-
nary hypertension, are important predictors of outcome
in ARDS.62,112
The proliferative stage occurs 1 to 3 weeks after the
initiation of injury and is characterized by attempted
repair of the disrupted alveolar-capillary membrane. The
mechanism of this repair requires not only the close coor-
dination of numerous growth factors but also an intact
basement membrane to provide a platform for cell adhe-
sion and migration.80
The ability of the lung to recover depends on the pres-
ence of functional epithelium to clear the alveolar fluid
and the bodys ability to attenuate the inflammatory
process. The ability of the alveolar epithelium to remove
edema fluid depends on the degree of inflammation and
injury in the exudative stage. After the initiation of the
injury, anti-inflammatory processes take place to limit the
degree of injury. Anti-inflammatory cytokines such as
870 SECTION XII Systemic Infectious Diseases
interleukin (IL)-10 and lipid mediators have been shown
to be important in the mitigation of this injury.63 If lung
injury and inflammation persist, the patient may develop
severe physiologic abnormalities and may progress to the
fibrotic stage of ARDS.
The fibrotic stage may be seen as early as 5 to 7 days
after the onset of disease, although the presence of this
injury becomes more clear after several weeks. Histologi-
cally, the alveolar space becomes filled with mesenchymal
cells and lung tissue is replaced by collagenous tissue.54
In addition, vascular changes in the fibrotic stage can lead
to increased thickness of the pulmonary vasculature and
even obliteration of small capillaries. Overall, these
changes markedly decrease the available surface area for
gas exchange and result in decreased effort tolerance in
survivors of ARDS. In some patients, intractable respira-
tory failure or chronic lung disease result, necessitating
prolonged ventilator support.
Immunomodulators
Numerous mediators of inflammation are implicated in
the pathogenesis of ARDS.88 Some of the more important
mediators include tumor necrosis factor (TNF), ILs, and
matrix metalloproteinases (MMPs).36 The identification
of these mediators potentially allows for development of
biomarkers to predict the severity of ARDS. In a study
involving 33 children with ARDS and 21 patients without
ARDS who required mechanical ventilation, active
MMP-9 in tracheal aspirates was significantly elevated in
the ARDS patients. Furthermore, elevation of MMP-8
and MMP-9 at 48 hours predicts a longer duration
of mechanical ventilation in children with ARDS, high-
lighting the potential use of MMPs as a biomarker in
pediatric ARDS. The effects of mediators and inflamma-
tory cells involved in ARDS, as well as regulatory mol-
ecules, are tightly woven and ultimately result in a balance
between proinflammatory and anti-inflammatory and
pro-edematous and anti-edematous factors.37 Although
inflammatory mediators could themselves disrupt the
capillary-alveolar membrane, they also may exert effects
to keep the inflammatory response in check. This may
account for the lack of success of pharmacologic inhibi-
tors to decrease the mortality associated with ARDS.
Research efforts continue to investigate potential ways to
more effectively modulate the inflammatory response
during ARDS.64,88
Increasing evidence indicates that the genetic makeup
of an individual influences the outcome of sepsis and
ARDS.109,115 One of the most commonly studied genetic
polymorphisms in sepsis is that pertaining to TNF, which
plays a central role in the cytokine storm in septic
shock. Both pediatric and adult studies have shown that
certain single nucleotide polymorphisms (SNPs) regulate
the susceptibility of septic patients in developing
ARDS.12,44 A study of 490 children with sepsis found that
changes in different SNPs in the TNF genotype affects
the risk for developing ARDS (i.e., TNF-308 GA geno-
type was protective, and TNF-863 CA genotype increases
the risk).12 Genetic polymorphisms may potentially
provide useful biomarkers for screening septic children
who are at risk for developing ARDS and to identify a
subgroup of patients who will benefit most from specific
therapeutic strategies.
TREATMENT
The goal in the treatment of patients with ARDS is to
treat the underlying disease (when possible), achieve
adequate tissue oxygenation, and minimize ventilator-
induced lung injury (VILI). In patients in whom ARDS
is secondary to sepsis, prompt administration of appro-
priate antibiotics is essential.29,58 The general antimicro-
bial approach depends on the local virulence and pattern
of drug resistance in the community and within a given
hospital. In the United States, where cases of infection
with cephalosporin-resistant S. pneumoniae and MRSA
are increasing, broad-spectrum gram-positive coverage
(e.g., vancomycin) often is necessary.29,53 The mainstay of
support in the ARDS patient is the provision of supple-
mental oxygen and mechanical ventilation. In addition,
nonpulmonary organ function must be meticulously
maintained to optimize the clinical care of children with
ARDS.
Pulmonary Management
Modes of Mechanical Ventilation
Multiple modes of mechanical ventilation are currently
used in clinical practice to provide respiratory support for
patients with ARDS. Conventional mechanical ventila-
tion, which delivers tidal volume breaths, can be achieved
effectively by either pressure-control or volume-control
modes. In the former, the clinician controls the amount
of inspiratory pressure in each breath delivered to the
patient and, depending on the pulmonary compliance,
the patient receives different tidal volumes. In volume-
control modes, the clinician determines the amount of
volume delivered to the patient and, with changing pul-
monary compliance, the inspiratory pressure changes.
Regardless of the conventional mechanical ventilation
mode(s) used, it is paramount that VILI be minimized
by paying meticulous attention to prevention of baro-
trauma and volutrauma. Prospective, randomized multi-
center studies comparing one ventilatory mode to another
in the setting of ARDS are limited and have not demon-
strated a single ventilatory mode as superior to any
other.34,83
In contrast to conventional mechanical ventilation,
high-frequency oscillatory ventilation is an alternative
mode that delivers extremely small-volume breaths
(i.e., less than dead space volume) at high rates (5 to
15Hz [equivalent to 300 to 900 breaths/min]). Although
use of high-frequency oscillatory ventilation has become
commonplace, the only definitive study of this method in
pediatric ARDS is a crossover trial conducted nearly 20
years ago that showed improved oxygenation and a reduc-
tion in the need for supplemental oxygen at 30 days.9
Despite the lack of robust evidence in support of high-
frequency oscillatory ventilation, it has become a
 65 Acute Respiratory Distress Syndrome in Children 871
standard technique in the management of ARDS in
PICUs worldwide.86
Low Tidal Volume Ventilation
A landmark study of adults with ARDS published in the
New England Journal of Medicine in 2000 showed that low
tidal volume mechanical ventilation (6mL/kg) decreased
mortality by 22 percent and increased the number of
ventilator-free days in contrast to a more traditional tidal
volume (12mL/kg).104 The mortality rate was 31.0
percent in the low tidal volume group and 39.8 percent
(p = .007) in the higher tidal volume group. Additionally,
the plateau pressure (Pplat), a major factor in creating
barotrauma in the lungs, was significantly decreased in
the low tidal volume group (26cm H2O) in contrast to
the control group (37 9cm H2O). This study is the only
investigation in either adult or pediatric ARDS that has
demonstrated a mortality benefit associated with a spe-
cific ventilatory approach. Although still unproved, these
results are likely applicable to infants and children with
ARDS and this low tidal volume approach has become
standard practice in the PICU setting.
Further data from other large mechanical ventilation
studies in adults demonstrated that outcomes are
improved when Pplat is limited to less than 32 to 35cm
H2O.6,18,100 No data exist in pediatric patients to guide
practitioners in the establishment of peak inspiratory
pressure or tidal volume, and ongoing investigation is
needed. It is possible that the critical limit on plateau
pressure for infants and children may be less than 32 to
35cm H2O, or there may be variation with patient age,
but without further studies, clinicians must rely on avail-
able data on adults and individual clinical expertise.
Without a similar large-scale, prospective, randomized
trial in pediatrics, a ventilatory strategy should be under-
taken that limits both tidal volume and inspiratory
pressure.
Positive End-Expiratory Pressure
PEEP is the constant pressure applied to the airways and
alveoli during exhalation and is an important component
of the ventilator strategies employed in the management
of ARDS. PEEP helps maintain alveolar patency and
restore functional residual capacity. PEEP is typically
titrated to a level that allows adequate oxygenation at an
acceptable Fio2 as described later in more detail.
The ARDS Network investigated the optimal PEEP-
Fio2 approach for adult patients with ARDS and showed
that both lower and higher PEEP strategies pro- discussion of permissive hypoxemia.
duced similar survival rates.20 The results of this study
suggest that as long as adequate PEEP is applied, higher
levels are not necessary but are acceptable. Thus, the
balance between PEEP and Fio2 (as long as alveolar col-
lapse is minimized) can be left to the discretion of the
clinician. PEEP- Fio2 tables for adult patients are readily
available10; however, no such generally accepted stan-
dards are available for infants and children. In summary,
once appropriate PEEP is applied to maintain the lungs
at an ideal volume, a further increase in PEEP in an
attempt to reduce the Fio2 does not lead to an improved
outcome.10
In a follow-up meta-analysis of almost 2300 patients,
Briel and colleagues16 demonstrated that patients with
pure ALI (i.e., recruitable lung) benefited from a higher
PEEP strategy, whereas those without recruitable lung
did not. Based on these data, a strategy that individualizes
PEEP based on the specific clinical circumstances seems
warranted.
It must be noted that an important consideration as
PEEP is titrated is the impact of increasing mean intra-
thoracic pressure on systemic venous return and cardiac
output. Increasing PEEP comes at a cost of increased
mean intrathoracic pressure and potentially a decrease in
systemic venous return and cardiac output.67 As a result
of these changes, patients with ARDS may need further
intravascular volume loading and possibly inotropic
support.82 A comprehensive discussion of the cardiorespi-
ratory effects of increasing PEEP is beyond the scope of
this chapter.
Gas Exchange Goals
Every child with ARDS is hypoxemic by definition. Pro-
longed administration of high concentrations of oxygen
can damage lungs, owing to the formation of oxygen free
radicals. Human and animal studies suggest that a pro-
longed Fio2 greater than 0.60 should be avoided to
prevent oxygen-induced pulmonary damage.52 However,
the exact Fio2 cutoff for oxygen toxicity in the ARDS
patient, especially in children, remains unknown and may
be less than 0.60. Increases in the set PEEP may allow
for a reduction of the delivered Fio2.
In the setting of ARDS, improved oxygenation has not
been associated with improved outcomes. This finding
was best demonstrated in the ARDS Network low tidal
volume study, in which the control (12mL/kg) group
demonstrated improved oxygenation for the first 72
hours of mechanical ventilation but ultimately had a
higher mortality in contrast to the lower tidal volume
(6mL/kg) group.104 In a pediatric study of 470 children,
no correlation was found between oxygenation or ventila-
tion measured during the first 14 days of PICU admission
in survivors or nonsurvivors of pediatric ALI.106 Other
studies in pediatric ARDS have demonstrated short-term
improvements in oxygenation parameters with no differ-
ence in mortality.30,31 The ideal target for oxygenation in
ARDS remains controversial, but it is clinically reason-
able to accept Sao2 under 90 percent as long as tissue
oxygen delivery is adequate, as described later in the
Permissive Hypercapnia
A consequence of low tidal volume ventilation is hyper-
capnia. Limiting the peak inspiratory pressure by reduc-
ing the tidal volume may decrease minute ventilation and
result in hypercapnia. Limited evidence suggests that
low-volume, pressure-limited ventilation with permissive
hypercapnia may improve outcomes in patients with
ARDS.47,48 In a 10-year study, Milberg and colleagues66
872 SECTION XII Systemic Infectious Diseases
reported a positive association between permissive hyper-
capnia and outcomes. Recent data from a laboratory
model of ischemia-reperfusion ALI indicate that hyper-
capnic acidosis is protective and that buffering of the
hypercapnic acidosis actually attenuates these protective
effects.56
In addition, permissive hypercapnia has been increas-
ingly studied in animal models with regard to its role in
modulating sepsis-induced ARDS.24,51 Permissive hyper-
capnia can potentially inhibit the immune response.57
This inhibition of the immune system is of particular
concern in patients with sepsis. However, recent animal
studies reported a beneficial effect of hypercapnic acido-
sis in reducing ALI in early and prolonged systemic
sepsis.23 Earlier concerns that hypercapnic acidosis is
harmful in patients with a pulmonary source of the sepsis
(i.e., by increasing bacterial load and worsening lung
injury) have been addressed by further studies that showed
that administration of antibiotics prevented these delete-
rious effects.22,73,74 These findings, along with data dem-
onstrating worsening mortality with each hour in which
antibiotics are delayed in septic patients,55 reinforce the
need for early administration of antibiotics in the man-
agement of pediatric sepsis and ARDS.17 Despite these
potential benefits and evidence suggesting that respira-
tory acidosis is not harmful, the exact degree of hyper-
capnia that can be safely tolerated remains controversial.
Most of the undesirable effects of hypercapnia are revers-
ible and minor when pH is greater than approximately
7.20.37 We eagerly await future clinical studies looking at
the role of permissive hypercapnia in sepsis-related lung
injury given the increasing preclinical evidence of its
potential therapeutic role.
Permissive Hypoxemia
In the situation of severe ARDS with elevated ventilator
support, clinicians must carefully titrate a balance between
avoiding toxic ventilator settings (e.g., elevated airway
pressures and Fio2) and accepting lower than normal
arterial oxygen saturations.1,84 This concept of accepting
lower arterial oxygen saturations is termed permissive
hypoxemia.1,84 PEEP and other ventilatory parameters
should be set so as to optimize oxygen delivery, with
tolerance of lower oxygen saturations to allow for mini-
mization of VILI. Because the minimal acceptable arte-
rial oxygen saturation remains controversial the optimal
oxygen saturation target for an individual patient remains
unknown; however, the goal should be to provide ade-
quate tissue/organ oxygenation while minimizing toxicity
of the ventilator settings.
ADJUNCTIVE THERAPIES
Corticosteroids
Given that inflammation is the cornerstone of the patho-
physiology of ARDS, corticosteroids have therapeutic
potential as immunomodulatory or anti-inflammatory
agents. There are, unfortunately, no studies of cortico-
steroids for treatment of ARDS in children. In the adult
ARDS population, an inherent difficulty in summarizing
the use of corticosteroids is the significant variability in
the timing and dose of steroids used in the various
studies. The timing of steroids in published clinical
studies ranges from 72 hours to 4 weeks of onset of
ARDS, and the doses of methylprednisolone (or its
equivalent) range from 1 mg/kg/day to 120mg/kg/day.78
Meta-analyses of corticosteroid used within the first 2
weeks in adults with established ARDS demonstrated
that steroids may reduce mortality and reduce total days
of mechanical ventilation.78,103 However, based on current
data, corticosteroids do not appear to have a role in pre-
vention of ARDS.78 The use of steroids was not associ-
ated with an increase in secondary infections.78,103
Inhaled Nitric Oxide
Pulmonary vascular dysfunction has been associated with
ARDS and is an important component of the pathophysi-
ologic process.21 This impact of ARDS on pulmonary
vascular tone has led to the extensive investigation of
inhaled nitric oxide, a potent vasodilator that works
exclusively in the pulmonary vasculature, as a potential
therapeutic option. Studies of inhaled nitric oxide for
pediatric ARDS have demonstrated temporary improve-
ment in oxygenation acutely but not improved sur-
vival.3,30,31 This finding is similar in the adult population.
The largest pediatric inhaled nitric oxide study to date
involved 108 children.31 Because of the crossover design,
the study was not able to describe mortality results, but
it did demonstrate that the groups of children who may
acutely benefit most are immunocompromised patients
and those with greater severity of hypoxemia.
A recent Cochrane Database Systematic Review
looking at 14 randomized controlled trials concluded that
inhaled nitric oxide cannot be recommended for either
children or adults with ARDS because it resulted in tran-
sient improvement in oxygenation without mortality
benefit.5 Furthermore, it appeared that inhaled nitric
oxide may increase the risk for renal impairment among
adults with ARDS.
Surfactant Replacement
In ARDS, injury occurs to type II pneumocytes, resulting
in decreased production of surfactant. This injury has
prompted studies examining the possibility of the effec-
tiveness of surfactant replacement in the management of
ARDS. A recent study of 153 pediatric patients reported
that exogenous surfactant acutely improved oxygenation
and significantly decreased mortality in infants and chil-
dren with ALI.114 However, this study revealed no signifi-
cant decrease in duration of mechanical ventilation,
length of PICU admission, or length of hospital stay. The
results of this study are controversial because a signifi-
cantly higher number of immunocompromised patients
(i.e., with a higher expected mortality) were included in
the control group.26 Follow-up studies have been com-
pleted, and data are currently being analyzed.
The evidence for benefit associated with surfactant
therapy in adults also is limited. A large, randomized trial
of nearly 450 patients did not show a mortality difference
 65 Acute Respiratory Distress Syndrome in Children 873
with use of surfactant.98 Other studies in adults also have
not demonstrated a benefit. Unlike in the neonatal popu-
lations, current data do not demonstrate wide-scale ben-
efits associated with surfactant use in pediatric or adult
ALI, but there may be select circumstances in which this
therapy is beneficial.
Prone Positioning
Through various mechanisms such as improvement in
ventilation/perfusion matching and chest wall mechanics,
prone positioning was first shown in a randomized con-
trolled trial to improve oxygenation in patients with
ARDS by Gattinoni and his Supine-Prone Study group.41
Despite promising results of prone positioning from
investigations in adults with ARDS, a study of prone
positioning for pediatric ALI was closed for futility.25 It
is likely that not all children with ARDS will benefit from
prone positioning. Experience from clinical studies in
adults with ARDS showed that there is likely to be a
subgroup of patients who benefit most from this maneu-
ver.101,102 Future pediatric studies should aim to identify
this particular subset of patients.
Nonpulmonary Supportive Management
Fluid Balance
Initial aggressive fluid resuscitation is important in main-
taining hemodynamics and improving clinical outcomes
in patients with shock.93 However, overhydration, once
hemodynamics are restored, may lead to pulmonary
edema. Fluids should be carefully titrated and fluid status
monitored while normalizing the patients intravascular
volume status and maintaining adequate cardiac output.8
The ARDS Network conducted a study to investigate
conservative and liberal fluid management strategies in
adult patients with ARDS.113 In this study, a difference of
6000mL was seen in the 7-day cumulative fluid balance
between the two groups; with patients in the conservative
fluid management group having improved lung function
and shorter duration of mechanical ventilation and ICU
length of stay. In critically ill children, the role of fluid
balance is less conclusive. Although some studies demon-
strate that fluid balance has an impact on oxygenation and
morbidity,8,49 other prospective pediatric studies have
shown otherwise.85 The Pediatric Acute Lung Injury and
Sepsis Investigators (PALISI) Network investigators
showed that cumulative fluid input and output did not
affect the speed of weaning from mechanical ventilation
or extubation outcomes.85
Sedation and Neuromuscular Blockade
Appropriate sedation and analgesia are important in chil-
dren who are on mechanical ventilation. Prolonged seda-
tion and neuromuscular blockage have been associated
with worse clinical outcomes.10,40 However, a recent study
demonstrated that early neuromuscular blockage
improved survival in adults with ARDS.76 In this study of
340 adults with ARDS, the use of cisatracurium for 48
hours (vs. placebo) improved 90-day survival by nearly
1.5 times without an increase in muscle weakness. In
contrast, growing evidence in adults indicates substantial
benefits associated with sedation weaning and promotion
of early mobilization.42,70 Given the lack of consistent
evidence in both adults and children, the use of neuro-
muscular blockade in children with ARDS remains con-
troversial. Overall, use of these agents should be driven
by a balance between maintaining adequate gas exchange
and the potential adverse effects of critical illness weak-
ness and myopathy.
Nutrition
As a general approach, adequate nutrition should be pro-
vided to optimize caloric intake and avoid a negative
nitrogen balance. However, few studies examining the
effects of nutrition in children with ARDS have been
conducted. Clinical guidelines with regard to nutritional
support of critically ill children are, at best, supported by
small, randomized trials with reasonable risk for bias in
their results.65 Two studies in adults with a total of 1200
patients showed that a trophic feeding strategy did not
increase the duration of mechanical ventilation or reduce
mortality in contrast to full enteral feeding. The patients
on trophic feeds, however, had fewer gastrointestinal side
effects such as vomiting and constipation.89,92
Although a growing number of studies are investigat-
ing the potential utility of nutritional supplementation in
ARDS, the results have not been consistent or encourag-
ing. Using bronchoalveolar and plasma biomarkers as
their end points, investigators examining the effect of
omega-3 oil on adults with ARDS did not note any dif-
ference in IL-8, IL-6, and leukotriene B4 levels between
patients with and without supplementation.99 This was
further supported by a recent clinical study that was
stopped early for futility.91 This study of twice-daily sup-
plementation of omega-3 fatty acids within 48 hours of
onset of ARDS showed a trend toward longer duration
of mechanical ventilation and higher mortality in the
treatment group.91
Patient Isolation
Even though infectious etiologies are the most common
cause of ARDS in children, routine isolation of all ARDS
patients is not warranted. In certain infective etiologies
such as viruses (e.g., influenza, RSV, adenovirus), resis-
tant bacteria, and mycobacteria (e.g., tuberculosis),
appropriate isolation measures should be instituted.111
Rescue Therapies
Some patients with severe ARDS become refractory to
maximal therapies and are unable to achieve acceptable
therapeutic goals while avoiding oxygen toxicity or intol-
erably high airway pressures. In these circumstances,
ECMO is becoming increasingly used as a rescue for
these patients.
ECMO involves withdrawing blood from the patient
by a mechanical pump and directing it to a membrane
oxygenator, where oxygenation and removal of carbon
dioxide occur before the blood is returned to the patient.
874 SECTION XII Systemic Infectious Diseases
In refractory ARDS patients, venovenous ECMO is com-
monly used, which involves blood being withdrawn from
the patient via a cannula placed in a central vein and
returned to the venous system. Cardiac function must be
sufficient to circulate this returned blood systemically
to the body. ECMO has been used successfully in a
wide range of clinical circumstances and is a viable treat-
ment strategy in adults and children with refractory
ARDS.19,45 Traditionally, ECMO has been implemented
in patients with an anticipated mortality that is extremely
high, exceeding 80 to 90 percent in many circumstances,
but reported survival from the Extracorporeal Life
Support Organization (ELSO) registry for adults and
children with ARDS is currently 50 and 65 percent,
respectively.19,32 In the past decade, use of ECMO has
continued to increase, as evidenced by reports from the
2009 to 2010 H1N1 influenza A pandemic.27,71,72,108 A
more detailed discussion of ECMO support for pediatric
and adult ARDS patients is beyond the scope of this
chapter.
SUMMARY
ARDS represents a spectrum of clinical disease of varying
pulmonary and nonpulmonary etiologies. Although much
progress has been made with regard to understanding the
pathophysiology of ARDS, the only ventilatory strategy
that has been proved to improve clinical outcome is low
tidal volume ventilation. It is anticipated that future clini-
cal studies are likely to combine therapeutic strategies
instead of simply focusing on a single intervention.
Although meticulous balance is important in each organ
system, limited data exist regarding the optimal support-
ive management strategies for children with ARDS.
Current approaches largely represent clinical experience
and extrapolation of the available data from the adult
population. Without doubt, basic science and genomics
studies will continue to be translated into clinical applica-
tion at the bedside to better individualize treatment strat-
egies for pediatric ALI.
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