PEDIATRIC ALLERGY, IMMUNOLOGY, AND PULMONOLOGY REVIEWS

Volume 32, Number 2, 2019

Mary Ann Liebert, Inc.
DOI: 10.1089/ped.2019.0999

The Current State of Pediatric Acute

Respiratory Distress Syndrome

Kirsten E. Orloff, MD, David A. Turner, MD, FCCM, FCCP, and Kyle J. Rehder, MD, FCCM, FCCP

Pediatric acute respiratory distress syndrome (PARDS) is a significant cause of morbidity and mortality in
children. Children with PARDS often require intensive care admission and mechanical ventilation. Un-
fortunately, beyond lung protective ventilation, there are limited data to support our management strategies in
PARDS. The Pediatric Acute Lung Injury Consensus Conference (PALICC) offered a new definition of PARDS
in 2015 that has improved our understanding of the true epidemiology and heterogeneity of the disease as well
as risk stratification. Further studies will be crucial to determine optimal management for varying disease
severity. This review will present the physiologic basis of PARDS, describe the unique pediatric definition and
risk stratification, and summarize the current evidence for current standards of care as well as adjunctive
therapies.

Keywords: pediatric, acute respiratory distress syndrome, Pediatric Acute Lung Injury Consensus Conference,
lung protective ventilation, oxygenation index, acute hypoxemic respiratory failure

Introduction Defining Pediatric Acute Respiratory

Distress Syndrome
A cute respiratory distress syndrome (ARDS) is a
clinical syndrome caused by disruption of the alveolar
epithelial–endothelial permeability barrier unrelated to car-
Historically, characterization of acute lung injury (ALI) or
ARDS in children was based on adult definitions determined
diogenic pulmonary edema.1 Injury may occur directly to by the 1994 American-European Consensus Conference
the alveolar epithelium (ie, pneumonia, inhaled toxins, etc.) (AECC) and the subsequent 2012 Berlin definition.4–6 Re-
or indirectly to the capillary endothelium secondary to cognizing that ARDS in children is different than adults, an
systemic inflammation as seen in conditions such as sepsis international panel of experts convened the Pediatric Acute
or pancreatitis.1 Disruption of the alveolar endothelial bar- Lung Injury Consensus Conference (PALICC) to establish
rier leads to accumulation of protein-rich fluid in the al- new definitions and guidelines for pediatric acute respiratory
veoli.2 Dysregulated inflammation and coagulation then distress syndrome (PARDS).4 The 2015 PALICC definition
ensue, resulting in impaired lymphatic drainage and surfac- broadens the radiographic requirement to include any new
tant degradation.2 Clinically, these alveolar changes result in parenchymal infiltrate(s).4 Additional key differences in the
a restrictive lung disease characterized by hypoxemia, ra- PARDS definition include allowing use of pulse oximetry to
diographic opacities, decreased functional residual capacity, avoid underestimating ARDS prevalence in children if arte-
increased physiologic dead space, and decreased lung rial blood oxygenation measurements are not available and
compliance.1 Resolution of the inflammation usually occurs SpO2 £ 97%, and utilization of the oxygenation index (OI)
after several weeks, with potential development of fibrosis.3 [(FiO2 · mean airway pressure · 100)/PaO2] and oxygenation
The most common cause of ARDS in children is viral re- saturation index (OSI) [(FiO2 · mean airway pressure · 100)/
spiratory infection, although ARDS can be associated with SpO2] rather than the PaO2/FiO2 (P/F) ratio to assess hyp-
many other underlying conditions, including pneumonia, oxemia4 (Table 1). Integration of OI into the definition ac-
sepsis, trauma, burns, pancreatitis, inhalation, transfusion, counts for variability in ventilator support when categorizing
and cardiopulmonary bypass.2 lung disease.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children’s Hospital, Durham, North Carolina.
ª Orloff et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative
Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use,
distribution, and reproduction in any medium, provided the original author(s) and the source are cited.

35
36 ORLOFF, TURNER, AND REHDER

Table 1. PARD Criteria (PALICC Guidelines)

a
PARDS baseline criteria
Acute onset; within 7 days of clinical insult
Chest imaging (radiograph or computed tomography) findings of new infiltrates (unilateral or bilateral) consistent with
acute parenchymal disease
Edema not fully explained by fluid overload or cardiac failure
May present as new acute lung disease in setting of chronic lung disease and/or heart disease
Exclusions
Perinatal lung disease
PARDS severity stratification
At-risk Mild Moderate Severe
OI <4 with O2 supplementation required to keep SpO2 > 88% 4£8 8 £ 16 ‡16
OSI <5 with O2 supplementation required to keep SpO2 > 88% 5 £ 7.5 7.5 £ 12.3 ‡12.3
Special considerations
Noninvasive ventilation
PARDS: P/F ratio £300 or SpO2/FiO2 ratio £264 on full face-mask noninvasive ventilation with minimum
CPAP/EPAP ‡5 cm H2O (no severity stratification)
At-risk: requiring FiO2 ‡40% to attain SpO2 88%–92% with nasal mask CPAP/BiPAP or requiring age-based oxygen
flow rate via mask or nasal cannula to maintain SpO2 88%–97%
<1 Year: 2 L/min
1–5 Years: 4 L/min
5–10 Years: 6 L/min
>10 Years: 8 L/min
Cyanotic heart disease: no specific OI or OSI cutoff; PARDS definition based on clinician determined ‘‘new-onset
hypoxemia’’ in patient meeting other baseline criteria
a
Pediatric acute respiratory distress syndrome.4
BIPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; EPAP, expiratory positive airway pressure; OI,
oxygenation index; OSI, oxygenation saturation index; PALICC, Pediatric Acute Lung Injury Consensus Conference; PARDS, pediatric
acute respiratory distress syndrome; P/F, PaO2/FiO2.

The PALICC criteria were recently compared to prior defi- disease severity (10%–15% for mild or moderate PARDS
nitions (Berlin, AECC) in 2 studies of pediatric patients in the versus 33% for severe PARDS).9 Measured OI at 6–12 h and
intensive care unit (ICU).7,8 Both studies concluded that the at 24 h after onset of PARDS has been found to more accu-
new criteria identified a higher number of PARDS patients. In rately stratify degree of lung injury than prognostication at
addition, when compared to Berlin and AECC definitions, pa- onset.13,14 The PARDIE study corroborated this finding, re-
tients meeting PALICC criteria for PARDS were found to have vealing that PARDS severity level at 6 h was more predictive
a lower overall mortality rate7 and a lower proportion of severe of ICU mortality than Berlin ARDS severity groups.9
ARDS and complications.8 Even more recently, the prospective Cause of death in PARDS is variable, given the heteroge-
international Pediatric Acute Respiratory Distress Syndrome nous etiology of the disease process. In a large retrospective
Incidence and Epidemiology (PARDIE) study, the largest study, neurologic failure and multisystem organ failure were the
PARDS study using the PALICC definition, demonstrated in primary causes of early and late deaths, respectively, and only a
over 700 children that the PALICC definition identified more minority of deaths were attributed to refractory hypoxemia.15
children as having PARDS than the Berlin definition.9 Notably, Significant predictors of mortality include immunocompro-
capturing more patients with milder forms of PARDS with the mised state, multiorgan dysfunction, older age, and severity
broader definition may have serious implications on future of hypoxemia.11,16 A recent prospective cohort study dem-
outcome studies if they are not stratified by disease severity. onstrated similar outcomes for direct and indirect PARDS,
whereas infectious PARDS was associated with lower severity
Epidemiology, Mortality, and Risk Stratification of illness and mortality compared with noninfectious PARDS.17
Moreover, immunocompromised state, a well-described pre-
Respiratory failure is the most common cause of death for dictor of mortality in ARDS, was not found to be associated
children admitted to pediatric intensive care units (PICUs),10 with mortality in noninfectious PARDS.17
and ARDS accounts for 1%–10% of PICU admissions.7,8,11 Overall, PARDS mortality has decreased in the last few
Mortality rates in PARDS are highly variable across studies, decades and is lower than adult ARDS mortality, which
likely attributable to varying comorbid conditions and dif- ranges from 35% to 46% with mild to severe.18 However,
ferent etiologies.11 A meta-analysis by Wong et al. found the PARDS mortality remains significant, and improvements in
pooled mortality rate in PARDS to be *24%, with an overall identification, risk stratification, and targeted management
downtrend in mortality over the last 3 decades.12 This trend will be crucial to further reduce the mortality burden.
likely reflects earlier awareness and diagnosis,12 improved
ventilation strategies, and changes in general ICU care.11 The Standards of Care
PARDIE study was the first to discriminate mortality risk by
PARDS severity as defined by PALICC, demonstrating a This section provides a review of the current best
significant, stepwise increase in mortality with increasing practice strategies for the management of PARDS. These
 Table 2. Current Evidence and Recommendations for Pediatric Acute Respiratory
Distress Syndrome Therapies
Therapy Evidence PALICC recommendation References
Lung-protective Decreased mortality and more Low tidal volumes ARDS Network
ventilation ventilator-free days with low 3–6 mL/kg if poor compliance (2000)22; Rimensberger
tidal volumes and limited 5–8 mL/kg if preserved and Cheifetz20
plateau pressure in adult compliance
ARDS (RCT). Pplateau £28 cm H2O
Permissive hypoxemia
Mild PARDS: 92%–97%
Severe PARDS: 88%–92% and
PEEP >10 cm H2O
Permissive hypercapnia
Moderate/severe: pH 7.15–7.30,
with exceptions for certain
populations.
Fluid management Conservative fluid management After initial resuscitation, use a National Heart, Lung,
improved lung function, goal-directed fluid management and Blood Institute
decreased duration of MV protocol to maintain intravascular Acute Respiratory
and ICU LOS in adult volume while minimizing fluid Distress Syndrome
ARDS. No mortality overload. (ARDS) Clinical Trials
difference (RCT). Network et al.,32
Observational pediatric Flori et al.,33
studies favor conservative Valentine et al.,34
approach. Valentine et al.35
Sedation Sedation protocol decreased Targeted sedation to ensure patients Curley et al.,38
sedation exposure without can tolerate MV to optimize Valentine et al.35
effect on MV duration or oxygen delivery/consumption.
long-term outcomes in Pain and sedation scales to titrate
pediatric respiratory failure sedation per a goal-directed
(RCT). protocol.
HFOV No benefit, potential harm in Consider HFOV in patients with Rimensberger and
adult ARDS (RCTs). Small moderate to severe PARDS and Cheifetz,20 El-Nawawy
pediatric RCTs and Pplateau >28 cm H2O. et al.,29 Ferguson et al.,41
observational studies show Young et al.,42 Arnold
improved oxygenation but no et al.,43 Gupta et al.,44
difference in mortality, Bateman et al.,45
duration of MV, or LOS. Qiao et al.46
PROSpect (pediatric RCT)
is ongoing.
Prone positioning 50% Mortality reduction in Consider prone positioning as an Curley et al.,27 Curley,48
severe ARDS (single RCT). option in cases of severe PARDS. Sud et al.,51
Adult systematic reviews Cannot recommend its use as a Guerin et al.,52
report improved oxygenation, routine therapy given current Tamburro and
safe, potential mortality pediatric data. Kneyber53
reduction when coupled with
other lung protective
strategies. Pediatric RCT
supports safety but no
difference in outcomes.
PROSpect is ongoing.
Recruitment Sustained inflation improves Careful incremental titration of Rimensberger and
maneuvers oxygenation in adults with PEEP. Cheifetz,20
higher lung compliance and Grasso et al.,54
incremental PEEP titration is Cruces et al.,55
safe and improved Povoa et al.56
oxygenation in ARDS and
PARDS. No data on
mortality or morbidity.
NMB Adult studies support NMB use Consider NMB if sedation alone is Valentine et al.,35
in early severe ARDS. inadequate to achieve effective Gainnier et al.,57
Pediatric observational study MV. Target minimal effective Forel et al.,58
demonstrates NMB improved dose. Papazian et al.,59
oxygenation. Murray et al.,60
Wilsterman et al.62

(continued)

37
38 ORLOFF, TURNER, AND REHDER

Table 2. (Continued)
Therapy Evidence PALICC recommendation References

Nitric oxide Pediatric RCTs, meta-analysis, Cannot recommend routine use of Tamburro and Kneyber,53
and retrospective data all iNO. Consider in patients with Day et al.,63 Dobyns
report improved oxygenation known pulmonary hypertension, et al.,64 Ibrahim et al.,65
with no impact on mortality. severe right ventricular Afshari et al.,66
dysfunction, or as bridge to Bhalla et al.67
ECMO.
Surfactant Large pediatric RCTs with Do not recommend routine use of Tamburro and Kneyber,53
mixed data; overall improved surfactant. Need further studies in Willson et al.,72 Willson
oxygenation but no difference specific populations. et al.,73 Thomas et al.,74
in duration of MV, LOS Thomas et al.75
or mortality.
Steroids Mixed data in adult ARDS. Do not recommend corticosteroids Tamburro and
Small pediatric RCT found as routine therapy. Need further Kneyber,53 Peter et al.,76
that methylprednisolone had studies in specific populations. Tang et al.,77
no difference in mortality, Meduri et al.,78
duration of MV, LOS. Drago et al.,79
Observational pediatric data Yehya et al.80
demonstrate longer duration
of MV with corticosteroids
>24 h.
ECMO Strong evidence in neonates. Consider ECMO in severe PARDS Refer to Extracorporeal
Recent adult RCTs show when lung-protective strategies Membrane Oxygenation
potential mortality benefit. result in inadequate gas section of the article for
No pediatric RCTs. exchange, after serial evaluations full list of neonatal
demonstrate deteriorating trend. references, Peek et al.,87
Disease process must be deemed Combes et al.,88
reversible or lung transplant a Dalton and Macrae89
suitable treatment.
ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; HFOV, high-frequency oscillatory ventilation;
ICU, intensive care unit; iNO, inhaled nitric oxide; LOS, length of stay; MV, mechanical ventilation; NMB, neuromuscular blockade; PEEP,
positive-end-expiratory pressure; PROSpect, PRone and OScillation Pediatric Clinical Trial; RCT, randomized controlled trial.

recommendations, along with those for adjunctive therapies higher tidal volumes, although the significance of these
covered in the following section, are summarized in Table 2. findings is not clear. These findings led to weak agreement
among the PALICC group regarding tidal volume targets,
Lung-protective ventilation but targets remain generally consistent with currently avail-
able lung protective tidal volume goals. These data do sug-
The goals of ARDS management are to treat the under- gest that the physiology and risk for VILI may be different in
lying cause, provide adequate oxygenation and ventilation, children when compared with adults, and a pediatric RCT
and protect the lungs from ventilator-induced lung injury is needed to better inform the optimal tidal volume strategy
(VILI). The aims of lung-protective ventilation are to avoid in children before routine deviation from current standards.
overdistension (volutrauma and barotrauma), minimize the Another important component of conventional mechani-
cyclic opening and closing of alveoli (atelectrauma),19,20 cal ventilation (CMV) in ARDS is positive-end-expiratory
and minimize injurious effects of biochemical mediators on pressure (PEEP). PEEP creates an open lung strategy by
the lung and distal organs (biotrauma).21 preventing lung collapse and atelectotrauma caused by re-
There are no randomized controlled trials (RCTs) out- opening collapsed alveoli with each breath cycle.20 Two
lining optimal ventilator mode or strategy in PARDS. Thus, meta-analyses in adults with ARDS indicate that higher
pediatric intensivists have relied on the landmark ARDS PEEP is associated with lower hospital mortality.20,24,25 A
Network trial evaluating adults with ALI and ARDS, which recent pediatric multicenter retrospective study by Khemani
found that mechanical ventilation with lower tidal volume et al. also demonstrated that PEEP levels lower than the
(6 mL/kg compared to 12 mL/kg) and limited plateau pres- ARDS Network model were associated with higher mor-
sure (30 cm H2O) resulted in decreased mortality and more tality.26 PALICC strongly recommends the use of PEEP up
ventilator-free days.22 Standard of care for mechanical ven- to 15 cm H2O or greater for severe PARDS.20
tilation in the PICU is generally consistent with the ARDS To minimize the potential toxicity of ventilatory support
Network study, and the PALICC guidelines recommend tidal required to oxygenate and ventilate PARDS patients, per-
volumes of 3–6 and 5–8 mL/kg for patients with poor and missive hypoxemia and hypercapnia should be considered.
more preserved respiratory compliance, respectively, along Given that improved oxygenation has not been shown to
with limiting inspiratory plateau pressure to 28 cm H2O.20 Of improve outcomes,22,27–29 PALICC recommends oxygen
note, some observational pediatric studies demonstrate de- saturation goals of 92%–97% for mild PARDS and 88%–92%
creased mortality16 and more ventilator-free days23 with and PEEP >10 cm H2O for severe PARDS.20 In patients
PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME 39

whose oxygen saturation is maintained <92%, it is important acute respiratory failure, but did note a more wakeful state
to follow markers of oxygen delivery, such as central venous and lower exposure to sedative medications.38 Long-term
saturation.20 Further PALICC recommendations include follow-up demonstrated no difference in functional status or
considering permissive hypercapnia for moderate to severe mental health risk between treatment arms.39
PARDS to minimize VILI, maintaining pH 7.15–7.30 using The PALICC recommendations align with this strategy,
lung-protective strategies.20 Laboratory data have demon- supporting targeted sedation to ensure that patients can
strated that hypercapnic acidosis itself—not simply as the tolerate mechanical ventilation to optimize oxygen delivery,
manifestation of low tidal volume ventilation—may attenuate oxygen consumption, and work of breathing.35 Further
VILI, further supporting this strategy.30,31 While most pop- recommendations include the use of pain and sedation scales
ulations will tolerate permissive hypercapnia and acidosis, to monitor and titrate sedation per a goal-directed protocol,
these guidelines should be avoided in patients with intracra- frequent interprofessional communication to define goals,
nial hypertension, severe pulmonary hypertension, certain and an individualized sedation weaning plan guided by
congenital heart disease lesions, hemodynamic instability, objective withdrawal assessment.35 There remains a need for
and significant ventricular dysfunction.20 additional investigations on the impact of pharmacogenetics
and critical illness, as well as the risks of neurotoxicity, im-
Fluid management munomodulation, sleep cycle disruption, and delirium asso-
ciated with sedation.40
To date, no pediatric RCTs have investigated fluid man-
agement strategies in PARDS. Two opposing strategies exist:
(1) fluid resuscitation to maintain adequate cardiac output and Adjunctive Therapies
extrapulmonary organ function in the setting of widespread High-frequency ventilation
inflammation and (2) fluid restriction to minimize pulmonary
edema.32 The multicentered, randomized Fluid and Catheter When CMV fails, high-frequency oscillatory ventilation
Treatment Trial (FACTT) comparing conservative versus lib- (HFOV) is often used as a ‘‘rescue’’ strategy for refractory
eral fluid management strategies for adults with ARDS favored hypoxemia. HFOV utilizes higher mean airway pressures in
the conservative approach, as it improved lung function, conjunction with lower than physiologic tidal volumes at
shortened duration of mechanical ventilation, and reduced ICU extremely high rates, with the goal of minimizing VILI and
stay without increasing extrapulmonary organ failure.32 How- improving gas exchange through an open-lung strategy.
ever, there was no mortality difference between the 2 groups. Early studies of HFOV in adults were promising, but
Several observational studies have evaluated fluid man- limited by small sample size and outdated ventilatory strat-
agement in pediatric ARDS and ALI. In 2011, a post hoc egies.41 Two recent adult RCTs, Oscillation for Acute Re-
analysis of an observational study suggested that positive spiratory Distress Syndrome Treated Early (OSCILLATE)41
fluid balance was associated with increased mortality and and High Frequency Oscillation in ARDS (OSCAR),42
prolonged mechanical ventilation, independent of multi- suggest no benefit and potential harm associated with
system organ failure and severity of hypoxemia.33 More HFOV. The OSCILLATE trial reported higher mortality and
recently, Valentine et al. applied a Bayesian statistical ap- increased use of vasopressors, sedation, and neuromuscular
proach based on the FACTT findings to a multicenter ob- blockage in the HFOV group. The OSCAR trial found no
servational pediatric study.34 Similar to previous studies, the significant difference in mortality between adult ARDS pa-
authors demonstrated an inverse relationship between posi- tients supported with HFOV compared to CMV.42 These
tive cumulative fluid balance and ventilator-free days, even studies remain controversial due to methodological concerns,
after adjusting for illness severity.34 These studies highlight and their applicability to PARDS is unclear.
the need for a prospective study of conservative fluid Although a 1994 RCT showed potential benefit from
management in children with PARDS. early HFOV use in pediatric respiratory failure, subsequent
PALICC recommendations reflect the need to balance pediatric studies have demonstrated no clear benefit with
end-organ function with the development of pulmonary HFOV.43 A recent retrospective, observational administra-
edema. After initial resuscitation, PALICC recommends a tive database study of >9,000 children with acute respiratory
goal-directed fluid management protocol to maintain intra- failure found longer duration of mechanical ventilation and
vascular volume while minimizing fluid overload.35 higher mortality associated with HFOV compared with
CMV.44 A secondary propensity score analysis of RE-
Sedation STORE study data also demonstrated increased ventilator
days with no mortality difference with early HFOV use
Adequate sedation of the mechanically ventilated child compared to CMV and/or late HFOV.45 More recently, a
will ideally optimize patient safety and respiratory support Turkish RCT of 200 children with PARDS found that
while providing analgesia and anxiolysis to maintain the HFOV improved oxygenation but showed no difference in
child in a calm but responsive state.35 Until recently, seda- mortality, duration of mechanical ventilation, or length of
tives have been used extensively in mechanically ventilated stay (LOS), compared to CMV.29 Consistent with other
pediatric patients without high-quality evidence to guide studies, the most common cause of death was multiorgan
clinical practice.36,37 The Randomized Evaluation of Seda- dysfunction rather than refractory hypoxemia. A meta-
tion Titration fOr Respiratory failurE (RESTORE) trial analysis of 6 RCTs with a total of 246 PARDS patients also
evaluated a nurse-driven sedation protocol in 2,900 me- demonstrated improved oxygenation with no significant
chanically ventilated children across 31 PICUs.38 The authors difference in mortality or duration of mechanical ventila-
found no reduction in duration of mechanical ventilation with tion.46 Despite these investigations evaluating HFOV in
the sedation protocol compared to usual care in children with pediatric ARDS, definitive data are lacking, and many
40 ORLOFF, TURNER, AND REHDER

experts agree that HFOV continues to have a role in the Neuromuscular blockade
management of severe respiratory failure. It is hoped that
the ongoing PRone and OScillation Pediatric Clinical Trial Neuromuscular blockade (NMB) is an important adjunct
(PROSpect)47 will provide needed clarity. PALICC recom- to sedation for mechanically ventilated patients to achieve
mendations include consideration of HFOV in patients with optimal oxygen delivery and lung mechanics. However, a
moderate to severe PARDS and elevated plateau pressures paucity of high-quality evidence exists to guide use of NMB
(>28 cm H2O).20 in mechanically ventilated children. Adult clinical trials and
guidelines support NMB use in adults with early severe
ARDS.57–60 Of note, these studies have evaluated cisa-
Prone positioning tricurium, while aminosteroids (ie, rocuronium, vecur-
Prone positioning was introduced in the 1970s as a onium) have been found to have a higher risk of myopathy
method to improve lung mechanics and oxygenation in and neuropathy and potentially deserve separate investiga-
mechanically ventilated patients. Its efficacy and safety in tion.61 To date, no RCTs have evaluated the utility of NMB
ARDS have been studied extensively over the last 2 de- in children with PARDS. A prospective physiologic study
cades, primarily in adults. A 1999 systematic review of 20 by Wilsterman et al. showed improved OI in pediatric pa-
clinical studies representing 297 adult and pediatric patients tients with acute hypoxemic respiratory failure who received
found improved oxygenation after prone positioning with continuous NMB during mechanical ventilation.62 Based
rare adverse events.48 largely on the available adult data, PALICC recommends
Three recent meta-analyses have assessed the impact of considering NMB in children with PARDS if sedation alone
prone positioning on mortality in adults with ARDS, with is inadequate to achieve effective mechanical ventilation,
varying results. The initial meta-analysis in 2008 assessed 13 targeting the minimal effective dose.35
studies, totaling >1,500 adult and pediatric patients, and found
prone positioning to improve oxygenation without significant Nitric oxide
effect on mortality.49 A follow-up study of 10 trials demon- Nitric oxide (NO) is produced in the vascular endothe-
strated that prone positioning was associated with decreased lium and causes relaxation of smooth muscle. Inhaled NO
mortality only in severe ARDS (P/F ratio <100 mHg).50 The (iNO) has been used as a pulmonary vasodilator to increase
most recent meta-analysis in 2014 of 11 RCTs found a sig- blood flow to areas with adequate ventilation, thus im-
nificant reduction in ARDS mortality with prone positioning proving ventilation/perfusion mismatch and oxygenation in
when coupled with lung protective ventilation.51 This meta- diseases such as ARDS.53 Three RCTs in children with
analysis included the Proning Severe ARDS Patients (PRO- PARDS have demonstrated transient improvement in oxy-
SEVA) study, which reported a 50% mortality reduction with genation with iNO, although these investigations were not
prone positioning in adults with severe ARDS.52 designed to study mortality.63–65 A meta-analysis of 14
Unlike many other management strategies in ARDS, a RCTs studying the effect of iNO in >1,300 adults and
multicenter RCT evaluating prone positioning in pediatrics children with ALI and ARDS again found transient im-
is available27 and demonstrated proning to be safe, but provement in oxygenation but no reduction in mortality.66
found no difference in duration of mechanical ventilation, Consistent with those findings, a recent retrospective cohort
mortality, or other health outcomes.27 The ongoing PRO- study of nearly 500 children with PARDS also demonstrated
Spect study hopes to better determine its efficacy in severe no improvement in either mortality or ventilator-free days
PARDS.47 The PALICC guidelines recommend considering with iNO.67 Given iNO has not been shown to improve
prone positioning as an option in cases of severe PARDS, patient outcomes in PARDS, PALICC does not recommend
but cannot recommend its use as a routine therapy in its routine use.53 However, the guidelines suggest consid-
PARDS given the current pediatric data.53 ering iNO in patients with known pulmonary hypertension,
severe right ventricular dysfunction, or as a bridge to ex-
Recruitment maneuvers tracorporeal life support in severe cases.
Recruitment maneuvers involve utilizing increased PEEP Surfactant
or sustained inflation to reopen regions of lung collapse.
Adult studies have demonstrated that sustained inflation or Surfactant dysfunction is part of the known pathophysi-
high levels of PEEP more successfully improve oxygenation ology of ARDS, and surfactant replacement has had great
in patients with higher lung compliance, such as those with success in infantile respiratory distress syndrome. However,
early ARDS with atelectasis or inflammatory edema, com- pediatric clinical trials of surfactant replacement have not
pared to those with decreased chest wall compliance.20,54 demonstrated a clear improvement in outcomes outside of
However, predicting which patients may respond to lung the neonatal population. An uncontrolled trial in 1996 of
recruitment may be difficult, and there are no data demon- calf lung surfactant (calfactant) in 29 children with acute
strating the impact of recruitment maneuvers on outcomes hypoxic respiratory failure demonstrated improvement in
such as mortality or duration of mechanical ventilation. There oxygenation and ability to wean ventilatory support with
is also concern that sustained inflation may preferentially calfactant administration.68 Two subsequent studies of por-
deliver pressure to lungs units that are already open, causing cine surfactant (curosurf) in infants with bronchiolitis
heterogeneous overdistension. Thus, PALICC recommends demonstrated improved oxygenation, decreased duration of
more measured recruitment through careful incremental ti- mechanical ventilation, and decreased ICU LOS with ex-
tration of PEEP, which has been shown to be safe and ef- ogenous surfactant.69,70 Mortality was not assessed as there
fective in improving oxygenation in both adult and pediatric were no deaths in either trial. Willson et al. then conducted a
ARDS, rather than sustained inflation maneuvers.20,55,56 prospective RCT that demonstrated the use of calfactant in
PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME 41

children with acute hypoxic respiratory failure was associ- data, ECMO use in children increased substantially from 2009
ated with similar findings of improved oxygenation and to 2015,86 with a 50% increase in the number of centers re-
decreased length of ventilation and ICU stay, with no dif- porting pediatric ECMO cases to the ELSO registry and a 24%
ference in mortality.71 annual increase in pediatric ECMO cases over that time peri-
Subsequent larger studies demonstrate mixed results. od.86 Survival to hospital discharge for children with respira-
A multicenter RCT of calfactant use in >150 infants and tory failure supported with ECMO is 60%, with variable
children with respiratory failure again demonstrated im- outcome based on etiology.86 PALICC guidelines suggest that
proved oxygenation, but no difference in duration of ven- ECMO should be considered in severe PARDS when toxic
tilation or LOS.72 The study found a reduction in mortality support is needed to maintain gas exchange.89 However,
with calfactant, which became nonsignificant after post hoc ECMO should only be considered after serial evaluations
adjustment for immunodeficiency. Subsequent trials of cal- demonstrate deteriorating trends and if the disease process is
factant in direct-injury PARDS and PARDS following stem deemed reversible or if lung transplant is a suitable treatment.89
cell transplant and lucinactant for PARDS demonstrated no
benefit for outcomes such as mortality, ventilation time, or Next Steps
LOS.73–75 Given these data, the PALICC guidelines do not
recommend routine use of surfactant in PARDS,53 but rec- Despite the importance of PARDS as a substantial source
ommend further studies to determine if other specific pop- of pediatric morbidity and mortality, high-quality data
ulations may benefit. around potential treatments are lacking, which limits our
understanding of which therapies lead to optimal outcomes
Steroids in our PARDS patients. Not surprisingly, this paucity of
definitive evidence has led to significant PARDS manage-
Dysregulated inflammation occurring in ARDS2 has ment variability across centers. A 2013 survey of 59 centers
prompted interest in use of steroids as an anti-inflammatory across 12 countries demonstrated that adjunctive therapies
treatment. Systematic reviews of studies of adults with are commonly utilized in clinical scenarios consistent with
ARDS demonstrate mixed results.76,77 A 2018 meta-analysis PARDS.90 More than 80% of respondents reported that they
by Meduri et al. evaluating 9 RCTs of low-to-moderate dose would use iNO, three-quarters would prone patients, and
prolonged glucocorticoid treatment in adult ARDS reported around half would consider exogenous surfactant, despite a
moderate-to-high evidence that steroid therapy is safe and lack of evidence to support the efficacy of these adjuncts.
reduces duration of mechanical ventilation, ICU and overall The ongoing PROSpect47 hopes to provide clarity around 2
LOS, and mortality.78 A small pediatric pilot RCT investi- adjunct therapies, prone positioning and HFOV. This phase
gating the use of methylprednisolone in PARDS found no III clinical trial (UG3 HL141736-01) aims to enroll 1,000
difference in mortality, duration of mechanical ventilation, severe PARDS patients at more than 50 international centers.
ICU LOS, or overall LOS with steroid therapy.79 A larger Additional work in PARDS is also underway investigating
observational PARDS study found fewer ventilator-free biomarkers that may better stratify mortality risk and identify
days and longer duration of mechanical ventilation with targeted treatments for future clinical trials.91–94 Beyond
corticosteroid exposure >24 h.80 Given the lack of clear these investigations, there remain robust opportunities for
evidence in pediatrics, PALICC recommends against corti- prospective study of the effect of various treatment strategies
costeroids as routine therapy in PARDS pending further on outcomes in PARDS, including but not limited to venti-
studies in specific populations.53 latory modes (including airway pressure release ventilation,
high-frequency jet ventilation, and neutrally adjusted venti-
Extracorporeal membrane oxygenation lator assist) and strategies, fluid management, NMB, surfac-
tant in specific populations, steroids, and ECMO.
Successes with extracorporeal membrane oxygenation Prior clinical trials have focused on all children with
(ECMO) in severe neonatal respiratory failure81–85 have led ARDS, which many experts suggest is the reason for neg-
to its use in children and adults. In PARDS, ECMO can ative trials. Children with mild to moderate PARDS have a
augment systemic oxygen delivery to allow the injured lungs relatively low mortality, and the inclusion of these children
to rest and recover. However, ECMO carries significant risk in large trials may dilute the potential treatment benefit that
and requires substantial resources and expertise. The inter- might exist in more severely ill patients. Recent adult in-
national Extracorporeal Life Support Organization (ELSO) vestigations suggest a focus on patients with severe ARDS
registry contains data on nearly 60,000 patients supported may increase the likelihood to demonstrate a positive
with ECMO.86 Over the last decade, there has been expo- treatment effect.52,59,88,95
nential growth of ECMO utilization in adults with severe There also remains a great need for outcomes data in
respiratory failure.87 The Conventional Ventilation or ECMO PARDS, particularly relating to morbidity. In adult survi-
for Severe Adult Respiratory Failure (CESAR) trial in adults vors of ARDS, highly morbid effects include decreased lung
found that ECMO was cost-effective and increased 6-month function, reduced quality of life, and decreased neurocog-
disability-free survival.87 However, the recent ECMO to nitive functioning.11 Similar studies are warranted in the
Rescue Lung Injury in Severe ARDS (EOLIA) trial showed pediatric population, as physical and neurocognitive devel-
no significant difference in 60-day mortality in adults with opment may be even more greatly impacted. The cumulative
severe ARDS supported with ECMO when compared to consequence of these morbidities on an individual and on
CMV.88 society is another opportunity for investigation. As noted
Unfortunately, despite strong evidence in neonates81–85 and above, stratifying outcome studies by disease severity will
potential benefit in adults,87,88 clinical trial evidence for be ever more important with the broadened definition of
ECMO use in PARDS is lacking. Despite this lack of definitive PARDS introduced in 2015.
42 ORLOFF, TURNER, AND REHDER

PARDS remains a disease process with significant mor- 16. Erickson S, Schibler A, Numa A, et al. Acute lung injury in
bidity and mortality. However, with improved understand- pediatric intensive care in Australia and New Zealand: a
ing of its epidemiology and heterogeneity in the last decade, prospective, multicenter, observational study. Pediatr Crit
as well as ever-growing gains in risk stratification, the future Care Med 2007; 8:317–323.
is ripe with opportunity for more tailored clinical trials to 17. Yehya N, Keim G, Thomas NJ. Subtypes of pediatric acute
determine best treatment strategies and improve outcomes. respiratory distress syndrome have different predictors of
mortality. Intensive Care Med 2018; 44:1230–1239.
18. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns
Author Disclosure Statement
of care, and mortality for patients with acute respiratory
No competing financial interests exist. distress syndrome in intensive care units in 50 countries.
JAMA 2016; 315:788–800.
19. Dreyfuss D, Saumon G. Ventilator-induced lung injury:
References
lessons from experimental studies. Am J Respir Crit Care
1. Sapru A, Flori H, Quasney MW, et al. Pathobiology of Med 1998; 157:294–323.
acute respiratory distress syndrome. Pediatr Crit Care Med 20. Rimensberger PC, Cheifetz IM. Ventilatory support in
2015; 16:S6–S22. children with pediatric acute respiratory distress syndrome:
2. Heidemann SM, Nair A, Bulut Y, et al. Pathophysiology proceedings from the Pediatric Acute Lung Injury Consensus
and management of acute respiratory distress syndrome in Conference. Pediatr Crit Care Med 2015; 16:S51–S60.
children. Pediatr Clin North Am 2017; 64:1017–1037. 21. Curley GF, Laffey JG, Zhang H, et al. Biotrauma and
3. Matthay MA, Zemans RL. The acute respiratory distress ventilator-induced lung injury: clinical implications. Chest
syndrome: pathogenesis and treatment. Annu Rev Pathol 2016; 150:1109–1117.
2011; 6:147–163. 22. Acute Respiratory Distress Syndrome Network, Brower
4. Pediatric acute respiratory distress syndrome: consensus rec- RG, Matthay MA, et al. Ventilation with lower tidal vol-
ommendations from the Pediatric Acute Lung Injury Con- umes as compared with traditional tidal volumes for acute
sensus Conference. Pediatr Crit Care Med 2015; 16:428–439. lung injury and the acute respiratory distress syndrome.
5. Bernard GR, Artigas A, Brigham KL, et al. The American- N Engl J Med 2000; 342:1301–1308.
European Consensus Conference on ARDS. Definitions, 23. Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal
mechanisms, relevant outcomes, and clinical trial coordi- volume in children with acute hypoxemic respiratory fail-
nation. Am J Respir Crit Care Med 1994; 149:818–824. ure. Intensive Care Med 2009; 35:1428–1437.
6. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute re- 24. Phoenix SI, Paravastu S, Columb M, et al. Does a higher
spiratory distress syndrome: the Berlin definition. JAMA positive end expiratory pressure decrease mortality in acute
2012; 307:2526–2533. respiratory distress syndrome? A systematic review and
7. Parvathaneni K, Belani S, Leung D, et al. Evaluating the meta-analysis. Anesthesiology 2009; 110:1098–1105.
performance of the Pediatric Acute Lung Injury Consensus 25. Briel M, Meade M, Mercat A, et al. Higher vs lower pos-
Conference definition of acute respiratory distress syn- itive end-expiratory pressure in patients with acute lung
drome. Pediatr Crit Care Med 2017; 18:17–25. injury and acute respiratory distress syndrome: systematic
8. Gupta S, Sankar J, Lodha R, et al. Comparison of prevalence review and meta-analysis. JAMA 2010; 303:865–873.
and outcomes of pediatric acute respiratory distress syndrome 26. Khemani RG, Parvathaneni K, Yehya N, et al. Positive end-
using Pediatric Acute Lung Injury Consensus Conference expiratory pressure lower than the ARDS network protocol
criteria and Berlin definition. Front Pediatr 2018; 6:93. is associated with higher pediatric acute respiratory distress
9. Khemani RG, Smith L, Lopez-Fernandez YM, et al. Pae- syndrome mortality. Am J Respir Crit Care Med 2018; 198:
diatric acute respiratory distress syndrome incidence and 77–89.
epidemiology (PARDIE): an international, observational 27. Curley MA, Hibberd PL, Fineman LD, et al. Effect of
study. Lancet Respir Med 2018; 7:115–128. prone positioning on clinical outcomes in children with
10. Burns JP, Sellers DE, Meyer EC, et al. Epidemiology of acute lung injury: a randomized controlled trial. JAMA
death in the PICU at five U.S. teaching hospitals. Crit Care 2005; 294:229–237.
Med 2014; 42:2101–2108. 28. Dobyns EL, Anas NG, Fortenberry JD, et al. Interactive
11. Quasney MW, Lopez-Fernandez YM, Santschi M, et al. effects of high-frequency oscillatory ventilation and in-
The outcomes of children with pediatric acute respiratory haled nitric oxide in acute hypoxemic respiratory failure in
distress syndrome: proceedings from the Pediatric Acute pediatrics. Crit Care Med 2002; 30:2425–2429.
Lung Injury Consensus Conference. Pediatr Crit Care Med 29. El-Nawawy A, Moustafa A, Heshmat H, et al. High fre-
2015; 16:S118–S131. quency oscillatory ventilation versus conventional me-
12. Wong JJ, Jit M, Sultana R, et al. Mortality in pediatric acute chanical ventilation in pediatric acute respiratory distress
respiratory distress syndrome: a systematic review and syndrome: a randomized controlled study. Turk J Pediatr
meta-analysis. J Intensive Care Med 2017. [Epub ahead of 2017; 59:130–143.
print]; DOI: 10.1177/0885066617705109. 30. Contreras M, Ansari B, Curley G, et al. Hypercapnic aci-
13. Yehya N, Servaes S, Thomas NJ. Characterizing degree of dosis attenuates ventilation-induced lung injury by a nu-
lung injury in pediatric acute respiratory distress syndrome. clear factor-kappaB-dependent mechanism. Crit Care Med
Crit Care Med 2015; 43:937–946. 2012; 40:2622–2630.
14. Yehya N, Thomas NJ, Khemani RG. Risk stratification using 31. Horie S, Ansari B, Masterson C, et al. Hypercapnic acidosis
oxygenation in the first 24 hours of pediatric acute respira- attenuates pulmonary epithelial stretch-induced injury via
tory distress syndrome. Crit Care Med 2018; 46:619–624. inhibition of the canonical NF-kappaB pathway. Intensive
15. Dowell JC, Parvathaneni K, Thomas NJ, et al. Epidemiol- Care Med Exp 2016; 4:8.
ogy of cause of death in pediatric acute respiratory distress 32. National Heart, Lung, and Blood Institute Acute Re-
syndrome. Crit Care Med 2018; 46:1811–1819. spiratory Distress Syndrome (ARDS) Clinical Trials Net-
PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME 43

work, Wiedemann HP, Wheeler AP, et al. Comparison of 50. Sud S, Friedrich JO, Taccone P, et al. Prone ventilation
two fluid-management strategies in acute lung injury. reduces mortality in patients with acute respiratory failure
N Engl J Med 2006; 354:2564–2575. and severe hypoxemia: systematic review and meta-
33. Flori HR, Church G, Liu KD, et al. Positive fluid balance is analysis. Intensive Care Med 2010; 36:585–599.
associated with higher mortality and prolonged mechanical 51. Sud S, Friedrich JO, Adhikari NK, et al. Effect of prone
ventilation in pediatric patients with acute lung injury. Crit positioning during mechanical ventilation on mortality
Care Res Pract 2011; 2011:854142. among patients with acute respiratory distress syndrome: a
34. Valentine SL, Sapru A, Higgerson RA, et al. Fluid balance systematic review and meta-analysis. CMAJ 2014; 186:
in critically ill children with acute lung injury. Crit Care E381–E390.
Med 2012; 40:2883–2889. 52. Guerin C, Reignier J, Richard JC, et al. Prone positioning in
35. Valentine SL, Nadkarni VM, Curley MA. Nonpulmonary severe acute respiratory distress syndrome. N Engl J Med
treatments for pediatric acute respiratory distress syndrome: 2013; 368:2159–2168.
proceedings from the Pediatric Acute Lung Injury Consensus 53. Tamburro RF, Kneyber MC. Pulmonary specific ancillary
Conference. Pediatr Crit Care Med 2015; 16:S73–S85. treatment for pediatric acute respiratory distress syndrome:
36. Hartman ME, McCrory DC, Schulman SR. Efficacy of proceedings from the Pediatric Acute Lung Injury Con-
sedation regimens to facilitate mechanical ventilation in the sensus Conference. Pediatr Crit Care Med 2015; 16:S61–
pediatric intensive care unit: a systematic review. Pediatr S72.
Crit Care Med 2009; 10:246–255. 54. Grasso S, Mascia L, Del Turco M, et al. Effects of re-
37. Playfor S, Jenkins I, Boyles C, et al. Consensus guidelines cruiting maneuvers in patients with acute respiratory dis-
on sedation and analgesia in critically ill children. Intensive tress syndrome ventilated with protective ventilatory
Care Med 2006; 32:1125–1136. strategy. Anesthesiology 2002; 96:795–802.
38. Curley MA, Wypij D, Watson RS, et al. Protocolized se- 55. Cruces P, Donoso A, Valenzuela J, et al. Respiratory and
dation vs usual care in pediatric patients mechanically hemodynamic effects of a stepwise lung recruitment ma-
ventilated for acute respiratory failure: a randomized clin- neuver in pediatric ARDS: a feasibility study. Pediatr
ical trial. JAMA 2015; 313:379–389. Pulmonol 2013; 48:1135–1143.
39. Watson RS, Asaro LA, Hertzog JH, et al. Long-term out- 56. Povoa P, Almeida E, Fernandes A, et al. Evaluation of a
comes after protocolized sedation versus usual care in recruitment maneuver with positive inspiratory pressure
ventilated pediatric patients. Am J Respir Crit Care Med and high PEEP in patients with severe ARDS. Acta An-
2018; 197:1457–1467. aesthesiol Scand 2004; 48:287–293.
40. Zuppa AF, Curley MAQ. Sedation analgesia and neuromus- 57. Gainnier M, Roch A, Forel JM, et al. Effect of neuro-
cular blockade in pediatric critical care: overview and current muscular blocking agents on gas exchange in patients
landscape. Pediatr Clin North Am 2017; 64:1103–1116. presenting with acute respiratory distress syndrome. Crit
41. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency Care Med 2004; 32:113–119.
oscillation in early acute respiratory distress syndrome. 58. Forel JM, Roch A, Marin V, et al. Neuromuscular blocking
N Engl J Med 2013; 368:795–805. agents decrease inflammatory response in patients pre-
42. Young D, Lamb SE, Shah S, et al. High-frequency oscil- senting with acute respiratory distress syndrome. Crit Care
lation for acute respiratory distress syndrome. N Engl J Med 2006; 34:2749–2757.
Med 2013; 368:806–813. 59. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular
43. Arnold JH, Hanson JH, Toro-Figuero LO, et al. Prospective, blockers in early acute respiratory distress syndrome.
randomized comparison of high-frequency oscillatory ven- N Engl J Med 2010; 363:1107–1116.
tilation and conventional mechanical ventilation in pediatric 60. Murray MJ, DeBlock H, Erstad B, et al. Clinical practice
respiratory failure. Crit Care Med 1994; 22:1530–1539. guidelines for sustained neuromuscular blockade in the
44. Gupta P, Green JW, Tang X, et al. Comparison of high- adult critically ill patient. Crit Care Med 2016; 44:2079–
frequency oscillatory ventilation and conventional me- 2103.
chanical ventilation in pediatric respiratory failure. JAMA 61. Price D, Kenyon NJ, Stollenwerk N. A fresh look at par-
Pediatr 2014; 168:243–249. alytics in the critically ill: real promise and real concern.
45. Bateman ST, Borasino S, Asaro LA, et al. Early high- Ann Intensive Care 2012; 2:43.
frequency oscillatory ventilation in pediatric acute respi- 62. Wilsterman MEF, de Jager P, Blokpoel R, et al. Short-term
ratory failure. A propensity score analysis. Am J Respir Crit effects of neuromuscular blockade on global and regional
Care Med 2016; 193:495–503. lung mechanics, oxygenation and ventilation in pediatric
46. Qiao JY, Li YZ, Wang HY, et al. A meta analysis of the acute hypoxemic respiratory failure. Ann Intensive Care
efficacy of high-frequency oscillatory ventilation versus 2016; 6:103.
conventional mechanical ventilation for treating pediatric 63. Day RW, Allen EM, Witte MK. A randomized, controlled
acute respiratory distress syndrome [in Chinese]. Zhongguo study of the 1-hour and 24-hour effects of inhaled nitric
Dang Dai Er Ke Za Zhi 2017; 19:430–435. oxide therapy in children with acute hypoxemic respiratory
47. The PRone and OScillation Pediatric Clinical Trial (PRO- failure. Chest 1997; 112:1324–1331.
Spect). 2018. www.prospect-network.org. Accessed January 64. Dobyns EL, Cornfield DN, Anas NG, et al. Multicenter
17, 2019. randomized controlled trial of the effects of inhaled nitric
48. Curley MA. Prone positioning of patients with acute re- oxide therapy on gas exchange in children with acute
spiratory distress syndrome: a systematic review. Am J Crit hypoxemic respiratory failure. J Pediatr 1999; 134:406–
Care 1999; 8:397–405. 412.
49. Sud S, Sud M, Friedrich JO, et al. Effect of mechanical ven- 65. Ibrahim TS, El-Mohamady HS. Inhaled nitric oxide and
tilation in the prone position on clinical outcomes in patients prone position: how far they can improve oxygenation in
with acute hypoxemic respiratory failure: a systematic review pediatric patients with acute respiratory distress syndrome?
and meta-analysis. CMAJ 2008; 178:1153–1161. J Med Sci 2007; 7:390–395.
44 ORLOFF, TURNER, AND REHDER

66. Afshari A, Brok J, Moller AM, et al. Inhaled nitric oxide newborn: a prospective randomized study. Pediatrics 1989;
for acute respiratory distress syndrome and acute lung in- 84:957–963.
jury in adults and children: a systematic review with meta- 83. Bifano EM, Hakanson DO, Hingre RV, et al. Prospective
analysis and trial sequential analysis. Anesth Analg 2011; randomized controlled trial of conventional treatment or
112:1411–1421. transport for ECMO in infants with persistent pulmonary
67. Bhalla AK, Yehya N, Mack WJ, et al. The association be- hypertension (PPHN) [abstract]. Pediatr Res 1992; 31:196A.
tween inhaled nitric oxide treatment and ICU mortality and 84. UK collaborative randomised trial of neonatal extracorpo-
28-day ventilator-free days in pediatric acute respiratory real membrane oxygenation. UK Collaborative ECMO
distress syndrome. Crit Care Med 2018; 46:1803–1810. Trail Group. Lancet 1996; 348:75–82.
68. Willson DF, Jiao JH, Bauman LA, et al. Calf’s lung sur- 85. Mugford M, Elbourne D, Field D. Extracorporeal mem-
factant extract in acute hypoxemic respiratory failure in brane oxygenation for severe respiratory failure in newborn
children. Crit Care Med 1996; 24:1316–1322. infants. Cochrane Database Syst Rev 2008; 3:CD001340.
69. Luchetti M, Casiraghi G, Valsecchi R, et al. Porcine- 86. Barbaro RP, Paden ML, Guner YS, et al. Pediatric Extra-
derived surfactant treatment of severe bronchiolitis. Acta corporeal Life Support Organization registry international
Anaesthesiol Scand 1998; 42:805–810. report 2016. ASAIO J 2017; 63:456–463.
70. Luchetti M, Ferrero F, Gallini C, et al. Multicenter, ran- 87. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and
domized, controlled study of porcine surfactant in severe economic assessment of conventional ventilatory support
respiratory syncytial virus-induced respiratory failure. Pe- versus extracorporeal membrane oxygenation for severe
diatr Crit Care Med 2002; 3:261–268. adult respiratory failure (CESAR): a multicentre rando-
71. Willson DF, Zaritsky A, Bauman LA, et al. Instillation of mised controlled trial. Lancet 2009; 374:1351–1363.
calf lung surfactant extract (calfactant) is beneficial in pe- 88. Combes A, Hajage D, Capellier G, et al. Extracorporeal
diatric acute hypoxemic respiratory failure. Members of the membrane oxygenation for severe acute respiratory distress
Mid-Atlantic Pediatric Critical Care Network. Crit Care syndrome. N Engl J Med 2018; 378:1965–1975.
Med 1999; 27:188–195. 89. Dalton HJ, Macrae DJ. Extracorporeal support in children
72. Willson DF, Thomas NJ, Markovitz BP, et al. Effect of with pediatric acute respiratory distress syndrome: pro-
exogenous surfactant (calfactant) in pediatric acute lung ceedings from the Pediatric Acute Lung Injury Consensus
injury: a randomized controlled trial. JAMA 2005; 293: Conference. Pediatr Crit Care Med 2015; 16:S111–S117.
470–476. 90. Santschi M, Randolph AG, Rimensberger PC, et al. Me-
73. Willson DF, Thomas NJ, Tamburro R, et al. Pediatric chanical ventilation strategies in children with acute lung
calfactant in acute respiratory distress syndrome trial. Pe- injury: a survey on stated practice pattern. Pediatr Crit Care
diatr Crit Care Med 2013; 14:657–665. Med 2013; 14:e332–e337.
74. Thomas NJ, Guardia CG, Moya FR, et al. A pilot, ran- 91. Dahmer MK, Quasney MW, Sapru A, et al. Interleukin-1 re-
domized, controlled clinical trial of lucinactant, a peptide- ceptor antagonist is associated with pediatric acute respiratory
containing synthetic surfactant, in infants with acute hyp- distress syndrome and worse outcomes in children with acute
oxemic respiratory failure. Pediatr Crit Care Med 2012; 13: respiratory failure. Pediatr Crit Care Med 2018; 19:930–938.
646–653. 92. Sapru A, Liu KD, Wiemels J, et al. Association of common
75. Thomas NJ, Spear D, Wasserman E, et al. CALIPSO: a genetic variation in the protein C pathway genes with
randomized controlled trial of calfactant for acute lung clinical outcomes in acute respiratory distress syndrome.
injury in pediatric stem cell and oncology patients. Biol Crit Care 2016; 20:151.
Blood Marrow Transplant 2018; 24:2479–2486. 93. Yehya N, Wong HR. Adaptation of a biomarker-based sepsis
76. Peter JV, John P, Graham PL, et al. Corticosteroids in the mortality risk stratification tool for pediatric acute respira-
prevention and treatment of acute respiratory distress syn- tory distress syndrome. Crit Care Med 2018; 46:e9–e16.
drome (ARDS) in adults: meta-analysis. BMJ 2008; 336: 94. Zinter MS, Orwoll BE, Spicer AC, et al. Incorporating
1006–1009. inflammation into mortality risk in pediatric acute respira-
77. Tang BM, Craig JC, Eslick GD, et al. Use of corticosteroids tory distress syndrome. Crit Care Med 2017; 45:858–866.
in acute lung injury and acute respiratory distress syn- 95. Writing Group for the Alveolar Recruitment for Acute
drome: a systematic review and meta-analysis. Crit Care Respiratory Distress Syndrome Trial (ART) Investigators,
Med 2009; 37:1594–1603. Cavalcanti AB, Suzumura EA, et al. Effect of lung re-
78. Meduri GU, Siemieniuk RAC, Ness RA, et al. Prolonged cruitment and titrated positive end-expiratory pressure
low-dose methylprednisolone treatment is highly effective (PEEP) vs low PEEP on mortality in patients with acute
in reducing duration of mechanical ventilation and mor- respiratory distress syndrome: a randomized clinical trial.
tality in patients with ARDS. J Intensive Care 2018; 6:53. JAMA 2017; 318:1335–1345.
79. Drago BB, Kimura D, Rovnaghi CR, et al. Double-blind,
placebo-controlled pilot randomized trial of methylpred- Address correspondence to:
nisolone infusion in pediatric acute respiratory distress Kirsten E. Orloff, MD
syndrome. Pediatr Crit Care Med 2015; 16:e74–e81. Division of Pediatric Critical Care Medicine
80. Yehya N, Servaes S, Thomas NJ, et al. Corticosteroid ex- Department of Pediatrics
posure in pediatric acute respiratory distress syndrome. Duke Children’s Hospital
Intensive Care Med 2015; 41:1658–1666. DUMC Box 3046
81. Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal Durham, NC 27710
circulation in neonatal respiratory failure: a prospective
randomized study. Pediatrics 1985; 76:479–487. E-mail: [email protected]
82. O’Rourke PP, Crone RK, Vacanti JP, et al. Extracorporeal
membrane oxygenation and conventional medical therapy Received for publication January 18, 2019; accepted after
in neonates with persistent pulmonary hypertension of the revision March 24, 2019.